Women and Thrombosis

Ahmad Shihada Silmi Msc, FIBMSStaff Specialist in Hematology

Medical Technology DepartmentIslamic 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/m2

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 20210 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 20210 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 20210 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;345:1787-93

Cerebral Vein Thrombosis Potential causes – postpartum, infection,

oral contraceptives, thrombophilias Factor V Leiden and prothrombin 21210

mutations play major role, especially in association with OCP useRelative risk with OCP alone 13-22

Relative risk with OCP + PT 21210 150

Relative risk with OCP + other thrombophilia 30

BMJ ‘98;316:589-92NEJM ‘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 VTEAcquired Antiphospholipid antibody syndrome - 5-22% develop VTE

Hereditary Antithrombin deficiency - 50% Protein C deficiency - 3-10% antepartum, 7-19% postpartum Protein S deficiency - 0-6% antepartum, 7-22% postpartum Factor V Leiden mutation – 2-6% heterozygotes, 17% homozygotes Prothrombin 20210 mutation Double heterozygote – 4-20%

Br J Haematol ’01;113(2):553-5Haematologica ’01;86(12):1305-9Thromb Haemost ’01;86(3):800-3

Pregnancy and Thrombophilia

Thrombophilia Risk of VTE

AT III ++++

FVL + PT 20210 ++++

FVL 2/2 +++

PT 20210 2/2 +++

FVL 1/2 ++

PT 20210 1/2 ++

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 (60-150 mg/day) UFH LMWH - less HIT and osteoporosis Heparin-like agents (danaparoid, fondaparinux) Coumarin derivatives – cross placenta

Bleeding Teratogenicity – 1st trimester nasal hypoplasia and

stippled epiphyses, any trimester CNS abnormalities

Direct thrombin inhibitors – cross placenta

Thrombophilia and Pregnancy Loss 1st Trimester (failure of implantation)

Antiphospholipid antibody syndrome Hyperhomocysteinemia

2nd Trimester (placental thrombosis) Factor V Leiden mutation Prothrombin 20210 gene mutation

Stillbirth (IUGR, preeclampsia, abruption) Antithrombin, protein C, or protein S deficiency Hyperhomocysteinemia Factor V Leiden mutation Prothrombin 20210 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. 2000Review of prospective and retrospective cohort studies

0.00%

5.00%

10.00%

15.00%

20.00%

25.00%

30.00%

35.00%

Abortions Anomalies TEC Death

WarfarinBothHeparinNothing

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 0.5-1.2 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; 340:1801-11

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; 340:1801-11

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; 340:1801-11

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