Browse the corpus
Walk the Even Hospital Database by book and chapter — the raw source passages that ground Ask, DDx, and the rest.
14 passages
1474 SECTION 18: Hematologic and Oncologic Disorders TABLE 233-9 Treatment of Disseminated Intravascular Coagulation (DIC) • Treat underlying precipitating disorder: volume resuscitation, antibiotics, external cooling • Platelet transfusions for thrombocytopenia <50,000/mm3 (<50 × 109/L) and active bleeding • Fresh frozen plasma for prolonged PT or aPTT (>2 times normal) or low fibrinogen (<100 milligrams/dL [1 gram/L]) and active bleeding • Fibrinogen concentrate for persistent low fibrinogen <100 milligrams/dL (<1 gram/L) • Vitamin K for prolonged PT • Consider venous thromboembolism prophylaxis with LMWH • Consider tranexamic acid for trauma-related DIC Abbreviations: aPTT = activated partial thromboplastin time; LMWH = low-molecular-weight heparin; PT = prothrombin time. is not of concern. Fibrinogen concentrate should be considered when hypofibrinogenemia persists despite use of plasma. Patients with a pro longed PT should receive parenteral vitamin K. There is no proven benefit in DIC with other coagulation factor products, such as prothrombin complex concentrate (human) or coagulation factor VIIa (recombinant). Due to high risk of thrombosis in DIC, lowmolecular-weight heparin is recommended in patients with DIC when bleeding is absent and platelet counts exceed 30,000/mm 3 (30 × 109/L).29 Antifibrinolytic medications (e.g., tranexamic acid) should generally be avoided in patients with DIC. One notable exception is in traumarelated DIC, where their use reduces mortality. CIRCULATING INHIBITORS OF COAGULATION Acquired inhibitors of blood coagulation, also known as circulating anticoagulants, are antibodies directed against one or more of the coagulation factors. Although inhibitors may develop spontaneously in previously healthy patients with normal hemostasis, most inhibitors develop in patients with hereditary bleeding disorders who receive transfusion of plasma products. Inhibitors have been described for most of the coagu lation factors; the two most common inhibitors are factor VIII inhibitors and antiphospholipid antibodies. Factor VIII inhibitors are “specific” inhibitors, directed only against factor VIII, as opposed to antiphospholipid antibodies, including lupus anticoagulant and anticardiolipin antibodies, which are “nonspecific” inhibitors directed against several of the coagulation factors. Lupus anticoagulant and anticardiolipin antibodies often result in thrombosis (see Chapter 234, “Clotting Disorders”). Factor VIII Inhibitors Factor VIII inhibitors most commonly develop in patients with hemophilia A (see Chapter 235, “Hemophilias and von Willebrand’s Disease”) but can also develop spontaneously in patients with previously normal hemostasis, a condition termed acquired hemophilia 31 Although rare, it is important to recognize this clinical entity because the mortality rate is over 20%. Approximately 85% of acquired hemophilia A cases occur in the elderly. In about half of cases, inhibitors develop in association with malignancy, autoimmune disorders, pregnancy, drugs (interferon, clopidogrel), blood transfusions, or infections. Patients who develop factor VIII inhibitors can present with massive spontaneous ecchymoses, hematomas, and hematuria. Laboratory studies classically show a normal PT, normal thrombin clotting time, and a greatly prolonged aPTT that does not correct with mixing. A factor VIII–specific assay will show very low or absent factor VIII activity.
