Thrombophilia=Tendency to Thrombosis

HEREDITARY ACQUIRED

Hereditary Hereditary ThrombophiliaThrombophiliaEgeberg Egeberg –– 1965: Norwegian 1965: Norwegian

family with absence ATIIIfamily with absence ATIII

Natural AnticoagulantsNatural Anticoagulants

AntithrombinAntithrombin: synthesized by liver: synthesized by liver

FunctionFunction: neutralization of thrombin (FIIa), : neutralization of thrombin (FIIa), FXIa, FIXa, FXa by formation heparan sulphate FXIa, FIXa, FXa by formation heparan sulphate complexcomplex

Protein CProtein C: synthesized by liver; Vit K-depend: synthesized by liver; Vit K-depend

FunctionFunction: decrease in generation of thrombin: decrease in generation of thrombin Protein SProtein S: synthesized by liver; Vit K-depend: synthesized by liver; Vit K-depend

FunctionFunction: decrease in generation of thrombin: decrease in generation of thrombin

Antithrombin, Protein C, Protein S Antithrombin, Protein C, Protein S deficiency (5-15% of VTE patients) deficiency (5-15% of VTE patients)

decrease in inhibition of coagulationdecrease in inhibition of coagulation Factor V Leiden mutation (Arg506Gln) Factor V Leiden mutation (Arg506Gln)

increase in thrombin generationincrease in thrombin generation Prothrombin mutation (G20210A)Prothrombin mutation (G20210A)

increase in prothrombin (FII) levelincrease in prothrombin (FII) level MTHFR mutation (C677T) MTHFR mutation (C677T) elevated elevated

HeyHey

Hereditary Hereditary Thrombophilia Thrombophilia

SyndromesSyndromes

antithrombinFII mutation

↑↑

Factor V Leiden

Age (1 in 10,000<40 1 in 100>75 Age (1 in 10,000<40 1 in 100>75 year)year)

Major surgeryMajor surgery Active malignancyActive malignancy Myeloproliferative disorderMyeloproliferative disorder Prolonged immobilizationProlonged immobilization OC, Pregnancy, HRTOC, Pregnancy, HRT APLA syndromeAPLA syndrome HyperhomocysteinemiaHyperhomocysteinemia

Acquired Acquired HypercoagulabilityHypercoagulability

Arg to Gln substitution at 506 of Arg to Gln substitution at 506 of factor Vfactor V

5-8 fold risk of venous 5-8 fold risk of venous thrombosis in heterozygotesthrombosis in heterozygotes

50-100 fold risk of venous 50-100 fold risk of venous thrombosis in homozygotesthrombosis in homozygotes

Risk factor for MI (controversial)Risk factor for MI (controversial) Asymptomatic carriers Asymptomatic carriers –– 5% 5%

Factor V Leiden- Factor V Leiden- Arg506GlnArg506Gln

G to A transition at 3G to A transition at 3’’20210 (Poort, 20210 (Poort, Blood 1996)Blood 1996)

Causes increase in Factor IICauses increase in Factor II 2-5 increase in the risk of venous 2-5 increase in the risk of venous

thrombosisthrombosis Risk factor for MI (controversial)Risk factor for MI (controversial) Risk factor for ischemic stroke Risk factor for ischemic stroke

(controversial)(controversial) Prevalence in normal population: 3%Prevalence in normal population: 3%

Prothrombin Mutation Prothrombin Mutation (G20210A)(G20210A)

C to T at nt.677: Ala to Val; C to T at nt.677: Ala to Val; ThermolabileThermolabile

Homozygotes: increased homocysteine Homozygotes: increased homocysteine levelslevels

Heterozygotes: normal homocysteine Heterozygotes: normal homocysteine levelslevels

12%- asymptomatic12%- asymptomatic 2-fold increased risk of venous 2-fold increased risk of venous

thrombosis (controversial)thrombosis (controversial) Risk factor for MI (controversial)Risk factor for MI (controversial)

MethylenetetrahydropholMethylenetetrahydropholate reductase (MTHFR)ate reductase (MTHFR)

High levels of Factor VIIIHigh levels of Factor VIII High levels of Factor IX (?)High levels of Factor IX (?) High levels of Factor XI (?)High levels of Factor XI (?) High levels of Fibrinogen (?)High levels of Fibrinogen (?) Increase in risk for VTE 3-6-fold (Lancet Increase in risk for VTE 3-6-fold (Lancet

1995, 345:152; NEJM 2000, 342:696)1995, 345:152; NEJM 2000, 342:696) Mechanism?: acute phase reactants, Mechanism?: acute phase reactants,

pregnancy, older age, smokingpregnancy, older age, smoking

Other abnormalities Other abnormalities associated with the risk associated with the risk

of VTof VT

Family History of venous thrombosisFamily History of venous thrombosis Thrombosis of young ageThrombosis of young age Recurrent venous thrombosisRecurrent venous thrombosis Idiopathic venous thrombosisIdiopathic venous thrombosis Thrombosis in an unusual siteThrombosis in an unusual site

