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Thrombotic Diseases

Thrombotic Diseases. Ahmad Shihada Silmi Faculty of Sciences IUG MED TECH DEP Room # B326. Thrombotic disorders.

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Thrombotic Diseases

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  1. Thrombotic Diseases Ahmad Shihada Silmi Faculty of Sciences IUG MED TECH DEP Room # B326

  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. Thrombus Formation • Clot is a Thrombus formed in an arterial or venous vessel • thrombophlebitis - Both inflammation and clots are present • Some thrombus can be superficial but it’s the DVT that’s a concern  embolism to lungs.

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

  5. Factor V LeidenProthrombin 20210AProtein C deficiencyProtein S deficiencyAntithrombin deficiency Hyperhomocysteinemia Antiphospholipid antibodies MalignancyImmobilizationSurgeryPregnancyEstrogenHeparin-induced thrombocytopenia

  6. Abnormal Blood Flow Abnormal Vessel Wall Abnormal Blood The Hypercoagulable State (thrombophilia) Dr. Rudolph Virchow 1821-1902

  7. Mechanisms of Thrombosis Clinical associations with thrombotic disease Immobility Obesity Smoking Cancer Pregnancy Estrogen therapy

  8. Types of Thrombosis Arterial: platelet-based (white) thrombus Platelet-VWF interactions critical Associated with end-stage atherosclerosis Venous: Fibrin-based (red) thrombus Coagulation factors critical Venous stasis

  9. Thrombus Formation • Arterial formation - begins w/ platelet adhesion to arterial vessel wall  Adenosine diphosphate (ADP) released from platelets  more platelet aggregation  Bld. flow inhibited  fibrin, platelets & RBC’s surround clot  build up of size structure  occludes bld vessels  tissue ischemia • The result of Arterial Thrombus is localized tissue injury from lack of perfusion

  10. Thrombus Formation • Venous Formation - Usually from slow bld flow - Can occur rapidly Stagnation of the blood flow initiate the coagulation cascade production of fibrinenmeshes RBC’s & platelets to form the thrombus. Venous thrombus has a long tail that can break off to produce an embolus. These travel to faraway sites then lodge in lung (capillary level)  inadequate O2 & CO2 exchange occur (ie. pulmonary embolism & cerebral embolism) • Oral & parenteral anticoagulants (Heparin/Warfarin) primarily act by preventing venous thrombosis • Antiplatelet drugs primarily act by preventing arterial thrombosis

  11. Types of Thrombosis • Occlusive Thrombus: occurs when the entire lumen of blood vessel is occupied by coagulated material & blood flow is obstructed. • Mural Thrombosis: occurs when the thrombus adheres to one site of the blood vessel only & blood is restricted but not arrested.

  12. Risk Factors for Thrombosis Acquired thrombophilia Hereditary thrombophilia Atherosclerosis Thrombosis Surgery trauma Immobility Estrogens Inflammation Malignancy

  13. THROMBOEMBOLIC DISORDERS • Venous thromboembolism • Arterial thromboembolism

  14. Risk Factors forVenous Thrombosis • Acquired • Inherited • Mixed/unknown

  15. Venous Thrombosis • Venous system: low flow & pressure • Thrombi are fibrin rich • Function of age, biologic conditions, genetic &environmental factors, and their interactions • Venous thromboembolism (VTE) – Deep vein thrombosis (DVT) – Pulmonary embolism (PE) – Superficial, portal, cerebral, or retinal vein thrombosis • Reasons for coagulation testing – Risk for recurrence of thrombosis – Treatment considerations (duration & intensity) – Genetic counseling for affected family members – Prophylaxis for high risk situations

  16. Venous Thrombosis • The most common is (DVT) deep venous thrombosis of the lower limbs. The main site, where there is maximum stasis and low blood flow. • Propagation of thrombus is associated with red cell entrapment……red thrombus. • Venus thrombi may become dislodged or fragment, resulting in the formation of circulating thrombi. This may result in pulmonary embolism.

  17. Pulmonary embolism • Presents with acute chest pain. • Breathlessness with shock. • Cough & hemopysis. • May be fatal.

  18. Venous Thrombosis symptoms • Typically presents with pain, swelling, discoloration & warmth in the affected area. However • (these symptoms may be absent & non of them is specific).

  19. Hematologic manifestations

  20. Cutaneous manifestations

  21. Genetic Risk Factors(Familial) • FV- Leiden (APCR: activated prot C resistance). • Protein C (deficiency). • Protein S (deficiency). • Antithrombin III (deficiency). • Abnormal Prothrombin (PT 20210 A). • Sticky platelet syndrome.

  22. Advancing age Prior Thrombosis Immobilization Major surgery Malignancy Estrogens Antiphospholipid antibody syndrome Myeloproliferative Disorders Heparin-induced thrombocytopenia (HIT) Prolonged air travel Risk Factors—Acquired

  23. Risk Factors—Mixed/Unknown • Hyperhomocysteinemia • High levels of factor VIII • Acquired Protein C resistance in the absence of Factor V Leiden • High levels of Factor IX, XI

  24. 1. FV- Leiden: • One of the most common causes for thrombophilia – 20% of clinical disease (AT, PC and PS – 5%) + risk factor. • Activated PC inhibits F Va and F VIIIa. • Inability of APC to inhibit the above complex due to mutated FV. • Heterozygous: 5-10 times increased risk for TE. • Homozygous: 50-100 times.

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

  26. Leiden Study Group Data 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

  27. 2. Protein C Deficiency: • Common cause (increasing TE with age). • Needs TM from endothelium wall. • Heterozygous: 50% of level of normal individuals. • Homozygous: babies are born with undetected levels (thrombi in microvascular of skin DIC necrosis purpura fulminans).