actor VIII inhibitors can present with massive spontaneous ecchymoses, hematomas, and hematuria. Laboratory studies classically show a normal PT, normal thrombin clotting time, and a greatly prolonged aPTT that does not correct with mixing. A factor VIII–specific assay will show very low or absent factor VIII activity. A hematologist should direct the management of an acute, clinically significant bleeding episode. Treatment options include administration of factor VIII, prothrombin complex concentrate (human), FEIBA (antiinhibitor coagulant complex), coagulation factor VIIa (recombinant), desmopressin acetate, and tranexamic acid. 31-33 Additionally, the use of aspirin, NSAIDs, and intramuscular injections should be avoided and conservative therapies should be considered, including compression and immobilization of the bleeding site. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Clotting Disorders Jessie G. Nelson THROMBOPHILIA INTRODUCTION Most patients develop arterial or venous thromboses because of local factors (e.g., a focal atherosclerotic lesion producing a thrombus in a coronary artery) or major systemic events (e.g., trauma, surgery, or prolonged immobilization). However, several inherited genetic mutations and acquired conditions predispose patients to venous thromboembolism with some studies finding up to 50% of patients with unprovoked venous thromboembolism having a hypercoagulable disorder or thrombophilia (Table 234-1). 1 No specific risk factor or condition guarantees abnormal thrombosis. Rather, similar to seizures, patients have a varying threshold for clotting. Risks for clotting from genetic, acquired, and environmental factors are additive and, in some cases, multiplicative. PATHOPHYSIOLOGY Several physiologic systems ensure that blood clots do not extend beyond the necessary area. The two most clinically important pathways involve antithrombin and protein C ( Table 234-2). Antithrombin (also called antithrombin III) is a plasma-based protein that inhibits several activated coagulation factors, primarily thrombin, factor Xa, and factor IXa. Both unfractionated heparin and low-molecular-weight heparin possess anticoagulant activity by increasing the rate by which antithrombin inhibits these factors: approximately 2000- to 4000-fold for thrombin, about 500- to 1000-fold for factor Xa, and about a million-fold for factor IXa. Protein C is a vitamin K–dependent plasma protein that binds to the endothelial cell surface and is activated by thrombin. Activated protein C cleaves both factor Va and factor VIIIa, inhibiting both the common pathway and the intrinsic pathway. Protein S, another vitamin K–dependent plasma protein, is a cofactor that increases the inhibitory action of activated protein C by about 20-fold. DIAGNOSIS Thrombophilic disorders are rarely diagnosed in the ED. Instead, the emergency physician’s primary responsibilities are to suspect the thrombophilia, recognize higher risk of thrombosis in patients with a known thrombophilia, obtain pertinent information to suspect an undiagnosed prothrombotic state, refer for evaluation, and appropriately manage acute thrombosis (Table 234-3). Laboratory testing specific for hypercoagulable conditions is not helpful in an ED setting. 4 Some factor levels cannot be reliably measured in CHAPTER TABLE 234-1 Hypercoagulable States Inherited Acquired Activated protein C resistance due to factor V Leiden mutation
ppropriately manage acute thrombosis (Table 234-3). Laboratory testing specific for hypercoagulable conditions is not helpful in an ED setting. 4 Some factor levels cannot be reliably measured in CHAPTER TABLE 234-1 Hypercoagulable States Inherited Acquired Activated protein C resistance due to factor V Leiden mutation Pregnancy Medications: Oral contraceptives/hormone replacement therapy, tamoxifen, lenalidomide Prothrombin gene mutation 20210A Malignancy Protein C deficiency Heparin-induced thrombocytopenia Protein S deficiency Antiphospholipid syndrome Antithrombin deficiency Warfarin-induced skin necrosis Hyperhomocysteinemia, severe Hyperviscosity syndromes ABO blood type (non-O) Human immunodeficiency virus (HIV)Tintinalli_Sec18_p1461-1522.indd 1474 8/2/19 8:37 PM
