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Thrombophilia & Diagnostic Tests.pdf
1. Alireza Moghaddam is a hematology supervisor at Pars Hospital Lab who discusses coagulation and thrombosis. 2. The document covers the coagulation cascade including its intrinsic and extrinsic pathways, as well as abnormalities that can cause a hypercoagulable state and increase thrombosis risk. 3. Both inherited and acquired risk factors for thrombosis are described such as deficiencies in natural anticoagulants, mutations in clotting factors, and autoimmune conditions like antiphospholipid syndrome.
Thrombophilia & Diagnostic Tests.pdf
- 1. Alireza Moghaddam Hematology Supervisor atPars Hospital Lab
- 2.
- 3. Blood mustbe fluid Must coagulate (clot) at appropriate time • Rapid • Localized • Reversible ➢ Thrombosis inappropriate coagulation
- 4. ➢ Vessel Wall Endothelium ➢Platelets ➢ Coagulation Cascade Coagulation Proteins ( Factors)
- 5. • Anti-platelet properties ▪Covers highly thrombogenic basement membrane ▪ Uninjured endothelium does not bind platelets ▪ PGI2 (prostacyclin) and NO from uninjured endothelium inhibit platelet binding ▪ ADPase counters the platelet aggregating effects of ADP
- 6. ➢ HEPARIN-LIKE MOLECULES:activate anti- thrombin III (inactivates active proteases) THROMBOMODULIN: changes specificity of thrombin (activates protein C , which inactivates factors Va and VIIIa Endothelial cells produce t- PA which activates fibrinolysis via plasminogen to plasmin
- 7. Prothrombotic Properties ofthe Endothelium •Synthesis of von Willebrand factor •Release of tissue factor •Production of plasminogen activator inhibitors (PAI) •Membrane phospholipids bind and facilitate activation of clotting factors via Ca++ bridges
- 10. Injury of vesselswall leads to contact between blood and subendothelial cells FXa binds to FVa on the cell surface The complex between TF and FVIIa activates FIX and FX Tissue factor (TF) is exposed and binds to FVIIa or FVII which is subsequently converted to FVIIa 1. Initiation phase
- 11. (PTT) (PT) ✓ All ClottingFactors are within a blood vessels ✓ Clotting Slower ✓ Initiating Factor is Outside the blood Vessels ( Tissue Factor) ✓ Clotting Faster (Blood Vessel Injury) (Tissue Injury)
- 13. The FXa/FVa complex convertssmall amounts of prothrombin into thrombin The small amount of thrombin generated activates FVIII, FV, FXI and platelets locally. FXIa converts FIX to FIXa 2. Amplification phase Activated platelets bind FVa, FVIIIa and FIXa
- 15. ➢ Disseminated IntravascularCoagulation (DIVC) ➢ Liver Disease ➢ Nephrotic Syndrome ➢ Pregnancy ➢ Warfarin Therapy ➢ Acute Inflammatory Processes ➢ Acute Thrombosis
- 16. • Immobilization MedicalDisorders ▪ Cancer/Anticancer Drugs * Hyperlipidemias • Antiphospholipid Syndrome * Nephrotic Syndrome • Vasculitis * Myeloproliferative Disease • Pregnancy * Paroxysmal Nocturnal • Oral Contraceptive Haemoglobinuria(PNH) • Hormone Replacement Therapy * Adams 13 Deficiency *Heparin Induce Thrombopathy * Obesity
- 17. • Antiphospholipid syndrome •Hyperhomocysteinemia • Miscellaneous • Thrombocythemia • Dysproteinemia • Heparin-induced thrombocytopenia (HITT) • Estrogens – Birth control pills – Hormone replacement therapy
- 18. ➢ Malignancy ➢ Pregnancy ➢Bed rest ➢ Surgery ➢ Trauma
- 19. • Activated proteinC resistance (factor V Leiden) • Protein S deficiency • Protein C deficiency • Antithrombin deficiency • Hyperhomocysteinemia • Prothrombin 20210A allele • Dysplasminogenemia • High plasminogen activator inhibitor • Dysfibrinogenemia • Elevated factor VIII
- 20. Physiologic Inhibitors of coagulation •Antithrombin III (serpin) • Activated Protein C + protein S – Inactivates Va and VIIIa (via proteolysis) – NB: Factor V Leiden • Thrombomodulin (EC glycoprotein) – Binds to thrombin – Decreases ability to produce fibrin – Increases ability to activate Protein C
- 21. Non-physiologic inhibitors ofcoagulation Vitamin K antagonists (in vivo only) Ca chelators (in vitro only) EDTA Citrate Oxalate * Heparin (in vivo and in vitro)
- 23. Abnormality Arterial Venous FactorV Leiden - + Prothrombin G20210A - + Anti Thrombin Deficiency - + Protein C Deficiency - + Protein S Deficiency - + Hyperhomocystinemia + + Antiphospholipid Syndrome + +
- 24.
- 25. ➢ Plasminogen ActivatorInhibitors ( PAIs) ➢ a2-antiplasmin (serpin)
- 27. Protein Cpathway • Factor V Leiden • Protein C deficiency • Protein S deficiency Prothrombin G20210A mutation Antithrombin deficiency Hyperhomocystinemia • C677T MTHFR mutation
- 28. Protein Cdeficiency • Type I – number and activity • Type II – activity Protein S deficiency • Type I – total and free forms • Type II – cofactor activity • Type III - free only Autosomal dominant • 0.2-0.5, 0.8 prevalence
- 29. Protein C Pathway C4BP S inactive Thrombin Endothelialsurface PC Thrombomodulin S active APC Platelet surface Va Vi VIIIa VIIIi PAIa PAIi
- 31. Mutation inFactor V • Protein C/S complex • Impaired anticoagulation 5-11% of white Europeans Heterozygous • Autosomal dominant Homozygous rare
- 34. Multiple mutations Most thrombogenic disorder Type I • Levels and activity Type II • Activity
- 35.
- 37. MTHFR and Thrombosis Hyperhomocystinemia implicated in both arterial and venous thrombosis Why is homocysteine thrombogenic? Theories: Direct toxicity to endothelial cells Inhibits Protein C activation Promotes endothelial tissue factor expression Surpresses endothelial cell surface heparin sulfate
- 38. Atherosclerosis, NTD,thromboembolism Severe – homozygous • 1 in 200,000-355,000 • Cystathionine -synthase Mild to moderate • Heterozygotes for CS mutation • Homozygous for 667C-T MTHFR (11%)
- 40. Autoimmune AcquiredProthrombotic Disorder Very High Risk for recurrent thromboembolic disease both venous and arterial Indefinite duration anticoagulation recommended +/- immunosuppression Strict Diagnostic Criteria