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Thrombophilia John F Eidt MD University of Arkansas for Medical Sciences.

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Presentation on theme: "Thrombophilia John F Eidt MD University of Arkansas for Medical Sciences."— Presentation transcript:

1 Thrombophilia John F Eidt MD University of Arkansas for Medical Sciences

2 Thrombophilia Acquired or inherited tendency toward accelerated thrombosisAcquired or inherited tendency toward accelerated thrombosis

3 Hemophilia is to Hemophiliac asHemophilia is to Hemophiliac as Thrombophilia is to ………?Thrombophilia is to ………? »THROMBOPHILIAC?

4 Classification of thrombophilia 1. Qualitative/quantitative defect of coagulation factor inhibitors – –a) Antithrombin deficiency – –b) Protein C deficiency – –c) Protein S deficiency – –d) Heparin cofactor II deficiency – –e) Tissue factor pathway inhibitor deficiency – –f) Thrombomodulin deficiency 2. Increased levels/function of coagulation factors – –a) Activated protein C resistance and factor V Leiden – –b) Prothrombin gene mutation (G20210A) – –c) Dysfibrinogenemia and hyperfibrinogenemia – –d) Elevated levels of clotting factors VII, VIII, IX, XI, and XII 3. Hyperhomocysteinemia 4. Defects of the fibrinolytic system – –a) Plasminogen – –b) Tissue plasminogen activator – –c) Thrombin-activatable fibrinolysis inhibitor – –d) Factor XIII – –e) Lipoprotein (a) 5. Altered platelet function – –a) Platelet glycoprotein GPIb-IX – –b) GPIa-IIa – –c) GPIIb-IIIa

5 Prevalence of thrombophilia

6 APLA20APLA20 Antithrombin deficiency20Antithrombin deficiency20 Protein C deficiency (Hetero)10Protein C deficiency (Hetero)10 Protein S deficiency10Protein S deficiency10 Homozygous Factor V Leiden80Homozygous Factor V Leiden80 Heterozygous Factor V Leiden 7Heterozygous Factor V Leiden 7 Elevated FVIII5Elevated FVIII5 Prothrombin gene mutation 202103Prothrombin gene mutation 202103 Homocystenemia3Homocystenemia3 OBCP4OBCP4 OBCP and heterozygous Factor V35OBCP and heterozygous Factor V35 Relative risk of first episode DVT

7 XIIXIIa ?

8 XIIXIIa XIXIa

9 XIIXIIa XIXIa IXIXa

10 XIIXIIa XIXIa IXIXa VIII VIIIa Ca++ PL TENASE Complex XXa

11 XIIXIIa XIXIa IXIXa XXa VIIVIIa Tissue Factor

12 XIIXIIa XIXIa IXIXa XXa

13 XIIXIIa XIXIa IXIXa XXa Va Ca++ PL PROTHROMBINASE Complex IIIIa (Thrombin)

14 XIIXIIa XIXIa IXIXa XXa Va Ca++ PL IIIIa (Thrombin) Thrombin is the central bioregulatory enzyme in hemostasis

15 XIIXIIa XIXIa IXIXa XXa IIIIa (Thrombin) IIa (Fibrin) Platelets PARS 1 &4 VIIIa Va XIIIaXIII Cross-linked Ia (Fibrin) vWF(ADAMST13) TAFI Pro-thrombotic actions of THROMBIN

16 XIIXIIa XIXIa IXIXa XXa IIIIa (Thrombin) VIIVIIa IIa (Fibrin) VVa VIIIVIIIa Tissue Factor XIIIaXIII Cross-linked Ia (Fibrin)

17 Anti-thrombotic actions of ECs Binding of thrombin to thrombomodulinBinding of thrombin to thrombomodulin Activation of protein CActivation of protein C Release of tPARelease of tPA ProstacyclinProstacyclin

18 ECPR Thrombin Protein C Activated Protein C TM

19 XIIXIIa XIXIa IXIXa XXa IIIIa (Thrombin) IIa (Fibrin) VVa VIIIVIIIa aPC (PS and FV are cofactors for aPC) aPC VIIVIIa Tissue Factor aPC Vac

20 XIIXIIa XIXIa IXIXa XXa IIIIa (Thrombin) IIa (Fibrin) VVa VIIIVIIIa aPC VIIVIIa Tissue Factor EC PAR1tPA Plasminogen Plasmin

21 XIIXIIa XIXIa IXIXa XXa IIIIa (Thrombin) VIIVIIa IIa (Fibrin) V LEIDENVa VIIIVIIIa Tissue Factor aPC FV Leiden is NOT deactivated by APC and does not act as cofactor (FVac) for FVIIIa inactivation

