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Hematologic lssues in Pregnancy as warfarin in preventing VTEs with less central nervous because of the high cost, significant risk of complications, and system bleeding, fatal bleeding, and use of blood product lack of data comparing the use of andexanet alfa to PCC. support. The bleeding risk is higher in patients taking con Idarucizumab is an FDA-approved monoclonal antibody frag comitant aspirin or clopidogrel and is further increased in ment that binds free and thrombin bound dabigatran and patients receiving dual antiplatelet therapy. No head to head neutralizes its activity. Idarucizumab was found to be safe and trials have been performed comparing the various DOACs. effective in reversing the anticoagulant effects ofdabigatran in Certain patient groups, including pregnant patients and patients who experienced serious, life-threatening bleeding those with mechanical heart valves, were excluded from the determined to require a reversal agent or who required an major trials of the DOACs. Some studies also excluded urgent invasive procedure. Its use is recommended in the ASH patients with BMI greater than 40 kg/m2 or weight greater 2018 guidelines on VTE treatment. Il idarucizumab is not than 120 kg (264.5 lb). Growing evidence shows that DOACs available, activated PCC is an alternative for patients with may be effective in this population, but caution is advised. dabigatran associated major bleeding. Nonadherent patients should not be treated with DOACs. In TEY POIl{IS patients with low risk APLAS, the role of DOACs remains unclear, but they should be avoided in patients with high- . Dabigatran, rivaroxaban, apixaban, and edoxaban have a rapid onset of activity, no need for laboratory moni risk disease. In patients with concern for gastrointestinal toring, and a therapeutic effect that is less likely than bleeding, dabigatran may not be preferred because of an warfarin to be influenced by changes in diet or medica increased rate of dyspepsia and gastrointestinal bleeding tions. compared with warfarin. A11 the DOACs are at least partially eliminated through o Direct oral anticoagulants (DOACs) are as effective as the kidney (see Table 36), and dose adjustment may be warfarin in preventing and treating venous thromboem- required in patients with advanced chronic kidney disease. bolism; although the overall rate of bleeding is compara- Apixaban has the lowest renal elimination rate and is ble, patients taking a DOAC have less central nervous approved for patients undergoing dialysis; however, caution system bleeding and less fatal bleeding. should be used. Data from a 2Ol9 systematic review and o The direct oral anticoagulants should not be used in meta analysis suggest that DOACs may be preferred in patients with valvular heart disease, severe obesity, preg- patients with early stage chronic kidney disease (estimated nancy, high-risk antiphospholipid antibody syndrome, glomerular filtration rate <60 mLlminl7.73 m2) and atrial or nonadherent patients. fibrillation. Additionally, the risk of bleeding with DOACs . Direct oral anticoagulants are as effective as low-molecular- appears to be no worse than with VKAs. DOACs should be weight heparin in managing venous thromboembolism used with caution or avoided in patients with Child-Pugh in patients with cancer. class B or C liver disease. Bridging therapy is typically unnecessary in patients tak- ing DOACs. Discontinuation of the DOAC depends on the half life of the drug, the type of procedure, and the patient's kidney function. DOACs should be stopped 24 to 48 hours before Hematologic lssues surgery with moderate bleeding risk and 72 hours before sur in Pregnancy gery with higher bleeding risk. In patients with impaired kidney function, DOACs should be stopped earlier. For proce- Gestational Anemia dures with low bleeding risk, DOACs can be resumed promptly During pregnancy, an increase in plasma volume occurs that when effective hemostasis is secured. For procedures with is greater than the increase in erythrocyte mass, resulting in a higher rates of bleeding, reinstitution is usually delayed 2 to physiologic decrease in measured hemoglobin level, although 3 days. it typically remains greater than 10.5 g/dl (105 g/L). If the The standard approach to patients experiencing bleeding hemoglobin level decreases further, additional evaluation of involves hemodynamic monitoring and resuscitation with the anemia is warranted. Iron, vitamin B,r, and folate levels fluid and blood products. Activated charcoal can be considered should be measured. if the DOAC was ingested recently (<6 hours). Hemodialysis Worldwide, iron deficiency during pregnancy remains a can be considered with dabigatran therapy ifnew kidney dis significant problem. ln 2017, the World Health Organization ease is found. For patients with life threatening bleeding who estimated that up to 60'l" ol pregnant women have anemia, are taking an oral direct Xa inhibitor, the ASH suggests stop- mostly attributed to iron deficiency. Because iron deficiency in ping the oral direct Xa inhibitor and considering treatment pregnancy leads to anemia in infants and is associated u.ith with either 4 factor PCC or andexanet alfa (off label use for developmental delays, iron levels should be monitored during edoxaban). Experts recommend caution in using andexanet pregnancy and low levels supplemented. Patients with severe alfa and restricting its use to patients receiving anti Xa antico- iron deficiency anemia in the third trimester may benefit from agulants who are experiencing life-threatening bleeding intravenous iron repletion.

