Thrombophilia • Acquired or inherited tendency toward accelerated thrombosis • Hemophilia is to Hemophiliac as • Thrombophilia is to ………? »THROMBOPHILIAC? Prevalence of thrombophilia Relative risk of.
Download ReportTranscript Thrombophilia • Acquired or inherited tendency toward accelerated thrombosis • Hemophilia is to Hemophiliac as • Thrombophilia is to ………? »THROMBOPHILIAC? Prevalence of thrombophilia Relative risk of.
Thrombophilia • Acquired or inherited tendency toward accelerated thrombosis • Hemophilia is to Hemophiliac as • Thrombophilia is to ………? »THROMBOPHILIAC? Prevalence of thrombophilia Relative risk of first episode DVT • • • • • • • • • • • APLA Antithrombin deficiency Protein C deficiency (Hetero) Protein S deficiency Homozygous Factor V Leiden Heterozygous Factor V Leiden Elevated FVIII Prothrombin gene mutation 20210 Homocystenemia OBCP OBCP and heterozygous Factor V 20 20 10 10 80 7 5 3 3 4 35 ? XII XIIa XII XIIa XI XIa XII XIIa XI XIa IX IXa XII XIIa XI XIa IX VIII TENASE Complex IXa Ca++ VIIIa PL X Xa XII XIIa XI XIa IX IXa X Xa Tissue Factor VIIa VII XII XIIa XI XIa IX IXa X Xa XII XIIa XI XIa PROTHROMBINASE IXa Complex IX X Xa Ca++ Va PL Va II IIa (Thrombin) XII XIIa XI XIa IX IXais the central Thrombin X Xa Ca++ bioregulatory enzyme in Va PL hemostasis Va II IIa (Thrombin) vWF(ADAMST13) XII XIIa XI Platelets PARS 1 &4 XIa IX IXa X VIIIa Xa II Va IIa (Thrombin) I TAFI Ia (Fibrin) XIIIa XIII Cross-linked Ia (Fibrin) Pro-thrombotic actions of THROMBIN XII XIIa XI XIa IX IXa X VIII Tissue Factor VIIa VII Xa VIIIa II V Va IIa (Thrombin) I Ia (Fibrin) XIIIa Cross-linked Ia (Fibrin) XIII Anti-thrombotic actions of ECs • • • • Binding of thrombin to thrombomodulin Activation of protein C Release of tPA Prostacyclin Activated Protein C Thrombin Protein C ECPR TM XII XIIa XI XIa IX aPC Tissue Factor VIIa VII IXa Vac VIII VIIIa aPC X Xa II V Va IIa (Thrombin) I aPC Ia (Fibrin) (PS and FV are cofactors for aPC) XII XIIa XI XIa IX VIII VIIIa Tissue Factor VIIa VII IXa aPC X Xa II V Va IIa (Thrombin) I aPC Ia (Fibrin) Plasmin Plasminogen tPA EC PAR1 XII XIIa XI Tissue Factor XIa VIIa aPC IX IXa X VIII VII Xa VIIIa II V LEIDEN Va IIa (Thrombin) I Ia (Fibrin) FV Leiden is NOT deactivated by APC and does not act as cofactor (FVac) for FVIIIa inactivation XII XIIa XI Tissue Factor TFPI XIa VIIa IX VII IXa VIIa Inhibitor X VIII Xa VIIIa II V Va IIa (Thrombin) I Ia (Fibrin) XII XIIa XI Tissue Factor XIa VIIa IX IXa X VIII VII Antithrombin Xa VIIIa II V Va IIa (Thrombin) I Ia (Fibrin) XII XIIa XI Tissue Factor XIa VIIa IX VII IXa Heparin X VIII Xa Antithrombin VIIIa II V Va IIa (Thrombin) I Ia (Fibrin) Antithrombin deficiency • • • • • Auto dom (males=females) 1% of VTE Homozygous lethal in utero Heterozygous 40-70% of normal AT level Clinical presentation late teens and early adulthood • 20-fold relative risk • May be acquired – nephrotic syndrome Clinical detection • Functional assay (HCII based) • Immunogenic assay for protein components – One or both assays may be deficient Protein C deficiency • • • • • • Auto Dom Vit K dependent (II, VII, IX, X, C & S) aPC inactivates Va and VIIIa 3-5% of pts with VTE 10 fold relative risk Both functional and immunogenic deficiencies have been described • Warfarin-induced skin necrosis • Homozygous neonatal purpura fulminans Protein S Deficiency • Auto Dom • Co-factor for aPC inactivation of Va and VIIIa • Low level direct (aPC independent) inactivation of Va and VIIIa • Produced by liver (vit K dependent), ECs and megakaryocytes • Free (40%) and bound (60%) to C4bBP • C4bBP increased in pregnancy, OBCP, inflammation and acute thrombosis results in decreased