thrombophilia john f eidt md university of arkansas for medical sciences
TRANSCRIPT
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ThrombophiliaThrombophilia
• Acquired or inherited tendency toward Acquired or inherited tendency toward accelerated thrombosisaccelerated thrombosis
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• Hemophilia is to Hemophiliac asHemophilia is to Hemophiliac as
• Thrombophilia is to ………?Thrombophilia is to ………?
»THROMBOPHILIAC?THROMBOPHILIAC?
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Prevalence of thrombophiliaPrevalence of thrombophilia
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• APLAAPLA 2020• Antithrombin deficiencyAntithrombin deficiency 2020• Protein C deficiency (Hetero)Protein C deficiency (Hetero) 1010• Protein S deficiencyProtein S deficiency 1010• Homozygous Factor V LeidenHomozygous Factor V Leiden 8080• Heterozygous Factor V Leiden Heterozygous Factor V Leiden 77• Elevated FVIIIElevated FVIII 55• Prothrombin gene mutation 20210Prothrombin gene mutation 20210 33• HomocystenemiaHomocystenemia 33• OBCPOBCP 44• OBCP and heterozygous Factor VOBCP and heterozygous Factor V 3535
Relative risk of first episode DVTRelative risk of first episode DVT
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XII XIIa?
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XII XIIa
XI XIa
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XII XIIa
XI XIa
IX IXa
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XII XIIa
XI XIa
IX IXa
VIII
VIIIa
Ca++
PL
TENASE Complex
X Xa
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XII XIIa
XI XIa
IX IXa
X Xa
VIIVIIa
Tissue Factor
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XII XIIa
XI XIa
IX IXa
X Xa
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XII XIIa
XI XIa
IX IXa
X Xa
Va
Va
Ca++
PL
PROTHROMBINASE Complex
II IIa (Thrombin)
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XII XIIa
XI XIa
IX IXa
X Xa
Va
Va
Ca++
PL
II IIa (Thrombin)
Thrombin is the central Thrombin is the central bioregulatory enzyme in bioregulatory enzyme in
hemostasishemostasis
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XII XIIa
XI XIa
IX IXa
X Xa
II IIa (Thrombin)
I Ia (Fibrin)
PlateletsPARS 1 &4
VIIIa
Va
XIIIa XIII
Cross-linked Ia (Fibrin)
vWF(ADAMST13)
TAFI
Pro-thrombotic actions of THROMBIN
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XII XIIa
XI XIa
IX IXa
X Xa
II IIa (Thrombin)
VIIVIIa
I Ia (Fibrin)V Va
VIII VIIIa
Tissue Factor
XIIIa XIII
Cross-linked Ia (Fibrin)
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Anti-thrombotic actions of ECsAnti-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
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ECPR
ThrombinProtein C
Activated Protein C
TM
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XII XIIa
XI XIa
IX IXa
X Xa
II IIa (Thrombin)
I Ia (Fibrin)V Va
VIII VIIIaaPC
(PS and FV are cofactors for aPC)
aPC
VIIVIIa
Tissue Factor
aPCVac
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XII XIIa
XI XIa
IX IXa
X Xa
II IIa (Thrombin)
I Ia (Fibrin)V Va
VIII VIIIaaPC
aPC
VIIVIIa
Tissue Factor
EC PAR1tPAPlasminogen
Plasmin
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XII XIIa
XI XIa
IX IXa
X Xa
II IIa (Thrombin)
VIIVIIa
I Ia (Fibrin)V LEIDEN Va
VIII VIIIa
Tissue Factor
aPC
FV Leiden is NOT deactivated by APC and does not act as cofactor (FVac) for FVIIIa
inactivation
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XII XIIa
XI XIa
IX IXa
X Xa
II IIa (Thrombin)
VIIVIIa
I Ia (Fibrin)V Va
VIII VIIIa
Tissue Factor
TFPI
VIIa Inhibitor
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XII XIIa
XI XIa
IX IXa
X Xa
II IIa (Thrombin)
VIIVIIa
I Ia (Fibrin)V Va
VIII VIIIa
Tissue Factor
Antithrombin
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XII XIIa
XI XIa
IX IXa
X Xa
II IIa (Thrombin)
VIIVIIa
I Ia (Fibrin)V Va
VIII VIIIa
Tissue Factor
Antithrombin
Heparin
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Antithrombin deficiencyAntithrombin 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 Clinical presentation late teens and early
adulthoodadulthood• 20-fold relative risk20-fold relative risk• May be acquired – nephrotic syndromeMay be acquired – nephrotic syndrome