Protein C deficiency Heparin-induced thrombocytopenia Protein S deficiency Antiphospholipid syndrome Antithrombin deficiency Warfarin-induced skin necrosis Hyperhomocysteinemia, severe Hyperviscosity syndromes ABO blood type (non-O) Human immunodeficiency virus (HIV)Tintinalli_Sec18_p1461-1522.indd 1474 8/2/19 8:37 PM CHAPTER 234: Clotting Disorders 1475 the setting of acute thrombosis or while the patient is taking a vitamin K antagonist such as warfarin or direct oral anticoagulants. The ED diagnostic approach to individual episodes of suspected thrombosis in a thrombophilic patient is site specific (e.g., cerebral arterial or venous circulation, coronary circulation, or peripheral venous system). Recorded characteristics in the derivation samples for the Wells Score 5 or Pulmonary Embolism Rule Out Criteria 6 excluded patients with known genetic causes for thrombophilia. Instead of risk stratifica tion tools, use the patient’s personal history of venous thromboembo lism (phenotypic evidence of thrombophilia). Using a normal serum d-dimer level to exclude venous thromboembolism in patients with known hypercoagulable disorders has not been validated. TREATMENT AND DISPOSITION Initial management and disposition of individual episodes of confirmed thrombosis in a patient with thrombophilia are similar to those of a patient without known thrombophilia, with exceptions discussed in specific conditions. 7 Patients not currently on anticoagulation should consider prophylactic anticoagulants for high-risk situations such as surgery, pregnancy and the postpartum period, and prolonged travel. Estrogen-based oral contraceptive pills and hormone replacement therapy should be avoided in patients with known thrombophilia because of the thrombotic risk. TABLE 234-2 Functions of Coagulation Proteins in Protein C and Antithrombin Systems Factor Function Pertinent Disorders Prothrombin (factor II) Precursor to thrombin, which converts fibrinogen to fibrin. Prothrombin mutations, 20210A and others Factor V, activated Complexes with factor Xa, calcium, and phospholipid to convert prothrombin to thrombin. Activated protein C resistance due to factor V Leiden mutation Protein C, activated Cleaves activated factors Va and VIIIa. Congenital protein C deficiency Activated protein C resistance due to factor V Leiden mutation Neonatal purpura fulminans Warfarin-induced skin necrosis Protein S
CHAPTER 234: Clotting Disorders 1475 the setting of acute thrombosis or while the patient is taking a vitamin K antagonist such as warfarin or direct oral anticoagulants. The ED diagnostic approach to individual episodes of suspected thrombosis in a thrombophilic patient is site specific (e.g., cerebral arterial or venous circulation, coronary circulation, or peripheral venous system). Recorded characteristics in the derivation samples for the Wells Score 5 or Pulmonary Embolism Rule Out Criteria 6 excluded patients with known genetic causes for thrombophilia. Instead of risk stratifica tion tools, use the patient’s personal history of venous thromboembo lism (phenotypic evidence of thrombophilia). Using a normal serum d-dimer level to exclude venous thromboembolism in patients with known hypercoagulable disorders has not been validated. TREATMENT AND DISPOSITION Initial management and disposition of individual episodes of confirmed thrombosis in a patient with thrombophilia are similar to those of a patient without known thrombophilia, with exceptions discussed in specific conditions. 7 Patients not currently on anticoagulation should consider prophylactic anticoagulants for high-risk situations such as surgery, pregnancy and the postpartum period, and prolonged travel. Estrogen-based oral contraceptive pills and hormone replacement therapy should be avoided in patients with known thrombophilia because of the thrombotic risk. TABLE 234-2 Functions of Coagulation Proteins in Protein C and Antithrombin Systems Factor Function Pertinent Disorders Prothrombin (factor II) Precursor to thrombin, which converts fibrinogen to fibrin. Prothrombin mutations, 20210A and others Factor V, activated Complexes with factor Xa, calcium, and phospholipid to convert prothrombin to thrombin. Activated protein C resistance due to factor V Leiden mutation Protein C, activated Cleaves activated factors Va and VIIIa. Congenital protein C deficiency Activated protein C resistance due to factor V Leiden mutation Neonatal purpura fulminans Warfarin-induced skin necrosis Protein S Cofactor for activated protein C. Congenital protein S deficiency Cofactor for tissue factor pathway inhibitor (which inhibits extrinsic pathway of coagulation). Neonatal purpura fulminans Counteracts factor Xa’s protection of factor Va from degradation. Warfarin-induced skin necrosis Antithrombin