Inferior vena cavaInferior vena cava Mesenteric vein thrombosisMesenteric vein thrombosis Cerebral vein thrombosisCerebral vein thrombosis Renal vein thrombosisRenal vein thrombosis Axillary vein thrombosisAxillary vein thrombosis

Clinical Manifestations Clinical Manifestations of Thrombophiliaof Thrombophilia

Screen for resistance to activated protein C Screen for resistance to activated protein C (APC) by clotting assay or genetic test for (APC) by clotting assay or genetic test for factor V-Arg506Gln (Factor V Leiden) factor V-Arg506Gln (Factor V Leiden) Confirm positive APC resistance assay with Confirm positive APC resistance assay with genetic testgenetic test

Genetic test for prothrombin or MTHFR Genetic test for prothrombin or MTHFR mutationsmutations

Functional assay of ATIII Functional assay of ATIII Functional assay of Protein CFunctional assay of Protein C Immunological assays of total and free Immunological assays of total and free

Protein SProtein S Measurement of fasting total plasma Measurement of fasting total plasma

homocysteine levelshomocysteine levels

Screening/laboratory Screening/laboratory evaluation for hereditary evaluation for hereditary

thrombophiliathrombophilia

ManagementManagement Acute VTE: Heparin/LMWH and CoumadinAcute VTE: Heparin/LMWH and Coumadin Continue Coumadin for 3 months if DVTContinue Coumadin for 3 months if DVT

was provoked by surgery, trauma, was provoked by surgery, trauma, immobilizationimmobilization

Continue Coumadin for 6-12 months if Continue Coumadin for 6-12 months if DVT was unprovokedDVT was unprovoked

Continue Coumadin indefnitely if: 2 or Continue Coumadin indefnitely if: 2 or more VTEs, 1 life-threatening event more VTEs, 1 life-threatening event (massive PE, CVT,(massive PE, CVT, IVC, MVT)IVC, MVT)

APLs, ATIII deficiency, more than 1 APLs, ATIII deficiency, more than 1 genetic defectgenetic defect (homozygous FVL or FVL (homozygous FVL or FVL and homozygous FII)and homozygous FII)

I had a DVT after the I had a DVT after the flight to Australia. flight to Australia.

Should I be evaluatedShould I be evaluated??

QuestionQuestion

Screen for resistance to activated protein C (APC) by clotting assay or genetic test for factor V-Arg506Gln (Factor V Leiden). Confirm positive APC resistance assay with genetic test

Genetic test for prothrombin or MTHFR mutations Functional assay of ATIII Functional assay of Protein C Immunological assays of total and free Protein S Clotting assay for Lupus Anticoagulant and ELISA for

APLA Measurement of fasting total plasma homocysteine levels

Screening/laboratory Screening/laboratory evaluation for evaluation for

thrombophilic patientsthrombophilic patients

I am on Warfarin for 3 I am on Warfarin for 3 months now. How long months now. How long

should I take itshould I take it??

QuestionQuestion

Following the cessation of therapy 24.8% to Following the cessation of therapy 24.8% to 27% recurrence at 5 years and 30.3% 27% recurrence at 5 years and 30.3% recurrence at 8 years (Ann Intern Med recurrence at 8 years (Ann Intern Med 1996, 125:1; NEJM 1999, 340:901)1996, 125:1; NEJM 1999, 340:901)

50% of recurrent DVT – in contralateral 50% of recurrent DVT – in contralateral legleg

Warfarin causes 95% reduction in Warfarin causes 95% reduction in recurrency but 0.25% /year incidence of recurrency but 0.25% /year incidence of fatal bleedingfatal bleeding

DVT is a Chronic DiseaseDVT is a Chronic Disease

מעברה א.מ.ל., ללא גורמי סיכון, מעברה א.מ.ל., ללא גורמי סיכון3434בת בת , עברה עברהAcute Inferoposterior MIAcute Inferoposterior MI:בברור קרישיות יתר נמצא:בברור קרישיות יתר נמצא

FVFVתקין תקין FIIFIIתקין תקין MTHFRMTHFRהומוזיגוטי הומוזיגוטי AnticardiolipinAnticardiolipinשלילי שלילי Circulating anticoagulantCirculating anticoagulant חיובי חיובי -מה האבחנה? ;;20.820.8הומוציסטאין- הומוציסטאין

APL syndromeAPL syndrome

תיאור מקרהתיאור מקרה

Mechanism of APL-induced thrombosis

ApoER2

’

EC

Platelet

A2 R

ApoER2’

Platelet

activation

EC activation

A2 R

Frequency of APL Ab in the general Frequency of APL Ab in the general population: 3-10% (Thromb Haemost population: 3-10% (Thromb Haemost 1997, 77:444)1997, 77:444)

Clinical manifestations:Clinical manifestations: Venous (DVT + PE Venous (DVT + PE –– 55%) and arterial 55%) and arterial

thrombosis (CVA + TIA thrombosis (CVA + TIA –– 50%; MI 50%; MI –– 25%) 25%) Recurrent pregnancy lossRecurrent pregnancy lossLaboratory findings:Laboratory findings: Ab against phospholipids (PL)-binding Ab against phospholipids (PL)-binding

proteins: proteins: ββ2GP1, (FII, annexin 5)2GP1, (FII, annexin 5) APL Ab increase the risk for VTE 9-fold APL Ab increase the risk for VTE 9-fold