free S • Warfarin-induced skin necrosis • Homozygous neonatal purpura fulminans Prothrombin Gene g20210a • 2-5% in healthy population • 7-18% in VTE patients • Mutation in non-transcribed portion of prothrombin gene resulting in elevated levels of prothrombin • Common in association with FV Leiden • May have higher risk of PE than FV Leiden • 1-3 fold increased risk of first VTE Factor V • Single chain 330kda glycoprotein • 25% of FV is stored in platelet alpha granules • Essential co-factor for Xa activation of prothrombin • Also acts as co-factor for aPC inactivation of VIIIa Factor V Leiden • Arg506gln • Most 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 VTE • Gene assay APC resistance • Addition of aPC does not prolong routine clotting assays (aPTT) • 90% - due to FV Leiden (point mutation preventing Va inactivation by APC) • 10% - due to increased plasma levels of factor VIII, the presence of antiphospholipid antibodies, older age, pregnancy, and the use of estrogens Factor elevations (VII, VIII, IX, XI) • FVIII elevation has been associated with 6-10 fold increased risk of VTE • Some believe it should be included in thrombophilia workup • Elevations of FVII, IX and XI of uncertain clinical relevance Dysfibrinogenemia • Variable susceptibility to degradation by plasmin • Over 250 fibrinogen mutations have been described Hyperhomocysteinemia • Produced in metabolism of methionine • Associated with arterial disease and venous thrombosis • Acquired due to vitamin deficiency (B6, B12 and folate) or genetic (MTHFR or CBS) Lupus anticoagulant • First detected prolongation of PT in a patient with SLE • Most result in prolongation of aPTT • Not an anticoagulant • Not only in SLE APLA Syndrome • • • • LA and/or APLA Arterial or venous thrombosis Thrombocytopenia Recurrent fetal loss APLA and Risk of Recurrent VTE • Marked elevation in the risk of recurrent thrombosis –20 fold – With anti-coagulants • 3 – 10% risk at 3 years – Without anti-coagulants • 10 -29% risk at 3 years 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 Treatment (1) • First time VTE with transient risk factor – E.g. surgery, immobilization • 3 months VKA Treatment (2) • First time IDIOPATHIC VTE • Recommend – 6-12 months VKA • Suggest – indefinite (esp PE) – Reliable patient – Risk factors for bleeding Treatment (3) • • • • • First time VTE and cancer Recommend – 3-6 months LMWH Then indefinite VKA CLOT - Fragmin study LEE LITE - Hull Treatment (4) • First time VTE – APLA – Combined (e.g. FV Leiden and PG20210) – Single factor and STRONG Family history • Recommend 12 months vs indefinite Treatment (5) • First time VTE – – – – – – – ATIII deficiency PC deficiency PS deficiency FV Leiden Prothrombin gene 20210 Homocysteine Elevated FVIII • Recommend 6-12 months • Prevent Low dose warfarin Treatment (6) • Recurrent VTE • Recommend indefinite VKA 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) Against screening • • • • Expensive Does not alter treatment Stigmatizes patient/anxiety May have insurance/employer ramifications 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. Who should be tested for inherited thrombophilia? • No one Who should be tested for inherited thrombophilia? • • • • • • • • • • Idiopathic first time VTE Recurrent VTE Venous thromboembolism at early age Thrombosis in an unusual site, eg mesenteric vein, cerebral vein etc Unexplained neonatal thrombosis Skin necrosis, particularly if on VKA Arterial thrombosis before the age 30 years Unexplained prolonged activated partial thromboplastin time Patients with recurrent fetal loss Relatives of patients with thrombophilic abnormality – very controversial