as warfarin in preventing VTEs with less central nervous because of the high cost, significant risk of complications, and system bleeding, fatal bleeding, and use of blood product lack of data comparing the use of andexanet alfa to PCC. support. The bleeding risk is higher in patients taking con Idarucizumab is an FDA-approved monoclonal antibody frag comitant aspirin or clopidogrel and is further increased in ment that binds free and thrombin bound dabigatran and patients receiving dual antiplatelet therapy. No head to head neutralizes its activity. Idarucizumab was found to be safe and trials have been performed comparing the various DOACs. effective in reversing the anticoagulant effects ofdabigatran in Certain patient groups, including pregnant patients and patients who experienced serious, life-threatening bleeding those with mechanical heart valves, were excluded from the determined to require a reversal agent or who required an major trials of the DOACs. Some studies also excluded urgent invasive procedure. Its use is recommended in the ASH patients with BMI greater than 40 kg/m2 or weight greater 2018 guidelines on VTE treatment. Il idarucizumab is not than 120 kg (264.5 lb). Growing evidence shows that DOACs available, activated PCC is an alternative for patients with may be effective in this population, but caution is advised. dabigatran associated major bleeding. Nonadherent patients should not be treated with DOACs. In TEY POIl{IS patients with low risk APLAS, the role of DOACs remains unclear, but they should be avoided in patients with high- . Dabigatran, rivaroxaban, apixaban, and edoxaban have a rapid onset of activity, no need for laboratory moni risk disease. In patients with concern for gastrointestinal toring, and a therapeutic effect that is less likely than bleeding, dabigatran may not be preferred because of an warfarin to be influenced by changes in diet or medica increased rate of dyspepsia and gastrointestinal bleeding tions. compared with warfarin. A11 the DOACs are at least partially eliminated through o Direct oral anticoagulants (DOACs) are as effective as the kidney (see Table 36), and dose adjustment may be warfarin in preventing and treating venous thromboem- required in patients with advanced chronic kidney disease. bolism; although the overall rate of bleeding is compara- Apixaban has the lowest renal elimination rate and is ble, patients taking a DOAC have less central nervous approved for patients undergoing dialysis; however, caution system bleeding and less fatal bleeding. should be used. Data from a 2Ol9 systematic review and o The direct oral anticoagulants should not be used in meta analysis suggest that DOACs may be preferred in patients with valvular heart disease, severe obesity, preg- patients with early stage chronic kidney disease (estimated nancy, high-risk antiphospholipid antibody syndrome, glomerular filtration rate <60 mLlminl7.73 m2) and atrial or nonadherent patients. fibrillation. Additionally, the risk of bleeding with DOACs . Direct oral anticoagulants are as effective as low-molecular- appears to be no worse than with VKAs. DOACs should be weight heparin in managing venous thromboembolism used with caution or avoided in patients with Child-Pugh in patients with cancer. class B or C liver disease. Bridging therapy is typically unnecessary in patients tak- ing DOACs. Discontinuation of the DOAC depends on the half life of the drug, the type of procedure, and the patient's kidney function. DOACs should be stopped 24 to 48 hours before Hematologic lssues surgery with moderate bleeding risk and 72 hours before sur in Pregnancy gery with higher bleeding risk. In patients with impaired kidney function, DOACs should be stopped earlier. For proce- Gestational Anemia dures with low bleeding risk, DOACs can be resumed promptly During pregnancy, an increase in plasma volume occurs that when effective hemostasis is secured. For procedures with is greater than the increase in erythrocyte mass, resulting in a higher rates of bleeding, reinstitution is usually delayed 2 to physiologic decrease in measured hemoglobin level, although 3 days. it typically remains greater than 10.5 g/dl (105 g/L). If the The standard approach to patients experiencing bleeding hemoglobin level decreases further, additional evaluation of involves