HEREDITARY THROMBOPHILIA

Remember that the most common reason is the acquired forms (Like Antiphospholipid antibody ) and not the hereditary forms ।



Testing for hereditary causes :
1-PT and aPTT(the first to start)

2-AT deficiency: Antithrombin deficiency(heparin cofactor 1)। inhibits thrombin and fact x॥ also heparin needs this factor to work !! , when can’t reach therapeutic PTT on heparin drip !! 2 type। don’t waste your time with heparin

3-Protein C deficiency: check activity first .2 type ,pro c and Z are Vit K dependent

4- Protein S deficiency: check activity first .2 type ,it binds to C4B with goes up in acute phase and will drop protein s level, you cab check c4b or free pro S

5-APC Resistance :activated Pro C resistance nothing to do with Pro C ! inhibits fac V and VIII, if positive check Factor V Leiden



6- Factor V Leiden: most common , major cause of APCR

7- Prothrombin G20210A Mutation :mutation will cause excess of prothrombin(II)

8-Factor VIII Excess (check fibrinogen at then same time, it is a acute phase pro and ..) excess level of 800 %

9-Homocysteine, excess level , treatment is not anticoagulation B12,6, folate
-MTHFR

10-Factor XII deficiency :even though it’s a part of intrinsic factor and one might think should cause bleeding it does the opposite (also involve in converting plasminogen to plasmin)

11-Protein Z deficiency: Vit K dependent like pro

12-Heparin cofactor II deficiency :inhibits thrombin (not factor X)

13-TFPI: tissue factor pathway inhibitor deficiency;inhibits X and VII

14-PAI-I :plasminogen activator inhibitor -1 ,inhibits fibrinolysis. Expensive, test if everything else negative.

