Risk of Venous Thrombosis

Risk of Venous Thrombosis

INHERITED THROMBOPHILIA Procoagulant Antifibrinolytic Anticoagulant Profibrinolytic Procoagulant Antifibrinolytic Anticoagulant Profibrinolytic There Are Five Proven Independent Genetic Risk Factors for VTE 4 are defects in physiologic anticoagulant pathways Antithrombin deficiency Protein C deficiency

Protein S deficiency Factor V Leiden 1 causes increased production of procoagulant Prothrombin G20210A gene mutation Many other genes affect coagulation the relative contributions of mutations in these genes to thrombotic risk are unknown FACTOR V LEIDEN A highly prevalent inherited risk factor for thrombosis Polymorphism eliminates a preferred protein C cleavage site, slows inactivation of factor Va by protein C Factor Va procoagulant activity not affected Not a deficiency

Same genotype responsible for all cases Diagnosed by DNA testing Very common About 5% of US population heterozygous, 0.05% homozygous High allele frequency implies evolutionary advantage FACTOR V LEIDEN Prevalence in different ethnic groups Group Allele

frequency Heterozygote frequency Homozygote frequency European 4.4% 8.6% 0.2% Asia Minor 0.6

1.2 0.004 African 0 0 0 SE Asian 0 0

0 Native American 0 0 0 Lancet 1995;346:1133 PROTHROMBIN G20210A GENE POLYMORPHISM Polymorphism in 3' untranslated (noncoding) part of prothrombin gene No effect on prothrombin structure or function Heterozygotes have 5-10% higher plasma levels of prothrombin, 2-3 fold relative risk

of venous thromboembolism About 1-2% of population heterozygous Diagnosis: DNA testing THROMBOPHILIA DUE TO DEFICIENCY OF ANTICOAGULANT PROTEIN Antithrombin, Protein C, Protein S Typically 30-60% of normal plasma activity of affected protein Dominant inheritance Genetically heterogeneous Thrombotic risk differs with different mutations Together account for approximately 10-15% of

cases of inherited thrombophilia Plasma levels of anticoagulant proteins are poor predictors of inherited deficiency Likelihood that a gene mutation is present if measured protein activity is 50% of normal: Antithrombin = 75% Protein C =60% Protein S = 25% Thromb Haemost 2012; 108: 247 Genetic testing for thrombophilia INHERITED THROMBOPHILIA Clinical Features Venous thromboembolism Much

less evidence for increased risk of arterial thrombosis Onset often in 20s and 30s About half of VTE episodes unprovoked Increased risk of pregnancy loss Thrombotic risk varies with type of thrombophilia Proportion of individuals from thrombophilic families who have an episode of VTE by age 50: Protein C, protein S or antithrombin deficiency: 40-50% Factor V Leiden or prothrombin polymorphism: 10-15% AT PC

PS FVL PT Blood 2009;113:5314 Relative risk of VTE in individuals with low plasma protein S vs known protein S mutation Low plasma protein S (general population) Protein S mutation in thrombophilic family Relative risk of

thrombosis 95% CI 0.7 0.3-1.8 11.5 4.3-30.6 Family history and (if possible) genotype should be taken into account when interpreting the results of thrombophilia testing Koster et al, Blood 1995;85:2756 Simmonds et al, Ann Intern Med 1998;128:8

0.6 0.6 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2

0.1 0.1 0 0 # Prothrombotic Alleles Risk of VTE N (% population) VTE is a multigenic disease EFFECT OF GENE DOSE Relative risk of thrombosis in heterozygous

and homozygous factor V Leiden Genotype Relative Risk Normal 1 Heterozygous 7 Homozygous 80 Rosendaal et al, Blood 1995;85:1504

Homozygotes have more severe disease Antithrombin III deficiency PHENOTYPE IN HOMOZYGOTES lethal? Protein C deficiency neonatal purpural fulminans Protein S deficiency neonatal purpural fulminans (? - rare) FVL Prothrombin mutation

Premature thrombosis in many (most?) - some asymptomatic CONDITION HOMOZYGOUS PROTEIN C DEFICIENCY WITH NEONATAL PURPURA FULMINANS Mutations have additive effects Co-inheritance of protein C deficiency and factor V Leiden within a family Gene Mutation Thrombosis present Thrombosis absent (%) (%)

