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Thrombotic Disorders Transfusion in Special TABLE 27. lndicationsforTherapeuticApheresisu Circumstances Plasmapheresis/Plasma Exchange Massive transfusion is defined as the transfusion of one blood Th rom botic throm bocytopen ic pu rpu ra volume in 24 hours or 50'X, in 4 hours. When whole blood is Hyperviscosity syndrome (Waldenstrom macroglobul inemia lost and replaced with crystalloid and PRBCs, a dilutional and multiple myeloma) coagulopathy develops that is often exacerbated by hypother- Paraproteinemic polyneuropathies mia, acidosis, and liver injury as well as concomitant DIC. Guillain-Barre syndrome (acute inflammatory demyelinating Contemporary practice is to transfuse plasma and platelets polyneuropathy) concurrently with PRBCs to avoid the development of dilu Chronic inflammatory demyelinating polyradiculoneuropathy tional coagulopathy. During resuscitation, patients must be Myasthenia gravis monitored for electrolyte disturbances such as hypocalcemia, ANCA-associated rapidly progressive glomerulonephritis hyperkalemia or hypokalemia, and metabolic alkalosis. Anti-glomerular basement membrane disease Warm reactive IgG erythrocyte autoantibodies are panag Recurrent focal segmental glomerulosclerosis glutinins that interfere with antibody identification and cross match procedures. Transfusions should be avoided in patients Severe, symptomatic cryoglobulinemia

volume in 24 hours or 50'X, in 4 hours. When whole blood is Hyperviscosity syndrome (Waldenstrom macroglobul inemia lost and replaced with crystalloid and PRBCs, a dilutional and multiple myeloma) coagulopathy develops that is often exacerbated by hypother- Paraproteinemic polyneuropathies mia, acidosis, and liver injury as well as concomitant DIC. Guillain-Barre syndrome (acute inflammatory demyelinating Contemporary practice is to transfuse plasma and platelets polyneuropathy) concurrently with PRBCs to avoid the development of dilu Chronic inflammatory demyelinating polyradiculoneuropathy tional coagulopathy. During resuscitation, patients must be Myasthenia gravis monitored for electrolyte disturbances such as hypocalcemia, ANCA-associated rapidly progressive glomerulonephritis hyperkalemia or hypokalemia, and metabolic alkalosis. Anti-glomerular basement membrane disease Warm reactive IgG erythrocyte autoantibodies are panag Recurrent focal segmental glomerulosclerosis glutinins that interfere with antibody identification and cross match procedures. Transfusions should be avoided in patients Severe, symptomatic cryoglobulinemia with warm antibody autoimmune hemoly'tic anemia, but if Antibody-mediated renal allograft rejection transfusion is urgently needed, ABO/Rh matched but cross Fulminant Wilson disease match incompatible blood may be issued. Patients who have Erythrocyte Exchange never been pregnant or received a transfusion are unlikely to Severe babesiosisb have hidden alloantibodies that could cause more fulminant Sickle cell disease with acute cerebral infarct acute hemolytic transfusion reactions. The hospitalist, hema- tologist, and blood bank specialist should closely coordinate Sickle cell disease with severe acute chest syndrome' the care ol these patients. Leukapheresis

with warm antibody autoimmune hemoly'tic anemia, but if Antibody-mediated renal allograft rejection transfusion is urgently needed, ABO/Rh matched but cross Fulminant Wilson disease match incompatible blood may be issued. Patients who have Erythrocyte Exchange never been pregnant or received a transfusion are unlikely to Severe babesiosisb have hidden alloantibodies that could cause more fulminant Sickle cell disease with acute cerebral infarct acute hemolytic transfusion reactions. The hospitalist, hema- tologist, and blood bank specialist should closely coordinate Sickle cell disease with severe acute chest syndrome' the care ol these patients. Leukapheresis XEY POIilIS o As patients requiring massive transfusion are resuscitated, Plateletpheresis they must be monitored for electrolyte disturbances such Symptomatic extreme th rom bocytosisd as hypocalcemia, hyperkalemia or hypokalemia, and Extracorporeal Photopheresis metabolic alkalosis. Cardiac al lograft rejection, prophylaxis . Patients with warm autoimmune hemolytic anemia Erythrodermic cutaneous T-cel I lymphoma/S6zary synd rome have autoantibodies that may make crossmatch- Selective Blood Component Removal compatible units impossible to find; these patients should be transfused with ABO and Rh type specific, LDL cholesterol for familial hypercholesterolemia

XEY POIilIS o As patients requiring massive transfusion are resuscitated, Plateletpheresis they must be monitored for electrolyte disturbances such Symptomatic extreme th rom bocytosisd as hypocalcemia, hyperkalemia or hypokalemia, and Extracorporeal Photopheresis metabolic alkalosis. Cardiac al lograft rejection, prophylaxis . Patients with warm autoimmune hemolytic anemia Erythrodermic cutaneous T-cel I lymphoma/S6zary synd rome have autoantibodies that may make crossmatch- Selective Blood Component Removal compatible units impossible to find; these patients should be transfused with ABO and Rh type specific, LDL cholesterol for familial hypercholesterolemia crossmatch incompatible blood. "This list includes diseases for whrch apheresis is an accepted part of front line therapy for a particular indication, either as the sole therapeutic modality or rn combination with other therapy. lt is not an all inclusive list. bEny,throcy,te exchange for severe malaria is a category ll indication (accepted Therapeutic Apheresis second-line therapy).

crossmatch incompatible blood. "This list includes diseases for whrch apheresis is an accepted part of front line therapy for a particular indication, either as the sole therapeutic modality or rn combination with other therapy. lt is not an all inclusive list. bEny,throcy,te exchange for severe malaria is a category ll indication (accepted Therapeutic Apheresis second-line therapy). Apheresis procedures collect whole blood and separate it into 'Erythrocyte exchange for acute chest syndrome is a category ll indication but recommended by many as first-line therapy for those severely affected. components. Specific components (plasma, platelets, erythro- dThe use of plateletpheresis is a category ll indication for patients with life cytes, leukocytes) can be removed as needed. Fluid is replaced threatening thrombosis or hemorrhage associated with thrombocytosis (e.9., in a patient with essential thromboc).tosis). with colloid and crystalloid. Complications include hypocalce Data from Padmanabhan A, Connelly-Smith L, Aqui N, et al. Gurdelines on the use mia, th rombocytopenia, and hypofi brinogenemia, so laboratory of therapeutic apheresis rn clinical practice evidence based approach from the studies must be monitored. Therapy for thrombotic thrombocy writing committee of the American Society for Apheresis: the eighth special issue. . J Clin Apher. 201 9;34: 1 7 1 354. IPMID: 31 1 80581 ] doi: 1 0.1 002/1ca.217 05 topenic purpura is more appropriately characterized as plasma exchange because fresh frozen plasma is provided as the replace ment fluid. The same cell separators can be used to perform plateletpheresis, erythrocyte exchange transfusion, and other embolism (PE), continues to increase despite better awareness procedures in patients with specific indications (Table 27). of risk factors and prevention options. The incidence of a first episode of venous thromboembolism (VTE) is approximately I to 2 per 1000 person/years.

Apheresis procedures collect whole blood and separate it into 'Erythrocyte exchange for acute chest syndrome is a category ll indication but recommended by many as first-line therapy for those severely affected. components. Specific components (plasma, platelets, erythro- dThe use of plateletpheresis is a category ll indication for patients with life cytes, leukocytes) can be removed as needed. Fluid is replaced threatening thrombosis or hemorrhage associated with thrombocytosis (e.9., in a patient with essential thromboc).tosis). with colloid and crystalloid. Complications include hypocalce Data from Padmanabhan A, Connelly-Smith L, Aqui N, et al. Gurdelines on the use mia, th rombocytopenia, and hypofi brinogenemia, so laboratory of therapeutic apheresis rn clinical practice evidence based approach from the studies must be monitored. Therapy for thrombotic thrombocy writing committee of the American Society for Apheresis: the eighth special issue. . J Clin Apher. 201 9;34: 1 7 1 354. IPMID: 31 1 80581 ] doi: 1 0.1 002/1ca.217 05 topenic purpura is more appropriately characterized as plasma exchange because fresh frozen plasma is provided as the replace ment fluid. The same cell separators can be used to perform plateletpheresis, erythrocyte exchange transfusion, and other embolism (PE), continues to increase despite better awareness procedures in patients with specific indications (Table 27). of risk factors and prevention options. The incidence of a first episode of venous thromboembolism (VTE) is approximately I to 2 per 1000 person/years. Thrombotic Disorders Many nosocomial VTEs are preventable, although throm- boprophylaxis continues to be underused. D-dimer testing The burden of venous thromboembolic disease, including and imaging for VTE diagnosis should be used within the superficial and deep venous thrombosis (DVT) and pulmonary context of appropriate clinical algorithms.

Thrombotic Disorders Many nosocomial VTEs are preventable, although throm- boprophylaxis continues to be underused. D-dimer testing The burden of venous thromboembolic disease, including and imaging for VTE diagnosis should be used within the superficial and deep venous thrombosis (DVT) and pulmonary context of appropriate clinical algorithms. 50

i Thrombotic Disorders I Opinions differ regarding the relevance of thrombophilia or by inhibiting clot lysis. All known inherited thrombophilias testing, and results usually do not affect treatment choices. are autosomal dominant; therefore, most affected patients are Treatment options continue to evolve. heterozygous for the disorder. The two most common inher- t ited thrombophilias are factor V Leiden (FVL) and prothrom bin G2O21OA gene mutation. Antithrombin deficiency and Pathophysiology of Th rom bosis protein C and S deficiencies are less common but are more Alterations in three primary physiologic processes predispose significant risk factors for VTE. persons to VTE. The Virchow triad, described by Rudolph Failure to identiff a thrombophilia through laboratory Vircho'"r, more than 150 years ago, includes reduced or turbu- testing does not mean one does not exist. Studies have shown lent blood flow alterations or injury to the vessel wall, and that even without an identified inherited disorder, a lamily his- changes in blood components that are prothrombotic or tory of thrombosis remains an independent risk factor for VTE. inhibit fibrinolysis (or both). VTE usually develops from the Although identification of the inherited thrombophilias synergistic effect of multiple risk factors. has advanced the understanding of VTE pathophysiologz, it has little influence on clinical management. The acute man agement of patients with VTE does not differ based on the Thrombophilia presence of an inherited thrombophilia. Management dura- tion is typically determined by whether the VTE event was Thrombophilia Testing provoked by a reversible or self-limited insult. Even if an One aspect ofl the Virchow triad is hypercoagulability, or inherited thrombophilia is found in a patient with VTE, thrombophilia. Thrombophilia can be inherited or acquired. asymptomatic family members should not undergo thrombo Although guidelines differ, most experts agree that thrombo philia testing. philia evaluation should not be routinely pursued in patients with VTE but may be considered in certain populations, Factor V Leiden including patients with thromboses at unusual sites (e.g., the FVL is the most common inherited thrombophilia type. portal venous system) or recurrent idiopathic thrombosis, Activated factor V combines with lactor X to produce throm patients younger than 45 years with unprovoked thrombosis, bin, which leads to clot formation. This process is regulated by patients with a clear family history of thrombosis in one or activated protein C, which inactivates factor V to stop the pro more first degree relatives, women with a history of recurrent cess of ongoing clot formation. In FVL, mutated factor V is fetal loss, and patients with warfarin induced skin necrosis. resistant to cleavage by activated protein C, leading to a pro- Many variables, including acute thrombosis and antico thrombotic state. Heterozygous FVL is found in about 5'2, of agulant use, can affect outcomes of thrombophilia testing and White people, whereas the homozygous form is found in less may lead to false-positive test results. Except for high-risk than 1%. FVL is rare in Asian, African, Black, and American antiphospholipid antibody syndrome, a known thrombophilia Indian populations. Although persons who are heterozygous will not change immediate management; therefore, testing have a fourfold to eightfold increased risk for developing a first should not be pursued in the acute setting. VTE compared with otherwise healthy persons, most remain xlv P0t 1{Is asymptomatic, and recent studies suggest that these patients . Thrombophilia testing may be considered in patients are not at higher risk for recurrent thrombosis compared with with thromboses at unusual sites or recurrent idiopathic healthy persons. FVL and the other inherited thrombophilias thrombosis, patients younger than 45 years with unpro- do not appear to be associated with arterial thrombosis. FVL voked thrombosis, patients with a clear family history of genetic testing or activated protein C resistance testing can be thrombosis in one or more first-degree relatives, women used to diagnose this condition. with a history of recurrent fetal loss, and patients with warfarin-induced skin necrosis. Prothrombin G2O21OA Gene Mutation The prothrombin G20210A gene mutation occurs in approxi- HVC . Thrombophilia testing is less accurate during episodes of mately 2% of Whites and 0.5% of Blacks and causes increased acute venous thromboembolism, and results generally production of prothrombin (factor II) through a guanine to do not change immediate management, except in high adenine substitution at nucleotide 20210. Persons with this risk antiphospholipid antibody syndrome; if thrombo- mutation are at a twofold to fourfold increased risk for devel philia testing is indicated, it should ideally be performed oping a first VTE, although most patients with this mutation after anticoagulation has been discontinued. do not experience VTE events. Data are unclear regarding risks with the homozygous state, which is rare. lnherited Thrombophilias Inherited thrombophilias typically affect components of the Antithrombin Defi ciency coagulation cascade (see Figure 26 in Bleeding Disorders) by Antithrombin III (ATIII) and proteins C and S serve as natural causing the prothrombotic system to continue unsuppressed anticoagulants in the body. Mutations leading to loss of

