Women and Thrombosis Ahmad Shihada Silmi Msc, FIBMS Staff Specialist in Hematology Medical Technology Department Islamic University of Gaza 2012

Thromboembolic Disease Venous system Deep venous thrombosis Pulmonary embolism Arterial system Stroke Myocardial infarction

Widely Known Risk Factors for Venous Thromboembolism (VTE) Age Surgery or trauma Immobilization Cancer or myeloproliferative disorder Pregnancy Hormonal therapy Increased body mass index > 24 kg/m 2 History of idiopathic thrombosis

Thrombophilia the tendency to thrombosis

Thrombophilic Syndromes Inherited thrombophilia Protein C and S deficiency Antithrombin deficiency Dysfibrinogenemia Factor V Leiden mutation Prothrombin mutation mutation in methylenetetrahydrofolate reductase (MTHFR) Acquired or mixed thrombophilia Hyperhomocysteinemia Antiphospholipid syndrome High levels of factors VIII, IX, XI, TAFI

Inherited Thrombophilia Recurrent or life-threatening VTE Family history of VTE Age less than 45 at presentation No acquired risk factors (surgery, trauma, immobilization, cancer, myeloproliferative disorder, pregnancy, hormonal therapy) History of multiple miscarriages or stillbirths

Associated with: Recurrent miscarriage Pre eclampsia IUGR Placental abruption Still birth

three important inherited thrombophilias : mutation in factor V causing Resistance to activated protein C (responsible of 20–30% of venous thromboembolism events.) mutation in prothrombin (guanine adenine ) mutation in methylenetetrahydrofolate reductase (MTHFR) (cytosine 677 thymine (C677T) ) The mutation is responsible for reduced MTHFR activity and is the most frequent cause of mild hyperhomocysteinemia and can be found in 5–15% of the population. Inherited Thrombophilia

A high rate of protein S deficiency, APCR, hyperhomocysteinemia and aCL IgG or IgM was found in women with severe preeclampsia. Dekker et al Am J Obstet Gynecol 1995

higher prevalence of FV Leiden mutation in women with severe preeclampsia compared to controls. Nagy et al Clin genet 1998

120 women with severe preeclampsia, (72% nulliparous) and 101 healthy matched for age and parity. 18.3% of preeclamptic women were carriers of the FV Leiden mutation compared to 3% in controls. Rigo et al Hypertens Pregnancy 2000

110 healthy women who had during pregnancy severe preeclampsia, IUGR, severe abruptio placentae and stillbirth were enrolled in the study. The control group comprised 110 healthy matched women with normal pregnancies. All 220 patients were tested for all known thrombophilias at least 2 months after delivery. The total prevalence of all thrombophilias detected in the 110 women with complications was 65% compared to 18% in controls. Kupferminc et al N Eng J Med 1999

in USA tested the genetic thrombophilic mutations in 110 women with severe preeclampsia and 97 controls. Most women were nulliparous and 60% of them were African Americans. No difference was found in the prevalence of thrombophilias between the women with severe preeclampsia and control women groups, or in fetal genetic thrombophilias. Livingstone et al Am J Obstet Gynecol 2001

tested 113 nulliparous women with preeclampsia: 100 with severe disease, 13 with mild disease and 103 controls for the C677T polymorphism of the MTHFR gene. No difference in homozygosity for MTHFR was found between the 2 groups (preeclampsia 3% vs controls 6%) Laivuori et al in Finland Obstet Gynecol 2000,

factor V Leiden(A506G) mutation adenine 506 guanine (A506G) mutation in factor V (factor V Leiden) (a substitution of glutamine for arginine at amino acid 506 of factor V) Factor V Leiden (FVL) is a mutation in the factor V molecule, rendering it resistant to cleavage by activated protein C. Factor V remains a procoagulant and thus predisposes the carrier to clot formation. It has been linked with an increased risk for venous thromboembolism due to Resistance to activated protein C and is responsible of 20–30% of venous thromboembolism events

The Factor V Leiden (FVL) mutation, present in 3- 8% of the general population, leads to less than normal anticoagulant response to activated protein C resulting in an increased risk for venous thrombosis. Individuals with one copy of the FVL gene mutation (heterozygotes) have a seven fold increased risk for thrombosis compared to the general population whereas homozygotes have an eighty fold increase. factor V Leiden (A506G) mutation

prothrombin (G20210A) mutation A change of G to A at position in prothrombin (prothrombin 20210A) elevates baseline prothrombin levels and thrombin formation.