Congenital protein C deficiency Activated protein C resistance due to factor V Leiden mutation Neonatal purpura fulminans Warfarin-induced skin necrosis Protein S Cofactor for activated protein C. Congenital protein S deficiency Cofactor for tissue factor pathway inhibitor (which inhibits extrinsic pathway of coagulation). Neonatal purpura fulminans Counteracts factor Xa’s protection of factor Va from degradation. Warfarin-induced skin necrosis Antithrombin Inhibits thrombin, factor Xa, and factor IXa. Antithrombin deficiency Binds heparins, leading to increased antithrombin activity. Phospholipids Present on cell membranes of endothelial cells that line blood vessels. Antiphospholipid syndrome
Cofactor for activated protein C. Congenital protein S deficiency Cofactor for tissue factor pathway inhibitor (which inhibits extrinsic pathway of coagulation). Neonatal purpura fulminans Counteracts factor Xa’s protection of factor Va from degradation. Warfarin-induced skin necrosis Antithrombin Inhibits thrombin, factor Xa, and factor IXa. Antithrombin deficiency Binds heparins, leading to increased antithrombin activity. Phospholipids Present on cell membranes of endothelial cells that line blood vessels. Antiphospholipid syndrome The activity of several proteins in the coagulation cascade is enhanced when bound to phospholipids. TABLE 234-3 Features Suggestive of Thrombophilia • Early thrombosis (age 45 y and younger) • Recurrent thrombotic events or fetal loss • Family history of thrombosis or recurrent fetal loss • Thrombosis in unusual location (mesenteric, cerebral, axillary, or portal veins) SPECIFIC CONDITIONS ASSOCIATED WITH THROMBOPHILIA INHERITED CLOTTING DISORDERS ACTIVATED PROTEIN C RESISTANCE (FACTOR V LEIDEN) Activated protein C resistance caused by the factor V Leiden mutation is the most prevalent inherited hypercoagulable disorder; approxi mately 5% of the U.S. population of European descent is heterozygous for this mutation. 8 In this disorder, the gene for factor V has a single point mutation that makes factor Va resistant to inhibition by activated protein C (factor V Leiden). This leads to overabundant conversion of prothrombin to thrombin. Factor V Leiden is inherited in an autosomal dominant pattern, with most patients being heterozygous for the mutation. Heterozygotes for factor V Leiden have a sevenfold increased risk of deep venous thrombosis compared with noncarriers, with homozy gotes having a 20-fold increase in risk. Factor V Leiden is more highly associated with deep vein thrombosis than pulmonary embolism 9 and has been observed in up to 21% of patients with first-time deep venous thrombosis. 10 Activated protein C resistance also produces pregnancy complications such as severe preeclampsia, placental abruption, fetal growth restriction, and stillbirth. PROTHROMBIN GENE MUTATION The most common mutation of the prothrombin gene (20210A) leads to increased prothrombin biosynthesis with about a 30% increase in circulating prothrombin levels, creating a prothrombotic state. Prothrombin mutations are inherited in an autosomal dominant manner, with mutations in the prothrombin gene present in about 2% of Caucasians. 2 Heterozygotes account for up to 10% of patients with initial episodes of deep venous thrombosis. 10 Patients with prothrombin gene mutation present with increased risk of venous thromboembolism and pregnancy complications, similar to activated protein C resistance from factor V Leiden. DEFICIENCIES OF CLOTTING INHIBITORS Antithrombin Deficiency Several mutations to the antithrombin gene exist, many leading to antithrombin deficiency. Two percent of patients with a history of thrombosis have an antithrombin deficiency, 11 and it is more prevalent in Asian populations. Antithrombin deficiency is classified into two main groups. In type 1, the measured level of antithrombin is diminished, whereas patients with type 2 have a normal amount of antithrombin, but the function is greatly diminished due to conforma tional changes in the protein. Antithrombin deficiency is inherited in an autosomal dominant fashion. Heterozygous patients have a fivefold increased risk of thrombotic events, typically pregnancy complications and venous thromboembolism. Homozygous antithrombin deficiency is incompatible with life. Protein C and Protein S Deficiencies Protein C and S deficiencies, like antithrombin deficiency, are transmitted in an autosomal domi nant fashion, but with more varied clinical presentations. Prevalence can only be estimated, because not all patients with heterozygous defects develop inappropriate thrombosis.