Opinions differ regarding the relevance of thrombophilia or by inhibiting clot lysis. All known inherited thrombophilias testing, and results usually do not affect treatment choices. are autosomal dominant; therefore, most affected patients are Treatment options continue to evolve. heterozygous for the disorder. The two most common inher- t ited thrombophilias are factor V Leiden (FVL) and prothrom bin G2O21OA gene mutation. Antithrombin deficiency and Pathophysiology of Th rom bosis protein C and S deficiencies are less common but are more Alterations in three primary physiologic processes predispose significant risk factors for VTE. persons to VTE. The Virchow triad, described by Rudolph Failure to identiff a thrombophilia through laboratory Vircho'"r, more than 150 years ago, includes reduced or turbu- testing does not mean one does not exist. Studies have shown lent blood flow alterations or injury to the vessel wall, and that even without an identified inherited disorder, a lamily his- changes in blood components that are prothrombotic or tory of thrombosis remains an independent risk factor for VTE. inhibit fibrinolysis (or both). VTE usually develops from the Although identification of the inherited thrombophilias synergistic effect of multiple risk factors. has advanced the understanding of VTE pathophysiologz, it has little influence on clinical management. The acute man agement of patients with VTE does not differ based on the Thrombophilia presence of an inherited thrombophilia. Management dura- tion is typically determined by whether the VTE event was Thrombophilia Testing provoked by a reversible or self-limited insult. Even if an One aspect ofl the Virchow triad is hypercoagulability, or inherited thrombophilia is found in a patient with VTE, thrombophilia. Thrombophilia can be inherited or acquired. asymptomatic family members should not undergo thrombo Although guidelines differ, most experts agree that thrombo philia testing. philia evaluation should not be routinely pursued in patients with VTE but may be considered in certain populations, Factor V Leiden including patients with thromboses at unusual sites (e.g., the FVL is the most common inherited thrombophilia type. portal venous system) or recurrent idiopathic thrombosis, Activated factor V combines with lactor X to produce throm patients younger than 45 years with unprovoked thrombosis, bin, which leads to clot formation. This process is regulated by patients with a clear family history of thrombosis in one or activated protein C, which inactivates factor V to stop the pro more first degree relatives, women with a history of recurrent cess of ongoing clot formation. In FVL, mutated factor V is fetal loss, and patients with warfarin induced skin necrosis. resistant to cleavage by activated protein C, leading to a pro- Many variables, including acute thrombosis and antico thrombotic state. Heterozygous FVL is found in about 5'2, of agulant use, can affect outcomes of thrombophilia testing and White people, whereas the homozygous form is found in less may lead to false-positive test results. Except for high-risk than 1%. FVL is rare in Asian, African, Black, and American antiphospholipid antibody syndrome, a known thrombophilia Indian populations. Although persons who are heterozygous will not change immediate management; therefore, testing have a fourfold to eightfold increased risk for developing a first should not be pursued in the acute setting. VTE compared with otherwise healthy persons, most remain xlv P0t 1{Is asymptomatic, and recent studies suggest that these patients . Thrombophilia testing may be considered in patients are not at higher risk for recurrent thrombosis compared with with thromboses at unusual sites or recurrent idiopathic healthy persons. FVL and the other inherited thrombophilias thrombosis, patients younger than 45 years with unpro- do not appear to be associated with arterial thrombosis. FVL voked thrombosis, patients with a clear family history of genetic testing or activated protein C resistance testing can be thrombosis in one or more first-degree relatives, women used to diagnose this condition. with a history of recurrent fetal loss, and patients with warfarin-induced skin necrosis. Prothrombin G2O21OA Gene Mutation The prothrombin G20210A gene mutation occurs in approxi- HVC . Thrombophilia testing is less accurate during episodes of mately 2% of Whites and 0.5% of Blacks and causes increased acute venous thromboembolism, and results generally production of prothrombin (factor II) through a guanine to do not change immediate management, except in high adenine substitution at nucleotide 20210. Persons with this risk antiphospholipid antibody syndrome; if thrombo- mutation are at a twofold to fourfold increased risk for devel philia testing is indicated, it should ideally be performed oping a first VTE, although most patients with this mutation after anticoagulation has been discontinued. do not experience VTE events. Data are unclear regarding risks with the homozygous state, which is rare. lnherited Thrombophilias Inherited thrombophilias typically affect components of the Antithrombin Defi ciency coagulation cascade (see Figure 26 in Bleeding Disorders) by Antithrombin III (ATIII) and proteins C and S serve as natural causing the prothrombotic system to continue unsuppressed anticoagulants in the body. Mutations leading to loss of 51

Thrombotic Disorders function or production ofthese components increase the risk considered because heparin requires ATIII to be effective. ATIII of VTE. concentrate can be used to treat this condition. ATIII deficiency, although rare, with a prevalence of 1 in 3000 to 5000 persons, is a more significant thrombophilic risk Protein C Deficiency factor than FVL or prothrombin G2O210A gene mutation. The Protein C is a vitamin K dependent protein that degrades acti main role of ATIII is to inhibit thrombin and activated factors IX vated factors V and VIII. Heterozygous protein C deflciency has { and X (IXa and Xa). Thrombosis occurs in 30% of patients with a prevalence of 2 to 5 per 1000 persons and is often associated heterozygous ATIII deficiency by age 30 years and in 65'l. by age with pregnancy morbidity or a thrombotic event before age 50 years. The thrombosis risk is particular$ high during preg 50 years, with a strong family history of thrombosis. Patients nanry, leading to WE-related pregnancy loss and pregnancy can develop warfarin induced skin necrosis (Figure 27) because morbidity. Acquired ATIII deflciency is much more common of rapid depletion of protein C, which proceeds faster than than congenital deficiency (Table 28). Repeat testing is typically depletion of the coagulation factors. Homozygous deficiency is required to determine whether the deficiency is persistent. rare and causes neonatal purpura fulminans. If protein C For patients in whom heparin is initiated and titration to deficiency is found, acquired causes should be ruled out (see a therapeutic range is difficult, ATIII deficiency should be Table 2B). Patients should not be tested during acute VTE events or while receiving warfarin. Protein C functional testing can be ordered to evaluate for deficiency; confirmatory testing TASTE 28. Conditions Associated With Acquired is often necessary. Decreased Anticoagulant Factor Levels Coagulation Acquired Condition Protein S Deficiency Factor Protein S is a vitamin K dependent protein that functions as Protein C Acute thrombosis a cofactor for protein C and degrades activated factors V and Warfarin therapy VIII. Deficiency is uncommon and bears many similarities to Liver disease protein C deficiency. Patients who are heterozygous for protein Protein-losi n g enteropathy S deficiency typically experience VTE at a younger age (<s0 years). Protein S circulates in a free form and is bound to Disseminated intravascular coagulation a complement-binding protein. Although case reports of lunc Nephrotic syndrome tional protein S deficiency are rare, immunoassay of the free Vitamin K deficiency form is usually sufficient for diagnosis. Protein S deficiency is Protein S Acute thrombosis likely the most difficult hereditary thrombophilia to confirm Warfarin therapy because multiple laboratory assays are available, but cutoffs Liver disease between norrnal and deficient are imprecise. lnflammatory states Other Inherited Disorders Estrogens (contraceptives, pregnancy, postpartum state, hormone replacement Methylene tetrahydrololate reductase (MTHFR) gene polymor therapy) phisms cause mild elevations in homocysteine levels, which Protein-losing enteropathy are associated with a slightly increased risk of cardiovascular and thrombotic disease. The heterozygous mutation is found Nephrotic syndrome Disseminated intravascu lar coagulation HIV

function or production ofthese components increase the risk considered because heparin requires ATIII to be effective. ATIII of VTE. concentrate can be used to treat this condition. ATIII deficiency, although rare, with a prevalence of 1 in 3000 to 5000 persons, is a more significant thrombophilic risk Protein C Deficiency factor than FVL or prothrombin G2O210A gene mutation. The Protein C is a vitamin K dependent protein that degrades acti main role of ATIII is to inhibit thrombin and activated factors IX vated factors V and VIII. Heterozygous protein C deflciency has { and X (IXa and Xa). Thrombosis occurs in 30% of patients with a prevalence of 2 to 5 per 1000 persons and is often associated heterozygous ATIII deficiency by age 30 years and in 65'l. by age with pregnancy morbidity or a thrombotic event before age 50 years. The thrombosis risk is particular$ high during preg 50 years, with a strong family history of thrombosis. Patients nanry, leading to WE-related pregnancy loss and pregnancy can develop warfarin induced skin necrosis (Figure 27) because morbidity. Acquired ATIII deflciency is much more common of rapid depletion of protein C, which proceeds faster than than congenital deficiency (Table 28). Repeat testing is typically depletion of the coagulation factors. Homozygous deficiency is required to determine whether the deficiency is persistent. rare and causes neonatal purpura fulminans. If protein C For patients in whom heparin is initiated and titration to deficiency is found, acquired causes should be ruled out (see a therapeutic range is difficult, ATIII deficiency should be Table 2B). Patients should not be tested during acute VTE events or while receiving warfarin. Protein C functional testing can be ordered to evaluate for deficiency; confirmatory testing TASTE 28. Conditions Associated With Acquired is often necessary. Decreased Anticoagulant Factor Levels Coagulation Acquired Condition Protein S Deficiency Factor Protein S is a vitamin K dependent protein that functions as Protein C Acute thrombosis a cofactor for protein C and degrades activated factors V and Warfarin therapy VIII. Deficiency is uncommon and bears many similarities to Liver disease protein C deficiency. Patients who are heterozygous for protein Protein-losi n g enteropathy S deficiency typically experience VTE at a younger age (<s0 years). Protein S circulates in a free form and is bound to Disseminated intravascular coagulation a complement-binding protein. Although case reports of lunc Nephrotic syndrome tional protein S deficiency are rare, immunoassay of the free Vitamin K deficiency form is usually sufficient for diagnosis. Protein S deficiency is Protein S Acute thrombosis likely the most difficult hereditary thrombophilia to confirm Warfarin therapy because multiple laboratory assays are available, but cutoffs Liver disease between norrnal and deficient are imprecise. lnflammatory states Other Inherited Disorders Estrogens (contraceptives, pregnancy, postpartum state, hormone replacement Methylene tetrahydrololate reductase (MTHFR) gene polymor therapy) phisms cause mild elevations in homocysteine levels, which Protein-losing enteropathy are associated with a slightly increased risk of cardiovascular and thrombotic disease. The heterozygous mutation is found Nephrotic syndrome Disseminated intravascu lar coagulation HIV L-asparaginase chemotherapy Vitamin K deficiency Antithrombin Acute thrombosis Heparin therapy Liver disease

function or production ofthese components increase the risk considered because heparin requires ATIII to be effective. ATIII of VTE. concentrate can be used to treat this condition. ATIII deficiency, although rare, with a prevalence of 1 in 3000 to 5000 persons, is a more significant thrombophilic risk Protein C Deficiency factor than FVL or prothrombin G2O210A gene mutation. The Protein C is a vitamin K dependent protein that degrades acti main role of ATIII is to inhibit thrombin and activated factors IX vated factors V and VIII. Heterozygous protein C deflciency has { and X (IXa and Xa). Thrombosis occurs in 30% of patients with a prevalence of 2 to 5 per 1000 persons and is often associated heterozygous ATIII deficiency by age 30 years and in 65'l. by age with pregnancy morbidity or a thrombotic event before age 50 years. The thrombosis risk is particular$ high during preg 50 years, with a strong family history of thrombosis. Patients nanry, leading to WE-related pregnancy loss and pregnancy can develop warfarin induced skin necrosis (Figure 27) because morbidity. Acquired ATIII deflciency is much more common of rapid depletion of protein C, which proceeds faster than than congenital deficiency (Table 28). Repeat testing is typically depletion of the coagulation factors. Homozygous deficiency is required to determine whether the deficiency is persistent. rare and causes neonatal purpura fulminans. If protein C For patients in whom heparin is initiated and titration to deficiency is found, acquired causes should be ruled out (see a therapeutic range is difficult, ATIII deficiency should be Table 2B). Patients should not be tested during acute VTE events or while receiving warfarin. Protein C functional testing can be ordered to evaluate for deficiency; confirmatory testing TASTE 28. Conditions Associated With Acquired is often necessary. Decreased Anticoagulant Factor Levels Coagulation Acquired Condition Protein S Deficiency Factor Protein S is a vitamin K dependent protein that functions as Protein C Acute thrombosis a cofactor for protein C and degrades activated factors V and Warfarin therapy VIII. Deficiency is uncommon and bears many similarities to Liver disease protein C deficiency. Patients who are heterozygous for protein Protein-losi n g enteropathy S deficiency typically experience VTE at a younger age (<s0 years). Protein S circulates in a free form and is bound to Disseminated intravascular coagulation a complement-binding protein. Although case reports of lunc Nephrotic syndrome tional protein S deficiency are rare, immunoassay of the free Vitamin K deficiency form is usually sufficient for diagnosis. Protein S deficiency is Protein S Acute thrombosis likely the most difficult hereditary thrombophilia to confirm Warfarin therapy because multiple laboratory assays are available, but cutoffs Liver disease between norrnal and deficient are imprecise. lnflammatory states Other Inherited Disorders Estrogens (contraceptives, pregnancy, postpartum state, hormone replacement Methylene tetrahydrololate reductase (MTHFR) gene polymor therapy) phisms cause mild elevations in homocysteine levels, which Protein-losing enteropathy are associated with a slightly increased risk of cardiovascular and thrombotic disease. The heterozygous mutation is found Nephrotic syndrome Disseminated intravascu lar coagulation HIV L-asparaginase chemotherapy Vitamin K deficiency Antithrombin Acute thrombosis Heparin therapy Liver disease Nephrotic syndrome Protein-losing enteropathy Disseminated intravascular coagulation

function or production ofthese components increase the risk considered because heparin requires ATIII to be effective. ATIII of VTE. concentrate can be used to treat this condition. ATIII deficiency, although rare, with a prevalence of 1 in 3000 to 5000 persons, is a more significant thrombophilic risk Protein C Deficiency factor than FVL or prothrombin G2O210A gene mutation. The Protein C is a vitamin K dependent protein that degrades acti main role of ATIII is to inhibit thrombin and activated factors IX vated factors V and VIII. Heterozygous protein C deflciency has { and X (IXa and Xa). Thrombosis occurs in 30% of patients with a prevalence of 2 to 5 per 1000 persons and is often associated heterozygous ATIII deficiency by age 30 years and in 65'l. by age with pregnancy morbidity or a thrombotic event before age 50 years. The thrombosis risk is particular$ high during preg 50 years, with a strong family history of thrombosis. Patients nanry, leading to WE-related pregnancy loss and pregnancy can develop warfarin induced skin necrosis (Figure 27) because morbidity. Acquired ATIII deflciency is much more common of rapid depletion of protein C, which proceeds faster than than congenital deficiency (Table 28). Repeat testing is typically depletion of the coagulation factors. Homozygous deficiency is required to determine whether the deficiency is persistent. rare and causes neonatal purpura fulminans. If protein C For patients in whom heparin is initiated and titration to deficiency is found, acquired causes should be ruled out (see a therapeutic range is difficult, ATIII deficiency should be Table 2B). Patients should not be tested during acute VTE events or while receiving warfarin. Protein C functional testing can be ordered to evaluate for deficiency; confirmatory testing TASTE 28. Conditions Associated With Acquired is often necessary. Decreased Anticoagulant Factor Levels Coagulation Acquired Condition Protein S Deficiency Factor Protein S is a vitamin K dependent protein that functions as Protein C Acute thrombosis a cofactor for protein C and degrades activated factors V and Warfarin therapy VIII. Deficiency is uncommon and bears many similarities to Liver disease protein C deficiency. Patients who are heterozygous for protein Protein-losi n g enteropathy S deficiency typically experience VTE at a younger age (<s0 years). Protein S circulates in a free form and is bound to Disseminated intravascular coagulation a complement-binding protein. Although case reports of lunc Nephrotic syndrome tional protein S deficiency are rare, immunoassay of the free Vitamin K deficiency form is usually sufficient for diagnosis. Protein S deficiency is Protein S Acute thrombosis likely the most difficult hereditary thrombophilia to confirm Warfarin therapy because multiple laboratory assays are available, but cutoffs Liver disease between norrnal and deficient are imprecise. lnflammatory states Other Inherited Disorders Estrogens (contraceptives, pregnancy, postpartum state, hormone replacement Methylene tetrahydrololate reductase (MTHFR) gene polymor therapy) phisms cause mild elevations in homocysteine levels, which Protein-losing enteropathy are associated with a slightly increased risk of cardiovascular and thrombotic disease. The heterozygous mutation is found Nephrotic syndrome Disseminated intravascu lar coagulation HIV L-asparaginase chemotherapy Vitamin K deficiency Antithrombin Acute thrombosis Heparin therapy Liver disease Nephrotic syndrome Protein-losing enteropathy Disseminated intravascular coagulation t ECMO (extra corporeal membrane circulation) and hemodialysis L-aspara ginase chemotherapy Severe trauma or burns tIGURE 27. Warfarin-induced skin necrosis. t 52 .l