22 XIIXIIa XIXIa IXIXa XXa IIIIa (Thrombin) VIIVIIa IIa (Fibrin) VVa VIIIVIIIa Tissue Factor TFPI VIIa Inhibitor

23 XIIXIIa XIXIa IXIXa XXa IIIIa (Thrombin) VIIVIIa IIa (Fibrin) VVa VIIIVIIIa Tissue Factor Antithrombin

24 XIIXIIa XIXIa IXIXa XXa IIIIa (Thrombin) VIIVIIa IIa (Fibrin) VVa VIIIVIIIa Tissue Factor Antithrombin Heparin

25

26 Antithrombin deficiency Auto dom (males=females)Auto dom (males=females) 1% of VTE1% of VTE Homozygous lethal in uteroHomozygous lethal in utero Heterozygous 40-70% of normal AT levelHeterozygous 40-70% of normal AT level Clinical presentation late teens and early adulthoodClinical presentation late teens and early adulthood 20-fold relative risk20-fold relative risk May be acquired – nephrotic syndromeMay be acquired – nephrotic syndrome

27 Clinical detection Functional assay (HCII based)Functional assay (HCII based) Immunogenic assay for protein componentsImmunogenic assay for protein components –One or both assays may be deficient

28 Clinical subtypes Type I - Decreased functional activity and decreased levels of normal proteinType I - Decreased functional activity and decreased levels of normal protein Type II - Decreased functional activity and normal protein levelType II - Decreased functional activity and normal protein level –Abnormalities in thrombin binding site –Abnormalities in heparin binding site (lower risk)

29 Protein C deficiency Auto DomAuto Dom Vit K dependent (II, VII, IX, X, C & S)Vit K dependent (II, VII, IX, X, C & S) aPC inactivates Va and VIIIaaPC inactivates Va and VIIIa 3-5% of pts with VTE3-5% of pts with VTE 10 fold relative risk10 fold relative risk Both functional and immunogenic deficiencies have been describedBoth functional and immunogenic deficiencies have been described Warfarin-induced skin necrosisWarfarin-induced skin necrosis Homozygous neonatal purpura fulminansHomozygous neonatal purpura fulminans

30 Protein S Deficiency Auto DomAuto Dom Co-factor for aPC inactivation of Va and VIIIaCo-factor for aPC inactivation of Va and VIIIa Low level direct (aPC independent) inactivation of Va and VIIIaLow level direct (aPC independent) inactivation of Va and VIIIa Produced by liver (vit K dependent), ECs and megakaryocytesProduced by liver (vit K dependent), ECs and megakaryocytes Free (40%) and bound (60%) to C4bBPFree (40%) and bound (60%) to C4bBP C4bBP increased in pregnancy, OBCP, inflammation and acute thrombosis results in decreased free SC4bBP increased in pregnancy, OBCP, inflammation and acute thrombosis results in decreased free S Warfarin-induced skin necrosisWarfarin-induced skin necrosis Homozygous neonatal purpura fulminansHomozygous neonatal purpura fulminans

31 Heparin Cofactor II Deficiency Direct thrombin inhibitor – accelerated by heparin, glycosoaminoglycansDirect thrombin inhibitor – accelerated by heparin, glycosoaminoglycans UncommonUncommon Low risk of thrombosisLow risk of thrombosis –Esp in association with another thrombotic factor

32 TFPI Tissue Factor Pathway Inhibitor Inhibits activation of factor X by tissue factor/VIIa pathwayInhibits activation of factor X by tissue factor/VIIa pathway Clinical relevance is uncertainClinical relevance is uncertain

33 Thrombomodulin deficiency ARIC inverse relationship between TM levels of and risk of CHDARIC inverse relationship between TM levels of and risk of CHD Clinical implications unknownClinical implications unknown Recombinant TM has been developed as novel anticoagulant with no hemorrhagic riskRecombinant TM has been developed as novel anticoagulant with no hemorrhagic risk

34 Prothrombin Gene g20210a 2-5% in healthy population2-5% in healthy population 7-18% in VTE patients7-18% in VTE patients Mutation in non-transcribed portion of prothrombin gene resulting in elevated levels of prothrombinMutation in non-transcribed portion of prothrombin gene resulting in elevated levels of prothrombin Common in association with FV LeidenCommon in association with FV Leiden May have higher risk of PE than FV LeidenMay have higher risk of PE than FV Leiden 1-3 fold increased risk of first VTE1-3 fold increased risk of first VTE

35 Prothrombin G20210A (carrier) effect on recurrent VTE RR 1.2 Haematologica/the hematology journal | 2007; 92(08) | 1107

36 Factor V Single chain 330kda glycoproteinSingle chain 330kda glycoprotein 25% of FV is stored in platelet alpha granules25% of FV is stored in platelet alpha granules Essential co-factor for Xa activation of prothrombinEssential co-factor for Xa activation of prothrombin Also acts as co-factor for aPC inactivation of VIIIaAlso acts as co-factor for aPC inactivation of VIIIa