hemodynamic monitoring and resuscitation with the anemia is warranted. Iron, vitamin B,r, and folate levels fluid and blood products. Activated charcoal can be considered should be measured. if the DOAC was ingested recently (<6 hours). Hemodialysis Worldwide, iron deficiency during pregnancy remains a can be considered with dabigatran therapy ifnew kidney dis significant problem. ln 2017, the World Health Organization ease is found. For patients with life threatening bleeding who estimated that up to 60'l" ol pregnant women have anemia, are taking an oral direct Xa inhibitor, the ASH suggests stop- mostly attributed to iron deficiency. Because iron deficiency in ping the oral direct Xa inhibitor and considering treatment pregnancy leads to anemia in infants and is associated u.ith with either 4 factor PCC or andexanet alfa (off label use for developmental delays, iron levels should be monitored during edoxaban). Experts recommend caution in using andexanet pregnancy and low levels supplemented. Patients with severe alfa and restricting its use to patients receiving anti Xa antico- iron deficiency anemia in the third trimester may benefit from agulants who are experiencing life-threatening bleeding intravenous iron repletion. 62

Hematologic lssues in Pregnancy (100 x 10e/L), although platelet counts may reach a nadir of Sickle Cell Disease 70,000/pL (70 x 10'q/L). Patients with gestational thrombocy- The physiologic stresses ofpregnancy are especially challenging topenia have no history of thrombocytopenia, and the platelet fbr women with sickle cell disease (SCD). Folate requirements count does not decrease until late in gestation. The fetus is increase because of the rapid tumover of erythrocytes, requiring unaffected, intervention is unnecessary and platelet counts additional folate supplementation. Iron and vitamin B,, stores spontaneously return to normal after delivery. must also be monitored. Although expert opinion varies, the I National Institutes of Health does not recommend prophylactic XEY POIilI transfusions in pregnancy for women with sickle cell anemia. o Patients with gestational thromboqtopenia have no his- HVC Other experts disagree, suggesting prophylactic transfusion in tory of thrombocytopenia, and because the thrombocy- pregnant women during the third trimester to achieve a hemo- topenia is not severe, without predisposition to bleeding, globin level of9 g/dl (90 g/L) or reserving such transfusions fbr and platelet counts resolve spontaneously, no treatment women with previous fetal loss, frequent acute painful events, or is necessary. history of acute chest syndrome. Frequent transfusions may lead to alloimmunization, increasing the risk of hemo\tic disease of lmmune Thrombocytopenic Purpura I the newbom. Although routine use ot prophylactic transfusion Immune thrombocytopenic purpura (lTP) (see Platelet is debatable, pregnant women with more severe and sympto Disorders) can occur in women of childbearing age and may matic anemia should be transfused as should those with acute manifest during pregnancy. Differentiating ITP from gestational chest syndrome or stroke. Pregnant women with SCD should be thrombocl.topenia may be difficult, but features suggesting ITP monitored closely with monthly complete blood counts. include earlier presentation (first trimester), lower platelet The risk of venous thromboembolism (VTE) is increased, count nadir (<70,000/pL [70 x 10r/L]), and history of thrombo and prophylactic anticoagulation should be administered cytopenia before pregnancy (even il it was only mild). If the in hospitalized patients. The increased cardiopulmonary platelet count remains greater than 30,000/pL (30 x 10'/L), the demands of pregnancy increase the risk of pulmonary hyper pregnancy is not at risk. Patients should receive intravenous tension. with an associated 16'1, mortality risk. Suggestive immune globulin or giucocorticoids at any time during preg- clinical f'eatures (e.g., new exertional dyspnea) should be eval nancy if the platelet count decreases to less than 30,000/pL uated by echocardiography. (30 x 10e/L). The target platelet count for delivery (vaginal or Medications used to control SCD, such as hydroxyurea cesarean section) is 50,000/pL (50 x 10'q/L), and therapy should and chelating agents, must be discontinued during