Thrombotic Disorders in 20',4, of Whites and 2'1, of Blacks but may be a marker of Cancer thrombotic risk rather than ir cause of thrombosis. Cancer is diagnosed in l0',1, of patients within I year of an Testing fbr the MTHFR mutation and measuring homo unprovoked VTE occurrence. Cancer of the ovary pancreas, cysteine levels, in addition to tactor VIII levels and plasmino and liver are most frequently tbund. The only randontized gen activator inhibitor activity, should not be part of the controlled clinical trial that compared routine :rge :rnd sex standard thrombophilia evlluation. because clinical trials indicated screening r,vith extensive malignancy screening regarding their importance have been inconclusive and results showed no survival benefit with extensive malignancy do not influence management. screening. rEY POIilIS Thrombosis remains a leading cause of death in patients with cancer and is a significirnt source of morbidity. Increased o Although the risk of venous thromboembolism is ! thrombotic risk has been irssociirted with numerous malig increased in patients who are heterozygous for factor V nancies. Thromboprophylaxis is not recommended in all Leiden or the prothrombin G20210A gene mutation, outpatients with cancer, but prophylaxis with apixaban, rivar most patients are asymptomatic. oxaban, or low molecular weigl.rt heparin (LMWH) can be o For patients in whom heparin is initiated and titration to given to patients at the highest risk for thrombosis (defined by a therapeutic range is difficult, antithrombin deficiency a Khorana score of 2 or greater; Table 29) befbre starting a new should be considered. systemic chemotherapy regimen after careful consideration HVC o Deficiencies of the vitamin K dependent factors pro and discussion of bleeding risks and benefits. In some patients tein C and S are rare, and testing for these deficiencies with multiple myeloma, aspirin or fixed low dose warfarin should not be performed during an acute thrombotic may be considered for thromboprophylaxis. event or anticoagulation with warfarin. HVC r Testing for methylene tetrahydrololate reductase, as Medication well as measuring homocysteine levels, factor VIII lev Hormones used in contraceptives and in the treatment of' els, and plasminogen activator inhibitor activity should menopause increase the risk of VTE. The risk in women using not be part of the standard thrombophilia evaluation oral contraceptives is increased approximately threefold, but ( because results do not influence management. the absolute number o1'patients affected remains small. VTE risk is highest with combined oral contraceptives containing both estrogen and progesterone. Regardless ofthe type of con Acquired Thrombophilias traceptive, VTE risk tends to be greater in u,omen who hirve VTFI is more likely to occur in the setting of an acquired rather obesity and in those 39 years or older. Women with il previous than an inherited thrombophilia. Many conditions predispose VTE event should avoid combined oral contraceptives and low patients to the development of thrombosis. dose estrogen replacement therapy when possible; however, experts do not recommend routine thrombophilia screening Surgery Trauma, Hospitalization, and Immobility before beginning contraceptive use. VTE risk is incre:rsed by Surgery trauma, hospitalization, and immobilization are some approximately twofold in menop:rusal women taking conju of the most significant risk factors fbr VTE. VTE occurs fre gated estrogen medroxyprogesterone hormone replacement quently in medical and surgic:rl patients; approximately half of therapy, but the absolute risk remains small. The VTE risk all new VTEs are diagnosed during or within 3 months of a hospital stay or surgical proceclure. If prophylaxis is not used, the risk of DVT in patients undergoing general surgery is 15'/, to TABLE 29. Khorana Scoreu :10',/,. The risk of DVT is approximately 60'l" after hip fracture Risk Factor Points surgery. Patients with cancer who undergo surgery and those Site of cancer undergoing orthopedic procedures, including knee arthro Very high risk (stomach, pancreas) 2 plasty, hip fracture repair, or hip replacement, are at particularly High risk (lung, Iymphoma, gynecologic, bladder, high risk. Nosocomial VTE risk is also increased for nonsurgical testicu lar) l.rospitalized patients, especially those who are immobilized, BMt>35 hirve acute neurologic illness, or are in the medical ICU. Decision Hemoglobin level <10 g/dL (100 g/L)(or use of support tools, including the Caprini score (https'//wrnrw.mdcalc. e ryth rocyte g rowth factors) com/caprini score venous thromboembolism 2005), can help Leukocyte count >1 1,000/ttL(1 1 x 1 0elL)(before stratify nosocomial VTE risk and are most helpful in the perio chemotherapy) perative setting. Platelet count >350,000/UL (350 x 1 oell) (before Certain medical conditions, including inflammatory con chemotherapy) clitions, nephrotic syndrome, irnd inflammatory bowel dis Low risk = 0 points; intermediate ilsk 1 2 points; high risk = >3 points ease, are associated with increased thron.rbotic risk. Obesitv is 'The Khorana score assesses venous thromboembolism risk in patients with cancer also associated with increased thronrbotic risk.

in 20',4, of Whites and 2'1, of Blacks but may be a marker of Cancer thrombotic risk rather than ir cause of thrombosis. Cancer is diagnosed in l0',1, of patients within I year of an Testing fbr the MTHFR mutation and measuring homo unprovoked VTE occurrence. Cancer of the ovary pancreas, cysteine levels, in addition to tactor VIII levels and plasmino and liver are most frequently tbund. The only randontized gen activator inhibitor activity, should not be part of the controlled clinical trial that compared routine :rge :rnd sex standard thrombophilia evlluation. because clinical trials indicated screening r,vith extensive malignancy screening regarding their importance have been inconclusive and results showed no survival benefit with extensive malignancy do not influence management. screening. rEY POIilIS Thrombosis remains a leading cause of death in patients with cancer and is a significirnt source of morbidity. Increased o Although the risk of venous thromboembolism is ! thrombotic risk has been irssociirted with numerous malig increased in patients who are heterozygous for factor V nancies. Thromboprophylaxis is not recommended in all Leiden or the prothrombin G20210A gene mutation, outpatients with cancer, but prophylaxis with apixaban, rivar most patients are asymptomatic. oxaban, or low molecular weigl.rt heparin (LMWH) can be o For patients in whom heparin is initiated and titration to given to patients at the highest risk for thrombosis (defined by a therapeutic range is difficult, antithrombin deficiency a Khorana score of 2 or greater; Table 29) befbre starting a new should be considered. systemic chemotherapy regimen after careful consideration HVC o Deficiencies of the vitamin K dependent factors pro and discussion of bleeding risks and benefits. In some patients tein C and S are rare, and testing for these deficiencies with multiple myeloma, aspirin or fixed low dose warfarin should not be performed during an acute thrombotic may be considered for thromboprophylaxis. event or anticoagulation with warfarin. HVC r Testing for methylene tetrahydrololate reductase, as Medication well as measuring homocysteine levels, factor VIII lev Hormones used in contraceptives and in the treatment of' els, and plasminogen activator inhibitor activity should menopause increase the risk of VTE. The risk in women using not be part of the standard thrombophilia evaluation oral contraceptives is increased approximately threefold, but ( because results do not influence management. the absolute number o1'patients affected remains small. VTE risk is highest with combined oral contraceptives containing both estrogen and progesterone. Regardless ofthe type of con Acquired Thrombophilias traceptive, VTE risk tends to be greater in u,omen who hirve VTFI is more likely to occur in the setting of an acquired rather obesity and in those 39 years or older. Women with il previous than an inherited thrombophilia. Many conditions predispose VTE event should avoid combined oral contraceptives and low patients to the development of thrombosis. dose estrogen replacement therapy when possible; however, experts do not recommend routine thrombophilia screening Surgery Trauma, Hospitalization, and Immobility before beginning contraceptive use. VTE risk is incre:rsed by Surgery trauma, hospitalization, and immobilization are some approximately twofold in menop:rusal women taking conju of the most significant risk factors fbr VTE. VTE occurs fre gated estrogen medroxyprogesterone hormone replacement quently in medical and surgic:rl patients; approximately half of therapy, but the absolute risk remains small. The VTE risk all new VTEs are diagnosed during or within 3 months of a hospital stay or surgical proceclure. If prophylaxis is not used, the risk of DVT in patients undergoing general surgery is 15'/, to TABLE 29. Khorana Scoreu :10',/,. The risk of DVT is approximately 60'l" after hip fracture Risk Factor Points surgery. Patients with cancer who undergo surgery and those Site of cancer undergoing orthopedic procedures, including knee arthro Very high risk (stomach, pancreas) 2 plasty, hip fracture repair, or hip replacement, are at particularly High risk (lung, Iymphoma, gynecologic, bladder, high risk. Nosocomial VTE risk is also increased for nonsurgical testicu lar) l.rospitalized patients, especially those who are immobilized, BMt>35 hirve acute neurologic illness, or are in the medical ICU. Decision Hemoglobin level <10 g/dL (100 g/L)(or use of support tools, including the Caprini score (https'//wrnrw.mdcalc. e ryth rocyte g rowth factors) com/caprini score venous thromboembolism 2005), can help Leukocyte count >1 1,000/ttL(1 1 x 1 0elL)(before stratify nosocomial VTE risk and are most helpful in the perio chemotherapy) perative setting. Platelet count >350,000/UL (350 x 1 oell) (before Certain medical conditions, including inflammatory con chemotherapy) clitions, nephrotic syndrome, irnd inflammatory bowel dis Low risk = 0 points; intermediate ilsk 1 2 points; high risk = >3 points ease, are associated with increased thron.rbotic risk. Obesitv is 'The Khorana score assesses venous thromboembolism risk in patients with cancer also associated with increased thronrbotic risk. 53

Thrombotic Disorders appears lower in menopausal women taking only estrogen and warfarin. The ideal management of low or intermediate risk in those using transdermal hormone replacement. APLAS is unknown. The antiestrogen, tamoxifen, also increases VTE risk in women with estrogen receptor positive breast cancer; this Other Acquired Thrombophilic Conditions risk increases further, approximately three times baseline, in The myeloproliferative neoplasms have been found to confer an women receiving tamoxifen with systemic chemotherapy. The increased risk of thrombosis, including PE, DVI, portal vein risk for VTE with aromatase inhibitors, such as anastrozole, is thrombosis, and Budd-Chiari syndrome (hepatic venous outflow lower than with tamoxifen. obstruction) (see MKSAP 19 Gastroenterologr and Hepatolory). Patients with multiple myeloma receiving an immu Evidence of a myeloproliferative neoplasm is discovered in nomodulatory agent, such as lenalidomide or pomalido approximately 50% ofpatients with Budd-Chiari slndrome, eren mide, have a significant risk for VTE that warrants when the complete blood count is normal. In the setting of prophylaxis with aspirin, LMWH, fixed-dose warfarin, or a splanchnic vein thrombosis (portal vein, splenic vein, hepatic factor Xa inhibitor, depending on the patient's risk profile. vein, or mesenteric vein thrombosis), evaluation for evidence of a The vascular endothelial growth factor inhibitor bevaciz- myeloproliferative neoplasm should be considered, including umab and newer multitargeted tyrosine kinase inhibitors, evaluation for the JAK2 tyrosine kinase mutation. such as sunitinib and sorafenib, also increase VTE risk. Paroxysmal noctumal hemoglobinuria is another acquired stem cell disorder associated with hemolytic anemia, bone Antiphospholipid Antibody S5mdrome marrow failure, and thrombosis (see Ery,'throcy'te Disorders). Antiphospholipid antibody syndrome (APLAS) is an autoim- A previous VTE is one of the most significant predictors of mune disorder associated with venous and arterial thrombo- a subsequent WE, regardless of whether an additional inher sis, as well as increased risk of fetal demise during pregnancy. ited or acquired thrombophilic risk factor is identified. APLAS evaluation includes the anticardiolipin antibodies, anti p, glycoprotein antibodies, and lupus anticoagulant. KEY POIilIS The diagnosis of APLAS is based on the clinical criteria of . Approximately half of all new venous thromboembolisms thromboembolism or pregnancy morbidity and laboratory are diagnosed during orwithin 3 months of a hospital stay findings of medium or high titer antiphospholipid antibodies or surgical procedure. on two or more occasions at least 12 weeks apart (Table 3O). A . Patients with cancer undergoing extensive surgery or clue to the presence of the lupus anticoagulant is activated patients undergoing knee arthroplasty, hip fracture partial thromboplastin time (aPTT) prolongation. repair, or hip replacement surgery are at especially high Typically, patients diagnosed with APLAS require long- risk for postoperative venous thromboembolism. term anticoagulation because ofthe risk ofrecurrent throm- o The diagnosis of antiphospholipid antibody syndrome bosis. Patients with high risk disease (triple positive for lupus is based on the clinical criteria of thromboembolism or anticoagulant, anti 92 glycoprotein antibodies, and anticar- pregnancy morbidity and laboratory findings of diolipin antibodies and with a history of thrombosis) require medium- or high-titer antiphospholipid antibodies pre- treatment with warfarin according to study results (TRAPS) sent on tvvo or more occasions at least 12 weeks apart. demonstrating an increased risk of thrombosis in "triple- (Continued) positive" patients receiving rivaroxaban compared with