th life. Protein C and Protein S Deficiencies Protein C and S deficiencies, like antithrombin deficiency, are transmitted in an autosomal domi nant fashion, but with more varied clinical presentations. Prevalence can only be estimated, because not all patients with heterozygous defects develop inappropriate thrombosis. Heterozygous protein C deficiency is thought to be present in 1:250 to 1:500 people, and het erozygous protein S deficiency is estimated to occur in about 1:500 individuals. 12 Homozygous protein C or S deficiency is rare and presents as neonatal purpura fulminans. Patients with heterozygous protein C or S deficiency are at higher risk for venous thromboembo lism, and like antithrombin deficiency, these disorders can be associ ated with either decreased total amount of protein C or S or decreased functional activity. In general, lower function is associated with higher risk and frequency of thrombotic events. Protein C and S deficiency, like antithrombin deficiency, is more prevalent in the Japanese and Chinese populations, with up to 32% percent of Japanese adults with venous thromboembolism having a deficiency of protein C, protein S, or antithrombin. Patients with heterozygous protein C or S deficiency are at higher risk for warfarin-induced skin necrosis because warfarin inhibits protein C Tintinalli_Sec18_p1461-1522.indd 1475 8/2/19 8:37 PM
to 32% percent of Japanese adults with venous thromboembolism having a deficiency of protein C, protein S, or antithrombin. Patients with heterozygous protein C or S deficiency are at higher risk for warfarin-induced skin necrosis because warfarin inhibits protein C Tintinalli_Sec18_p1461-1522.indd 1475 8/2/19 8:37 PM 1476 SECTION 18: Hematologic and Oncologic Disorders and S synthesis. Warfarin-induced skin necrosis is rare and is prevented by both avoiding loading doses of warfarin and continuing heparin products until the INR is therapeutic. Therefore, any patient who develops warfarin-induced skin necrosis should be evaluated for protein C or S deficiency. Early evidence suggests direct oral anticoagulants are not as efficacious for protein S deficiency compared to other inherited thrombophilias. OTHER INHERITED CONDITIONS Hyperhomocysteinemia is associated with increased risk for various vascular diseases as well as venous thromboembolic disease, primarily through pathogenic effects of elevated homocysteine levels on vascula ture. 14 In recent years, mounting evidence exists showing an association between non-O blood groups (i.e., A, B, and AB) and a modest but statistically significant increased risk of both venous and arterial thromboembolic events. 15 The pathogenesis of this interaction is incompletely understood. ACQUIRED CLOTTING DISORDERS PREGNANCY AND ESTROGEN USE The coagulation changes in pregnancy (Table 234-4) represent an adaptive measure to prevent excessive hemorrhage with delivery. 16 Many of these changes are anatomic in nature, whereas some are related to the relatively high estrogen state. These changes promoting thrombosis are similar but less profound in women taking oral contraceptives and hormone replacement therapy. The exact mechanism of how exogenous estrogen therapy leads to a hypercoagulable state is complex and not completely understood, but high doses of estrogen clearly confer a higher risk for clotting. The current low doses for estrogens in oral contraceptives are associated with a smaller but still clinically significantly increased risk of throm bosis. Estrogen use has been associated with modest increases in several procoagulant proteins (factors VII, VIII, and X, prothrombin, and fibrinogen) as well as decreases in anticoagulant proteins (antithrombin, protein S, protein C). Use of oral contraceptives or hormone replace ment therapy in a patient with known heterozygosity for factor V Leiden puts the patient at an even higher risk for thrombosis, approximately a 15-fold increase. MALIGNANCY Malignancy is associated with increased risk for thrombus forma tion, but the exact mechanisms are not completely understood. 17,18 For patients with a new diagnosis of cancer, the risk of venous thrombo embolism is highest in the first 3 months after diagnosis, with an odds ratio of about 50. Some types of cancers are more likely to promote thrombosis than others, with pancreatic, brain, acute myelogenous leukemia, gastric, esophageal, gynecologic, kidney, and lung cancers having the highest association with thrombosis. Cancer also increases the incidence of arterial thrombotic events, such as myocardial infarc tion and ischemic stroke. 17 Other manifestations of hypercoagulability in cancer patients include chronic disseminated intravascular coagulation, nonbacterial thrombotic endocarditis, migratory superficial thrombo phlebitis, and thrombotic microangiopathy. Chemotherapy itself can also affect coagulation in many ways, such as downregulation of proteins C and S, induction of tissue factor production by endothelial cells, and direct cell damage. Use low-molecular-weight heparin for the initial treatment of venous thromboembolism in patients with active cancer.
