Thrombotic disorders

This is my seminar topic in General Medicine

1. Thrombotic Diseases Somu.Venkatesh Roll 118

2. Thrombotic disorders Congenital and acquired diseases characterized by formation of thrombus that obstructs vascular blood flow locally or detaches and embolizes to occlude blood flow downstream (thromboembolism).

3. Classification: 1. Familial – physiological 2. Non-familial (acquired) – physiological or pathological

4. Factor V Leiden Prothrombin 20210A Protein C deficiency Protein S deficiency Antithrombin deficiency Hyperhomocysteinemia Antiphospholipid antibodies Malignancy Immobilization Surgery Pregnancy Estrogen Heparin-induced thrombocytopenia

5. Antithrombin deficiency It is familial deficiency of AT Autosomal dominant 70% of affected individuals will have an episode of VTE before age of 60 years. Pregnancy is a high-risk period for VTE and this requires large doses of LMWH(≥100U/kg/day). AT concentrate (either plasma derived or recombinant) is required for cardiopulmonary bypass and may be used as an adjunct to heparin in surgical prophylaxis.

6. Antithrombin deficiency Increased thrombosis- DVT/PE, mesenteric vein Diagnosis- low functional level of AT-III Treatment- large dose heparin lifelong Warfarin

7. Protein C and S deficiencies Protein C and S are Vit K-dependent natural anticoagulants involved in switching off coagulation factor activation (factor Va and VIIIa ) and thrombin generation. Inherited deficiency of either protein C and protein S results in a prothrombotic state with a fivefold relative risk of VTE compared with the background population. Treatment- heparin, followed by Warfarin

8. Factor V Leiden Results from single base pair mutation which prevents cleavage and hence inactivation of activated factor V. Heterozygous: 5-10 times increased risk for TE. Homozygous: 50-100 times.

9. Factor Va Arg 306 Arg 506 Arg 1765 Arginine CGA Glutamine CAA Factor Va resistant to APC cleavage Factor V Leiden

10. Relative Risk for Venous Thrombosis Factor V Leiden Heterozygote x 7 Factor V Leiden Homozygote x 80 Oral Contraceptives x 3 Oral Contraceptives + Factor V Leiden x 35 Leiden Study Group Data

11. Prothrombin G20210A Due to mutation in the non-coding 3´ end of the prothrombin gene is associated with an increased plasma level of prothrombin. Increased levels of prothrombin enhanced thrombin formation . In the heterozygous state, it is associated with a 2-3 fold increase in risk of VTE Only way for diagnosis: DNA-PCR technique .

12. Antiphospholipid Syndrome(APS) Syndrome characterized by venous and/or arterial thrombosis, thrombocytopenia, or recurrent fetal loss; associated with antibodies to phospho-lipid-protein Complexes . May present in isolation (primary APS) or in associated conditions like

13. Conditions associated with secondary APS Systemic lupus erythematosus Rheumatoid arthritis Systemic sclerosis Behcet’s syndrome Temporal arteritis Sjögren’s syndrome

14. Antiphospholipid Syndrome Antiphospholipid antibodies are heterogenous and typically are directed against proteins which bind to phospholipids. Targets for antiphospholipid antibodies ß2-glycoprotein 1 Protein C Annexin V Prothrombin (may result in haemorrhagic presentation)

15. Clinical features Adverse pregnancy ourcome Recurrent 1 st trimester abortion (≥3) Unexplained death of morphologically normal fetus after 10 wks of gestation Severe early pre- eclampsia Venous thromboembolism Arterial thromboembolism Livedo reticularis , catastrophic APS, transverse myelitis, skin necrosis, chorea

16. Investigation Anticardiolipin antibody test Lupus anticoagulant test

17. M anagement Arterial thrombosis, typically stroke, associated with APS should be treated with warfarin, as opposed to aspirin. APS-associated VTE is one of the situation in which the predicted recurrence rate is high enough to indicate long-term anticoagulation after a first event. In women with APS, it is likely that intervention with heparin and possibly aspirin increases the chance of successful pregnancy outcome.

18. Disseminated Intravascular Coagulation

19. Disseminated Intravascular Coagulation It is an acquired condition in which normal physiology of coagulation is disturbed leading to widespread intravascular coagulation process associated with injury to microvasculature which results in organ dysfunction, capillary leak & shock. Occurs due to simultaneous action of the following 4 mechanisms Increased thrombin generation Suppressed physiological anticoagulant pathways Activation & subsequent impairment of fibrinolysis Activation of inflammatory pathways

20. ETIOLOGY Infection/sepsis Trauma Obstetric, e.g. amniotic fluid embolism, placental abruption, pre- eclampsia Severe liver failure Malignancy, e.g. solid tumours and leukaemias Tissue destruction, e.g. pancreatitis, burns Vascular abnormalities, e.g. vascular aneurysms, liver haemangiomas Toxic/immunological, e.g. ABO incompatibility, snake bite, recreational drugs

21. Disseminated Intravascular Coagulation Bleeding signs and symptoms Petechiae Purpura Arterial line oozing Venipuncture site bleeding Clinical manifestation

22. ISTH Scoring

23. treatment Disseminated Intravascular Coagulation Elimination of the precipitating factor if possible Replacement of coagulation factors and platelets Inhibition of the clotting process with heparin or other agents.

24. Thrombotic Thrombocytopenic Purpura Rare E nzyme ADAMTS13, responsible for cleaving large multimers of vWF into normal functional units and its deficiency due to antibodies binding to it and results in large vWF multimers which cross-link platelets. Causes extensive microscopic thrombosis, with platelet consumption Microthromboses cause end- organ dysfunction Hemolysis is due to shear stress, producing schistocytes

25. Cause Idiopathic- autoimmune, severely decreased ADAMTS13 activity Secondary- associated with Cancer BMT Pregnancy HIV-1 infection Drugs- Quinine, Clopidogrel, cyclosporine, Tacrolimus, Mitomycin-C, Interferon Hereditary- Upshaw-Schulman syndrome

26. Clinical presentation- pentad Thrombocytopenia Microangiopathic haemolytic anaemia Neurological sequelae Fever Renal impairement

27. Management Diagnosis clinical, thrombocytopenia, normal PT/ aPTT Treatment Plasmapheresis, with supportive treatment Refractory- steroids, aspirin, cyclophosphamide, rituximab S plenectomy

28. Thank you