appears lower in menopausal women taking only estrogen and warfarin. The ideal management of low or intermediate risk in those using transdermal hormone replacement. APLAS is unknown. The antiestrogen, tamoxifen, also increases VTE risk in women with estrogen receptor positive breast cancer; this Other Acquired Thrombophilic Conditions risk increases further, approximately three times baseline, in The myeloproliferative neoplasms have been found to confer an women receiving tamoxifen with systemic chemotherapy. The increased risk of thrombosis, including PE, DVI, portal vein risk for VTE with aromatase inhibitors, such as anastrozole, is thrombosis, and Budd-Chiari syndrome (hepatic venous outflow lower than with tamoxifen. obstruction) (see MKSAP 19 Gastroenterologr and Hepatolory). Patients with multiple myeloma receiving an immu Evidence of a myeloproliferative neoplasm is discovered in nomodulatory agent, such as lenalidomide or pomalido approximately 50% ofpatients with Budd-Chiari slndrome, eren mide, have a significant risk for VTE that warrants when the complete blood count is normal. In the setting of prophylaxis with aspirin, LMWH, fixed-dose warfarin, or a splanchnic vein thrombosis (portal vein, splenic vein, hepatic factor Xa inhibitor, depending on the patient's risk profile. vein, or mesenteric vein thrombosis), evaluation for evidence of a The vascular endothelial growth factor inhibitor bevaciz- myeloproliferative neoplasm should be considered, including umab and newer multitargeted tyrosine kinase inhibitors, evaluation for the JAK2 tyrosine kinase mutation. such as sunitinib and sorafenib, also increase VTE risk. Paroxysmal noctumal hemoglobinuria is another acquired stem cell disorder associated with hemolytic anemia, bone Antiphospholipid Antibody S5mdrome marrow failure, and thrombosis (see Ery,'throcy'te Disorders). Antiphospholipid antibody syndrome (APLAS) is an autoim- A previous VTE is one of the most significant predictors of mune disorder associated with venous and arterial thrombo- a subsequent WE, regardless of whether an additional inher sis, as well as increased risk of fetal demise during pregnancy. ited or acquired thrombophilic risk factor is identified. APLAS evaluation includes the anticardiolipin antibodies, anti p, glycoprotein antibodies, and lupus anticoagulant. KEY POIilIS The diagnosis of APLAS is based on the clinical criteria of . Approximately half of all new venous thromboembolisms thromboembolism or pregnancy morbidity and laboratory are diagnosed during orwithin 3 months of a hospital stay findings of medium or high titer antiphospholipid antibodies or surgical procedure. on two or more occasions at least 12 weeks apart (Table 3O). A . Patients with cancer undergoing extensive surgery or clue to the presence of the lupus anticoagulant is activated patients undergoing knee arthroplasty, hip fracture partial thromboplastin time (aPTT) prolongation. repair, or hip replacement surgery are at especially high Typically, patients diagnosed with APLAS require long- risk for postoperative venous thromboembolism. term anticoagulation because ofthe risk ofrecurrent throm- o The diagnosis of antiphospholipid antibody syndrome bosis. Patients with high risk disease (triple positive for lupus is based on the clinical criteria of thromboembolism or anticoagulant, anti 92 glycoprotein antibodies, and anticar- pregnancy morbidity and laboratory findings of diolipin antibodies and with a history of thrombosis) require medium- or high-titer antiphospholipid antibodies pre- treatment with warfarin according to study results (TRAPS) sent on tvvo or more occasions at least 12 weeks apart. demonstrating an increased risk of thrombosis in "triple- (Continued) positive" patients receiving rivaroxaban compared with TABLE 3O. Diagnosis of Antiphospholipid Antibody Syndrome" Vascular Thrombosis Pregnancy Morbidity Laboratory Criteriab One or more objectively confirmed One or more unexplained deaths of a Lupus anticoagulant, detected according episodes of arterial, venous, or small vessel morphologically normalfetus at or beyond to the guidelines of the lnternational thrombosis occurring in any tissue or the 1Oth week of gestation; or Society on Thrombosis and Haemostasis organ One or more premature births of a Anticardiolipin antibody of lgG and/or lgM morphologically normal neonate before isotype, present in medium or high titer the 34th week of gestation because of (greaterthan 40 GPLor MPL, or greater eclampsia, pre-eclampsia, or placental than the 99th percentile), measured by a insufficiency; or standardized ELISA Three or more unexplained consecutive Anti-B2-glycoprotein-1 antibody of lgG spontaneous abortions before the 1 Oth and/or lgM isotype, present in titer greater week of gestation than the 99th percentile, measured by a standardized ELISA ELISA = enzyme-linked immunosorbent assay; GPL = specificity for lgG phospholipid antigens; MPL = specificity for lgM phospholipid antigens.

TABLE 3O. Diagnosis of Antiphospholipid Antibody Syndrome" Vascular Thrombosis Pregnancy Morbidity Laboratory Criteriab One or more objectively confirmed One or more unexplained deaths of a Lupus anticoagulant, detected according episodes of arterial, venous, or small vessel morphologically normalfetus at or beyond to the guidelines of the lnternational thrombosis occurring in any tissue or the 1Oth week of gestation; or Society on Thrombosis and Haemostasis organ One or more premature births of a Anticardiolipin antibody of lgG and/or lgM morphologically normal neonate before isotype, present in medium or high titer the 34th week of gestation because of (greaterthan 40 GPLor MPL, or greater eclampsia, pre-eclampsia, or placental than the 99th percentile), measured by a insufficiency; or standardized ELISA Three or more unexplained consecutive Anti-B2-glycoprotein-1 antibody of lgG spontaneous abortions before the 1 Oth and/or lgM isotype, present in titer greater week of gestation than the 99th percentile, measured by a standardized ELISA ELISA = enzyme-linked immunosorbent assay; GPL = specificity for lgG phospholipid antigens; MPL = specificity for lgM phospholipid antigens. "Diagnosis is based on the presence of vascular thrombosis OR pregnancy morbidity PLUS relevant laboratory criteria. bThe presence of one or more of the following antiphospholipid antibodies on two or more occasions at least 1 2 weeks apan.

TABLE 3O. Diagnosis of Antiphospholipid Antibody Syndrome" Vascular Thrombosis Pregnancy Morbidity Laboratory Criteriab One or more objectively confirmed One or more unexplained deaths of a Lupus anticoagulant, detected according episodes of arterial, venous, or small vessel morphologically normalfetus at or beyond to the guidelines of the lnternational thrombosis occurring in any tissue or the 1Oth week of gestation; or Society on Thrombosis and Haemostasis organ One or more premature births of a Anticardiolipin antibody of lgG and/or lgM morphologically normal neonate before isotype, present in medium or high titer the 34th week of gestation because of (greaterthan 40 GPLor MPL, or greater eclampsia, pre-eclampsia, or placental than the 99th percentile), measured by a insufficiency; or standardized ELISA Three or more unexplained consecutive Anti-B2-glycoprotein-1 antibody of lgG spontaneous abortions before the 1 Oth and/or lgM isotype, present in titer greater week of gestation than the 99th percentile, measured by a standardized ELISA ELISA = enzyme-linked immunosorbent assay; GPL = specificity for lgG phospholipid antigens; MPL = specificity for lgM phospholipid antigens. "Diagnosis is based on the presence of vascular thrombosis OR pregnancy morbidity PLUS relevant laboratory criteria. bThe presence of one or more of the following antiphospholipid antibodies on two or more occasions at least 1 2 weeks apan. 54

Thrombotic Disorders rtY POlllL (rifinadlt TABLE 31 . Wells Criteria for Deep Venous Thrombosis . Evidence of a myeloproliferative neoplasm is found in Clinical Characteristic Points approximately 50% of patients with Budd-Chiari syn- Active cancer (treatment within the previous +1 drome, and lAK2lyrosine kinase mutation testing 6 months or current palliative treatment) should be performed even if blood counts are normal. Paralysis, paresis, or recent immobilization of the +1 lower extremities Recently bedridden for )3 days, or major surgery +1 Deep Venous Thrombosis and within previous 12 weeks requiring anesthesia Pulmonary Embolism Swelling of the entire leg +1

rtY POlllL (rifinadlt TABLE 31 . Wells Criteria for Deep Venous Thrombosis . Evidence of a myeloproliferative neoplasm is found in Clinical Characteristic Points approximately 50% of patients with Budd-Chiari syn- Active cancer (treatment within the previous +1 drome, and lAK2lyrosine kinase mutation testing 6 months or current palliative treatment) should be performed even if blood counts are normal. Paralysis, paresis, or recent immobilization of the +1 lower extremities Recently bedridden for )3 days, or major surgery +1 Deep Venous Thrombosis and within previous 12 weeks requiring anesthesia Pulmonary Embolism Swelling of the entire leg +1 Prevention Localized tenderness along the deep venous system +1 A11 hospitalized patients should be assessed for the risk of Calf swelling >3 cm larger than on asymptomatic +1 developing a VTE and treated with appropriate prophylaxis side (measured 10 cm below tibial tuberosity) (see MKSAP 19 General Internal Medicine 2) because VTE is a Pitting edema confined to symptomatic leg +t major preventable cause of hospital morbidity and mortality. Collateral superficial veins (nonvaricose) +1 Generally, unless a clear contraindication to prophylaxis exists, Previously documented deep venous thrombosis +1 pharmacologic treatment is preferred to mechanical prophy- Alternative diagnosis at least as likely -l laxis. No additional benefit exists to using pneumatic com pression devices with pharmacologic prophylaxis. Patients 0-1 points=DVTunlikely;obtainD-dimerassay.l{theresultisnegative,nofurther evaluation; if the D-dimer is elevated, obtain Doppler ultrasonography. with cancer or stroke history or those in the ICU, have a par >1 point = DW likely; obtain Doppler ultrasonography. ticularly high risk for VTE. Despite the well-recognized risks of Reprinted with permission from Wells PS, Anderson DR, Rodger M, Forgie M, VTE, the rate of appropriate prophylaxis remains low in hospi Kearon C, Dreyer J, et al. Evaluation of o-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med.2003;349:1227 35. JPMID: 145079481 talized patients. Most patients do not require continued phar- doi:1 0.1 056/NEJMoa023 1 53 Reprinted with permission from Massachusetts macologic VTE prevention after discharge. However, patients Medical Society.

Prevention Localized tenderness along the deep venous system +1 A11 hospitalized patients should be assessed for the risk of Calf swelling >3 cm larger than on asymptomatic +1 developing a VTE and treated with appropriate prophylaxis side (measured 10 cm below tibial tuberosity) (see MKSAP 19 General Internal Medicine 2) because VTE is a Pitting edema confined to symptomatic leg +t major preventable cause of hospital morbidity and mortality. Collateral superficial veins (nonvaricose) +1 Generally, unless a clear contraindication to prophylaxis exists, Previously documented deep venous thrombosis +1 pharmacologic treatment is preferred to mechanical prophy- Alternative diagnosis at least as likely -l laxis. No additional benefit exists to using pneumatic com pression devices with pharmacologic prophylaxis. Patients 0-1 points=DVTunlikely;obtainD-dimerassay.l{theresultisnegative,nofurther evaluation; if the D-dimer is elevated, obtain Doppler ultrasonography. with cancer or stroke history or those in the ICU, have a par >1 point = DW likely; obtain Doppler ultrasonography. ticularly high risk for VTE. Despite the well-recognized risks of Reprinted with permission from Wells PS, Anderson DR, Rodger M, Forgie M, VTE, the rate of appropriate prophylaxis remains low in hospi Kearon C, Dreyer J, et al. Evaluation of o-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med.2003;349:1227 35. JPMID: 145079481 talized patients. Most patients do not require continued phar- doi:1 0.1 056/NEJMoa023 1 53 Reprinted with permission from Massachusetts macologic VTE prevention after discharge. However, patients Medical Society. with cancer or other high-risk features who are undergoing major surgical procedures, patients undergoing knee arthro- TABLE 32. Wells Criteria for Pulmonary Embolism plasty, and those with hip fracture repair or hip replacement require extended VTE prophylaxis after discharge. Variables Points Symptoms and Signs Diagnosis Hemoptysis 1

with cancer or other high-risk features who are undergoing major surgical procedures, patients undergoing knee arthro- TABLE 32. Wells Criteria for Pulmonary Embolism plasty, and those with hip fracture repair or hip replacement require extended VTE prophylaxis after discharge. Variables Points Symptoms and Signs Diagnosis Hemoptysis 1 VTE causes significant morbidity and requires efficient evalu Heart rate >1 00/min 1.5 ation and diagnosis. Previous VTE, positive family history and Clinical signs and symptoms of DW ? other thrombophilia risk factors, especially cancer, should be History assessed, as well as other potential causes of leg or respiratory symptoms. The typical clinical presentation of DVT involves Previously documented DW or PE 1.5 unilateral swelling, pain, warmth, and erythema of the Active cancer extremity. Patients with PE may present with chest pain, dysp Bedridden >3 days or major surgery in previous 1.5 nea, and tachypnea; less common symptoms may include 4 weeks

VTE causes significant morbidity and requires efficient evalu Heart rate >1 00/min 1.5 ation and diagnosis. Previous VTE, positive family history and Clinical signs and symptoms of DW ? other thrombophilia risk factors, especially cancer, should be History assessed, as well as other potential causes of leg or respiratory symptoms. The typical clinical presentation of DVT involves Previously documented DW or PE 1.5 unilateral swelling, pain, warmth, and erythema of the Active cancer extremity. Patients with PE may present with chest pain, dysp Bedridden >3 days or major surgery in previous 1.5 nea, and tachypnea; less common symptoms may include 4 weeks cough, fever, cyanosis, syncope, or shock. Other CT angiography has significantly improved the accurary of PE is most likely diagnosis PE evaluation, generally replacing the less speciflc ventilation DW = deep venous thrombosis; Pf = pulmonary embolism. perfusion scan and avoiding the need for more invasive pulmo- s4 points = PE unlikely; obtain D-dimer nary arteriographSz However, the overuse ofCT angiography and 4 6 points = moderate possibility of PE. D-dimer measurement in outpatients at low risk for PE need- >6 points = high probability of PE. lessly exposes patients to additional radiation and expense. For patients with symptoms suspicious for an acute VTE, validated Data from Wells PS, Anderson DR, Rodger M, Ginsberg JS, Kearon C, Gent N4, et al. Derivation of a simple clinical model to categorize patients probability of prediction rules have been developed that use D-dimer testing to pulmonary embolism: increasing the models utility with the SimpliRED D-dimen Thromb Haemost. 2000;83:41 6-20. IPM lD: 107 44147] help effectively evaluate patients. The Wells criteria for diagnosis of DVT (Table 31) and PE (Table 32) are well-studied tools. A subset of patients at very low risk may be identified using the In patients at low risk with a PERC score greater than Pulmonary Embolism Rule Out Criteria (PERC) (Table 33). Ifthe zero, D dimer testing should be pursued. If the result is nega PERC score is zero, no D-dimer testing or CT angiography should tive, no imaging is warranted. If the result is positive, further be performed. A meta-analysis of 12 studies found that if the evaluation is merited. If a patient has a moderate or high PERC were applied, only 0.3% of PEs would have been missed, pretest probability, imaging studies are indicated. D-dimer and22%, of D dimer testing would have been safely avoided. testing may be considered in patients with moderate pretest

cough, fever, cyanosis, syncope, or shock. Other CT angiography has significantly improved the accurary of PE is most likely diagnosis PE evaluation, generally replacing the less speciflc ventilation DW = deep venous thrombosis; Pf = pulmonary embolism. perfusion scan and avoiding the need for more invasive pulmo- s4 points = PE unlikely; obtain D-dimer nary arteriographSz However, the overuse ofCT angiography and 4 6 points = moderate possibility of PE. D-dimer measurement in outpatients at low risk for PE need- >6 points = high probability of PE. lessly exposes patients to additional radiation and expense. For patients with symptoms suspicious for an acute VTE, validated Data from Wells PS, Anderson DR, Rodger M, Ginsberg JS, Kearon C, Gent N4, et al. Derivation of a simple clinical model to categorize patients probability of prediction rules have been developed that use D-dimer testing to pulmonary embolism: increasing the models utility with the SimpliRED D-dimen Thromb Haemost. 2000;83:41 6-20. IPM lD: 107 44147] help effectively evaluate patients. The Wells criteria for diagnosis of DVT (Table 31) and PE (Table 32) are well-studied tools. A subset of patients at very low risk may be identified using the In patients at low risk with a PERC score greater than Pulmonary Embolism Rule Out Criteria (PERC) (Table 33). Ifthe zero, D dimer testing should be pursued. If the result is nega PERC score is zero, no D-dimer testing or CT angiography should tive, no imaging is warranted. If the result is positive, further be performed. A meta-analysis of 12 studies found that if the evaluation is merited. If a patient has a moderate or high PERC were applied, only 0.3% of PEs would have been missed, pretest probability, imaging studies are indicated. D-dimer and22%, of D dimer testing would have been safely avoided. testing may be considered in patients with moderate pretest 55