roangiopathy. Chemotherapy itself can also affect coagulation in many ways, such as downregulation of proteins C and S, induction of tissue factor production by endothelial cells, and direct cell damage. Use low-molecular-weight heparin for the initial treatment of venous thromboembolism in patients with active cancer. 18,19 Long-term anticoagulation following the diagnosis of venous thromboembolism in these patients uses low-molecular-weight heparin for 6 months as opposed to warfarin. 18 Evolving data indicate the effectiveness of direct oral anticoagulants; however, because of their increased risk of GI bleed ing, it is suggested to avoid these agents in patients with GI malignan cies.19,20 Prophylactic anticoagulation for primary prevention of venous thromboembolism in ambulatory medical oncology patients is not recommended. HEPARIN-INDUCED THROMBOCYTOPENIA Heparin-induced thrombocytopenia is a consumptive coagulopathy in which components of the clotting cascade are inappropriately activated, forming arterial and venous thrombus. 21 Platelet factor 4 is a cell-signaling molecule that plays a central role in this syndrome. Platelet factor 4 neutralizes heparin and heparin-like endogenous compounds, and the heparin–platelet factor 4 combination inhibits local antithrombin activity, thereby promoting coagulation. Heparin-induced thrombocytopenia develops when patients develop antibodies against the heparin–platelet factor 4 complex. A complex of heparin, platelet factor 4, and the anti body binds to platelets, activating them. The platelets then form small microparticles that initiate clot formation. The measured platelet count falls because platelets are bound in both small and large clots. Also, the heparin–platelet factor 4 antibody complex can stimulate endothelial cells and monocytes to release tissue factor, which further stimulates the coagulation cascade. The typical presentation of heparin-induced thrombocytopenia has the platelet count falling to 50,000 to 70,000/mm 3 (50 to 70 × 10 9/L) within 5 to 15 days after starting heparin treatment. Despite the low platelet counts, the patient is hypercoagulable for days to weeks, even after heparin is stopped. Rarely, patients can develop a rapid-onset presentation within hours of initiation of heparin. Case reports of heparin-induced thrombocytopenia-like illness without prior exposure to heparin products exist. With more outpatients being treated with heparin products for venous thromboembolism or other thrombophilias, patients with heparin-induced thrombocytopenia may present to the ED with this syndrome. The diagnosis of heparin-induced thrombocytopenia hinges on laboratory findings and cannot be definitely diagnosed on clinical grounds alone. 21 Thrombocytopenia is almost universally present (with the exception being patients with preexisting thrombocytosis). Suspect the syndrome when platelets have dropped approximately 50% from a recent value in a patient currently or recently taking a heparin product. All heparin products, both unfractionated and low-molecular-weight, must be stopped. These patients need anticoagulation because the risk for thrombosis is highest in the first week after diagnosis. 21 Patients are typically treated with direct thrombin inhibitors (argatroban or bivalirudin) or indirect factor Xa inhibitors (danaparoid). 22 Hematology consultation should be sought. WARFARIN-INDUCED SKIN NECROSIS Warfarin inhibits the production of vitamin K–dependent coagula tion factors, with the serum levels of the individual factors decreasing according to their half-life. Upon initiation of warfarin, protein C is decreased before most of the procoagulant proteins.