pregnancy. begin approximately l weekbefore the expected delivery date to Painful vaso occlusive crises increase during pregnancy; pain achieve that goal. Neuraxial anesthesia requires a platelet count should be managed with opioid analgesics, and NSAIDs should greater than approximately 80,000/pL (SO x tOn/L). be avoided after the 30th week of gestation to avoid premature ITP autoantibodies can cross the placenta and affect the closure of the fetal patent ductus arteriosus. fetus; 20'1, to 30'1, of neonates are reported to have platelet Pregnant patients with SCD are also at increased risk for counts less than 50,000/pL (50 x 10e/L), especially if an older complications of the pregnancy itself, including intrauterine sibling was born with thrombocytopenia. Neonatal platelet growth restriction, eclampsia, preterm labor, piacental abrup- counts can continue to decrease for 2 to 5 days after delivery. tion, and stillbirth. Fetal thrombocytopenia is not influenced by maternal treat- ment with either glucocorticoids or intravenous immune X EY PO I IITS globulin. Despite the increased likelihood of neonatal throm . Although the use of routine prophylactic transfusion in bocytopenia, the risk of intracerebral hemorrhage is less than pregnant women with sickle cell anemia remains con 1'1, and is unaffected by cesarean section delivery. troversial, transfusions should be given to those with more severe and symptomatic anemia or those who XEY POIt{IS develop additional complications such as acute chest o Differentiating immune thrombocytopenic purpura from syndrome or stroke. gestational thrombocltopenia may be difficult, but sug . Medications used to control sickle cell disease. such as gestive features include earlier presentation (first trimes-

(100 x 10e/L), although platelet counts may reach a nadir of Sickle Cell Disease 70,000/pL (70 x 10'q/L). Patients with gestational thrombocy- The physiologic stresses ofpregnancy are especially challenging topenia have no history of thrombocytopenia, and the platelet fbr women with sickle cell disease (SCD). Folate requirements count does not decrease until late in gestation. The fetus is increase because of the rapid tumover of erythrocytes, requiring unaffected, intervention is unnecessary and platelet counts additional folate supplementation. Iron and vitamin B,, stores spontaneously return to normal after delivery. must also be monitored. Although expert opinion varies, the I National Institutes of Health does not recommend prophylactic XEY POIilI transfusions in pregnancy for women with sickle cell anemia. o Patients with gestational thromboqtopenia have no his- HVC Other experts disagree, suggesting prophylactic transfusion in tory of thrombocytopenia, and because the thrombocy- pregnant women during the third trimester to achieve a hemo- topenia is not severe, without predisposition to bleeding, globin level of9 g/dl (90 g/L) or reserving such transfusions fbr and platelet counts resolve spontaneously, no treatment women with previous fetal loss, frequent acute painful events, or is necessary. history of acute chest syndrome. Frequent transfusions may lead to alloimmunization, increasing the risk of hemo\tic disease of lmmune Thrombocytopenic Purpura I the newbom. Although routine use ot prophylactic transfusion Immune thrombocytopenic purpura (lTP) (see Platelet is debatable, pregnant women with more severe and sympto Disorders) can occur in women of childbearing age and may matic anemia should be transfused as should those with acute manifest during pregnancy. Differentiating ITP from gestational chest syndrome or stroke. Pregnant women with SCD should be thrombocl.topenia may be difficult, but features suggesting ITP monitored closely with monthly complete blood counts. include earlier presentation (first trimester), lower platelet The risk of venous thromboembolism (VTE) is increased, count nadir (<70,000/pL [70 x 10r/L]), and history of thrombo and prophylactic anticoagulation should be administered cytopenia before pregnancy (even il it was only mild). If the in hospitalized patients. The increased cardiopulmonary platelet count remains greater than 30,000/pL (30 x 10'/L), the demands of pregnancy increase the risk of pulmonary hyper pregnancy is not at risk. Patients should receive intravenous tension. with an associated 