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PATHOPHYSIOLOGY OF THROMBOSIS “Virchow’s Triad”

PATHOPHYSIOLOGY OF THROMBOSIS “Virchow’s Triad”. Injury to blood vessels Trauma, atherosclerosis, surgery Stasis of blood Immobility, venous incompetence, heart failure Increased coagulability of blood - “thrombophilia” Various inherited and acquired conditions

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PATHOPHYSIOLOGY OF THROMBOSIS “Virchow’s Triad”

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  1. PATHOPHYSIOLOGY OF THROMBOSIS“Virchow’s Triad” • Injury to blood vessels Trauma, atherosclerosis, surgery • Stasis of blood Immobility, venous incompetence, heart failure • Increased coagulability of blood - “thrombophilia” Various inherited and acquired conditions • In general, vessel injury is the most important contributing factor to arterial thrombosis (heart attack, stroke) while stasis and increased coagulability are more important in venous thrombosis

  2. INHERITED THROMBOPHILIA • Venous >> arterial thrombosis • Most venous thrombi in legs • Occasionally mesenteric, portal, cerebral,retinal veins • Prevalence of thrombosis varies between families • Thrombotic problems may begin in 20s and 30s – rarely in childhood • About half of thrombotic episodes occur in association with other identifiable risk factors (pregnancy, oral contraceptives, surgery, etc)

  3. DEEP VENOUS THROMBOSIS

  4. PULMONARY EMBOLISM Arrow points to large clot in pulmonary artery Clot dissolved after administration of fibrinolytic drug

  5. THERE ARE MANY POTENTIAL GENETIC CAUSES OF THROMBOPHILIA “If something can go wrong, it will” (Murphy)

  6. THERE ARE FIVE KNOWN CAUSES OF INHERITED THROMBOPHILIA Defects in physiologic anticoagulant pathways • Antithrombin deficiency • Protein C deficiency • Protein S deficiency • Factor V Leiden Increased production of procoagulant • Prothrombin G20210A gene mutation

  7. QUANTITATIVE VS QUALITATIVE DEFICIENCY OF CLOTTING PROTEINS • Quantitative deficiency: decreased protein production (gene deletion, nonsense mutation, etc) • Both antigen and activity low • “Type I” deficiency • Qualitative deficiency: normal protein production, decreased activity (missense mutation) • Antigen normal, activity low • “Type II” deficiency

  8. ANTITHROMBINAKA “ANTITHROMBIN III” • Serine protease inhibitor • Made in liver • 20 mg/dl plasma concentration • Inhibits thrombin, Xa, other clotting enzymes • Activity enhanced by heparin and heparin-like molecules on endothelium

  9. THE ANTITHROMBIN SYSTEM

  10. Serine protease mechanism

  11. ANTITHROMBIN-HEPARIN INHIBITORS OF MULTIPLE STEPS IN THE CLOTTING CASCADE XIIa Inhibits all serine protease clotting factors except VIIa TF VII(a) XIa VIIIa IXa Xa Va ANTITHROMBIN IIa HEPARIN

  12. INHERITED ANTITHROMBIN DEFICIENCY • Prevalence: 0.2-0.4% of population; 2-5% of inherited thrombophilia • Dominant inheritance with variable penetrance • No homozygotes known (lethal?)

  13. ANTITHROMBIN ASSAYS • Patient plasma + heparin + thrombin • Thrombin activity measured with chromogenic substrate • Measure decay of thrombin activity with time • Detects both quantitative and qualitative deficiency • Other serine protease inhibitors in plasma may contribute to measured activity causing decreased sensitivity • Alternative assay uses factor Xa rather than thrombin, greater specificity and sensitivity

  14. THE PROTEIN C SYSTEM • PROTEIN C • Proenzyme precursor of serine protease • Made in liver, vitamin K-dependent • 0.4 mg/dl in blood • When activated by thrombin, degrades Va and VIIIa • PROTEIN S • No intrinsic enzymatic activity • Made in liver, endothelium, vitamin K-dependent • Bound/inactive and free/active forms in plasma • Cofactor for protein C • THROMBOMODULIN • Endothelial cell surface component • Binds thrombin • TM-bound thrombin activates protein C

  15. THE PROTEIN C SYSTEM Vi VIIIi Va VIIIa APC + P S IIa P C P C IIa IIa TM TM E C E C

  16. PROTEIN C DEFICENCY • Dominant form: 30-60% of normal protein C activity in blood • Found in about 5% of inherited thrombophilia • Both quantitative and qualitative deficiency can occur • Recessive form: < 10% of normal protein C activity • Parents (heterozygous) have about 50% of normal level, asymptomatic • Rare affected individuals (homozygous) have severe thrombotic tendency that may begin in infancy • Biologic basis for dominant vs recessive forms unknown

  17. DOMINANT INHERITANCE OF PROTEIN C DEFICIENCY 32 30 24 22 19 30 26 21 22 18 17 13 8 Protein C deficient Protein C normal History of thrombosis

  18. RECESSIVE INHERITANCE OF PROTEIN C DEFICIENCY

  19. HOMOZYGOUS PROTEIN C DEFICIENCY CAUSES NEONATAL PURPURA FULMINANS

  20. PROTEIN C LEVELS DROP FASTER THAN LEVELS OF OTHER VITAMIN K-DEPENDENT PROTEINS DURING WARFARIN TREATMENT Prothrombin Protein C