15-Elevated factor XI and V and II



Balance between adequate blood flow in normal vessels and rapid cessation of bleeding in injured vesselsInteraction between coagulation cascade and fibrinolysisBegins with endothelial injury à platelet activation à activation of clotting cascade à anticoagulants à fibrinolysis à resolution of clotImbalance in HemostasisThrombosis:Multigenic/MultifactorialTwo hit hypothesis: more than one risk factor required to develop thrombosisAntithrombin Antithrombin Manufactured in liverOther designationsHeparin cofactor I Antithrombin IIISerine protease inhibitorRequires heparan or heparin to functionHeparin requires antithrombin to functionAntithrombin Natural anticoagulant activityInactivates thrombin and factors Xa, IXa and XIaForms 1:1 complex with themDeficiency results in thrombosisVenous – more commonArterial Antithrombin DeficiencyEstimated frequency = 1%Types of deficiencyType I - quantitativeA = normal molecule, decreased amountB = abnormal molecule, abnormal amountType II – qualitative, abnormal moleculeA = activity and heparin binding siteB = activity onlyC = binding site onlyAntithrombin DeficiencyLaboratory testingAntithrombin activity or functionalChromogenic, if availableTreatmentAnticoagulationAntithrombin III concentrate (Thrombate III)Activation of Protein CProtein CManufactured in liverVitamin K dependentZymogen (must be activated)Thrombin combines with thrombomodulinRequires Protein S as cofactorProtein C DeficiencyNatural anticoagulant activityInactivates factors Va and VIIIaInactivates PAI-IDeficiency results in thrombosisVenous – more commonArterialPurpura fulminansHomozygous childrenPurpura FulminansProtein C DeficiencyEstimated frequency = 5%Types of deficiencyType I – quantitativeDecreased activity & decreased amountType II – qualitativeDecreased activityNormal amountProtein C DeficiencyLaboratory testingProtein C Activity or functionalChromogenic, if availableTreatmentAnticoagulationWarfarin-induced skin necrosis may occurProtein C concentrate Warfarin-induced Skin NecrosisProtein SManufactured in liver, endothelial cells, megakaryocytes, testes, kidney & brainVitamin K dependentMost of Protein S circulates bound to C4b binding proteinAcute phase reactantIncreases with inflammationProtein SFree Protein S is active formNatural anticoagulant activityCofactor for Protein CCombined with Protein CInactivates factors Va and VIIIaAloneWeak activity to inactivate factors Va, VIIIa and XaProtein S DeficiencyDeficiency results in thrombosisVenous – common with inactivityArterial – common in cerebral vesselsPurpura fulminansEstimated frequency = 3%Protein S DeficiencyTypes of deficiencyType I – quantitativeDecreased total, free and functionalType II – qualitativeNormal total and freeDecreased functionalType III – associated with increased C4bNormal totalDecreased free and functionalProtein S DeficiencyLaboratory testingProtein S activity or functionalProtein S freeC4b binding proteinChromogenic, if availableTreatmentAnticoagulationWarfarin-induced skin necrosisFactor XII Factor XIIManufactured in liverHageman factorSerine proteaseActivated by kallikrein (Fletcher Factor)Factor XIIa linked to kinin system, intrinsic fibrinolysis & complement systemsConverts plasminogen to plasminEstimated frequency of deficiency is lowFactor XII DeficiencyDeficiency decreases fibrinolysisDeficiency results in thrombosisVenous – more commonArterial – rareLaboratory testingFactor XII levelsTreatmentAnticoagulation Protein ZProtein ZVitamin K dependentCofactor for PZ-dependent protease inhibitor (PZI)Results in inactivation of factor XaFrequency of deficiency unknownDeficiency results in venous thrombosisLaboratory testing = Protein Z levelsTreatment = anticoagulationHeparin Cofactor IIHeparin Cofactor IIGlycoprotein, serine protease inhibitor familyActivated by heparan, heparin or dermatan sulfateResults in inhibition of thrombinNO effect on factor XaHeparin Cofactor II DeficiencyDecreased inhibition of thrombinDeficiency results in venous thrombosisActual risk is unknown at this timeLaboratory testingHeparin cofactor II levelsTreatmentAnticoagulation Tissue Factor Pathway Inhibitor (TFPI)TFPILocated in endothelial cellsBound to heparan sulfateHeparin increases plasma concentrationCombines with free factor Xa à Xa:TFPIXa:TFPI combines with VIIa:TFDecreased production of factor XInactivation of VIIa:TFTFPI DeficiencyFrequency unknownDeficiency causes:Venous thrombosisIntrauterine lethality (fetal loss)Neointimal proliferationLaboratory testingTFPI levelsTreatmentAnticoagulation Activated Protein C Resistance(APCR)APC ResistanceFrequency difficult to determine – may be as high as 30-50%Normal Protein C and Protein SNormal levels of activated Protein C with