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Bleeding Disorders confirmed by finding a reduction in von Willebrand antigen increase fibrinogen levels to greater than 100 mgrdL (1 grL) (quantitative analysis) and reduced vWF ristocetin colactor and platelet transfusions to maintain a platelet count greater activigz (a measurement of the functional effect) (see Table 24). than 50,000r'pL (50 x 10e/L). Correction of modest thrombo Management depends on the severity of bleeding, the cytopenia (platelet count >75,000/pL [75 x 10e/L]) or coagu- type of vWD, and the clinical setting. Desmopressin is effec- lopathy (lNR <2) is unnecessary in patients with liver disease tive in patients with fype 1 vWD, releasing preformed vWF who are undergoing paracentesis, thoracentesis, or routine and factor VIII from endothelial cells. It can be given intrave upper endoscopy. Thrombopoietin agonists, such as ava nously before a surgical procedure or intranasally as needed trombopag, are alternatives to platelet transfusion before a in the outpatient setting. Patients with rare type 28 vWD procedure but require approximately 10 days to raise the should not receive desmopressin because it induces platelet platelet count to reduce the risk of procedure-related bleed aggregation, which may cause secondary thrombocytopenia. ing. Fresh frozen plasma can be given to correct INRs greater Desmopressin is ineffective in patients with type 3 vWD. vWF than 2, but the short half life of plasma components and risk concentrates are the preferred treatment for patients with of volume overload limit the effectiveness of plasma admin these two subgroups. Antifibrinolytic therapy (e aminocaproic istration. Prothrombin complex concentrates are costly and acid and tranexamic acid) is useful after surgical procedures associated with thrombotic complications; they should not to protect against delayed bleeding and can be used to treat be routinely used in managing the coagulopathy of liver menorrhagia. disease.

confirmed by finding a reduction in von Willebrand antigen increase fibrinogen levels to greater than 100 mgrdL (1 grL) (quantitative analysis) and reduced vWF ristocetin colactor and platelet transfusions to maintain a platelet count greater activigz (a measurement of the functional effect) (see Table 24). than 50,000r'pL (50 x 10e/L). Correction of modest thrombo Management depends on the severity of bleeding, the cytopenia (platelet count >75,000/pL [75 x 10e/L]) or coagu- type of vWD, and the clinical setting. Desmopressin is effec- lopathy (lNR <2) is unnecessary in patients with liver disease tive in patients with fype 1 vWD, releasing preformed vWF who are undergoing paracentesis, thoracentesis, or routine and factor VIII from endothelial cells. It can be given intrave upper endoscopy. Thrombopoietin agonists, such as ava nously before a surgical procedure or intranasally as needed trombopag, are alternatives to platelet transfusion before a in the outpatient setting. Patients with rare type 28 vWD procedure but require approximately 10 days to raise the should not receive desmopressin because it induces platelet platelet count to reduce the risk of procedure-related bleed aggregation, which may cause secondary thrombocytopenia. ing. Fresh frozen plasma can be given to correct INRs greater Desmopressin is ineffective in patients with type 3 vWD. vWF than 2, but the short half life of plasma components and risk concentrates are the preferred treatment for patients with of volume overload limit the effectiveness of plasma admin these two subgroups. Antifibrinolytic therapy (e aminocaproic istration. Prothrombin complex concentrates are costly and acid and tranexamic acid) is useful after surgical procedures associated with thrombotic complications; they should not to protect against delayed bleeding and can be used to treat be routinely used in managing the coagulopathy of liver menorrhagia. disease. XEY POITT' XEY POITIS . Von Willebrand factor deficiency in von Willebrand . Although measuring the factor VIII level (elevated in disease leads to mucocutaneous bleeding symptoms, liver disease but consumed during intravascular coagu including bleeding gums, epistaxis, menorrhagia, and lation) could theoretically distinguish coagulopathy of easy bruising, that mimic thrombocytopenia. liver disease from disseminated intravascular coagula- o Desmopressin, which stimulates release of preformed tion, patients may have components of both disorders, von Willebrand factor and factor VIII, is used to treat and the management is usually analogous regardless of minor bleeding in most patients with von Willebrand this distinction. disease and is given prophylactically before surgery or . Active bleeding in patients with coagulopathy of liver procedures. disease should be managed with cryoprecipitate to main o Von Willebrand factor concentrates are used for major tain fibrinogen levels greater than 100 mg/dl (f glL) and bleeding and to treat patients with rare subtypes 28 platelet transfusions to achieve a platelet count greater and 3. than 50,000/pL (50 x 10e/L). o Fresh frozen plasma can be administered to patients with coagulopathy of liver disease, active bleeding, and Acquired Bleeding Disorders an INR greater than 2, but the short half-life of plasma coagulation factors and risk of volume overload limit its Coagulopathy