Thrombotic Disorders TABTE 33. Pulmonary Embolism Rule-Out Criteria for '.*.s Predicting Probability of Pulmonary Embolism in Patients '- - *B-.* With Low Pretest Probability '!'-'+**. Cli nica I Characteristic Meets Does Not Criterion Meet Criterion :trrqr Age <50 y -**1* 0 lnitial heart rate <100 beats/min 0 e*#F lnitial oxygen saturation >9402 0 on room air No unilateral leg swelling 0 No hemoptysis 0 No surgery or trauma within 0 4 weeks No history of venous 0 thromboembolism No estrogen use 0 ,ry€ Pretest probability with score of 0 is <1%. Reprinted with permission from Raja AS, Greenberg JO, Oaseem A, et al; Clinical Guidelines Committee of the American College of Physicians. Evaluation of patients with suspected acute pulmonary embolism: best practice advice from the clinical guidelines committee of the American College of Physicians. Ann lntern Med. 20 1 5;1 63:70 1 -1 1 . [PMID: 2641 4967] Copytght 20 1 5 American College of flGU RE 28, The ultrasound demonstrates abnormal compression Physicians. doi: 1 0.7326/M1 4-17 7 2 (noncompressibility) of the common femoral vein consistent with deep venous thrombosis. Normally, the anterior and posterior walls of a vei n (b/ue anows) will touch

Reprinted with permission from Raja AS, Greenberg JO, Oaseem A, et al; Clinical Guidelines Committee of the American College of Physicians. Evaluation of patients with suspected acute pulmonary embolism: best practice advice from the clinical guidelines committee of the American College of Physicians. Ann lntern Med. 20 1 5;1 63:70 1 -1 1 . [PMID: 2641 4967] Copytght 20 1 5 American College of flGU RE 28, The ultrasound demonstrates abnormal compression Physicians. doi: 1 0.7326/M1 4-17 7 2 (noncompressibility) of the common femoral vein consistent with deep venous thrombosis. Normally, the anterior and posterior walls of a vei n (b/ue anows) will touch probability (-20'1,) but should not be pursued in those with with the application of gentle pressure with the probe (compressibility), whereas the arlery (red arrowslis minimally compressible with pressure. high pretest probability because results would not change the need for imaging. proximal lower extremit5r ultrasonography without D-dimer In patients with kidney disease or in whom intravenous testing. No additional testing is recommended if the whole leg contrast is contraindicated, a ventilation/perfusion lung scan ultrasound is negative. For patients with high pretest probabil- can be pursued. A normal ventilation/perfusion scan effec- ity, duplex ultrasonography is also recommended. In patients tively rules out PE. A high probability study result in a patient with moderate or high probability of DVT, a second proximal with a high likelihood of disease has a strong positive predic leg ultrasonography should be performed 1 week later if no tive value. The sensitivity and specificity of low probability or alternative diagnosis for the leg syrnptoms is identified. intermediate probability study results may not be accurate Patients with a confirmed PE do not require routine enough to establish or rule out PE. MRI avoids ionizing radia duplex imaging of the lower extremities, and patients with tion and can visualize intraluminal filling defects in the pul acute DVT in the absence of respiratory symptoms do not monaryvasculature, but not as well as CT. New MRI techniques require CT angiography. Patients with established PE can are being evaluated that may enhance its role in VTE diagnosis. undergo echocardiography (rigtrt ventricular strain and pul Presently, CT is still considered the diagnostic standard. Duplex monary hypertension indicating a more massive PE) or testing ultrasonography (B mode imaging with Doppler assessment of serum troponin and B type natriuretic peptide for risk of blood flow) is the imaging modality of choice for suspected stratification. DVT, although in recent years growing evidence shows that point of care compression ultrasonography performed by f,lY P0rrI5 hospital medicine providers may potentially eliminate the . Patients with a Pulmonary Embolism Rule Out Criteria HVC need for duplex ultrasonography (Figure 28). Lower extremity score of zero do not require further testing with D dimer DVT is considered proximal if the popliteal. femoral, or iliac or imaging. veins are involved and is considered distal ifonly the calfveins . Patients with a low-probability Wells criteria score for HVC (peroneal, posterior, and anterior tibial) are involved. The DVT or PE should undergo D-dimer testing; if the results American Society of Hematolos/ (ASH) recommends a strat- are norrnal, no further imaging is necessary. egz of D-dimer measurement to exclude DVT in a population o Patients with a moderate- or high-probability Wells crite- with low probability of DVT (<tO'Z,) followed by proximal ria score do not require D-dimer testing but should lower extremity ultrasonography or whole leg ultrasonogra undergo duplex imaging of the lower extremities for phy for patients requiring additional testing. For patients symptoms suggesting deep venous thrombosis or CT angi with a moderate probability of DVT (-25%), the ASH guideline ography for ryrnptoms suggesting pulmonary embolism. recommends beginning the evaluation with whole leg or

probability (-20'1,) but should not be pursued in those with with the application of gentle pressure with the probe (compressibility), whereas the arlery (red arrowslis minimally compressible with pressure. high pretest probability because results would not change the need for imaging. proximal lower extremit5r ultrasonography without D-dimer In patients with kidney disease or in whom intravenous testing. No additional testing is recommended if the whole leg contrast is contraindicated, a ventilation/perfusion lung scan ultrasound is negative. For patients with high pretest probabil- can be pursued. A normal ventilation/perfusion scan effec- ity, duplex ultrasonography is also recommended. In patients tively rules out PE. A high probability study result in a patient with moderate or high probability of DVT, a second proximal with a high likelihood of disease has a strong positive predic leg ultrasonography should be performed 1 week later if no tive value. The sensitivity and specificity of low probability or alternative diagnosis for the leg syrnptoms is identified. intermediate probability study results may not be accurate Patients with a confirmed PE do not require routine enough to establish or rule out PE. MRI avoids ionizing radia duplex imaging of the lower extremities, and patients with tion and can visualize intraluminal filling defects in the pul acute DVT in the absence of respiratory symptoms do not monaryvasculature, but not as well as CT. New MRI techniques require CT angiography. Patients with established PE can are being evaluated that may enhance its role in VTE diagnosis. undergo echocardiography (rigtrt ventricular strain and pul Presently, CT is still considered the diagnostic standard. Duplex monary hypertension indicating a more massive PE) or testing ultrasonography (B mode imaging with Doppler assessment of serum troponin and B type natriuretic peptide for risk of blood flow) is the imaging modality of choice for suspected stratification. DVT, although in recent years growing evidence shows that point of care compression ultrasonography performed by f,lY P0rrI5 hospital medicine providers may potentially eliminate the . Patients with a Pulmonary Embolism Rule Out Criteria HVC need for duplex ultrasonography (Figure 28). Lower extremity score of zero do not require further testing with D dimer DVT is considered proximal if the popliteal. femoral, or iliac or imaging. veins are involved and is considered distal ifonly the calfveins . Patients with a low-probability Wells criteria score for HVC (peroneal, posterior, and anterior tibial) are involved. The DVT or PE should undergo D-dimer testing; if the results American Society of Hematolos/ (ASH) recommends a strat- are norrnal, no further imaging is necessary. egz of D-dimer measurement to exclude DVT in a population o Patients with a moderate- or high-probability Wells crite- with low probability of DVT (<tO'Z,) followed by proximal ria score do not require D-dimer testing but should lower extremity ultrasonography or whole leg ultrasonogra undergo duplex imaging of the lower extremities for phy for patients requiring additional testing. For patients symptoms suggesting deep venous thrombosis or CT angi with a moderate probability of DVT (-25%), the ASH guideline ography for ryrnptoms suggesting pulmonary embolism. recommends beginning the evaluation with whole leg or 56

Thrombotic Disorders Treatment cardiopulmonary disease who have submassive PE and a low Most patients with DVT can be efficiently and safely diagnosed bleeding risk. For acute DV'I, thrombolysis is indicated in and treated without hospitalization. A subset of patients with patients with massive thrornbus leading to impaired venous PE with an excellent prognosis can also avoid inpatient care. drainage, severe edema, and acute limb ischemia. The original Pulmonary Embolism Severity lndex (PESI) is a Therapy duration varies based on the clinical scenario validated prediction tool for clinical severity and outcomes of (Table 35). In provoked thrombosis with reversible risk factors, patients with PE. Using 11 clinical criteria, patients with PE are 3 to 6 months of anticoaguiation is adequate. Extended ther categorized into classes I through V with class I and class ll apy should be considered in patients with irreversible risk considered low risk for adverse outcomes. ln a multicenter, lactors fbr recurrent VTE. At'ter initial full-dose anticoagula prospective, open 1abel, randomized trial of patients with low tion, prophylactic dosing of apixaban or rivaroxaban could risk PE as determined by the PESI score, no difference was also be considered in patients with unpn.rvctked VTE with low found between outpatient and inpatient management in bleeding risk. Ifextended therapy is chosen, the risks, benefits, recurrent VTE, major bleeding, or 90 day mortality. A simpli- and choice ofanticoagulant should be re evaluated yearly. In fied version of the PESI defines patients with pE who are patients with unprovoked VTE in whom anticoagulation is B0 years or younger without significant comorbidity, who have discontinued, aspirir-r is associated with an approximately 30'1, a pulse rate less than 110/min, systolic blood pressure of 100 mm to 4O"/,, risk reduction in recurrent VTE compared with pla Hg or greater, and oxygen saturation of907, or greater breathing cebo. The 2016 American College of Chest Physicians (ACCP) ambient air as low risk for adverse outcomes (Table 3a). guidelines recommend aspirin if'a patient with unprovoked For most patients, anticoagulation is the primary treat VTE does not continue long term anticoagulation; however, ment for VTE. Anticoagulant options fbr acute VTE include continued anticoagulation is preferred acctirding to the ASH unfractionated heparin (UFH), LMWH, fbndaparinux, warfa 2020 guideline. rin, or a direct oral anticoagulant (DOAC). Patients taking In patients with malignancy and VTE, the ASH 2020 LMWH or fondaparinux must learn injection techniques. guideline recommends initial anticoagulation with apixaban, Warfarin, dabigatran, and edoxaban require initial concomi, rivaroxaban, or LMWH. If heparin is selected as initial antico tant parenteral heparin therapy. Apixaban and rivaroxaban are agulation, LMWH is preferred to UFH in the absence of severe effective as monotherapy. For patients receiving anticoagula kidney disease. For the initial 3 to 6 months of anticoagulation, tion therapy for VTE who experience major bleeding, the ASH apixaban, rivaroxaban, or edoxaban are preferred to LMWH suggests restarting oral anticoagulation therapy within 90 days. or warfarin. Anticoagulation should be extended beyond Patients who require hospitalization should avoid initial treat 6 months in select patients with active cancer, such as in those ment with UFH because of its unpredictable bioavailability with metastatic disease or those receiving chemotherapy. compared with LMWH; however, because of its short half life, Inferior vena cava (lVC) filters have been used to prevent UFH may be preferred in patients who are unstable and who death from PE but are known to increase the risk of DVl'. 'l'he may need emergent surgery or thrombolytic therapy. ACCP and ASH recommend against IVC filters fbr patients According to the 2020 ASH VTE guideline, thrombolytic treated with anticoagulants but support the use of IVC filters therapy is reasonable in select younger patients or in those in those with an acute proximal DVI'or an acute PE with a at high risk for decompensation because of concomitant contraindication to anticoagulation. tf an IVC fllter is placed, a temporary filter should be used and removed as soon as the indication for the filter has resolved. TABTE 34, Simplified Pulmonary Embolism Severity Patients with asymptomatic or mildly symptomatic distal lndex (PESI) DVTs do not usually require anticoagulation (see Table 35). Variable Simplified According to ACCP guidelines, anticoagulation similar to that PESI'Score Ibr proximal DV'l' is suggested in patients with moderate to Age >80 y severe symptoms or those with cer-tain risk factors for exten History of cancer sion, including a positive D dimer test result, extensive throm Chronic cardiopulmonary diseaseb bosis or proximity to proximal veins, no reversible provoking Pulse >1 10/min factor for DVT, active cancer, history of Vl'E, and inpatient status. SBP <1 00 mm Hg