37 Factor V Leiden Arg506glnArg506gln Most common inherited thrombophiliaMost common inherited thrombophilia –2-10% of healthy population –20-50% of first-time VTE Common in Caucasians, but not found in other ethnic groups such as African, Chinese or Japanese A single mutational event occurred approximately 21,000 years ago 5-10 fold increased risk of first VTE5-10 fold increased risk of first VTE Gene assayGene assay

38 APC resistance Addition of aPC does not prolong routine clotting assays (aPTT)Addition of aPC does not prolong routine clotting assays (aPTT) 90% - due to FV Leiden (point mutation preventing Va inactivation by APC)90% - due to FV Leiden (point mutation preventing Va inactivation by APC) 10% - due to10% - due to increased plasma levels of factor VIII, the presence of antiphospholipid antibodies, older age, pregnancy, and the use of estrogens

39

40 Factor V Leiden (carrier) on risk of recurrent VTE RR 1.4 haematologica/the hematology journal | 2007; 92(08) | 1107

41 Factor elevations (VII, VIII, IX, XI) FVIII elevation has been associated with 6-10 fold increased risk of VTEFVIII elevation has been associated with 6-10 fold increased risk of VTE Some believe it should be included in thrombophilia workupSome believe it should be included in thrombophilia workup Elevations of FVII, IX and XI of uncertain clinical relevanceElevations of FVII, IX and XI of uncertain clinical relevance

42 Dysfibrinogenemia Variable susceptibility to degradation by plasminVariable susceptibility to degradation by plasmin Over 250 fibrinogen mutations have been describedOver 250 fibrinogen mutations have been described

43 Hyperhomocysteinemia Produced in metabolism of methionineProduced in metabolism of methionine Associated with arterial disease and venous thrombosisAssociated with arterial disease and venous thrombosis Acquired due to vitamin deficiency (B6, B12 and folate) or genetic (MTHFR or CBS)Acquired due to vitamin deficiency (B6, B12 and folate) or genetic (MTHFR or CBS)

44 Lupus anticoagulant First detected prolongation of PT in a patient with SLEFirst detected prolongation of PT in a patient with SLE Most result in prolongation of aPTTMost result in prolongation of aPTT Not an anticoagulantNot an anticoagulant Not only in SLENot only in SLE

45 APLA Syndrome LA and/or APLALA and/or APLA Arterial or venous thrombosisArterial or venous thrombosis ThrombocytopeniaThrombocytopenia Recurrent fetal lossRecurrent fetal loss

46 Sapporo Criteria

47 APLA and Risk of Recurrent VTE Marked elevation in the risk of recurrent thrombosis –20 foldMarked elevation in the risk of recurrent thrombosis –20 fold –With anti-coagulants 3 – 10% risk at 3 years3 – 10% risk at 3 years –Without anti-coagulants 10 -29% risk at 3 years10 -29% risk at 3 years

48 How do APLAs lead to thrombosis? Inhibition of prostacyclin (PGI2)Inhibition of prostacyclin (PGI2) Inhibition of PC activationInhibition of PC activation Increase PAIsIncrease PAIs Direct platelet activationDirect platelet activation Activation of endothelial cellsActivation of endothelial cells Increased TF expression on monocytesIncreased TF expression on monocytes

49 Testing Lupus anticoagulant (prolonged aPTT)Lupus anticoagulant (prolonged aPTT) –PL –CA++ –Contact factor activator (a) Antiphospholipid antibodiesAntiphospholipid antibodies

50 Common APLA immunoassays Anticardiolipin (not physiological) Anti-prothrombin Anti-beta-2-glycoprotein I Anti-phosphatidyl-serine Anti-phosphatidyl-ethanolamine Anti-phosphatidyl-choline Anti-phosophatidyl-inositol

51 What is cardiolipin and why test for an antibody to it? Cardiolipin is not physiologically relevantCardiolipin is not physiologically relevant It is a widely available laboratory reagentIt is a widely available laboratory reagent It is used in the test for syphilisIt is used in the test for syphilis

52 APLA and VTE Anticoagulation for duration of positive APLAAnticoagulation for duration of positive APLA –INR 2.0 – 3.0 (contrary to previous recs) Check APLA Q 6-12 mosCheck APLA Q 6-12 mos Discontinue anticoagulant if APLA negative x2Discontinue anticoagulant if APLA negative x2

53 Asymptomatic APLA Antiplatelet agents widely recommended but no proven benefitAntiplatelet agents widely recommended but no proven benefit No role for therapeutic “prophylactic” anticoagulationNo role for therapeutic “prophylactic” anticoagulation Prophylaxis indicated for high risk events (long distance travel, surgery, immobilzation)Prophylaxis indicated for high risk events (long distance travel, surgery, immobilzation) Role of HRT and OBCP uncertainRole of HRT and OBCP uncertain Patient education - should be informed of presence of APLAs and symptoms of VTEPatient education - should be informed of presence of APLAs and symptoms of VTE