of Liver Disease effectiveness. Liver disease results in reduced procoagulant and anticoagu, o Because of their cost and association with prothrom- HVC lant factors and in mild to moderate thrombocytopenia. The reduction ofprocoagulant factors can result in PT and aPTT botic complications, prothrombin complex concen prolongation; however, these results do not correlate with trates should not be routinely used to manage the bleeding risk because they do not reflect the parallel reduc- coagulopathy of liver disease. tion in anticoagulant factors. Bleeding can occur because of portal hypertension, thrombocytopenia, or intercurrent Disseminated lntravascular Coagulation problems that disturb the balance between procoagulant DIC results from the simultaneous activation of coagulation and anticoagulant factors. Distinguishing between liver dis- and fibrinolysis. It is associated with severe sepsis. usually ease and disseminated intravascular coagulation (DIC) may with septic shock; with disseminated malignancy. most clas- be challenging because patients sometimes have compo sically with mucin-secreting pancreatic adenocarcinoma: nents of both disorders, and the clinical management is and in pregnancy with complications of placental abruption often analogous. Measuring the factor VIII level may be use- and eclampsia. The initial pathogenesis involves r,l,idespread ful, because factor VIII is often elevated in liver disease but endothelial injury and circulating procoagulants that lead to consumed in DIC. disseminated microvascular thrombi. with consumption of Asymptomatic patients do not require treatment, but platelets and clotting factors, and erythrocyte shearing vitamin K supplementation should be considered if defi- injury leading to hemolysis. Fibrinolysis is accelerated, ciency is suspected. Patients experiencing bleeding may resulting in dissolution of the microvascular thrombus, require blood product replacement, with cryoprecipitate to usually before thrombotic complications are noted. Classic

XEY POITT' XEY POITIS . Von Willebrand factor deficiency in von Willebrand . Although measuring the factor VIII level (elevated in disease leads to mucocutaneous bleeding symptoms, liver disease but consumed during intravascular coagu including bleeding gums, epistaxis, menorrhagia, and lation) could theoretically distinguish coagulopathy of easy bruising, that mimic thrombocytopenia. liver disease from disseminated intravascular coagula- o Desmopressin, which stimulates release of preformed tion, patients may have components of both disorders, von Willebrand factor and factor VIII, is used to treat and the management is usually analogous regardless of minor bleeding in most patients with von Willebrand this distinction. disease and is given prophylactically before surgery or . Active bleeding in patients with coagulopathy of liver procedures. disease should be managed with cryoprecipitate to main o Von Willebrand factor concentrates are used for major tain fibrinogen levels greater than 100 mg/dl (f glL) and bleeding and to treat patients with rare subtypes 28 platelet transfusions to achieve a platelet count greater and 3. than 50,000/pL (50 x 10e/L). o Fresh frozen plasma can be administered to patients with coagulopathy of liver disease, active bleeding, and Acquired Bleeding Disorders an INR greater than 2, but the short half-life of plasma coagulation factors and risk of volume overload limit its Coagulopathy of Liver Disease effectiveness. Liver disease results in reduced procoagulant and anticoagu, o Because of their cost and association with prothrom- HVC lant factors and in mild to moderate thrombocytopenia. The reduction ofprocoagulant factors can result in PT and aPTT botic complications, prothrombin complex concen prolongation; however, these results do not correlate with trates should not be routinely used to manage the bleeding risk because they do not reflect the parallel reduc- coagulopathy of liver disease. tion in anticoagulant factors. Bleeding can occur because of portal hypertension, thrombocytopenia, or intercurrent Disseminated lntravascular Coagulation problems that disturb the balance between procoagulant DIC results from the simultaneous activation of coagulation and anticoagulant factors. Distinguishing between liver dis- and fibrinolysis. It is associated with severe sepsis. usually ease and disseminated intravascular coagulation (DIC) may with septic shock; with disseminated malignancy. most clas- be challenging because patients sometimes have compo sically with mucin-secreting pancreatic adenocarcinoma: nents of both disorders, and the clinical management is and in pregnancy with complications of placental abruption often analogous. Measuring the factor VIII level may be use- and eclampsia. The initial pathogenesis involves r,l,idespread ful, because factor VIII is often elevated in liver disease but endothelial injury and circulating procoagulants that lead to consumed in DIC. disseminated microvascular thrombi. with consumption of Asymptomatic patients do not require treatment, but platelets and clotting factors, and erythrocyte shearing vitamin K supplementation should be considered if defi- injury leading to hemolysis. Fibrinolysis is accelerated, ciency is suspected. Patients experiencing bleeding may resulting in dissolution of the microvascular thrombus, require blood product replacement, with cryoprecipitate to usually before thrombotic complications are noted. Classic 44