Treatment cardiopulmonary disease who have submassive PE and a low Most patients with DVT can be efficiently and safely diagnosed bleeding risk. For acute DV'I, thrombolysis is indicated in and treated without hospitalization. A subset of patients with patients with massive thrornbus leading to impaired venous PE with an excellent prognosis can also avoid inpatient care. drainage, severe edema, and acute limb ischemia. The original Pulmonary Embolism Severity lndex (PESI) is a Therapy duration varies based on the clinical scenario validated prediction tool for clinical severity and outcomes of (Table 35). In provoked thrombosis with reversible risk factors, patients with PE. Using 11 clinical criteria, patients with PE are 3 to 6 months of anticoaguiation is adequate. Extended ther categorized into classes I through V with class I and class ll apy should be considered in patients with irreversible risk considered low risk for adverse outcomes. ln a multicenter, lactors fbr recurrent VTE. At'ter initial full-dose anticoagula prospective, open 1abel, randomized trial of patients with low tion, prophylactic dosing of apixaban or rivaroxaban could risk PE as determined by the PESI score, no difference was also be considered in patients with unpn.rvctked VTE with low found between outpatient and inpatient management in bleeding risk. Ifextended therapy is chosen, the risks, benefits, recurrent VTE, major bleeding, or 90 day mortality. A simpli- and choice ofanticoagulant should be re evaluated yearly. In fied version of the PESI defines patients with pE who are patients with unprovoked VTE in whom anticoagulation is B0 years or younger without significant comorbidity, who have discontinued, aspirir-r is associated with an approximately 30'1, a pulse rate less than 110/min, systolic blood pressure of 100 mm to 4O"/,, risk reduction in recurrent VTE compared with pla Hg or greater, and oxygen saturation of907, or greater breathing cebo. The 2016 American College of Chest Physicians (ACCP) ambient air as low risk for adverse outcomes (Table 3a). guidelines recommend aspirin if'a patient with unprovoked For most patients, anticoagulation is the primary treat VTE does not continue long term anticoagulation; however, ment for VTE. Anticoagulant options fbr acute VTE include continued anticoagulation is preferred acctirding to the ASH unfractionated heparin (UFH), LMWH, fbndaparinux, warfa 2020 guideline. rin, or a direct oral anticoagulant (DOAC). Patients taking In patients with malignancy and VTE, the ASH 2020 LMWH or fondaparinux must learn injection techniques. guideline recommends initial anticoagulation with apixaban, Warfarin, dabigatran, and edoxaban require initial concomi, rivaroxaban, or LMWH. If heparin is selected as initial antico tant parenteral heparin therapy. Apixaban and rivaroxaban are agulation, LMWH is preferred to UFH in the absence of severe effective as monotherapy. For patients receiving anticoagula kidney disease. For the initial 3 to 6 months of anticoagulation, tion therapy for VTE who experience major bleeding, the ASH apixaban, rivaroxaban, or edoxaban are preferred to LMWH suggests restarting oral anticoagulation therapy within 90 days. or warfarin. Anticoagulation should be extended beyond Patients who require hospitalization should avoid initial treat 6 months in select patients with active cancer, such as in those ment with UFH because of its unpredictable bioavailability with metastatic disease or those receiving chemotherapy. compared with LMWH; however, because of its short half life, Inferior vena cava (lVC) filters have been used to prevent UFH may be preferred in patients who are unstable and who death from PE but are known to increase the risk of DVl'. 'l'he may need emergent surgery or thrombolytic therapy. ACCP and ASH recommend against IVC filters fbr patients According to the 2020 ASH VTE guideline, thrombolytic treated with anticoagulants but support the use of IVC filters therapy is reasonable in select younger patients or in those in those with an acute proximal DVI'or an acute PE with a at high risk for decompensation because of concomitant contraindication to anticoagulation. tf an IVC fllter is placed, a temporary filter should be used and removed as soon as the indication for the filter has resolved. TABTE 34, Simplified Pulmonary Embolism Severity Patients with asymptomatic or mildly symptomatic distal lndex (PESI) DVTs do not usually require anticoagulation (see Table 35). Variable Simplified According to ACCP guidelines, anticoagulation similar to that PESI'Score Ibr proximal DV'l' is suggested in patients with moderate to Age >80 y severe symptoms or those with cer-tain risk factors for exten History of cancer sion, including a positive D dimer test result, extensive throm Chronic cardiopulmonary diseaseb bosis or proximity to proximal veins, no reversible provoking Pulse >1 10/min factor for DVT, active cancer, history of Vl'E, and inpatient status. SBP <1 00 mm Hg Arterial oxyhemoglobin saturation level <90%

Treatment cardiopulmonary disease who have submassive PE and a low Most patients with DVT can be efficiently and safely diagnosed bleeding risk. For acute DV'I, thrombolysis is indicated in and treated without hospitalization. A subset of patients with patients with massive thrornbus leading to impaired venous PE with an excellent prognosis can also avoid inpatient care. drainage, severe edema, and acute limb ischemia. The original Pulmonary Embolism Severity lndex (PESI) is a Therapy duration varies based on the clinical scenario validated prediction tool for clinical severity and outcomes of (Table 35). In provoked thrombosis with reversible risk factors, patients with PE. Using 11 clinical criteria, patients with PE are 3 to 6 months of anticoaguiation is adequate. Extended ther categorized into classes I through V with class I and class ll apy should be considered in patients with irreversible risk considered low risk for adverse outcomes. ln a multicenter, lactors fbr recurrent VTE. At'ter initial full-dose anticoagula prospective, open 1abel, randomized trial of patients with low tion, prophylactic dosing of apixaban or rivaroxaban could risk PE as determined by the PESI score, no difference was also be considered in patients with unpn.rvctked VTE with low found between outpatient and inpatient management in bleeding risk. Ifextended therapy is chosen, the risks, benefits, recurrent VTE, major bleeding, or 90 day mortality. A simpli- and choice ofanticoagulant should be re evaluated yearly. In fied version of the PESI defines patients with pE who are patients with unprovoked VTE in whom anticoagulation is B0 years or younger without significant comorbidity, who have discontinued, aspirir-r is associated with an approximately 30'1, a pulse rate less than 110/min, systolic blood pressure of 100 mm to 4O"/,, risk reduction in recurrent VTE compared with pla Hg or greater, and oxygen saturation of907, or greater breathing cebo. The 2016 American College of Chest Physicians (ACCP) ambient air as low risk for adverse outcomes (Table 3a). guidelines recommend aspirin if'a patient with unprovoked For most patients, anticoagulation is the primary treat VTE does not continue long term anticoagulation; however, ment for VTE. Anticoagulant options fbr acute VTE include continued anticoagulation is preferred acctirding to the ASH unfractionated heparin (UFH), LMWH, fbndaparinux, warfa 2020 guideline. rin, or a direct oral anticoagulant (DOAC). Patients taking In patients with malignancy and VTE, the ASH 2020 LMWH or fondaparinux must learn injection techniques. guideline recommends initial anticoagulation with apixaban, Warfarin, dabigatran, and edoxaban require initial concomi, rivaroxaban, or LMWH. If heparin is selected as initial antico tant parenteral heparin therapy. Apixaban and rivaroxaban are agulation, LMWH is preferred to UFH in the absence of severe effective as monotherapy. For patients receiving anticoagula kidney disease. For the initial 3 to 6 months of anticoagulation, tion therapy for VTE who experience major bleeding, the ASH apixaban, rivaroxaban, or edoxaban are preferred to LMWH suggests restarting oral anticoagulation therapy within 90 days. or warfarin. Anticoagulation should be extended beyond Patients who require hospitalization should avoid initial treat 6 months in select patients with active cancer, such as in those ment with UFH because of its unpredictable bioavailability with metastatic disease or those receiving chemotherapy. compared with LMWH; however, because of its short half life, Inferior vena cava (lVC) filters have been used to prevent UFH may be preferred in patients who are unstable and who death from PE but are known to increase the risk of DVl'. 'l'he may need emergent surgery or thrombolytic therapy. ACCP and ASH recommend against IVC filters fbr patients According to the 2020 ASH VTE guideline, thrombolytic treated with anticoagulants but support the use of IVC filters therapy is reasonable in select younger patients or in those in those with an acute proximal DVI'or an acute PE with a at high risk for decompensation because of concomitant contraindication to anticoagulation. tf an IVC fllter is placed, a temporary filter should be used and removed as soon as the indication for the filter has resolved. TABTE 34, Simplified Pulmonary Embolism Severity Patients with asymptomatic or mildly symptomatic distal lndex (PESI) DVTs do not usually require anticoagulation (see Table 35). Variable Simplified According to ACCP guidelines, anticoagulation similar to that PESI'Score Ibr proximal DV'l' is suggested in patients with moderate to Age >80 y severe symptoms or those with cer-tain risk factors for exten History of cancer sion, including a positive D dimer test result, extensive throm Chronic cardiopulmonary diseaseb bosis or proximity to proximal veins, no reversible provoking Pulse >1 10/min factor for DVT, active cancer, history of Vl'E, and inpatient status. SBP <1 00 mm Hg Arterial oxyhemoglobin saturation level <90% "A total point score is obtained by adding the points. The score corresponds with . Most patients with deep venous thrombosis and those HVC the following risk classes: 0 = low risk; >1 = high risk. with pulmonary embolism who have a good prognosis bCombined variable of history of hean failure and history of chronic lung disease. (defined as age <80 years, no significant comorbidity, Reprinted with permission from Fermann GJ, Erkens PM, Prins IMH, et al. Treatment and stable vital signs) can be safely managed without of pulmonary embolism with rivaroxabanioutcomes by simplified Pulmonary Embolism Severity lndex score from a post hoc analysis ofthe EINSTEIN PE study. hospitalization. Acad Emerg Med. 201 5 ;22:299 307. [PM D: 257 1 6463) doi:1 0.1 1 1 1 / ace m.1 261 5 (Continued)

"A total point score is obtained by adding the points. The score corresponds with . Most patients with deep venous thrombosis and those HVC the following risk classes: 0 = low risk; >1 = high risk. with pulmonary embolism who have a good prognosis bCombined variable of history of hean failure and history of chronic lung disease. (defined as age <80 years, no significant comorbidity, Reprinted with permission from Fermann GJ, Erkens PM, Prins IMH, et al. Treatment and stable vital signs) can be safely managed without of pulmonary embolism with rivaroxabanioutcomes by simplified Pulmonary Embolism Severity lndex score from a post hoc analysis ofthe EINSTEIN PE study. hospitalization. Acad Emerg Med. 201 5 ;22:299 307. [PM D: 257 1 6463) doi:1 0.1 1 1 1 / ace m.1 261 5 (Continued) 57

Thrombotic Disorders TABLE 35. Duration of AnticoagulantTherapy for Venous Thromboembolismu Type of Thrombotic Event Duration of Anticoagulant TheraPy Superficial vein thrombophlebitis No anticoagulation suggested Treat with supportive care (analgesia, warm compresses, and NSAIDs) and image if symptoms progress Superficial vein thrombosis Anticoagulate for 6 weeks i{ >5 cm in length, close to the deep venous system, or otherthrombophilic risk factors exist lf not anticoagulated, follow up in 1 week and image i{ symptoms are persistent or worsening Distal leg DW Provoked or unprovoked, asymptomatic or mild symptoms No anticoagulation suggested in healthy patients, but monitorwith serial duplex ultrasonography within 1-2 weeks Provoked or unprovoked, moderate to severe symptoms 3-6 months Proximal leg DW or PE Provoked (by surgery, trauma, immobility) 3-6 months Unprovoked Extendedb Recu rrent Duration of therapy depends on whether WE events were provoked or unprovoked Upper extremity DW, proximal 3 months or as long as a central venous catheter remains in place

Superficial vein thrombosis Anticoagulate for 6 weeks i{ >5 cm in length, close to the deep venous system, or otherthrombophilic risk factors exist lf not anticoagulated, follow up in 1 week and image i{ symptoms are persistent or worsening Distal leg DW Provoked or unprovoked, asymptomatic or mild symptoms No anticoagulation suggested in healthy patients, but monitorwith serial duplex ultrasonography within 1-2 weeks Provoked or unprovoked, moderate to severe symptoms 3-6 months Proximal leg DW or PE Provoked (by surgery, trauma, immobility) 3-6 months Unprovoked Extendedb Recu rrent Duration of therapy depends on whether WE events were provoked or unprovoked Upper extremity DW, proximal 3 months or as long as a central venous catheter remains in place Cancer-associated DW or PE As long as the cancer is active or being treated LMWH or DOACs are the preferred anticoagulants' Chronic thromboembolic pulmonary hypertension Extended DOAC = direct oral anticoagu lant; DW = deep venous thrombosis; LMWH = low,molecular weight heparin; PE = pulmonary embolism; WE = venous thromboembolism. "Decisions regarding duration of anticoagulation must always weigh the risk of VTE recurrence, risk o{ bleeding, and Patient preference. clinical study results and new anticoagulant drugs.

DOAC = direct oral anticoagu lant; DW = deep venous thrombosis; LMWH = low,molecular weight heparin; PE = pulmonary embolism; WE = venous thromboembolism. "Decisions regarding duration of anticoagulation must always weigh the risk of VTE recurrence, risk o{ bleeding, and Patient preference. clinical study results and new anticoagulant drugs. 'Key NS, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients wlth cancer: ASCO clinical practice guideline update. J Clin Oncol. 2020:38:496 520. IPMID: 31 38 1 464] doi:1 0.1 20O/ JCO.19.O1461 Data from Ortel TL, Neumann l, Ageno W, et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv. 2020;4:4693-4738. IPMl D: 33007077] doi:1 0.1 1 82lbloodadvances.2020001 830

'Key NS, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients wlth cancer: ASCO clinical practice guideline update. J Clin Oncol. 2020:38:496 520. IPMID: 31 38 1 464] doi:1 0.1 20O/ JCO.19.O1461 Data from Ortel TL, Neumann l, Ageno W, et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv. 2020;4:4693-4738. IPMl D: 33007077] doi:1 0.1 1 82lbloodadvances.2020001 830 XEY POlt{Tt (rpndnucd) and ulceration in the affected limb. Treatment includes leg exer- . If patients with deep venous thrombosis or pulmonary cises, avoiding dependent positions for lengthy periods, and using compression stockings. Emollients and a low moderate embolism require hospitalization, they should be potency topical glucocorticoid may be used for stasis dermatitis treated initially with low-molecular-weight heparin, (see MKSAP 19 General Internal Medicine 2). fondaparinux, or direct oral anticoagulants (apixaban or Patients with PE can also develop chronic thromboem- rivaroxaban) instead of unfractionated heparin, unless bolic pulmonary hypertension (see MKSAP 19 Pulmonary and they are unstable and at risk for requiring emergent Critical Care Medicine), cardiopulmonary dysfunction, or surgery or thrombolytic therapy. decreased exercise tolerance. . In patients with a provoked thrombosis with reversible risk factors, 3 to 6 months of anticoagulation is ade- quate, but in patients at low bleeding risk with unpro Other Sites of Thrombosis voked VTE or with irreversible risk factors, extended Additional sites of thromboses, such as splanchnic, cerebral, therapy should be considered. and retinal vein thromboses are discussed elsewhere (see MKSAP 19 Gastroenterologz, Neurolory, and General Internal Long-term Complications Medicine, respectively). Patients with DVT or PE can develop long term complications affecting function and quality of life. Approximately 25% to 40% Superficial Vein Thrombosis and of patients with qimptomatic DVT develop aspects of postthrom Thrombophlebitis botic sl,ndrome and chronic venous insufficiency which often Superficial thrombophlebitis describes thrombus and associ- develop within 2 years of VTE. Symptoms of postthrombotic ated inflammation in a vein located near the skin s surface: it s),ndrome include pain, heaviness, swelling, stasis dermatitis, is a common inflammatory-thrombotic disorder that does not