ultation should be sought. WARFARIN-INDUCED SKIN NECROSIS Warfarin inhibits the production of vitamin K–dependent coagula tion factors, with the serum levels of the individual factors decreasing according to their half-life. Upon initiation of warfarin, protein C is decreased before most of the procoagulant proteins. This decrease in protein C leads to a transient relative protein C deficiency, which can lead to clinically significant hypercoagulability. Warfarin-induced skin necrosis presents with painful, red lesions usually located over the extremities, breasts, trunk, or penis. 23 Lesions typically start with an initial central erythematous macule, extending TABLE 234-4 Factors Contributing to Hypercoagulable State in Pregnancy Anatomic Hematologic Venous occlusion from gravid uterus. Increased thrombin generation from placental secretion of tissue factorTrauma to pelvic veins during delivery. Tissue injury during surgical delivery. Increased production of procoagulant proteins Left iliac vein crosses over left iliac artery, leading to relative compression (left leg deep venous thrombosis is three times more likely than right in pregnant patients). Decreased free and total protein C Increased platelet activation and platelet turnover Tintinalli_Sec18_p1461-1522.indd 1476 8/2/19 8:37 PM
oteins Left iliac vein crosses over left iliac artery, leading to relative compression (left leg deep venous thrombosis is three times more likely than right in pregnant patients). Decreased free and total protein C Increased platelet activation and platelet turnover Tintinalli_Sec18_p1461-1522.indd 1476 8/2/19 8:37 PM CHAPTER 234: Clotting Disorders 1477 over hours to a localized edema, developing central purpuric zones and then necrosis. Thrombin inhibitors, such as low-molecular-weight heparin, are administered and continued until therapeutic anticoagulation is achieved with warfarin to prevent this complication. 23 Rarely, warfarininduced skin necrosis occurs despite appropriate heparin treatment. When it does, approximately one third of patients will prove to have an inherited protein C deficiency. ANTIPHOSPHOLIPID SYNDROME Antiphospholipid syndrome is an autoimmune disorder defined by the development of venous and/or arterial thrombosis and pregnancy morbidity in the presence of antiphospholipid antibodies. 24 Many of the specific antibodies discovered have targets that are not phospholipids, but rather proteins that interact with phospholipids, such as prothrom bin, protein C, and protein S. The most common specific antibodies associated with antiphospholipid syndrome are lupus anticoagulant, 2-glycoprotein I, and anticardiolipin antibodies. Lupus anticoagulant was initially discovered in patients with systemic lupus erythematosus and prolongation of the activated thromboplastin time; hence, the name lupus anticoagulant. However, in vivo, the lupus anticoagulant acts as a procoagulant and is associated with thrombosis. Up to 5% of normal, healthy young people have antiphospholipid antibodies; this number increases with age and comorbid conditions, but only a minority of these patients develop antiphospholipid syn drome (40 to 50 per 100,000 persons). Antiphospholipid antibodies are positive in approximately 13% of patients with stroke, 11% with myocardial infarction, and 9.5% with deep venous thrombosis. 25 As with most autoimmune disorders, antiphospholipid syndrome is more common in women and is diagnosed from a combination of laboratory findings and clinical findings (Table 234-5). Most patients with antiphospholipid syndrome have no predisposing conditions (primary antiphospholipid syndrome). A minority have conditions thought to be associated with their antiphospholipid syndrome (secondary antiphospholipid syndrome), such as rheumatologic or autoimmune disorders (systemic lupus), infections, and drug exposures (e.g., phenytoin, hydralazine, cocaine). Although most patients with antiphospholipid syndrome present with isolated, recurrent thrombotic events, about 1% have a rapidly progres sive form known as catastrophic antiphospholipid syndrome, representing acceleration in the pathophysiologic processes of antiphospholipid syndrome with widespread small-vessel occlusions in multiple organs. Common triggers for the catastrophic course include infection, surgery, oral anticoagulant withdrawal, oral contraceptive use, obstetric complications, and cancer. However, 40% of the time, no obvious trigger can be found. Mortality of catastrophic antiphospholipid syndrome is approximately 50% despite treatment. Obviously, antiphospholipid syndrome patients with recurrent thrombotic events need lifelong anticoagulation. Pregnant women with antiphospholipid syndrome need anticoagulation with subcutaneous unfractionated or low-molecular-weight heparin or low-dose aspirin therapy. Because many normal healthy patients have antiphospholipid antibodies, prophylaxis without a personal history of thrombosis is not recommended.