Transfusion Medicine laboratory findings include thrombocytopenia, prolonged cases are associated with pregnancy and the postpartum state, aPTT and PT, elevated INR, hypofibrinogenemia, and ele malignancy, and autoimmune disorders, as well as with vated D dimer levels. Management is directed primarily at medications. the inciting cause and supported with platelet transfusions, Laboratory evaluation shows a normal platelet count and cryoprecipitate, and liesh frozen plasma as needed. PT with a prolonged aPTT. Mixing studies do not correct the aPTT. Factor analysis shows a low factor VIII level; an inhibitor I(EY POITT can be quantified with the Bethesda assay. One Bethesda unit o Classic laboratory findings of disseminated intravascu is defined as the reciprocal of the dilution of patient plasma lar coagulation include thrombocytopenia, prolonged that results in 50% inactivation. activated partial thromboplastin and prothrombin Factor VIII concentrates typically do not correct the times, elevated INR, hypofibrinogenemia, and elevated problem because the autoantibody will still block the factor D-dimer levels. VIII concentrate activity. Acute bleeding management requires plasma derivatives or recombinant coagulation factors that bypass the inhibited f'actor, such as activated prothrombin Vitamin K Deficiency complex concentrates or recombinant activated factor VII. Although vitamin K is fbund in green vegetables. a signilicant Recombinant porcine factor VIII is not cross reactive with proportion of the daily requirement comes from gut micro human factor VIII and can provide effective hemostasis, but it tlora (which may be destroyed by antibiotics); absorption may be limited in availability. lmmunosuppression, using requires biliary and pancreatic function because vitamin K is glucocorticoids, usually combined with rituximab or cyclo. fat solubie. It acts as a cofactor fbr carboxylation and activation phosphamide, is required to eliminate the autoantibody and of coagulation factors ll, Vll. IX, and X, as well as for the prevent continued inhibitor production. endogenous anticoagulants, protein C, and protein S. Patients Acquired hemophilia A is the classic example of an auto who cannot take anything by mouth, have poor oral intake immune factor deficiency. Acquired inhibitors can occur while taking long courses of antibiotics, and have fat malab against any factor and should be considered whenever a sorption are especially at risk for vitamin K deficiency. Vitamin patient presents with a new bleeding diathesis and an unex K supplements safely and efl'ectively correct the deficiency, so pectedly low factor level. this diagnosis should always be considered when evaluating a patient with a prolonged PT; the response to supplementation t(EY POIXTT occurs rvithin hours. Vitamin K can be administered orally for . Acquired hemophilia from an autoantibody directed patients who are able to eat. Critically ill patients or those against a clotting factor, usually factor VIII, should be unable to take anything by mouth should receive vitamin K by considered when a patient presents with a new bleed- slow intravenous infusion. Subcutaneous vitamin K is not reli ing diathesis, prolongation ofthe activated partial ably absorbed and is unlikely to be safer than intravenous thromboplastin or prothrombin time, and a low level vitamin K. of an isolated clotting factor. . Factor VIII concentrates are ineffective in patients with Acquired von Willebrand Disease acquired hemophilia because ofthe presence ofan Acquired vWD occurs in conditions with high circulatory inhibitor; instead, patients should receive activated pro- shear stress (valvular heart disease, hypertrophic cardio thrombin complex concentrates, recombinant activated myopathy, circulatory assist devices, and extracorporeal factor VII, or recombinant porcine factor VIII for man- membrane oxygenation systems) caused by excessive degra- agement of acute bleeding. dation of high molecular weight von Willebrand multimers by the proteolytic enzyme ADAMTSl3. Acquired vWD can also occur from autoimmune I'actors (systemic lupus erythe- matosus), lymphoproliferative disease, monoclonal gan.r Transfusion Medicine mopathy, and myeloproliferative disease characterized by marked thrombocytosis. AfTected patients develop bleeding Blood Donor Screening conditions similar to those in hereditary vWD. Desmopressin Blood donor screening comprises questions regarding the and vWF concentrates have been used lbr management. donor's general health and any high risk behaviors. Blood Hydroxyurea can be used to lower platelet counts in myelo undergoes Iaboratory testing lbr hepatitis B and C viruses, HIV proliferative disease. human T cell lymphotropic virus I/ll, and West Nile virus; serologic testing for syphilis; and, in select regions ofthe coun Acquired Hemophilia try, testing for antibodies to Trypanosoma cruzi (agent for Acquired hemophilia results from an autoantibody directed Chagas disease), Babesia. and Zika virus. Platelet components against factor VIII. Patients present with bleeding symptoms are also screened fbr bacterial contamination befbre being that mimic hereditary hemophilia A. Approximately half of all released Ibr transfusion.