16'1, mortality risk. Suggestive immune globulin or giucocorticoids at any time during preg- clinical f'eatures (e.g., new exertional dyspnea) should be eval nancy if the platelet count decreases to less than 30,000/pL uated by echocardiography. (30 x 10e/L). The target platelet count for delivery (vaginal or Medications used to control SCD, such as hydroxyurea cesarean section) is 50,000/pL (50 x 10'q/L), and therapy should and chelating agents, must be discontinued during pregnancy. begin approximately l weekbefore the expected delivery date to Painful vaso occlusive crises increase during pregnancy; pain achieve that goal. Neuraxial anesthesia requires a platelet count should be managed with opioid analgesics, and NSAIDs should greater than approximately 80,000/pL (SO x tOn/L). be avoided after the 30th week of gestation to avoid premature ITP autoantibodies can cross the placenta and affect the closure of the fetal patent ductus arteriosus. fetus; 20'1, to 30'1, of neonates are reported to have platelet Pregnant patients with SCD are also at increased risk for counts less than 50,000/pL (50 x 10e/L), especially if an older complications of the pregnancy itself, including intrauterine sibling was born with thrombocytopenia. Neonatal platelet growth restriction, eclampsia, preterm labor, piacental abrup- counts can continue to decrease for 2 to 5 days after delivery. tion, and stillbirth. Fetal thrombocytopenia is not influenced by maternal treat- ment with either glucocorticoids or intravenous immune X EY PO I IITS globulin. Despite the increased likelihood of neonatal throm . Although the use of routine prophylactic transfusion in bocytopenia, the risk of intracerebral hemorrhage is less than pregnant women with sickle cell anemia remains con 1'1, and is unaffected by cesarean section delivery. troversial, transfusions should be given to those with more severe and symptomatic anemia or those who XEY POIt{IS develop additional complications such as acute chest o Differentiating immune thrombocytopenic purpura from syndrome or stroke. gestational thrombocltopenia may be difficult, but sug . Medications used to control sickle cell disease. such as gestive features include earlier presentation (first trimes- hydroxyurea and chelating agents, must be discontinued ter), Iower platelet count nadir (<70,000 l1Ll7o x 10e/Ll),

(100 x 10e/L), although platelet counts may reach a nadir of Sickle Cell Disease 70,000/pL (70 x 10'q/L). Patients with gestational thrombocy- The physiologic stresses ofpregnancy are especially challenging topenia have no history of thrombocytopenia, and the platelet fbr women with sickle cell disease (SCD). Folate requirements count does not decrease until late in gestation. The fetus is increase because of the rapid tumover of erythrocytes, requiring unaffected, intervention is unnecessary and platelet counts additional folate supplementation. Iron and vitamin B,, stores spontaneously return to normal after delivery. must also be monitored. Although expert opinion varies, the I National Institutes of Health does not recommend prophylactic XEY POIilI transfusions in pregnancy for women with sickle cell anemia. o Patients with gestational thromboqtopenia have no his- HVC Other experts disagree, suggesting prophylactic transfusion in tory of thrombocytopenia, and because the thrombocy- pregnant women during the third trimester to achieve a hemo- topenia is not severe, without predisposition to bleeding, globin level of9 g/dl (90 g/L) or reserving such transfusions fbr and platelet counts resolve spontaneously, no treatment women with previous fetal loss, frequent acute painful events, or is necessary. history of acute chest syndrome. Frequent transfusions may lead to alloimmunization, increasing the risk of hemo\tic disease of lmmune Thrombocytopenic Purpura I the newbom. Although routine use ot prophylactic transfusion Immune thrombocytopenic purpura (lTP) (see Platelet is debatable, pregnant women with more severe and sympto Disorders) can occur in women of childbearing age and may matic anemia should be transfused as should those with acute manifest during pregnancy. Differentiating ITP from gestational chest syndrome or stroke. Pregnant women with SCD should be thrombocl.topenia may be difficult, but features suggesting ITP monitored closely with