Protein C and Factor V 16 (73) 6 (27) Protein C 5 (31) 11 (69) Factor V 2 (13) 11 (87)

None 0 11 (100) Koeleman et al, Blood 1994;84:1031 Genetic and acquired risk are additive 0.6 Genetic Risk 0.6 0.5 0.5

0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0 0

# Prothrombotic Alleles Risk of VTE N (% population) Genetic + Acquired Risk FACTOR V LEIDEN + ORAL CONTRACEPTIVE RISK FACTOR RELATIVE RISK OF THROMBOSIS Oral contraceptive 4

Factor V Leiden 8 Both 35 Vandenbroucke et al, Lancet 1994;344:1453 FACTOR V LEIDEN + ESTROGEN REPLACEMENT RISK FACTOR RELATIVE RISK OF THROMBOSIS Estrogen replacement

3.5 Factor V Leiden 4.6 Both 11 Rosendaal, 2001 IS THE MANAGEMENT OF PATIENTS WITH VTE AFFECTED BY THE RESULTS OF THROMBOPHILIA TESTING? The risk of recurrent venous thromboembolism is higher

in patients with idiopathic events Lancet 2003; 362: 52326 Idiopathic VTE Other risk factor Postop VTE The risk of recurrent VTE is not significantly affected by the presence of inherited thrombophilia Lancet 2003; 362: 52326 Hazard ratio 1.50 (95% CI = 0.82-2.77) p=0.187 The presence of inherited thrombophilia does not usually affect treatment of patients with VTE

Idiopathic VTE is a strong independent predictor of recurrence risk, and so is a potential indication for long-term anticoagulation The presence of inherited thrombophilia is not a good predictor of VTE recurrence risk and so should not generally be used as the basis for prolonging therapy Warfarin-induced skin necrosis in a protein C-deficient patient Compound heterozygote for FVL and protein C deficiency Day 5 of warfarin treatment, on heparin


THE ABSOLUTE RISK OF VENOUS EVENTS IN ASYMPTOMATIC RELATIVES OF THROMBOPHILIC PATIENTS IS LOW Vossen et al, J Thrombos Haemost 2005;3:459 Bleeding risk with long term anticoagulation estimated at 1-3%/year Laboratory evidence of thrombophilia does not predict thrombotic risk in the absence of a family hx of VTE Event in proband leading to diagnosis of thrombophilia Incidence of VTE in relatives per 1000 patient-yrs (95% CI) Carriers Non-carriers

VTE 1.6 (1.2-2.2) 0.5 (0.3-1.0) Arterial thrombosis 0.5 (0.1-2.8) 0.8 (0.2-3.0) Obstetric complication 0.6 (0.2-1.6) 0.0 (0-0.8) Asymptomatic

0.3 (0.1-1.2) 0.0 (0-0.7) Thromb Haemost 2011;106:646 INCIDENCE OF FIRST VTE EVENTS IN SPECIFIC RISK SITUATIONS IN THROMBOPHILIC INDIVIDUALS Vossen et al, J Thrombos Haemost 2005;3:459 THROMBOPHILIC INDIVIDUALS CONTROLS Travel > 8h 0% (0/504)

0% (0/1244) Surgery or immobilization > 2 w 2% (3/176) 0.04% (2/407) Plaster cast 0% (0/33) 0% (0/71) Cancer 10% (1/10)

6% (1/17) Pregnancy 7% (2/28) 0% (0/75) RISK SITUATION Analysis restricted to individuals not given prophylaxis INCREASED RISK OF FETAL LOSS IN WOMEN WITH HERITABLE THROMBOPHILIA European Prospective Cohort on Thrombophilia (1384 women) Lancet 1996;348:913 CONDITION