laboratory findings include thrombocytopenia, prolonged cases are associated with pregnancy and the postpartum state, aPTT and PT, elevated INR, hypofibrinogenemia, and ele malignancy, and autoimmune disorders, as well as with vated D dimer levels. Management is directed primarily at medications. the inciting cause and supported with platelet transfusions, Laboratory evaluation shows a normal platelet count and cryoprecipitate, and liesh frozen plasma as needed. PT with a prolonged aPTT. Mixing studies do not correct the aPTT. Factor analysis shows a low factor VIII level; an inhibitor I(EY POITT can be quantified with the Bethesda assay. One Bethesda unit o Classic laboratory findings of disseminated intravascu is defined as the reciprocal of the dilution of patient plasma lar coagulation include thrombocytopenia, prolonged that results in 50% inactivation. activated partial thromboplastin and prothrombin Factor VIII concentrates typically do not correct the times, elevated INR, hypofibrinogenemia, and elevated problem because the autoantibody will still block the factor D-dimer levels. VIII concentrate activity. Acute bleeding management requires plasma derivatives or recombinant coagulation factors that bypass the inhibited f'actor, such as activated prothrombin Vitamin K Deficiency complex concentrates or recombinant activated factor VII. Although vitamin K is fbund in green vegetables. a signilicant Recombinant porcine factor VIII is not cross reactive with proportion of the daily requirement comes from gut micro human factor VIII and can provide effective hemostasis, but it tlora (which may be destroyed by antibiotics); absorption may be limited in availability. lmmunosuppression, using requires biliary and pancreatic function because vitamin K is glucocorticoids, usually combined with rituximab or cyclo. fat solubie. It acts as a cofactor fbr carboxylation and activation phosphamide, is required to eliminate the autoantibody and of coagulation factors ll, Vll. IX, and X, as well as for the prevent continued inhibitor production. endogenous anticoagulants, protein C, and protein S. Patients Acquired hemophilia A is the classic example of an auto who cannot take anything by mouth, have poor oral intake immune factor deficiency. Acquired inhibitors can occur while taking long courses of antibiotics, and have fat malab against any factor and should be considered whenever a sorption are especially at risk for vitamin K deficiency. Vitamin patient presents with a new bleeding diathesis and an unex K supplements safely and efl'ectively correct the deficiency, so pectedly low factor level. this diagnosis should always be considered when evaluating a patient with a prolonged PT; the response to supplementation t(EY POIXTT occurs rvithin hours. Vitamin K can be administered orally for . Acquired hemophilia from an autoantibody directed patients who are able to eat. Critically ill patients or those against a clotting factor, usually factor VIII, should be unable to take anything by mouth should receive vitamin K by considered when a patient presents with a new bleed- slow intravenous infusion. Subcutaneous vitamin K is not reli ing diathesis, prolongation ofthe activated partial ably absorbed and is unlikely to be safer than intravenous thromboplastin or prothrombin time, and a low level vitamin K. of an isolated clotting factor. . Factor VIII concentrates are ineffective in patients with Acquired von Willebrand Disease acquired hemophilia because ofthe presence ofan Acquired vWD occurs in conditions with high circulatory inhibitor; instead, patients should receive activated pro- shear stress (valvular heart disease, hypertrophic cardio thrombin complex concentrates, recombinant activated myopathy, circulatory assist devices, and extracorporeal factor VII, or recombinant porcine factor VIII for man- membrane oxygenation systems) caused by excessive degra- agement of acute bleeding. dation of high molecular weight von Willebrand multimers by the proteolytic enzyme ADAMTSl3. Acquired vWD can also occur from autoimmune I'actors (systemic lupus erythe- matosus), lymphoproliferative disease, monoclonal gan.r Transfusion Medicine mopathy, and myeloproliferative disease characterized by marked thrombocytosis. AfTected patients develop bleeding Blood Donor Screening conditions similar to those in hereditary vWD. Desmopressin Blood donor screening comprises questions regarding the and vWF concentrates have been used lbr management. donor's general health and any high risk behaviors. Blood Hydroxyurea can be used to lower platelet counts in myelo undergoes Iaboratory testing lbr hepatitis B and C viruses, HIV proliferative disease. human T cell lymphotropic virus I/ll, and West Nile virus; serologic testing for syphilis; and, in select regions ofthe coun Acquired Hemophilia try, testing for antibodies to Trypanosoma cruzi (agent for Acquired hemophilia results from an autoantibody directed Chagas disease), Babesia. and Zika virus. Platelet components against factor VIII. Patients present with bleeding symptoms are also screened fbr bacterial contamination befbre being that mimic hereditary hemophilia A. Approximately half of all released Ibr transfusion. 45