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Clinical detectionClinical detection
• Functional assay (HCII based)Functional assay (HCII based)
• Immunogenic assay for protein componentsImmunogenic assay for protein components– One or both assays may be deficientOne or both assays may be deficient
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Protein C deficiencyProtein 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 Both functional and immunogenic
deficiencies have been describeddeficiencies have been described• Warfarin-induced skin necrosisWarfarin-induced skin necrosis• Homozygous neonatal purpura Homozygous neonatal purpura
fulminansfulminans
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Protein S DeficiencyProtein 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 Low level direct (aPC independent) inactivation
of Va and VIIIaof Va and VIIIa• Produced by liver (vit K dependent), ECs and Produced by liver (vit K dependent), ECs and
megakaryocytesmegakaryocytes• Free (40%) and bound (60%) to C4bBPFree (40%) and bound (60%) to C4bBP• C4bBP increased in pregnancy, OBCP, C4bBP increased in pregnancy, OBCP,
inflammation and acute thrombosis results in inflammation and acute thrombosis results in decreased free Sdecreased free S
• Warfarin-induced skin necrosisWarfarin-induced skin necrosis• Homozygous neonatal purpura fulminansHomozygous neonatal purpura fulminans
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Prothrombin Gene g20210aProthrombin 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 Mutation in non-transcribed portion of prothrombin gene resulting in prothrombin gene resulting in elevated elevated levels of prothrombinlevels of prothrombin
• Common in association with FV LeidenCommon in association with FV Leiden
• May have higher risk of PE than FV May have higher risk of PE than FV LeidenLeiden
• 1-3 fold increased risk of first VTE1-3 fold increased risk of first VTE
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Factor VFactor 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 Essential co-factor for Xa activation of prothrombinprothrombin
• Also acts as co-factor for aPC inactivation of Also acts as co-factor for aPC inactivation of VIIIaVIIIa
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Factor V LeidenFactor V Leiden• Arg506glnArg506gln• Most common inherited thrombophiliaMost common inherited thrombophilia
– 2-10% of healthy population 2-10% of healthy population – 20-50% of first-time VTE20-50% 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
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APC resistanceAPC resistance
• Addition of aPC does not prolong Addition of aPC does not prolong routine clotting assays (aPTT)routine clotting assays (aPTT)
• 90% - due to FV Leiden (point 90% - due to FV Leiden (point mutation preventing Va inactivation mutation preventing Va inactivation by APC)by APC)
• 10% - due to 10% - due to increased plasma levels of factor VIII, the presence of antiphospholipid antibodies, older age, pregnancy, and the use of estrogens
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Factor elevations (VII, VIII, IX, XI)Factor elevations (VII, VIII, IX, XI)
• FVIII elevation has been associated with 6-10 FVIII elevation has been associated with 6-10 fold increased risk of VTEfold increased risk of VTE
• Some believe it should be included in Some believe it should be included in thrombophilia workupthrombophilia workup
• Elevations of FVII, IX and XI of uncertain Elevations of FVII, IX and XI of uncertain clinical relevanceclinical relevance
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DysfibrinogenemiaDysfibrinogenemia
• Variable susceptibility to degradation by Variable susceptibility to degradation by plasminplasmin
• Over 250 fibrinogen mutations have been Over 250 fibrinogen mutations have been describeddescribed
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HyperhomocysteinemiaHyperhomocysteinemia
• Produced in metabolism of methionineProduced in metabolism of methionine
• Associated with arterial disease and venous Associated with arterial disease and venous thrombosisthrombosis
• Acquired due to vitamin deficiency (B6, B12 Acquired due to vitamin deficiency (B6, B12 and folate) or genetic (MTHFR or CBS)and folate) or genetic (MTHFR or CBS)