XEY POlt{Tt (rpndnucd) and ulceration in the affected limb. Treatment includes leg exer- . If patients with deep venous thrombosis or pulmonary cises, avoiding dependent positions for lengthy periods, and using compression stockings. Emollients and a low moderate embolism require hospitalization, they should be potency topical glucocorticoid may be used for stasis dermatitis treated initially with low-molecular-weight heparin, (see MKSAP 19 General Internal Medicine 2). fondaparinux, or direct oral anticoagulants (apixaban or Patients with PE can also develop chronic thromboem- rivaroxaban) instead of unfractionated heparin, unless bolic pulmonary hypertension (see MKSAP 19 Pulmonary and they are unstable and at risk for requiring emergent Critical Care Medicine), cardiopulmonary dysfunction, or surgery or thrombolytic therapy. decreased exercise tolerance. . In patients with a provoked thrombosis with reversible risk factors, 3 to 6 months of anticoagulation is ade- quate, but in patients at low bleeding risk with unpro Other Sites of Thrombosis voked VTE or with irreversible risk factors, extended Additional sites of thromboses, such as splanchnic, cerebral, therapy should be considered. and retinal vein thromboses are discussed elsewhere (see MKSAP 19 Gastroenterologz, Neurolory, and General Internal Long-term Complications Medicine, respectively). Patients with DVT or PE can develop long term complications affecting function and quality of life. Approximately 25% to 40% Superficial Vein Thrombosis and of patients with qimptomatic DVT develop aspects of postthrom Thrombophlebitis botic sl,ndrome and chronic venous insufficiency which often Superficial thrombophlebitis describes thrombus and associ- develop within 2 years of VTE. Symptoms of postthrombotic ated inflammation in a vein located near the skin s surface: it s),ndrome include pain, heaviness, swelling, stasis dermatitis, is a common inflammatory-thrombotic disorder that does not 58

Thrombotic Disorders usually cause significant morbidity or progress to PE. It typically and thrombus occurs with strenuous upper extremity activity. occurs in the setting of cancer or an underlying hypercoagula Expert recommendations vary regarding the use of throm- ble state. Cannulated veins of the hands and arms can throm- bolysis or thoracic outlet decompression surgery in addition to bose after infusions or intravenous catheter placement; this anticoagulation. ACCP guidelines recommend that treatment condition does not require anticoagulant therapy (see Table 35). of primary and secondary upper extremity DVT follow similar Superficial vein thrombosis (SVT) often affects the lower guidelines as lower extremity DVT. extremities and is thought to account for 10% of lower extrem- XEY POIXI ity thromboses. When affecting the great saphenous vein (also o Provoked upper extremity deep venous thrombosis (DVT) referred to as the greater or long saphenous uein), SVT may progress into the deep venous system. In a randomized trial of should be managed with 3 months of anticoagulation; however, in patients with catheter-associated DVT, anti- fondaparinux versus placebo for lower extremity SVT, it was found that fondaparinux was safe and effective in preventing coagulation should continue for as long as the catheter PE; therefore, anticoagulation may be indicated in select remains in place. patients (see Table 35).

usually cause significant morbidity or progress to PE. It typically and thrombus occurs with strenuous upper extremity activity. occurs in the setting of cancer or an underlying hypercoagula Expert recommendations vary regarding the use of throm- ble state. Cannulated veins of the hands and arms can throm- bolysis or thoracic outlet decompression surgery in addition to bose after infusions or intravenous catheter placement; this anticoagulation. ACCP guidelines recommend that treatment condition does not require anticoagulant therapy (see Table 35). of primary and secondary upper extremity DVT follow similar Superficial vein thrombosis (SVT) often affects the lower guidelines as lower extremity DVT. extremities and is thought to account for 10% of lower extrem- XEY POIXI ity thromboses. When affecting the great saphenous vein (also o Provoked upper extremity deep venous thrombosis (DVT) referred to as the greater or long saphenous uein), SVT may progress into the deep venous system. In a randomized trial of should be managed with 3 months of anticoagulation; however, in patients with catheter-associated DVT, anti- fondaparinux versus placebo for lower extremity SVT, it was found that fondaparinux was safe and effective in preventing coagulation should continue for as long as the catheter PE; therefore, anticoagulation may be indicated in select remains in place. patients (see Table 35). rEY POIilI5 Anticoagulants . Patients with lower extremity superficial vein thrombo- Parenteral sis managed conservativelywith warm compresses, Unfi :actionated Heparin analgesics, and NSAIDs require follow up evaluation UFH works by binding to antithrombin, potentiating its after l week to determine whether symptoms have action, resulting in inactivation of thrombin and factor Xa. resolved; duplex imaging is indicated for symptoms that The aPTT is used in monitoring heparin therapy. In the persist or worsen. setting of lupus anticoagulant (which prolongs the aPTT), . In patients with lower extremity superficial vein throm- heparin resistance, or markedly elevated factor VIII, anti factor Xa monitoring can be used. Although ideal dosing is bosis of at least 5 cm in length, close to the deep venous controversial, a weight based nomogram is usually used, and system, or with other thrombophilic risk factors, most hospitals follow a specific dosing algorithm. Typically, an including cancer or previous venous thromboembolism, initial bolus dose of 80 to 100 U/kg is given. UFH is available in anticoagulation is recommended. intravenous and subcutaneous preparations, although the intravenous form is typically used for treatment of VTE. Unexplained Arterial Thrombosis The rate of heparin-associated major bleeding is approxi With few exceptions, such as APLAS or myeloproliferative mately 3%. Failure to follow a dosage adjustment algorithm is disorders, thrombophilias do not play a significant role in arte- associated with increased bleeding risk. When major bleeding rial thrombosis. The primary causes of arterial thrombosis are occurs, protamine sulfate can be administered to reverse anti arteriosclerosis and atrial fibrillation with systemic arterial coagulation, using a dose of 1 mg of protamine per 100 units embolism. Patients with arterial thrombosis resulting from of heparin administered in the previous 2 hours. Protamine arteriosclerosis are typically treated with antiplatelet therapy. adverse effects include allergic reactions, hypotension, brady It is unknown whether patients with arterial clots in whom a cardia, and respiratory toxicity. strong thrombophilia is fbund are more effectively treated Although weight based nomograms and specific algo with antiplatelet therapy or anticoagulants. rithms for adjusting dose based on aPTT results have enhanced the safety and efficacy of UFH, variations in bioavailability and I([Y POIIIT potential delay in arriving at a therapeutic dose are still more . Patients with arterial thrombosis resulting from arterio- likely than with LMWH. UFH should therefore be reserved for sclerosis are typically treated with antiplatelet therapy. patients in whom LMWH is contraindicated or in those who require anticoagulation that can be stopped quickly, generally Upper Extremity Deep Venous Thrombosis in anticipation of an invasive procedure or surgery. Heparin-induced thrombocl.topenia is a severe complica- Upper extremity DVT accounts for 10% ofall DVT occurrences, most olwhich (approximately two thirds) are associated with tion of heparin that can result in a catastrophic thrombotic event (see Platelet Disorders). central venous catheter use or malignancy. Treatment consists of anticoagulation for 3 months or at least the duration that l(EY P0t1{rs the catheter remains in place. The ASH recommends against . A weight-based nomogram is usually used to determine catheter removal because of thrombosis. the initial dose of unfractionated heparin, and algorithms Primary upper extremity DVT is uncommon and usually are used to calculate subsequent dose modifications based caused by anatomic abnormalities of the thoracic outlet sys- on the activated partial thromboplastin time. tem leading to axillosubclavian compression and thrombosis (Continued) (venous thoracic outlet syndrome). Patients are usually young,

rEY POIilI5 Anticoagulants . Patients with lower extremity superficial vein thrombo- Parenteral sis managed conservativelywith warm compresses, Unfi :actionated Heparin analgesics, and NSAIDs require follow up evaluation UFH works by binding to antithrombin, potentiating its after l week to determine whether symptoms have action, resulting in inactivation of thrombin and factor Xa. resolved; duplex imaging is indicated for symptoms that The aPTT is used in monitoring heparin therapy. In the persist or worsen. setting of lupus anticoagulant (which prolongs the aPTT), . In patients with lower extremity superficial vein throm- heparin resistance, or markedly elevated factor VIII, anti factor Xa monitoring can be used. Although ideal dosing is bosis of at least 5 cm in length, close to the deep venous controversial, a weight based nomogram is usually used, and system, or with other thrombophilic risk factors, most hospitals follow a specific dosing algorithm. Typically, an including cancer or previous venous thromboembolism, initial bolus dose of 80 to 100 U/kg is given. UFH is available in anticoagulation is recommended. intravenous and subcutaneous preparations, although the intravenous form is typically used for treatment of VTE. Unexplained Arterial Thrombosis The rate of heparin-associated major bleeding is approxi With few exceptions, such as APLAS or myeloproliferative mately 3%. Failure to follow a dosage adjustment algorithm is disorders, thrombophilias do not play a significant role in arte- associated with increased bleeding risk. When major bleeding rial thrombosis. The primary causes of arterial thrombosis are occurs, protamine sulfate can be administered to reverse anti arteriosclerosis and atrial fibrillation with systemic arterial coagulation, using a dose of 1 mg of protamine per 100 units embolism. Patients with arterial thrombosis resulting from of heparin administered in the previous 2 hours. Protamine arteriosclerosis are typically treated with antiplatelet therapy. adverse effects include allergic reactions, hypotension, brady It is unknown whether patients with arterial clots in whom a cardia, and respiratory toxicity. strong thrombophilia is fbund are more effectively treated Although weight based nomograms and specific algo with antiplatelet therapy or anticoagulants. rithms for adjusting dose based on aPTT results have enhanced the safety and efficacy of UFH, variations in bioavailability and I([Y POIIIT potential delay in arriving at a therapeutic dose are still more . Patients with arterial thrombosis resulting from arterio- likely than with LMWH. UFH should therefore be reserved for sclerosis are typically treated with antiplatelet therapy. patients in whom LMWH is contraindicated or in those who require anticoagulation that can be stopped quickly, generally Upper Extremity Deep Venous Thrombosis in anticipation of an invasive procedure or surgery. Heparin-induced thrombocl.topenia is a severe complica- Upper extremity DVT accounts for 10% ofall DVT occurrences, most olwhich (approximately two thirds) are associated with tion of heparin that can result in a catastrophic thrombotic event (see Platelet Disorders). central venous catheter use or malignancy. Treatment consists of anticoagulation for 3 months or at least the duration that l(EY P0t1{rs the catheter remains in place. The ASH recommends against . A weight-based nomogram is usually used to determine catheter removal because of thrombosis. the initial dose of unfractionated heparin, and algorithms Primary upper extremity DVT is uncommon and usually are used to calculate subsequent dose modifications based caused by anatomic abnormalities of the thoracic outlet sys- on the activated partial thromboplastin time. tem leading to axillosubclavian compression and thrombosis (Continued) (venous thoracic outlet syndrome). Patients are usually young, 59

Thrombotic Disorders XEY POIilIS (oodnued/ Fondaparinux has no reversal agent. Caution should be . Protamine sulfate can be administered to reverse the used in patients at risk for bleeding because the hall life is 17 hours. Prothrombin complex concentrates (PCCs) and fiesh anticoagulant ef'fects of unfractionated heparin. frozen plasma have been administered rt'ith positive outcomes . Variations in bioavailability of unfractionated heparin in patients erperier.rcing bleeding. lead to an increased likelihood of delay in achieving a steady state therapeutic dose compared with treatment I(EY POIXI with low molecular weight heparin. . Because fondaparinux is cleared through the kidney. it should be avoided in patients with creatinine clearance Low-Molecular-Weight Heparin less than 30 ml/min.

XEY POIilIS (oodnued/ Fondaparinux has no reversal agent. Caution should be . Protamine sulfate can be administered to reverse the used in patients at risk for bleeding because the hall life is 17 hours. Prothrombin complex concentrates (PCCs) and fiesh anticoagulant ef'fects of unfractionated heparin. frozen plasma have been administered rt'ith positive outcomes . Variations in bioavailability of unfractionated heparin in patients erperier.rcing bleeding. lead to an increased likelihood of delay in achieving a steady state therapeutic dose compared with treatment I(EY POIXI with low molecular weight heparin. . Because fondaparinux is cleared through the kidney. it should be avoided in patients with creatinine clearance Low-Molecular-Weight Heparin less than 30 ml/min. LMWH is derived from UFH through a chemical depolymeri zation producing fiagments that are one third the size o1' Oral heparin. Warfarin I-MWH does not aflect the aPT'f because the smaller frag Warfarin is a vitamin K antagonist (VKA). It inhibits vitan.rin K ment size does not bind as readily to thrombin but retains the epoxide reductase. which leads to inhibition of 1 carboxl'lation ability to inactivate factor Xa. It is usually administered in ofprecursor coagulation factors I[, VII. IX. and X and proteins weight adjusted doses. Dosing is more predictable, and labo- C and S. Laboratory monitoring involves the prothrombin time ratory testing is generally unnecessary. LMWH is cleared and INR. through the kidney. and the biological halflife is increased in Because warfarin lowers protein C levels before inducing patients with kidney disease. For patients with kidney dys its anticoagulant efl'ect, it can initially cause a prothrombotic f'unction (creatinine clearance <30 mL/min) receiving LMWH state. For this reason. when warfirrin is used to treat acute VTE. therapy, the ASH suggests against using anti factor Xa con it should be administered initially with a parenteral anticoagu centration monitoring to guide LMWH dose adjustment: lant (e.g., UFH or LMWH). 1'he parenteral agent should be instead, the organization cor.tsiders using doses adjusted lor given fbr at least 5 days and continued until the INR is 2 or kidney function as reconlmended in product labeling or greater fbr at least 24 hours. switching to an alternative anticoagulant. In patients with Although DOACs have changed the landscape ot treat obesity, dosing is based on actual body weight. ment Ibr patients with VTE. warlarin remains a reasonable LMWH is preferred t<-r UFH. In a meta analysis ol DVT anticoagulant for some patients. including those with kidney treatment, LMWII was associated with less major bleeding. disease, morbid obesity, a mechanical heart valve, or high risk decreased r.nortality. and decreased thrombotic recurrence APLAS conditions fbr which alternate oral anticoagulants are compared with UFlt. not routinely used. Pmtamine does not fully reverse tl.re anti Xa effect ot' Patients must have access to continued outpatient INR LMWH but provides some ber-refit in restoring hemostasis and monitoring. Common reasons lbr fluctuations in INR include is recommended fbr lilb threatening bleeding. It should be changes in vitamin K intake. medications. and nonadherence. given at a dose of 1 n.rg of protamine per 1 mg of LMWH. Srudies attempting to decrease INR variability with lo'*' dose daily vitamin K supplen.rentation showed no benefit. I(EY POITTS Bleeding is the most significant conrplication in patients . Low molecular weight heparin typically does not treated with warfarin. occurring in 1',1, to 3'X, of patients per require laboratory monitoring and is associated with less year. 'fhe risk is higl.rer at warflrin initiation and during epi bleeding, decreased recurrent thrombosis, and improved sodes of concurrent acute illness. The bleeding risk increases mortality compared with unfractionated heparin. further in patients with an INR greater than 5. Independent of . Patients with severe obesity or creatinine clearance less lNR. bleeding risk is increased in patients older than 75 years than 30 ml/min who are treated with low molecular- or in those with previous stroke. gastrointestinal bleeding. or weight heparin do not require anti -tactorXa level other chronic comorbidities. Concomitant aspirin. clopid monitoring; doses should be adjusted based on kidney ogrel. and NSAID use increases the bleeding risk. The indica function or actual body weight. tion lbr antiplatelet agents for patients taking warfarin should be caref ully reviewed. and dual antiplatelet therapy should be Fondaparinux avoided il possible. Acetaminophen should be used instead of In a clinical trial, fondaparinux, dose adjusted based on NSAIDs when f'easible. patients' weights, was noninlerior to enoxaparin with respect Concern is often expressed when older adults begin oral to tl.re primary endpoint of recurrent V'l'E at 3 months (3.9'X, anticoagulation. because age is an important risk factor for vs. 4.1')1,). Fondaparinux is cleared through the kidney ar.rd bleeding complications associated with warfarin. Oral antico should be avoided in patients with creatinine clearance less agulation may be prematurely excluded as a therapeutic option than 3O ml/min. As with LMWH or UF'H. treatment with for.r because ol a perceived "fall risk." 'l'he true risk ofserious bleed daplrinux and wartarin should overlap fbr 5 days. ing related to a fall while taking an anticoagulant is unclear,

