Management thrombophilia

introduction Twenty percent of maternal deaths in the United States during that period were attributed to PE. Inherited thrombophilias are associated with an increased risk of venous thromboembolism.thromboembolism Since thrombophilias are a common and important risk factor for VTE in pregnancy, the obstetrician must be familiar with appropriate screening for thrombophilia disorders and the management of thrombophilias. The most important risk factor for a women experiencing pregnancy- related VTE is prior personal history of VTE. The second most common risk factor is thrombophilia, [12, 13, 14] which is present in 8%-15% of whites.

Obstetrical complications  Spontaneous abortion, fetal loss and stillbirth  Fetal growth restriction  Preeclampsia  Abruption The association between inherited thrombophilias and adverse obstetric outcomes such as RPL, preeclampsia, abruption, intrauterine fetal growth restriction (IUGR), and intrauterine fetal demise (IUFD) is controversial. Available evidence that suggests an association between inherited thrombophilias and adverse pregnancy outcomes rest on small case-control studies heterozygous factor V Leiden and prothrombin mutations may be associated with an approximately twofold risk of miscarriage, IUFD, preeclampsia, and a 4- to 8-fold risk of abruption.

In contrast, an association between antiphospholipid antibody syndrome and adverse pregnancy outcomes has been shown.antiphospholipid antibody syndrome Furthermore, evidence supports the use of antithrombotic therapy with low-dose aspirin and heparin in decreasing the risk of early pregnancy loss in women with lupus anticoagulant and antiphospholipid antibodies. Antiphospholipid antibody syndrome is considered an acquired thrombophilia and is diagnosed based on clinical history and laboratory testing.

Who should be test?

The American College of Obstetricians and Gynecologists (ACOG) suggests screening for thrombophilia when the results will affect pregnancy/postpartum management, and suggests avoiding screening when treatment is indicated because of patient-specific risk factors 1.in women with history of VTE associated with a non recurrent risk factor, such as femoral fracture, surgery, or prolonged immobilization, 2. Testing is also reasonable in asymptomatic (no prior VTE) women planning a pregnancy who have a first degree relative with a history of a high-risk thrombophilia

When to test?

Ideally, laboratory testing is performed remote (at least six weeks) from the thrombotic event while the patient is not pregnant not taking an anticoagulant or hormonal therapy, for the following reasons : Heparin induces a decline in AT levels and warfarin decreases protein C and protein S concentrationswarfarin The levels of free and total protein S are significantly reduced in normal pregnancy Pregnancy is associated with increased resistance to activated protein C (APC) in "first generation" coagulation assays, due to increased factor VIII levels and decreased protein S levels. Screening for inherited thrombophilias should include evaluation for FVL mutation, Prothrombin G20210A mutation, and AT, protein C, and protein S deficiencies

INHERITED THROMBOPHILIAS  Factor V Leiden  Prothrombin mutation  Protein S deficiency  Protein C deficiency  AT III deficiency  PAI – 1  MTHFR mutation

Anticoagulation should ideally be initiated in the first trimester since the risk of VTE increases early in pregnancy. Anticoagulation should be discontinued at onset of labor or before scheduled induction or cesarean delivery to minimize risk of hemorrhagic complications, including those related to placement of neuraxial anesthesia; timing depends on the type and dose of anticoagulant.

high-risk thrombophilias lower-risk thrombophilias  Homozygous factor V Leiden  Homozygous prothrombin G20210A mutation  Compound heterozygous factor V Leiden with prothrombin mutation  Antithrombin deficiency Heterozygous factor V Leiden Heterozygous prothrombin G20210A mutation Protein S deficiency Protein C deficiency

We use the following terminology to describe heparin anticoagulation dosing: Prophylactic dose anticoagulation refers to the use of low doses of anticoagulants, which aims to reduce the risk of thromboembolism while minimizing bleeding complications. ● Intermediate dose anticoagulation refers to the adjustment of prophylactic dose anticoagulation with weight gain during pregnancy. ● Therapeutic dose anticoagulation refers to the use of anticoagulants at doses typically reserved for treatment of thromboembolic disease. Despite the nomenclature, therapeutic dosing may be used prophylactically (ie, to prevent thromboembolism in the setting of severe thrombophilias, mechanical heart valves and other high risk situations). For LMW heparin, therapeutic dosing is based on weight and anti-factor Xa levels. For unfractionated heparin, therapeutic dosing is titrated to keep the activated partial thromboplastin time in the therapeutic range (eg, 1.5 to 2.5 times baseline).

Clinical setting Antepartum management Postpartum management Lower-risk thrombophilia* without personal history of VTE Surveillance for VTE without anticoagulation therapy. Anticoagulation may be warranted for individual patients with additional factors that place them at greater risk of thrombosis (eg, prolonged immobility, first degree relative with unprovoked VTE at age <50 years). Postpartum anticoagulation for women who deliver by cesarean Prophylactic dose

Clinical setting Antepartum management Postpartum management Lower-risk thrombophilia* with personal history of previous VTE Anticoagulation therapy Prophylactic or intermediate-dose LMWH/UFH Postpartum anticoagulation therapy or intermediate-dose LMWH/UFH Heterozygous factor V Leiden Heterozygous prothrombin G20210A mutation Protein S deficiency Protein C deficiency

Clinical setting Antepartum management Postpartum management Higher-risk thrombophilia with or without previous VTE Anticoagulation therapy Prophylactic, intermediate- dose, or adjusted- dose LMWH/UFH regimen Postpartum anticoagulation therapy, or intermediate or adjusted-dose LMWH/UFH for six weeks (therapy level should be at least as high as antepartum treatment)

Management typeDosage Prophylactic LMWH* Enoxaparin, 40 mg SC once daily Dalteparin, 5000 units SC once daily Tinzaparin, 4500 units SC once daily Therapeutic LMWH (Also referred to as weight-adjusted, full- treatment dose ) Enoxaparin, 1 mg/kg every 12 hours Dalteparin, 200 units/kg once daily Tinzaparin, 175 units/kg once daily Dalteparin, 100 units/kg every 12 hours

Minidose prophylactic UFH UFH, 5000 units SC every 12 hours Prophylactic UFH UFH, 5000 to 10,000 units SC every 12 hours UFH, 5000 to 7500 units SC every 12 hours in first trimester UFH, 7500 to 10,000 units SC every 12 hours in the second trimester UFH, 10,000 units SC every 12 hours in the third trimester, unless the aPTT is elevated Therapeutic UFH (Also referred to as weight- adjusted, full-treatment dose) UFH, 10,000 units or more SC every 12 hours in doses adjusted to target aPTT in the therapeutic range (1.5 to 2.5) six hours after injection

Postpartum anticoagulation Prophylactic LMWH/UFH for four to six weeks OR Vitamin K antagonists for four to six weeks with a target INR of 2.0 to 3.0, with initial UFH or LMWH therapy overlap until the INR is 2.0 or more for two days

Fetal surveillance and timing of delivery we suggest weekly fetal assessment with nonstress tests beginning at ≥36 weeks of gestation delivery at 39 weeks of gestation in the absence of an obstetrical complication such as preeclampsia, abruption, or fetal growth restriction. For women who have been anticoagulated, heparin should be discontinued before scheduled delivery. If obstetrical complications are present, fetal surveillance should be initiated earlier and delivery timed to optimize maternal and neonatal outcomes.

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