(Blood 1995 85:3685)(Blood 1995 85:3685)

Antiphospholipid Antiphospholipid Syndrome (APL)Syndrome (APL)

Coagulation-based tests: Coagulation-based tests: prolongation of PL-depended prolongation of PL-depended coagulation test: DRVVT, aPTT, coagulation test: DRVVT, aPTT, Kaolin clotting timeKaolin clotting time

Immunoassays: anticardiolipin Immunoassays: anticardiolipin Ab, Ab, anti anti 2GPI Ab2GPI Ab, anti , anti prothrombin Abprothrombin Ab

Laboratory tests for APL Laboratory tests for APL AbAb

For VTE: Warfarin aiming INR 2-3 (Am J For VTE: Warfarin aiming INR 2-3 (Am J Med, 1998, 104:332)Med, 1998, 104:332)

For arterial thrombosis: Warfarin aiming For arterial thrombosis: Warfarin aiming INR 3 (Hematology, Education Program INR 3 (Hematology, Education Program 2001, 2005)2001, 2005)

Anticoagulated patients do not benefit Anticoagulated patients do not benefit from addition of Aspirin (NEJM 1995, from addition of Aspirin (NEJM 1995, 126:2136)126:2136)

Long-term anticoagulation: Recurrence Long-term anticoagulation: Recurrence rate 50% at 2 years; 78% at 8 years (Ann rate 50% at 2 years; 78% at 8 years (Ann Rheum Dis 1993; 52:689)Rheum Dis 1993; 52:689)

Treatment of APL Treatment of APL syndromesyndrome

Oral contraceptivesOral contraceptives Normal pregnancyNormal pregnancy Pregnancy complicationsPregnancy complications Hormone replacement therapyHormone replacement therapy

Women issues in Women issues in ThrombophiliaThrombophilia

My sister has Factor V My sister has Factor V Leiden and had a DVT on Leiden and had a DVT on

birth control pillsbirth control pills..

Can I take birth control pillsCan I take birth control pills ??

QuestionQuestion

Second generation OC and hetero for Second generation OC and hetero for FVL increase the risk for VTE 20 to FVL increase the risk for VTE 20 to 35- fold (Lancet 1994, 344:1453)35- fold (Lancet 1994, 344:1453)

Third generation OC and VTE Third generation OC and VTE increase the risk 50-fold (Lancet increase the risk 50-fold (Lancet 1995, 345:1593)1995, 345:1593)

OC and hetero for FII mutation OC and hetero for FII mutation increase the risk for VTE 16-fold increase the risk for VTE 16-fold (ATVB 1999, 19:700). (ATVB 1999, 19:700).

The risk for CVT The risk for CVT –– 150-fold (NEJM 150-fold (NEJM 1998, 338:1793)1998, 338:1793)

OC and risk of VTE in OC and risk of VTE in Thrombophilic patientsThrombophilic patients

I have Factor V LeidenI have Factor V Leiden..

Will I have problems with Will I have problems with pregnancypregnancy??

QuestionQuestion

Pregnancy = Hypercoagulable statePregnancy = Hypercoagulable state

Venous stasis

Increase in coagulation factors: VWF, FVIII, FV, Fng, APCR

Decrease in Protein S

Decrease in fibrinolysis (increase in PAI-1 and PAI-2)

, על טיפול הורמונלי תחליפי, , על טיפול הורמונלי תחליפי, 5050בת בת cerebral vein cerebral veinעברה אירוע של עברה אירוע של

thrombosisthrombosis בירור קרישיות יתר . בירור קרישיות יתר .יכלול בין היתר גם:יכלול בין היתר גם:

רמת פיברינוגן בפלזמהרמת פיברינוגן בפלזמה1.1.

.2.2Lupus AnticoagulantLupus Anticoagulant

שומנים בדםשומנים בדם3.3.

.4.4Factor V LeidenFactor V Leiden -מוטציה ב- , מוטציה ב ,FIIFII

.5.52+42+4

החולה הנ"ל מטופלת בקומדין. החולה הנ"ל מטופלת בקומדין. המלצותיך להמשך הטיפול בקומדין:המלצותיך להמשך הטיפול בקומדין:

חודשים בלבד חודשים בלבד1.133.

חודשים חודשים2.266.

חודשים חודשים3.31212.

כל החייםכל החיים4.4.

עם חסר אנטיתרומבין ואירוע של עם חסר אנטיתרומבין ואירוע של 2828בת בת Rt DVTRt DVT:המלצותיך לטיפול:. המלצותיך לטיפול .

קומדין לכל החייםקומדין לכל החיים1.1.

.2.2Low Mol Weight HeparinLow Mol Weight Heparin

חודשים חודשים66קומדין ל- קומדין ל- 3.3.

אספיריןאספירין4.4.