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Hypercoag state
- 1. Hypercoagulable states Dr Prashant Raman MMC & RGGH, Chennai
- 2. • >6L/yr- USA • 20% mortality • Virchow’s triad
- 3. Pathophysiology • Platelet activation- Plug- activation of coag protein- thrombin- further platelet activation- acts upon fibrinogen- insoluble fibrin clot • Poorly understood mechanism- hyperhomocysteinemia Lp(a)
- 4. • Arterial thrombosis- • Conditions affecting vascular wall and endothelium • Others- increased level of fibrinogen/ vWF- enhances platelet function
- 5. Congenital hypercoag states • Cowther & Kelton classified • Type 1- Reduced natural anticoag • Type 2- Gain of procoag(low risk, more common)
- 6. Group 1 • Rare -<1% • 30-50% heterozygote- symptomatic thrombotic events <60 Y • Routine prophylaxis in ambulant – No benefit • Prophylaxis for known risk status
- 7. AT III • Most Important inhibitor of thrombin and other clotting factors (Xa, IXa & VIIa) • Heparin potentiates- × 1000 • Rare <0.02% • 4-7.5% in VTE pts • >250 mutations • Homozygosity – incompatible with life
- 8. • Types • 1- function/Ag level • 2-function • 3-moderate activity due to impaired interaction with heparin • Measurements:- Functional assay
- 9. • 60%- Type I &II- Thrombosis <60 Y • Predominantly- lower extremity with/without PE • Recurrence • Atypical events • Preg- High risk- Heparin throughout preg and cont. postpartum
- 10. • Breakthrough events- AT concentrates • Acquired Form- Fatty liver of preg- Treatment • Plasma • AT concentrates
- 11. Protein C deficiency • Vit K dependent anticoag protein- activated by thrombin to APC • thrombin binds with TMchanges the specificity of thrombin from cleaving fibrinogen/ activating platelets to activating protein C Protein C binds to its receptorAPCSerine protease anticoagcleaves cofactor VIIIa/Vamodulates thrombin generation/clot formation
- 12. • 0.2%- general population • 2.5-6%- VTE • Types • 1- Function/ Ag • 2- Function • Heterozygotes- activity level<60%
- 13. • VTE- Lower extremity • Unusual sites same as AT III • Life long anticoag- umprovoked/<40 Y • Homozygotes- Neonatal disorder- Purpura fulminans- Immediate Heparin/Plasma. Protein C Concentrates • Heterozygotes- higher dose of warfarin- similar presentation. • T/t: FFP/ Vit K/ Heparin
- 14. Protein S def • Vit K dependent cofactor- necessary for the inactivation of factor Va & VIIIa by APC • Pathophysio- Same as Protein C def • 2 forms • Active and bound to complement binding C4b • Functionally active free form- 20-40%
- 15. • Most pt with def- Activity level- 50-75% • Types: • 1. Function/Ag • 2. function • 3. free active protein S due to enhanced C4b binding • Type I & III- m/c
- 16. • Measurement confounded by- • Preg- Level • Active Ca/ SLE/ APLAS/ Sepsis/ Chr Inflammatory disorders/ Active HIV
- 17. Clinical presentation • VTE-frequently reported in association with venous thrombosis in atypical site • Neonatal purpura fulminans –also seen
- 18. Group 2 • Factor V Leiden (Activated Protein C Resistance) • Cofactor –that accelerates the conversion of Factor IIthrombin(in presence of Xa) • Normally degraded by serine protease • Mutation- renders it resistant
- 19. • 2-7% of European ancestry • Rare – Asian/African • risk of thrombosis • Homozygotes-80✕
- 20. Clinical Presentation/Mgmt • Overwhelming Venous • Rare- unusual sites • Triggered by risk factors • No mortality • No prophylaxis for carriers • Antepartum – not recommended except for previous h/o thrombosis/ recurrent fetal loss
- 21. Prothrombin Gene mutation • Mutation affects 5’ end cleavage signal- prothrombin mRNA stability • Thrombotic risk- reatively low • Rare- African/Asian • Predominantly LL VTE • Rare- unsusual sites • risk in women on OCs
- 22. Elevated factor VIII, XI & IX • Factor VIII->150%- 4.8% RR • No relation with Ocs • VTE • Measurement confounded- APR/ bleeding/ inflammation • Simultaneous- ESR/CRP
- 23. Clinical Presentation • VTE- LL • vWF- arterial • Factor IX/ XI- 2✕
- 24. others • Homocysteneimia- metab- • 1. B6 dependent Cystathione beta synthetase • 2. B12/ Folate – 5,10 MTHFR & methionine synthase • Folate supplementation- brings Normal range
- 25. • Reported mech • Toxic • platelet activation • Oxidation of LDL • Inflamm- d • endoth. TM • vWF/ Factor VIII