  28. 3. Protein S Deficiency: • Non-enzymatic co-factor for PC. • Binds to TM-PC. • Same properties as PC. • Two forms: free in plasma and bound to C4b binding protein (60%). Only free fraction functions as co-factor for APC. • Sometimes difficult to get accurate measures of PS because of the latter. • Like PC can be acquired: liver disease, Warfarin, pregnancy, cancer, DIC and chemo.

  29. 4. Antithrombin III Deficiency: • Common cause (incidence 1/2000 – 1/5000; heterozygotes; 50% DVT): Quantitative vs Qualitative disorder. (Acquired: DIC, cirrhosis, NS). • Bind to and inactivate thrombin, Factors IXa, Xa, XIa and XIIa (AT/heparin complex - rate of inhibition 1000-fold increased). • Not necessarily a risk factor to be involved in heterozygotes to give TE. • Increased incidence with ageing: 80% at 55 years.

  30. 5. Abnormal Prothrombin (PT 20210 A): • Common. • Increased levels of prothrombin enhanced thrombin formation. • Only way for diagnosis: DNA-PCR technique.

  31. 6. Sticky Platelet Syndrome: • Especially in arterial thrombosis (MI) and development of recurrent TE while on Warfarin. • 3 Forms. • If on aspirin, it should be stopped 14 days prior to testing. Also remember: PC, PS and AT III are inhibitors of clotting.

  32. Non-familial (Acquired): • Antiphospholipid Syndrome: • Antibodies directed against phospholipid cell membrane = APA (Antiphospholipid Ab). • APA: ACA or LA. • Primary (PAPS) or secondary (autoimmune disorders, e.g. SLE) • ACA (Anticardiolipin Ab): IgM + IgG. • IgG: the clinically important one. • IgM: pregnancy, infection (viral), trauma and post-op. • LA (Lupus anticoagulant): Ab which affect clotting tests (LA-PTT, RVV, Kaolin). • PAPS = TE, miscarriage, IUD.

  33. Antiphospholipid Syndrome 􀂞 Antiphospholipid syndrome (APS): – Syndrome characterized by venous and/or arterial thrombosis, thrombocytopenia, or recurrent fetal loss; associated with antibodies to phospho-lipid- protein Complexes. 􀂞 Antiphospholipid antibodies (aPL) – IgG, IgM, or IgA antibodies that are directed to target proteins, such as cardiolipin, beta2-Glycoprotein I (β2GPI),or Prothrombin, all of which bind to phospholipids – Lupus anticoagulant (LA) • Antiphospholipid antibodies identified by in vitro phospholipid dependent clot-based assays; antibodies are targeted against Prothrombin or β2GPI and prolong clotting times

  34. Antiphospholipd Antibodies

  35. Lupus Anticoagulant

  36. Conditions where screening for APS is indicated: • The first thrombotic event below the age of 40. • History of recurrent TED. • Recurrent fetal loss in the 1st or the 2nd trimester. • Patient with SLE. • Pre-hormone replacement therapy.

  37. Non-familial (Acquired) continued: • TPA (Tissue Plasminogen Activator): decreased levels impaired fibrinolysis. • PAI (Plasminogen Activator Inhibitor): increased levels decreased TPA. • Dysfibrinogenemia. • F XII deficiency: Hageman factor. • Fibrinogen (increased). • F VIII (increased). • Plasminogen. • Hyperhomocyteinemia – enzyme (folate).

  38. Investigation (Thrombotic Profile): NB: Patients can be on Warfarin, but not Heparin! • FBC, PLT & ESR • PT, aPTT, TT & Fibrinogen • PC & PS • AT III • APCR (if + screening, submit for PCR) • PT 20210A (PCR) • Lupus anticoagulant (RVVT, KT, LA-PTT) • Cardiolipin antibodies (antiphospholipid syndrome) • Sticky platelet syndrome (aspirin!) • ANA screening • PNH screening

  39. When to test: • Younger: < 50 years, recurrent TE, unusual sites, TE on Warfarin. • Not ideal to test after acute episode (inhibitors of clotting may be low). • Ideal: test after 6 weeks after settlement of hemostasis. • Most patients are on Warfarin then (PC & PS are Vit K dependent, may be falsely low). • My view: if long-term Warfarin is planned, do immediately/ according to duration of treatment it can be done after cessation of treatment.

  40. When to test (continued): • Practical (my experience): before treatment – if AT, PS, PC are low  repeat after Rx has been stopped. • SPS: platelet aggregation studies (problem: sometimes aspirin cannot be stopped). • Remember the effect of the vessel wall on clotting, especially in arterial thrombosis. • Every woman on contraception, HRT?

  41. Arterial Thrombosis

  42. Arterial Thrombosis

  43. Arterial Thrombosis • Results as sever o2 starvation of the left ventricle of the heart. • This leads to myocardial ischemia & may progress to myocardial infarction or ischemic left ventricular fibrillation & sudden death. • Similar episodes involving the cerebral circulation result in transient ischemic attacks & thrombotic stroke.

  44. Myocardial Infarction Symptom • Crushing tightness of the chest with sweating, nausea, breathlessness & collapse. • Chest pain may radiates to the arm, throat & jaw. • Chest pain may confused with sever indigestion in it’s early stages.

  45. Transient Ischemic attacks • It’s usually accompanied with neurological dysfunction or loss of vision.

  46. Completed thrombotic stroke • It’s accompanied by similar symptoms which persist for more than 24 hours that may be severely & permanently disabling.

  47. Risk factors for arterial & venous thrombosis

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