1.0-2.8 PROTEIN C DEFICIENCY 2.3 0.6-8.3 1.4 0.9-2.2 PROTEIN S DEFICIENCY 3.3 1.0-11.3

1.2 0.7-1.9 FACTOR V LEIDEN 2 0.5-7.7 0.9 0.5-1.5 COMBINED DEFECTS 14.3

2.4-86.0 0.8 0.2-3.6 ALL THROMBOPHILIA 3.6 1.4-9.4 1.27 0.94-1.71 BUT There is no evidence that

anticoagulant (LMWH) or antiplatelet (ASA) prophylaxis improves pregnancy outcomes in women with inherited thrombophilia WHO TO TEST? Inherited thrombophilia is more likely if a patient with VTE Is young Has a family history of VTE Had unprovoked VTE Had warfarin-induced skin necrosis (protein C)

Acute thrombosis and antithrombotic therapy may affect blood levels of AT, PC, PS Testing should be done only if the result will affect patient management Is there benefit to testing family members of a thrombophilic patient? Negative tests do not rule out genetic risk Positive test may create undue anxiety or lead to inappropriate intervention by physicians Chronic anticoagulation not warranted in asymptomatic individuals who test positive Testing may be warranted in families with a thrombotic phenotype and high-risk thrombophilia (AT, PC, PS) Family history predicts thrombotic risk just as well

as laboratory testing for thrombophilia A case-control study Fam Hx VTE Odds ratio for thrombosis (95% CI) Negative 1 (reference) Any relative 2.2 (1.9-2.6) Relative < 50 2.7 (2.2-3.4)

> 1 Relative 3.9 (2.7-5.7) Event OR for event with positive FH OR for event with positive test for thrombophilia Unprovoked VTE 2.5 2.3


Condom 1st VTE/100 pregancy-yr 0.55 0.25 0.25 0.25 VTE/100,000 pregnancy-yr 550 250

250 250 Unintended pregnancies/ 100,000 p-y 200 700 1400 12,000 Additional cases of VTE

6 20 40 336 Total # VTE 556 270 290 586

Blood 2011;118:2055 ACQUIRED THROMBOPHILIA Antiphospholipid syndrome Hyperhomocysteinemia (may be inherited) Inflammatory bowel disease Cancer Nephrotic syndrome Myeloproliferative disorders Pregnancy Oral contraceptive/estrogen Hyperviscosity HOMOCYSTEINE CAUSES OF HYPERHOMOCYSTEINEMIA SEVERE (plasma levels 5-10 x normal) homozygous cystathione beta-synthase deficiency

(1:250,000) homozygous methylenetetrahydrofolate reductase deficiency MILD OR MODERATE heterozygous CBS deficiency (0.3-1.4% of population) C677T polymorphism in MTHFR (10% of population homogyzous) B12, folate or B6 deficiency Aging Chronic renal failure HIGHER HOMOCYSTEINE LEVELS ARE ASSOCIATED WITH VASCULAR RISK Meta-analysis Condition Increase in risk per 5 micromole increase in plasma HC (95% CI)

Ischemic heart disease 1.32 (1.19-1.45) Stroke 1.59 (1.29-1.96) VTE 1.60 (1.15-2.22) BMJ 2002;325:1202 BUT LOWERING HOMOCYSTEINE DOES NOT DECREASE VASCULAR RISK

VISP trial (JAMA 2004): Moderate reduction in HC had no effect on vascular risk during 2 yr followup HOPE 2 trial (NEJM 2006): Vitamin supplements lowered HC levels but had no effect on vascular risk NORVIT trial (NEJM 2006): More aggressive vitamin supplementation associated with increased vascular risk VITRO study (Blood 2007): Lowering HC did not prevent recurrent VTE Note these studies did not include individuals with very high plasma HC levels Is testing for MTHFR mutations useful?

Very common C677T polymorphism in MTHFR associated with modest elevations in homocysteine in some individuals Several studies have shown that this MTHFR mutation is NOT an independent risk factor for thrombosis NOT USEFUL Antiphospholipid Syndrome Antiphospholipid Antibodies Lupus anticoagulant Cardiolipin antibodies (IgG, IgM) Beta-2 glycoprotein I antibodies (IgG, IgM) Thrombotic risk associated with higher

antibody levels, positive tests for more than one type of antibody Triple positive patients appear to be at highest risk Who has antiphospholipid antibodies? PATIENT GROUP ANTIBODY TYPE APPROX INCIDENCE SLE LAC 30%

SLE aCL 40% Blood donors aCL 2% Healthy elderly aCL 52% Love and Santoro, Ann Intern Med 1990