- 26. • Measurement confounders • Vit def • Renal insufficiency • Improper plasma collection • Best performed: fastong state/ fresh sample
- 27. Lp(a) • Consists of low density lipid particles with a disulfide link to a polypeptide chain- Apolipoprotein(a) • Compete with tPA/plasminogen/plasmin for binding to fibrin & endothelial annexin • Inhibits fibrinolysis • May as APR
- 28. Sticky platelet syndrome • AD • Young- MI/PVD • Precupitated with stress • Hyperactivity to Epi/ ADP- but normal response to thrombin/collagen/arachidonic acid
- 29. • 3 types • 1. Activity to Epi/ADP • 2. Epi only • 3. ADP only • Low dose ASA (81mg)
- 30. Idiopathic VTE • Underlying inflamm. States • IL-6/IL-8, Low levels of IL-10
- 31. Acquired • APLAS • Ca • PNH- Platelet activation and leukocyte tissue factor • MPS- unusual sites • Esp with JAK-2 mutation
- 32. APLAS • Art/Ven Thrombosis • Presence of LA and titer IgG ACL Ab- 3.6✕ LA & either antiprothrombin or anti beta-2 GP- 10✕ Syndrome- paradox aPTT Complement C5a mediated inflammation has been demonstrated- thrombosis/fetal loss
- 33. Diag • Ig G/ IgM Ab - ACL • Abti beta2 GP1
- 34. Clinical presentation • Art/venous • Unusual sites- NBTE • Recurrence- 50% • Moderate intensity warfarin • Catastrophic APLA- prompt recog/ Heparin/ Plasmapharesis
- 35. Cancer • Expression of tissue factor • Malig induced inflammation • Prothrombotic hemostatic changes • fibrinogen/ Factor VIII & platelet count • Mechanical and invasive • Chemo induced • With ca 7✕ • With mets20✕
- 36. • 3✕ recurrence/ risk of bleeding • Against the use of warfarin/ in favour of LMWH • Arterial thrombosis: 10-30% of thrombotic complications • Chemo+ antiangiogenic(bevacizumab)- 2✕
- 37. • NBTE- m/c /c- stroke with solid tumors
- 38. Preg and OCs • Preg- acquired prothrombotic state • Hormone related elevation of fibrinogen, Factor VIII, Protein S, depressed fibrinolysis • Cong. Def- Protein C/S- more likely VTE • Postpartum – 50% of all • Lt leg- 90%
- 39. • Cong def- Ante/post partum prophylaxis • Factor V- Peri/Postpartum(6wks) except for previous events • Active thrombosis- Full dose LMWH
- 40. OCs • Estrogen alone/ with Progestrone • 1st gen • 2nd gen- Levonorgestrel/ norgestrione/norgestrel • 3rd gen- Desgestrel/Gestodene • 3rd gen ✕2
- 41. • Combination with inherited thrombophilia- multiplicative
- 42. HIT • Arterial/Venous • No bleeding • IgG Ab directed Hep-PF4 complex- Activation- release membrane microparticles- Express P selectin capable of activating monocytes and inducing tissue factor expression- Coag cascade • V:A::4:1
- 43. Diag/Mgmt • Thrombocytopenia/ thrombosis during or immediately following heparin use- > 50% • Thrombotic sequelae- 30-70% • Severe thrombocytopenia- <20% rare • Median Nadir- 50-60K • Development of new thrombosis/ progression of existing in a pt receiving heparin
- 44. • In heparin naïve pt- platelet count every other day beginning 5 days after starting Heparin • With previous exposure- monitor with the start of Heparin use • Development of platelet activating, non- complement fixing IgG Ab directed against the complex of heparin+PF4 - hallmark
- 45. • Ab detection • Functional assay- detects Ab capable of inducing platelet activation (serotonin release assay)- C14 SRA or heparin induced washed platelet aggregation assay • PF4- heparin immunoassay (ELISA)
- 46. • Prompt recognition • Immediate cessation of all forms of heparin • Rapid initiation of direct thrombin inhibitors- such as Argatroban, Lepirudin or Bivalrudin. • Essential for preserving – limb/ life • Warfarin alone – not protective.
- 47. • Patients within 100 days of diag- should not receive any form of heparin therapy • Beyond 100 days- may receive if indicated • Ideally daily platelet count monitoring
- 48. Obesity • >25 Kg/m2: combination of tall stature/ obesity • - presence of metab synd- abd obesity/imapired gluc metab/ SHTN/ dyslipidemia
- 49. Evaluation • Patients with VTE eho should be tested: • <50 Y- unprovoked • Unprovoked+ Recurrent • Thrombosis including those associated with a transient risk factor, if there is a strong family H/O VTE • In younger pts <50 Y – without DM- unprovoked arterial thrombosis- screening evaluation can identify prothrombotic risk factors.