MTHFR (C677T) mutation cytosine 677 thymine (C677T) mutation (a C to T change at position 677 of MTHFR) is responsible for reduced MTHFR activity results in decreased synthesis of 5-methyltetrahydrofolate, the primary methyl donor in the conversion of homocysteine to methionine and the resulting increase in plasma homocysteine concentrations ( Hyperhomocysteinemia ) is a risk factor for thrombosis Dietary restriction of folate and vitamin B12 remains the most common cause.

A homozygous methylenetetrahydrofolate reductase (MTHFR) mutation, present in 1- 4% of the general population, is associated with a three fold increased risk for DVT or PE, as well as preeclampsia and placental abruption. MTHFR (C677T) mutation

Protein S deficiency Protein S deficiency (PSD), present in up to 2% of the general population, is found in approximately 15% of individuals with a DVT or PE and 6% of women with obstetrical complications including a relatively high risk for stillbirth.

Protein C deficiency Protein C deficiency (PCD), present in about 1.5% of the general population, is associated with a lower risk for obstetrical complications than PSD and is found in 3-5% of individuals with a DVT or PE. Furthermore, PCD combined with a FVL mutation is a relatively common cause of DVTs and show a higher risk for thrombosis compared to FVL alone.

Antithrombin III deficiency Antithrombin III deficiency (ATIII), present in less than 0.5 % of the general population, as with PSD and PCD, may rarely result from mutational events Because of its relative rarity, actual risks for thrombotic events are difficult to estimate, but without question this entity contributes to thrombotic risks during pregnancy.

Hyperhomocysteinemia Amino acid formed during conversion of methionine to cysteine Induces endothelial cell desquamation, oxidizes LDL, promotes monocyte adhesion and thrombin generation Either congenital or acquired Risk factor for CAD, PVD, CVD, VTE

Oral Contraceptives and Thrombosis Thromboembolic disease described soon after introduction in early 1960’s Deep venous thrombosis Pulmonary embolism Stroke (ischemic, hemorrhagic) Myocardial infarction

Procoagulant Effects of OCP Increased levels of factor VII, factor VIII, factor X, prothrombin, and fibrinogen Decreased levels of protein S and antithrombin Decreased levels of factor V (cofactor in inactivation of FVIIIa mediated by APC) Acquired resistance to activated protein C

Fibrinolytic Effects of OCP Increased fibrinolytic activity Increased levels of thrombin-activatable fibrinolysis inhibitor (TAFI) Removes lysine residues from fibrin needed for binding and activation of plasminogen Elevated levels a risk factor for VTE Overall clot-lysis time unchanged

Risk of VTE with Thrombophilia and OCP Use Protein C and S, or antithrombin deficiency: 6- to 8-fold increase over baseline Prothrombin 20210: 4- to 8-fold increase over baseline High factor VIII levels: 2-fold increase over baseline

Screening for Factor V Leiden Mutation Not cost effective Adverse psychological and insurance effects 8000 Screened 400 FVL 1 DVT More than 500,000 women would need to be screened to prevent 1 death from PE

Screening for Factor V Leiden Mutation ? Selective screening of patients with 1st and 2nd degree relatives with VTE Sensitivity 16% Positive predictive value 9% BMJ 2001; 322:1024-5

Oral Contraceptives and MI Risk of myocardial infarction doubled by current OCP use 3/100,000 woman-years Low-dose estrogens carry lower risk Third-generation OCP may be safer (wide confidence interval) Other risk factors play a major role – smoking, HTN, DM, hypercholesterolemia, obesity NEJM ‘01;345:

Cerebral Vein Thrombosis Potential causes – postpartum, infection, oral contraceptives, thrombophilias Factor V Leiden and prothrombin mutations play major role, especially in association with OCP use Relative risk with OCP alone13-22 Relative risk with OCP + PT Relative risk with OCP + other thrombophilia30 BMJ ‘98;316: NEJM ‘98; 338:1793-7

Pregnancy and Thrombosis Venous thromboembolism (VTE) Placental infarction Miscarriage Intrauterine growth retardation Pre-eclampsia Abruption Intrauterine death

Pregnancy and Risk of VTE 0.5-3/1000 pregnancies Most common cause of maternal mortality (2.1/100,000 live births or 11% of maternal deaths) Incidence same for all trimesters? Incidence 5- to 10-fold higher after Cesarean section than vaginal delivery Greatest for left leg (90% vs. 10%) and iliofemoral veins

Pregnancy and Virchow’s Triad Hypercoagulability Increased fibrinogen, factor VIII Acquired resistance to APC Decreased protein S Increased plasminogen activator inhibitor Platelet activation Venous stasis Progesterone-related increase in venous capacitance IVC compression by gravid uterus Vascular damage