54 APLA and arterial thrombosis Antiplatelet agents - ASAAntiplatelet agents - ASA No clear evidence of benefitNo clear evidence of benefit Most authors do not recommend anticoagulantsMost authors do not recommend anticoagulants

55 High risk for thrombosis: Prolonged duration of anticoagulation Antiphospholipid syndrome More than one thrombophilic defect (e.g. FV Leiden and Prothrombin gene mutation)) Previous VTE at unusual site Strong family history of thrombosis

56 Treatment (1) First time VTE with transient risk factorFirst time VTE with transient risk factor –E.g. surgery, immobilization 3 months VKA3 months VKA

57 Treatment (2) First time IDIOPATHIC VTEFirst time IDIOPATHIC VTE Recommend – 6-12 months VKARecommend – 6-12 months VKA Suggest – indefinite (esp PE)Suggest – indefinite (esp PE) –Reliable patient –Risk factors for bleeding

58 Treatment (3) First time VTE and cancerFirst time VTE and cancer Recommend – 3-6 months LMWHRecommend – 3-6 months LMWH Then indefinite VKAThen indefinite VKA CLOT - Fragmin study LEECLOT - Fragmin study LEE LITE - HullLITE - Hull

59 Treatment (4) First time VTEFirst time VTE –APLA –Combined (e.g. FV Leiden and PG20210) –Single factor and STRONG Family history Recommend 12 months vs indefiniteRecommend 12 months vs indefinite

60 Treatment (5) First time VTEFirst time VTE –ATIII deficiency –PC deficiency –PS deficiency –FV Leiden –Prothrombin gene 20210 –Homocysteine –Elevated FVIII Recommend 6-12 monthsRecommend 6-12 months Prevent Low dose warfarinPrevent Low dose warfarin

61 Treatment (6) Recurrent VTERecurrent VTE Recommend indefinite VKARecommend indefinite VKA

62 Pregnancy and venous thromboembolism Pregnancy is a hypercoagulable statePregnancy is a hypercoagulable state No recommendations for widespread screeningNo recommendations for widespread screening No prophylaxis for prior VTE and transient risk factorNo prophylaxis for prior VTE and transient risk factor Prophylaxis with LMWH for pregnancy and thrombophilia (prior VTE or strong family history)Prophylaxis with LMWH for pregnancy and thrombophilia (prior VTE or strong family history) Post partum anticoagulation for all with prior VTE - 6 weeksPost partum anticoagulation for all with prior VTE - 6 weeks

63 Screening for thrombophilia The main argument in favor of screening asymptomatic relatives of patients with thrombophilia is the possibility of giving advice for primary antithrombotic prevention during circumstances potentially leading to VTE but not usually covered with prophylaxis in normal individuals (e.g. low-risk surgery or pregnancy and pueperium)

64 Against screening ExpensiveExpensive Does not alter treatmentDoes not alter treatment Stigmatizes patient/anxietyStigmatizes patient/anxiety May have insurance/employer ramificationsMay have insurance/employer ramifications

65 Screening SOMMA J, SUSSMAN II, RAND JH. An evaluation of thrombophilia screening in an urban tertiary care medical center: a ‘‘real world’’ experience. Am J Clin Pathol 2006 July;126(1):120e127.

66 Does a positive family history increase the likelihood of detecting inherited thrombophilia? N=314 pts with VTEN=314 pts with VTE Prevalence of thrombophiliaPrevalence of thrombophilia –Overall 35% –Positive FH (at least 1 first deg rel) - 42% –Strong FH (at least 2 first deg rel)- 46% Family history and inherited thrombophilia Journal of Thrombosis and Haemostasis 4: 2182–2187 2006

67 No oneNo one Who should be tested for inherited thrombophilia?

68 Idiopathic first time VTEIdiopathic first time VTE Recurrent VTERecurrent VTE Venous thromboembolism at early ageVenous thromboembolism at early age Thrombosis in an unusual site, eg mesenteric vein, cerebral vein etcThrombosis in an unusual site, eg mesenteric vein, cerebral vein etc Unexplained neonatal thrombosisUnexplained neonatal thrombosis Skin necrosis, particularly if on VKASkin necrosis, particularly if on VKA Arterial thrombosis before the age 30 yearsArterial thrombosis before the age 30 years Unexplained prolonged activated partial thromboplastin timeUnexplained prolonged activated partial thromboplastin time Patients with recurrent fetal lossPatients with recurrent fetal loss Relatives of patients with thrombophilic abnormality – very controversialRelatives of patients with thrombophilic abnormality – very controversial


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