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Thrombophilia

Thrombophilia . Thrombophilia . Now considered a multicausal disease, with an interplay of acquired and genetic thrombotic risk factors

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Thrombophilia

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  1. Thrombophilia

  2. Thrombophilia • Now considered a multicausal disease, with an interplay of acquired and genetic thrombotic risk factors • Approximately half of venous thromboembolic episodes in patients with inherited thrombophilias occur in relation to events that are generally recognizedas a predisposing states, such surgery, pregnancy, and immobilization

  3. Inherited thrombophilic states (1) • Antithrombin deficiency • Abnormalities in protein C and protein S system - protein C deficiency - protein S deficiency - abnormal thrombomodulin • Resistance to activated protein C (FV Leiden, FV Cambridge)

  4. Inherited thrombophilic states (2) • Hyperprothrombinemia (prothrombin variant G20210A) • Dysfibrynogeneimia • Abnormalities in fibrinolytic system - hypo- or dysplasminogenemia - elevated plasminogen activator inhibitor - decreased tissue plasminogen activator • Hyperhomocysteinemia • Heparin cofactor II defciency • Elevated histidine-rich glycoprotein • Factor XII deficiency

  5. Frequency (%) of inherited thrombophilic syndromes in the general population and in patients with venous thrombosis (VT) *- age < 45 years and/or recurrent thrombosis

  6. Molecular basis of inherited thrombophilia caused by impaired anticoagulant mechanisms (1)

  7. Molecular basis of inherited thrombophilia caused by impaired anticoagulant mechanisms (2)

  8. Clinical features of patients with inherited deficiencies of AT, PC, PS, and APC-resistance • Venous thrombosis (>90%of cases) • Deep vein thrombosis of the lower limbs (common) • Pulmonary embolism (common) • Superficial thrombophlebitis • Mesenteric vein thrombosis (rare but characteristic) • Cerebral vein thrombosis (rare but characteristic) • Frequent family history of thrombosis • First thrombosis usually at young age (<40yr*) • Frequent recurrences* • Neonatal purpura fulminans (homozygous PC or PS deficiency) *- all these features are less evident in patients with APC-resistance, who appear to be less severely affected clinically

  9. Laboratory diagnosis of inherited thrombophilia (1)

  10. Laboratory diagnosis of inherited thrombophilia (2)

  11. Guidelines for prophylaxis and treatment of thrombosis in patients with inherited thrombophilia (1)

  12. Guidelines for prophylaxis and treatment of thrombosis in patients with inherited thrombophilia (2)

  13. 2nd 1st Crossed immunoelectrophoresis of antithrombin in the presence of heparin in 1st dimension and AT antibody in the 2nd dimension

  14. Characteristics of AT deficiency • Autosomal dominant inheritance • Quantitative and qualitative defects • Thrombotic phenomena in adolescence or even earlier • Frequently pulmonary embolism as first clinical manifestation

  15. Characteristics of PC deficiency • Autosomal dominant inheritance • Quantitative and qualitative defects • Homozygotes die because of thrombosis in infancy • Thrombotic phenomena in adolescence • Skin necrosis when warfarin therapy introduced

  16. Characteristics of PS deficiency • Autosomal dominant inheritance • Quantitative and qualitative defects • Homozygotes die because of thrombosis „in utero” or in the early infancy • Thrombotic phenomena in adolescence • Skin necrosis when warfarin therapy introduced

  17. Odds ratios (95% CI) for fetal loss and type of thrombophilia, with control group as reference, adijusted for number of pregnancies and centre (Preston et al., Lancet 1996) Type All spontaneous Miscarriage Stillbirth fetal losses Antitrombin 2.1(1.2 - 3.6)1.7(1.0 - 2.8)5.2(1.5 - 18.1) Protein C 1.4(0.9 - 2.2)1.4(0.9 - 2.2)2.3(0.6 - 8.3) Protein S 1.3(0.8 - 2.1)1.2(0.7 - 1.9)3.3(1.0 - 11.3) Factor VLeiden1.0(0.6 - 1.7)0.9(0.5 - 1.5)2.0(0.5 - 7.7) Combined defects 2.0(0.5 - 8.1)0.8(0.2 - 3.6)14.3(2.4 - 86.0)

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