Pregnancy and VTE Acquired Antiphospholipid antibody syndrome % develop VTE Hereditary Antithrombin deficiency - 50% Protein C deficiency % antepartum, 7-19% postpartum Protein S deficiency - 0-6% antepartum, 7-22% postpartum Factor V Leiden mutation – 2-6% heterozygotes, 17% homozygotes Prothrombin mutation Double heterozygote – 4-20% Br J Haematol ’01;113(2):553-5 Haematologica ’01;86(12): Thromb Haemost ’01;86(3):800-3

Pregnancy and Thrombophilia ThrombophiliaRisk of VTE AT III++++ FVL + PT FVL 2/2+++ PT /2+++ FVL 1/2++ PT /2++ Prot S++ Prot C++ MTHFR+ OB/Gyn Clin ‘01; 28:1-17

Pregnancy and VTE Prophylaxis No data on primary prophylaxis in women with known thrombophilia and no history of VTE Do need secondary prophylaxis in women with documented thrombophilia and VTE in a prior pregnancy No need for secondary prophylaxis in women without thrombophilia and a single episode of VTE in a prior pregnancy

Anticoagulation During Pregnancy ASA - safe in low doses ( mg/day) UFH LMWH - less HIT and osteoporosis Heparin-like agents (danaparoid, fondaparinux) Coumarin derivatives – cross placenta Bleeding Teratogenicity – 1 st trimester nasal hypoplasia and stippled epiphyses, any trimester CNS abnormalities Direct thrombin inhibitors – cross placenta

Thrombophilia and Pregnancy Loss 1 st Trimester (failure of implantation) Antiphospholipid antibody syndrome Hyperhomocysteinemia 2 nd Trimester (placental thrombosis) Factor V Leiden mutation Prothrombin gene mutation Stillbirth (IUGR, preeclampsia, abruption) Antithrombin, protein C, or protein S deficiency Hyperhomocysteinemia Factor V Leiden mutation Prothrombin gene mutation

Prophylaxis of Pregnancy Loss Antiphospholipid antibody syndrome – low-dose aspirin + LMWH Hyperhomocysteinemia – supplementation with folic acid, vitamin B12, and vitamin B6 Congenital thrombophilias – unknown if antithrombotic therapy beneficial but small uncontrolled trials have resulted in higher gestational ages and birth weights

Antiphospholipid Antibody Syndrome and Pregnancy Increased risk of both VTE and pregnancy loss Primary prophylaxis - ? surveillance vs. UFH/LMWH Secondary prophylaxis ASA + prednisone of no benefit ASA + heparin > ASA alone

Pregnancy and Prosthetic Heart Valves Commonly used approaches Warfarin throughout UFH from 6-12 weeks, warfarin otherwise except near delivery UFH throughout ? LMWH

Chan et al Review of prospective and retrospective cohort studies

LMWH for Heart Valve Prophylaxis During Pregnancy Combined case reports of 15 patients 12 delivered at term 3 fetal deaths 0 thromboembolic complications

Dosing of LMWH During Pregnancy Two options for therapeutic dosing: Change dose in proportion to weight change Check anti-Xa level weekly 4 hours after morning injection, adjust to keep U/mL Dalteparin 5000 U or enoxaparin 40 mg SQ once daily for DVT prophylaxis Discontinue 24 hours prior to elective induction of labor

Anticoagulation When Breast Feeding Heparin and LMWH – not secreted into breast milk Warfarin – does not induce an anticoagulant effect in the breast-fed infant

Effect of Estrogen on CV System 1.Increases vasodilatation  Smooth muscle relaxation occurs within 5-20 minutes (nongenomic)  Ca-activated K channels opened through NO- and cGMP-dependent pathways  NO released after activation of NO synthase  Increased expression of prostacyclin synthase and NO synthase (genomic) NEJM ‘99; 340:

Effect of Estrogen on CV System 2. Inhibits response of blood vessels to injury  Accelerated endothelial growth due to inc’d expression of VEGF  Inhibition of migration and proliferation of smooth muscle 3. Inhibits development of atherosclerosis  Decreases total cholesterol, LDL, serum Lp(a) lipoprotein  Increases HDL, triglyceride NEJM ‘99; 340:

Effect of Estrogen on Coagulation Procoagulant Effects Increased factor VII levels and APC resistance Decreased levels of protein S and antithrombin III Anticoagulant Effects Decreased fibrinogen Decreased PAI-1 NEJM ‘99; 340:

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