monthly complete blood counts. include earlier presentation (first trimester), lower platelet The risk of venous thromboembolism (VTE) is increased, count nadir (<70,000/pL [70 x 10r/L]), and history of thrombo and prophylactic anticoagulation should be administered cytopenia before pregnancy (even il it was only mild). If the in hospitalized patients. The increased cardiopulmonary platelet count remains greater than 30,000/pL (30 x 10'/L), the demands of pregnancy increase the risk of pulmonary hyper pregnancy is not at risk. Patients should receive intravenous tension. with an associated 16'1, mortality risk. Suggestive immune globulin or giucocorticoids at any time during preg- clinical f'eatures (e.g., new exertional dyspnea) should be eval nancy if the platelet count decreases to less than 30,000/pL uated by echocardiography. (30 x 10e/L). The target platelet count for delivery (vaginal or Medications used to control SCD, such as hydroxyurea cesarean section) is 50,000/pL (50 x 10'q/L), and therapy should and chelating agents, must be discontinued during pregnancy. begin approximately l weekbefore the expected delivery date to Painful vaso occlusive crises increase during pregnancy; pain achieve that goal. Neuraxial anesthesia requires a platelet count should be managed with opioid analgesics, and NSAIDs should greater than approximately 80,000/pL (SO x tOn/L). be avoided after the 30th week of gestation to avoid premature ITP autoantibodies can cross the placenta and affect the closure of the fetal patent ductus arteriosus. fetus; 20'1, to 30'1, of neonates are reported to have platelet Pregnant patients with SCD are also at increased risk for counts less than 50,000/pL (50 x 10e/L), especially if an older complications of the pregnancy itself, including intrauterine sibling was born with thrombocytopenia. Neonatal platelet growth restriction, eclampsia, preterm labor, piacental abrup- counts can continue to decrease for 2 to 5 days after delivery. tion, and stillbirth. Fetal thrombocytopenia is not influenced by maternal treat- ment with either glucocorticoids or intravenous immune X EY PO I IITS globulin. Despite the increased likelihood of neonatal throm . Although the use of routine prophylactic transfusion in bocytopenia, the risk of intracerebral hemorrhage is less than pregnant women with sickle cell anemia remains con 1'1, and is unaffected by cesarean section delivery. troversial, transfusions should be given to those with more severe and symptomatic anemia or those who XEY POIt{IS develop additional complications such as acute chest o Differentiating immune thrombocytopenic purpura from syndrome or stroke. gestational thrombocltopenia may be difficult, but sug . Medications used to control sickle cell disease. such as gestive features include earlier presentation (first trimes- hydroxyurea and chelating agents, must be discontinued ter), Iower platelet count nadir (<70,000 l1Ll7o x 10e/Ll), during pregnancy. and history of thrombocyopenia befbre pregnancy. . Women should receive intravenous immune globulin or glucocorticoids to treat immune thrombocytopenic pur- Thrombocytopenia in Pregnancy pura if the platelet count decreases to less than 30,000/pL (30 x 10'q/L) at any time during the pregnancy as well as Gestationa I Throm bocytopen ia 1 week before delivery to achieve a platelet count of at Gestational thrombocytopenia affects approximately 5'7, of least 50,000/pL (50 x 10e/L) for delivery or 80,000/pL pregnant women. The cause is uncertain. Most patients are (80 x 10'/L) ifneuraxial anesthesia is anticipated. asymptomatic, with platelet counts greater than 100,000/pL

during pregnancy. and history of thrombocyopenia befbre pregnancy. . Women should receive intravenous immune globulin or glucocorticoids to treat immune thrombocytopenic pur- Thrombocytopenia in Pregnancy pura if the platelet count decreases to less than 30,000/pL (30 x 10'q/L) at any time during the pregnancy as well as Gestationa I Throm bocytopen ia 1 week before delivery to achieve a platelet count of at Gestational thrombocytopenia affects approximately 5'7, of least 50,000/pL (50 x 10e/L) for delivery or 80,000/pL pregnant women. The cause is uncertain. Most patients are (80 x 10'/L) ifneuraxial anesthesia is anticipated. asymptomatic, with platelet counts greater than 100,000/pL 63