nticoagulation. Pregnant women with antiphospholipid syndrome need anticoagulation with subcutaneous unfractionated or low-molecular-weight heparin or low-dose aspirin therapy. Because many normal healthy patients have antiphospholipid antibodies, prophylaxis without a personal history of thrombosis is not recommended. In the rare event of catastrophic antiphospholipid syndrome, a multipronged approach involving anticoagulation, steroids, immunosuppressive therapy, plasmapheresis, and/or IV immunoglobulin is typically used. HYPERCOAGULABILITY ASSOCIATED WITH OTHER DISORDERS Many other conditions are associated with increased risk of clotting. Patients with nephrotic syndrome have an increased risk of hyper coagulability for complex reasons. In several cases, this is simply a matter of increased urinary excretion of anticoagulant proteins. The nephrotic syndrome can also lead to increased endothelial injury and platelet aggregation. Patients with several forms of vasculitis, such as Behçet’s syndrome, antineutrophil cytoplasmic antibody–associ ated vasculitis, and granulomatosis with polyangiitis, have a slightly increased risk of thrombosis. Hyperviscosity syndromes, such as TABLE 234-5 Clinical Manifestations of Antiphospholipid Syndrome System Examples Venous Deep venous thrombosis: extremities, cerebral, portal, hepatic, renal, retinal Arterial Premature atherosclerosis Acute coronary syndrome Ischemic stroke Vascular stenosis or occlusion: extremities, aorta, renal, retinal Obstetric Fetal loss: often after 10-wk gestation Preterm labor Low birth weight Preeclampsia Neurologic Migraine Sneddon’s syndrome—clinical triad of stroke, hypertension, and livedo reticularis Cognitive dysfunction Subcortical dementia Chorea Dysphagia Guillain-Barré syndrome Seizures Optic neuritis Skin Livedo reticularis Cardiac Valvular abnormalities (Libman-Sacks endocarditis) Syndrome X (angina-like chest pain, cardiac stress test positive for ischemia, normal coronary angiography) Skeletal Osteonecrosis Renal Thrombotic microangiopathy Renal artery or vein thrombosis Renal artery stenosis with hypertension Pulmonary Pulmonary embolus Pulmonary hypertension (from recurrent emboli)
Valvular abnormalities (Libman-Sacks endocarditis) Syndrome X (angina-like chest pain, cardiac stress test positive for ischemia, normal coronary angiography) Skeletal Osteonecrosis Renal Thrombotic microangiopathy Renal artery or vein thrombosis Renal artery stenosis with hypertension Pulmonary Pulmonary embolus Pulmonary hypertension (from recurrent emboli) Budd-Chiari syndrome (hepatic vein thrombosis) Mesenteric ischemia Hepatic infarction Acalculous cholecystitis with gallbladder necrosis Hematologic (other than thrombosis) Bleeding diathesis (rare) Acquired hypoprothrombinemia Thrombocytopenia Hemolytic anemia Catastrophic antiphospholipid syndrome Fulminant multisystem organ failure essential thrombocythemia, polycythemia vera, Waldenström’s mac roglobulinemia, multiple myeloma, and sickle cell disease, also place patients at increased risk for thrombosis. Most risk factors for cardio vascular disease, such as obesity and diabetes, are also risk factors for venous thromboembolism to varying degrees. 27 Diabetes alone slightly increases the risk for thrombosis in younger patients without other obvious risks for thrombosis. 28 Patients with human immunodeficiency virus have a 2- to 10-fold increased risk for venous thromboembolism compared to the general population. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Tintinalli_Sec18_p1461-1522.indd 1477 8/2/19 8:37 PM