LMWH is derived from UFH through a chemical depolymeri zation producing fiagments that are one third the size o1' Oral heparin. Warfarin I-MWH does not aflect the aPT'f because the smaller frag Warfarin is a vitamin K antagonist (VKA). It inhibits vitan.rin K ment size does not bind as readily to thrombin but retains the epoxide reductase. which leads to inhibition of 1 carboxl'lation ability to inactivate factor Xa. It is usually administered in ofprecursor coagulation factors I[, VII. IX. and X and proteins weight adjusted doses. Dosing is more predictable, and labo- C and S. Laboratory monitoring involves the prothrombin time ratory testing is generally unnecessary. LMWH is cleared and INR. through the kidney. and the biological halflife is increased in Because warfarin lowers protein C levels before inducing patients with kidney disease. For patients with kidney dys its anticoagulant efl'ect, it can initially cause a prothrombotic f'unction (creatinine clearance <30 mL/min) receiving LMWH state. For this reason. when warfirrin is used to treat acute VTE. therapy, the ASH suggests against using anti factor Xa con it should be administered initially with a parenteral anticoagu centration monitoring to guide LMWH dose adjustment: lant (e.g., UFH or LMWH). 1'he parenteral agent should be instead, the organization cor.tsiders using doses adjusted lor given fbr at least 5 days and continued until the INR is 2 or kidney function as reconlmended in product labeling or greater fbr at least 24 hours. switching to an alternative anticoagulant. In patients with Although DOACs have changed the landscape ot treat obesity, dosing is based on actual body weight. ment Ibr patients with VTE. warlarin remains a reasonable LMWH is preferred t<-r UFH. In a meta analysis ol DVT anticoagulant for some patients. including those with kidney treatment, LMWII was associated with less major bleeding. disease, morbid obesity, a mechanical heart valve, or high risk decreased r.nortality. and decreased thrombotic recurrence APLAS conditions fbr which alternate oral anticoagulants are compared with UFlt. not routinely used. Pmtamine does not fully reverse tl.re anti Xa effect ot' Patients must have access to continued outpatient INR LMWH but provides some ber-refit in restoring hemostasis and monitoring. Common reasons lbr fluctuations in INR include is recommended fbr lilb threatening bleeding. It should be changes in vitamin K intake. medications. and nonadherence. given at a dose of 1 n.rg of protamine per 1 mg of LMWH. Srudies attempting to decrease INR variability with lo'*' dose daily vitamin K supplen.rentation showed no benefit. I(EY POITTS Bleeding is the most significant conrplication in patients . Low molecular weight heparin typically does not treated with warfarin. occurring in 1',1, to 3'X, of patients per require laboratory monitoring and is associated with less year. 'fhe risk is higl.rer at warflrin initiation and during epi bleeding, decreased recurrent thrombosis, and improved sodes of concurrent acute illness. The bleeding risk increases mortality compared with unfractionated heparin. further in patients with an INR greater than 5. Independent of . Patients with severe obesity or creatinine clearance less lNR. bleeding risk is increased in patients older than 75 years than 30 ml/min who are treated with low molecular- or in those with previous stroke. gastrointestinal bleeding. or weight heparin do not require anti -tactorXa level other chronic comorbidities. Concomitant aspirin. clopid monitoring; doses should be adjusted based on kidney ogrel. and NSAID use increases the bleeding risk. The indica function or actual body weight. tion lbr antiplatelet agents for patients taking warfarin should be caref ully reviewed. and dual antiplatelet therapy should be Fondaparinux avoided il possible. Acetaminophen should be used instead of In a clinical trial, fondaparinux, dose adjusted based on NSAIDs when f'easible. patients' weights, was noninlerior to enoxaparin with respect Concern is often expressed when older adults begin oral to tl.re primary endpoint of recurrent V'l'E at 3 months (3.9'X, anticoagulation. because age is an important risk factor for vs. 4.1')1,). Fondaparinux is cleared through the kidney ar.rd bleeding complications associated with warfarin. Oral antico should be avoided in patients with creatinine clearance less agulation may be prematurely excluded as a therapeutic option than 3O ml/min. As with LMWH or UF'H. treatment with for.r because ol a perceived "fall risk." 'l'he true risk ofserious bleed daplrinux and wartarin should overlap fbr 5 days. ing related to a fall while taking an anticoagulant is unclear, 60

I i Thrombotic Disorders i I and small studies have not shown an increased risk of major XEY POIXIS I bleeding in patients taking oral anticoagulants who were con o Warlarin must be administered initially with at least i 5 sidered at high risk fbr falls. Risk lactors fbr falls sl.rould be 5 days of a parenteral anticoagulant (usually unfraction- I thoroughly evaluated and appropriate steps must be used tbr ! ated or low molecular weight heparin) for the treatment prevention (see MKSAP 19 General Internal Medicine l). i of venous thrrimboembolism. Recommendations suggest tl.rat neither age nor fall risk is rea son to withhold anticoagulation fitim a patient who meets . Bridging thcrapy, which uses unfractionated heparin or HVC I low molecular-weight heparin during warfarin discon clinical criteria warranting such therapy. Patients with asymptomatic INR elevation between 4.5 tinuation before an invasive procedure, is not indicated t and 10 can often be managed by simply withholding warfarin. for most patients because it is associated with more For INRs greater than 10 in patients without bleeding, oral bleeding complications without any reduction in : vitarnin K should be giver.r. In patients experiencing life thrombotic events. threatening bleeding, in addition to intravenous vitamin K. 4 factor PCC should be given. 'fhree factor PCCs contain pro Direct Oral Anticoagulants teir.rs C and S and firctors I[, tX, and X; 4-factor PCC also con 'l'he DOACs have emerged as safe and effective treatment tair.rs thctor Vll. ln a clinical trial of' VKA related bleeding. options fbr patients with VTE. In the 2016 CHEST guidelines 4 tactor PCC was fbund to be noninferior to fiesh frozer.r and the 2020 ASH guidelines fbr DVT and PE treatment, plasma Ibr hemostatic eflficacy. Four factor PCC is preferred DOACs are suggested as the treatment of choice for anticoagu because ol its rapid reversal oi lNR, rapid iniusion and admin lation. The DOACs available for use in the United States are istration, and lack of volume overload. Recombinarnt factor dabigatran, rivaroxaban, apixaban, and edoxaban. Dabigatran VIIa is not recommended fbr warfarin reversal. tunctions as a direct thrombin inhibitor, whereas the other Bridgir.rg therap): using heparir.r or LMWH when warfarin agents are fact<-rr Xa inhibitors (Table 36). Dabigatran and is temporarily stopped for an invasive procedure. is not neces edoxaban require initial treatment with a parenteral agent. sary fbr most patients and is associated with increased bleed Rivaroxaban and apixaban are approved as monotherapy for ing complications without additional anticoagulant benefit. patients with DV'l'and PE. The exception to this may be patients with V'f E'within the past Routine coagulation studies do not reliably measure the 4 weeks, history of VTE during anticoagulant interruption firr degree of coaglllation activity with DOACs. However, the surgery or a procedure with very high VTE risk, such as ortho thrombin time is cluite sensitive to the presence of dabigatran pedic surgery. Bridging is also indicated in patients with atrial and, if normal, iudicates that the anticoagulant effect of dabig fibrillation who have had a stroke or transient ischemic attack atran is no longer significant. in the preceding year, in patients who have rnultiple risk fac- Adv:rntages ot the DOACs include no need fbr routine tors for stnike (CHADS, score of 5 6), and in most patients r.uonitoring, rapid onset of action, short half life, fixed dos- with a mechanical heart valve. ing, and fewer drug drug interactions. DOACs are as effective

and small studies have not shown an increased risk of major XEY POIXIS I bleeding in patients taking oral anticoagulants who were con o Warlarin must be administered initially with at least i 5 sidered at high risk fbr falls. Risk lactors fbr falls sl.rould be 5 days of a parenteral anticoagulant (usually unfraction- I thoroughly evaluated and appropriate steps must be used tbr ! ated or low molecular weight heparin) for the treatment prevention (see MKSAP 19 General Internal Medicine l). i of venous thrrimboembolism. Recommendations suggest tl.rat neither age nor fall risk is rea son to withhold anticoagulation fitim a patient who meets . Bridging thcrapy, which uses unfractionated heparin or HVC I low molecular-weight heparin during warfarin discon clinical criteria warranting such therapy. Patients with asymptomatic INR elevation between 4.5 tinuation before an invasive procedure, is not indicated t and 10 can often be managed by simply withholding warfarin. for most patients because it is associated with more For INRs greater than 10 in patients without bleeding, oral bleeding complications without any reduction in : vitarnin K should be giver.r. In patients experiencing life thrombotic events. threatening bleeding, in addition to intravenous vitamin K. 4 factor PCC should be given. 'fhree factor PCCs contain pro Direct Oral Anticoagulants teir.rs C and S and firctors I[, tX, and X; 4-factor PCC also con 'l'he DOACs have emerged as safe and effective treatment tair.rs thctor Vll. ln a clinical trial of' VKA related bleeding. options fbr patients with VTE. In the 2016 CHEST guidelines 4 tactor PCC was fbund to be noninferior to fiesh frozer.r and the 2020 ASH guidelines fbr DVT and PE treatment, plasma Ibr hemostatic eflficacy. Four factor PCC is preferred DOACs are suggested as the treatment of choice for anticoagu because ol its rapid reversal oi lNR, rapid iniusion and admin lation. The DOACs available for use in the United States are istration, and lack of volume overload. Recombinarnt factor dabigatran, rivaroxaban, apixaban, and edoxaban. Dabigatran VIIa is not recommended fbr warfarin reversal. tunctions as a direct thrombin inhibitor, whereas the other Bridgir.rg therap): using heparir.r or LMWH when warfarin agents are fact<-rr Xa inhibitors (Table 36). Dabigatran and is temporarily stopped for an invasive procedure. is not neces edoxaban require initial treatment with a parenteral agent. sary fbr most patients and is associated with increased bleed Rivaroxaban and apixaban are approved as monotherapy for ing complications without additional anticoagulant benefit. patients with DV'l'and PE. The exception to this may be patients with V'f E'within the past Routine coagulation studies do not reliably measure the 4 weeks, history of VTE during anticoagulant interruption firr degree of coaglllation activity with DOACs. However, the surgery or a procedure with very high VTE risk, such as ortho thrombin time is cluite sensitive to the presence of dabigatran pedic surgery. Bridging is also indicated in patients with atrial and, if normal, iudicates that the anticoagulant effect of dabig fibrillation who have had a stroke or transient ischemic attack atran is no longer significant. in the preceding year, in patients who have rnultiple risk fac- Adv:rntages ot the DOACs include no need fbr routine tors for stnike (CHADS, score of 5 6), and in most patients r.uonitoring, rapid onset of action, short half life, fixed dos- with a mechanical heart valve. ing, and fewer drug drug interactions. DOACs are as effective TABLE 36. Key Features of the Direct Oral Anticoagulants Dabigatran Rivaroxaban Apixaban Edoxaban Class of anticoagulant Direct {actor lla inhibitor Direct factor Xa inhibitor Direct factor Xa inhibitor Direct factor Xa inhibitor T, (h) 2 3 3 1-2 ", Half-li{e (h) 12-17 7 -11 9-14 9-11 Protein binding )EO/ 95% 87"/o I AO/

TABLE 36. Key Features of the Direct Oral Anticoagulants Dabigatran Rivaroxaban Apixaban Edoxaban Class of anticoagulant Direct {actor lla inhibitor Direct factor Xa inhibitor Direct factor Xa inhibitor Direct factor Xa inhibitor T, (h) 2 3 3 1-2 ", Half-li{e (h) 12-17 7 -11 9-14 9-11 Protein binding )EO/ 95% 87"/o I AO/ Renal elimination 80"/o 66% (33% as active 25"/" 35o/" metabolite) FDA approved Atrialfibrillation Atrial fibrillation Atrial fibrillation Atrial fibrillation ind ications VTE treatment VTE treatment' VTE treatmentu VTE treatment VTE preventiont' WE preventionl' VTE preventionb Reversal agent ldarucizumab Andexanet alfa or Andexanet alfa or Andexanet alfa'or 4t-PCC 4f-PCC 4f-PCC h=hour; NA=notapplicablej T,,,".=tintetomaxlmumconcentr.Lron;VTE=venousthromboembolism. ,4fPCC=4factorprothronrbincoorpiexconcentrate; 'Approved as rnonotherapy for VTE. VTE, as well as {or VTE prevention after hip and knee replacement. alfa s used off labe for reversal of edoxaban. 61