  21. WARFARIN-INDUCED SKIN NECROSIS IN A PROTEIN C-DEFICIENT PATIENT

  22. PROTEIN C ASSAYS • Immunologic • Detects only quantitative deficiency • Functional, chromogenic substrate • Snake venom enzyme activates protein C in test plasma • Activated protein C cleaves chromogenic substrate • Detects quantitative, most qualitative deficiency • Functional, clotting time-based • Detects any deficiency • Not useful in patients taking warfarin

  23. Bound (inactive) Free (active) PROTEIN S Crossed immunoelectrophoresis showing bound and free forms

  24. PROTEIN S DEFICIENCY • Dominant inheritance, prevalence unknown Found in about 5% of inherited thrombophilia • Three patterns of deficiency • Reduced (30-60%) total protein S antigen with proportionate reduction in free protein S • Reduced free protein S with normal total protein S antigen • Reduced protein S activity with normal total and free protein S antigen

  25. PROTEIN S ASSAYS • Total protein S (immunologic) • Detects only type 1 deficiency • Free protein S (immunologic) • Detects type 1 and type 2 deficiency • Protein S activity • Theoretically should detect any deficiency • Some assays give false positive result in patients with activated protein C resistance due to factor V Leiden

  26. PROTEIN C AND SAcquired deficiency states • Warfarin treatment • Vitamin K deficiency • Liver disease • Newborn • DIC (protein C) • Inflammation (free protein S) • Pregnancy (protein S) • Oral contraceptive use (protein S)

  27. MEASURING PROTEIN C AND S IN WARFARIN-TREATED PATIENTS • Problem: warfarin causes decreased protein C and protein S level • Solution: compare levels of these proteins to another vitamin K-dependent protein (factor X) • Low ratio of protein C or S to factor X suggests underlying deficiency state • Requires steady state warfarin treatment (same dose for at least a week) • Only applicable to antigen measurements

  28. Factor V Leiden Missense mutation changes amino acid 506 of factor V from arginine to glycine Mutation is at preferred protein C cleavage site, slows inactivation of factor Va by protein C Factor Va procoagulant activity not affected Single mutation responsible for almost all cases Very common (up to 5% of population heterozygous) Accounts for up to 50% of inherited thrombophilia

  29. Vi VIIIi Va VIIIa APC + P S IIa P C P C IIa IIa TM TM E C E C

  30. MODIFIED FUNCTIONAL ASSAY FOR FVL 1. Mix patient plasma with factor V deficient plasma (1:4) 2. Plasma mixture aPTT 3. Mixture + APC aPTT aPTT with APC aPTT without APC APC ratio = 4.

  31. THE FACTOR V LEIDEN MUTATION

  32. NORMAL HETEROZYGOUS HOMOZYGOUS DNA TESTING FOR FACTOR V LEIDEN FVL DNA AMPLIFIED BY PCR, DIGESTED WITH RESTRICTION ENZYME

  33. PROTHROMBIN G20210A GENE MUTATION Mutation in 3' untranslated (non-coding) part of prothrombin gene No effect on prothrombin structure or function Heterozygotes have 5-10% higher plasma levels of prothrombin Heterozygotes have 2-3 fold risk of venous thromboembolism Risk in homozygotes uncertain About 1-2% of population heterozygous; 5-7% of young patients with DVT/PE Diagnosis: DNA testing

  34. COMPARISON OF INHERITED THROMBOPHILIAS

  35. INHERITED THROMBOPHILIA: GENE DOSE Relative risk of thrombosis in heterozygous and homozygous factor V Leiden Genotype Relative Risk Normal 1 Heterozygous 7 Homozygous 80 Rosendaal et al, Blood 1995;85:1504

  36. INHERITED THROMBOPHILIA: GENE INTERACTIONS Co-inheritance of protein C deficiency and factor V Leiden within a family Thrombosis present (%) Thrombosis absent (%) Gene Mutation Protein C and Factor V 16 (73) 6 (27) Protein C 5 (31) 11 (69) Factor V 2 (13) 11 (87) None 0 11 (100) Koeleman et al, Blood 1994;84:1031

  37. RISK OF VENOUS THROMBOSIS Factor V Leiden plus oral contraceptive RELATIVE RISK OF THROMBOSIS RISK FACTOR Oral contraceptive 4 Factor V Leiden 8 Both 35 Vandenbroucke et al, Lancet 1994;344:1453

  38. INHERITED THROMBOPHILIA IS A RISK FACTOR, NOT A DISEASE Thrombophilia is a weak (not statistically significant) predictor of recurrence in patients with venous thrombosis

  39. Unaffected (no defect) PT FVL, PT mutation: Most carriers remain asymptomatic FVL PC, PS, AT deficiency: Higher chance of thrombosis, but many carriers asymptomatic PC AT PS RISK OF VENOUS THROMBOSIS IN AFFECTED VS UNAFFECTED RELATIVES OF THROMBOPHILIC PATIENTS Blood 2009;113:5314

  40. When is it indicated? TESTING FOR INHERITED THROMBOPHILIA Young patient Family history Thrombosis in absence of known risk factors Warfarin-induced skin necrosis (protein C) Neonatal purpura fulminans (protein C, S)

  41. What's next? DIAGNOSIS OF INHERITED THROMBOPHILIA Rapid, cheap (?) screening for large numbers of mutations and polymorphisms using DNA chip technology More accurate diagnosis of inherited antithrombin, protein C, protein S deficiency Discovery of many new genetic conditions that affect thrombotic risk More information than we know what to do with

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