Antiphospholipid syndrome Persistent positive tests for antiphospholipid antibodies Thrombosis (arterial and venous) often recurrent Recurrent fetal loss Hematologic abnormalities: Immune thrombocytopenia Immune hemolytic anemia Arthritis & Rheumatism 2002;46:1019-27 ANTIPHOSPHOLIPID SYNDROME CLINICAL CRITERIA

1. One or more documented episodes of arterial, venous, or small vessel thrombosis (other than superficial venous thrombosis) in any tissue or organ 2. Thrombosis must be confirmed by objective validated criteria For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall Pregnancy morbidity a. b. c.

One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus, or One or more premature births of a morphologically normal neonate before the 34th week of gestation because of: (i) eclampsia or severe pre-eclampsia defined according to standard definitions, or (ii) recognized features of placental insufficiency, or Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded J Thromb Haemost 2006;4:295 ANTIPHOSPHOLIPID SYNDROME LABORATORY CRITERIA 1. 2.

3. Lupus anticoagulant (LAC) present in plasma, on two or more occasions at least 12 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Haemostasis (Scientific Subcommittee on LACs/phospholipid- dependent antibodies) Anticardiolipin antibody (aCL) of IgG and/or IgM isotype in serum or plasma, present in medium or high titer (i.e., > 40 GPL or MPL, or > the 99th percentile), on two or more occasions at least 12 weeks apart, measured by a standardized ELISA Anti-2 glycoprotein-I antibody of IgG and/or IgM isotype in serum or plasma (in titer >the 99th percentile), present on two or more occasions at least 12 weeks apart, measured by a standardized ELISA, according to recommended procedures APL syndrome considered present if at least one of the clinical and one of the laboratory criteria are present

J Thromb Haemost 2006;4:295 Treatment of Patients with Antiphospholipid Antibodies Asymptomatic: no treatment (risk of thrombosis < 1%/yr) History of thrombosis: Consider prolonged treatment in selected patients Recurrent or unprovoked thrombosis (arterial or venous) All 3 APL antibody tests strongly positive Most patients can be treated with standard anticoagulant regimen (heparin/LMWH warfarin) Target INR 2-3 recommended: Two RCTs have shown inferior outcomes with high intensity warfarin treatment A few patients exhibit warfarin failure consider long term LMWH treatment (no data yet on newer oral anticoagulants)

DOACs not well-studied in this setting Although a positive APLA test appears to predict an increased risk of recurrence in patients with a first VTE, the strength of this association is uncertain because the available evidence is of very low quality Blood 2013;122:817-824 TRAPS Trial: Rivaroxaban In High Risk Antiphospholipid Syndrome Patients with thrombosis and triple positive APS randomized to warfarin or rivaroxaban (standard dosing) Trial stopped early (1.5 yrs, 120 patients) due to higher rate of adverse events with rivaroxaban (19% vs 3% with warfarin)

All thrombotic events arterial (stroke or MI) DOACs should be used with caution in patients with antiphospholipid syndrome, particularly in those with a history of arterial events Blood 2018;132:1365 Catastrophic antiphospholipid syndrome (Asherson, 1992) Rare: 1% or less of APL patients Generalized vasculopathy (?thrombotic or inflammatory) Livedo reticularis

Multiple organ injury Renal failure Hypertension ARDS CNS Rapid progression; high mortality Treatment: anticoagulation, plasma exchange, immunosuppresion ANTIPHOSPHOLIPID ANTIBODIES AND FETAL LOSS Antiphospholipid antibodies associated with lower live birth rates in unselected low-risk pregnancies Live birth rates in untreated women with APL and at least one fetal loss have ranged from 10-85% in published studies Aspirin and heparin have been associated with higher live-birth rates in several studies, but most

of these did not include a placebo-treated arm Arth Rheum 2004;50:1028 Treatment of Pregnant Women With APS Women with obstetric APS, no history of thrombosis: Antepartum prophylactic or intermediatedose LMWH plus low dose ASA Women with APS and history of thrombosis: Low-dose ASA + therapeutic dose LMWH during pregnancy and 6 weeks postpartum Garcia and Erkan, NEJM 2018

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