normal activityAPC unable to combine with factor Va for inactivationAPC ResistanceDefective factor VaReceptor for APC defectiveAPC unable to bind & inactivateNow looking at areas on factor VIIIaDefects in APC binding siteResults in venous & arterial thrombosisLaboratory testing = APC resistance assayTreatment = anticoagulation Inactivation of Factor VaFactor V LeidenMajor cause of APC ResistanceFrequency estimated at 20%Single point mutation (1691 Gà A) results in 506 Arg/Gln substitutionAffects first of three APC cleavage sitesAPC cannot down-regulate Factor VaFactor Va forms prothrombinase complex with factor Xa à conversion of prothrombin to thrombinProlonged procoagulant activityFactor V LeidenMost common genetic risk factor for thrombosisVenous and arterial Heterozygotes: 3 – 10X increased riskHomozygotes: 80X increased riskLaboratory testingRT-PCR for Factor V LeidenTreatment = anticoagulationOther Factor V MutationsFactor V Hong KongSingle point mutation results in 306 Arg/GlyRare cause of venous thrombosisFactor V CambridgeSingle point mutation results in 306 Arg/ThrRare cause of thrombosisFactor V LiverpoolSingle point mutation at Arg 679Rare cause of venous thrombosisHR2 HaplotypeSeveral mutationsRisk of venous thrombosis unknown at this timeThrombin: Central Role in HemostasisProthrombin G20210A MutationProthrombin G20210AEstimated frequency is 6%Mutation in location of 3’-UT regionResults in increased levels of ProthrombinVenous and possible arterial thrombosisHeterozygotes 3X increased risk of venous thrombosis Prothrombin G20210ALaboratory testingRT-PCR testing for gene mutationDo NOT measure factor II levelsTreatmentAnticoagulation Metabolism of HomocysteineHomocysteineTwo enzymesCystathionine B-synthaseConverts homocysteine to cystathionineDefect results in homocysteinuriaMTHFR (methylene tetrahydrofolate reductase)Converts homocysteine to methionineDefect causes homocysteinemia in presence of folate depletionThree vitamins – folate, B6 & B12HyperhomocysteinemiaElevated homocysteineDamage to endothelial cellsIncreased smooth muscle cell proliferationIncreased binding of Lp(a)Decreased vascular reactivity (decreased nitric oxide synthesis) Premature atherosclerosisIncreased tissue factor & factor Va releasedDecreased thrombomodulin (protein C activation) & heparan activityBlocked endothelial cell mediated fibrinolysis Venous/arterial thrombosisPregnancy-related vascular disorders = fetal lossHyperhomocysteinemiaLaboratory testingHomocysteine levelsMTHFR mutation by RT-PCRTreatmentVitamin supplementationFolate, B6 & B12Anticoagulation, if necessaryElevated Factor VIIIEstimated frequency is 16%Manufactured in endothelial cells & megakaryocytesAcute phase reactant with levels to ~400%Factors VIIIa & IXa form tenase complex (converts factor X to Xa)Factor Xa converts factor II to thrombinElevated Factor VIIILevels >400% are dangerousResult in increased thrombinIncrease in all factor VIII componentsVenous thrombosis occursPossible arterialLaboratory testing = Factor VIII levelsTreatment = anticoagulationOther Elevated Factor LevelsRisk factor for venous thrombosisLevels above the 90th percentileInclude factors XI, V and IIProbable genetic associationTestingSpecific factor levelTreatment = anticoagulationIncreased PAI-IPlasminogen Activator Inhibitor-IInhibits fibrinolysis (conversion of plasminogen to plasmin)Decreased fibrinolysis à increased and persistent clotting (venous thrombosis)Rare but may be cause when other tests are negativeTreatment = anticoagulationLABORATORY TESTINGWhen To TestHistory of recurrent thrombosisVTE prior to 45 years of ageUnprovoked VTE – any ageThrombosis in unusual sitesThrombosis + positive family history of thrombosisVTE secondary to pregnancy, OCT, hormone replacement therapyRecurrent fetal lossEarly onset atherosclerosisLaboratory TestingPattern the testing to the clinical presentationBe sure patient is clotting (not bleeding) before ordering tests for ThrombophiliaTry to test when patient is not acutely ill and not on anticoagulantsSeveral weeks after thrombotic eventSeveral weeks after anticoagulants discontinuedRecommended Lab TestingPT & aPTTNatural anticoagulants Antithrombin activityProtein C functionalProtein S functional & freeAPC resistanceFactor V LeidenProthrombin G20210AFactor VIIIFibrinogen Additional TestingHomocysteine levelMTHFROther factor levels (for increase)FibrinolysisPlasminogenPAI-IRecurrent Fetal LossAntiphospholipid SyndromeProtein C, S & ATIIIFactor V LeidenProthrombin G20210ACombinationPoints to RememberAvoid testing during acute eventUse functional assays firstConsider age & genderAlways confirm with repeat testingIf one abnormality identified, continue testing for others (combined common)Use PCR when available