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Lupus anticoagulantLupus anticoagulant
• First detected prolongation of PT in a patient First detected prolongation of PT in a patient with SLEwith SLE
• Most result in prolongation of aPTTMost result in prolongation of aPTT
• Not an anticoagulantNot an anticoagulant
• Not only in SLENot only in SLE
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APLA SyndromeAPLA Syndrome
• LA and/or APLALA and/or APLA
• Arterial or venous thrombosisArterial or venous thrombosis
• ThrombocytopeniaThrombocytopenia
• Recurrent fetal lossRecurrent fetal loss
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APLA and Risk of Recurrent VTEAPLA and Risk of Recurrent VTE
• Marked elevation in the risk of recurrent Marked elevation in the risk of recurrent thrombosis –20 foldthrombosis –20 fold– With anti-coagulantsWith anti-coagulants
• 3 – 10% risk at 3 years3 – 10% risk at 3 years
– Without anti-coagulantsWithout anti-coagulants• 10 -29% risk at 3 years10 -29% risk at 3 years
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High risk for thrombosis:High risk for thrombosis:Prolonged duration of anticoagulationProlonged 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
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Treatment (1)Treatment (1)
• First time VTE with transient risk factorFirst time VTE with transient risk factor– E.g. surgery, immobilizationE.g. surgery, immobilization
• 3 months VKA3 months VKA
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Treatment (2)Treatment (2)
• First time IDIOPATHIC VTE First time IDIOPATHIC VTE
• Recommend – 6-12 months VKARecommend – 6-12 months VKA
• Suggest – indefinite (esp PE)Suggest – indefinite (esp PE)– Reliable patientReliable patient– Risk factors for bleedingRisk factors for bleeding
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Treatment (3)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
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Treatment (4)Treatment (4)
• First time VTEFirst time VTE– APLAAPLA– Combined (e.g. FV Leiden and PG20210)Combined (e.g. FV Leiden and PG20210)– Single factor and STRONG Family historySingle factor and STRONG Family history
• Recommend 12 months vs indefiniteRecommend 12 months vs indefinite
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Treatment (5)Treatment (5)
• First time VTEFirst time VTE– ATIII deficiencyATIII deficiency– PC deficiencyPC deficiency– PS deficiencyPS deficiency– FV LeidenFV Leiden– Prothrombin gene 20210Prothrombin gene 20210– HomocysteineHomocysteine– Elevated FVIIIElevated FVIII
• Recommend 6-12 monthsRecommend 6-12 months• Prevent Low dose warfarinPrevent Low dose warfarin
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Treatment (6)Treatment (6)
• Recurrent VTERecurrent VTE
• Recommend indefinite VKARecommend indefinite VKA
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Screening for thrombophiliaScreening 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)
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Against screeningAgainst screening
• ExpensiveExpensive
• Does not alter treatmentDoes not alter treatment
• Stigmatizes patient/anxietyStigmatizes patient/anxiety
• May have insurance/employer ramificationsMay have insurance/employer ramifications
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ScreeningScreening
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.
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• No oneNo one
Who should be tested for inherited Who should be tested for inherited thrombophilia? thrombophilia?
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Who should be tested for inherited Who should be tested for inherited thrombophilia? thrombophilia?
• 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 Thrombosis in an unusual site, eg mesenteric
vein, cerebral vein etcvein, 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 Unexplained prolonged activated partial
thromboplastin timethromboplastin time• Patients with recurrent fetal lossPatients with recurrent fetal loss• Relatives of patients with thrombophilic Relatives of patients with thrombophilic
abnormality – very controversialabnormality – very controversial