Bleeding and Thrombosis PDF
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University of Sulaymaniyah College of Medicine
Dr. Ali Ibrahim Mohammed
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This document is a lecture summary on bleeding and thrombosis from the University of Sulaimania College of Medicine. It includes details on coagulation disorders, learning objectives, hemostasis, platelets and coagulation pathways.
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Bleeding and Thrombosis Hematopathology block University of Sulaimania College of medicine Dr. Ali Ibrahim Mohammed Assistant professor of haematopathology Coagulation disorders Learning objectives 1. 2. 3. 4. 5. 6. Introduction to main 5 component of normal coagulation systems including platelets,...
Bleeding and Thrombosis Hematopathology block University of Sulaimania College of medicine Dr. Ali Ibrahim Mohammed Assistant professor of haematopathology Coagulation disorders Learning objectives 1. 2. 3. 4. 5. 6. Introduction to main 5 component of normal coagulation systems including platelets, blood vessel, coagulation factors, natural coagulation inhibitors and fibrinolytic system. What happen when the blood vessel is injured? How patient with bleeding tendency can be presented. What you do when the patient presented with bleeding manifestations. Classification of bleeding disorders. Thrombophilia: types and pathogenesis. Hemostasis and blood coagulation Hemostasis: is the physiological arrest of hemorrhage at sites of vascular injury. There are mainly 5 systems involve in the hemostasis including: Platelets. Vascular wall (endothelial cell ECM). Coagulation factors. Natural coagulation inhibitors. Fibrinolytic system. Response to vascular injury Final insoluble stable fibrin strands Platelets Produce from the BM by process called megakaryopoiesis. Through fragmentation of the cytoplasm of megakaryocytes by blood flow. Main growth factor for platelet production is thrombopoietin (TPO). Normal platelet count in adult blood is 150 - 400 x 109/L. Normal half-life of platelet is 7-10 days and 1/3 of platelets trapped normally in the spleen. Function in primary hemostasis through sequence of events (adhesion, shape changes, aggregation, and release of mediators), procoagulant activity and clot retraction. ADP and TXA2 are major positive mediators for platelets aggregation while the PGI2 (prostocycline) which synthesis in ECs, it potent inhibitor in platelets aggregation. Marrow megakaryocytes Peripheral platelet Coagulation Pathways All coagulation factors synthesis from the liver. Half-life of all factors range from 10-65 hrs except FVII of shorter half-life5-7 hrs. Coagulation pathways of old version depend on extrinsic, intrinsic and common pathways. Coagulation pathways of new version consist of: Initiation: TF binding to VII and form VIIa. Amplification:thrombin activate platelets bound Va,VIIIa and IXa Propagation : convertion of large amounts of prothrombin into thrombin Feedback inhibition by TFPI, anti-thrombin and activated protein C. Fibrinolysis system. Fibrinogen Prothrombin Tissue factor Calcium Proaccelerin; labile factor Proconvertin Antihemophilic factor (AHF) Christmas factor Stuart-Prower factor Plasma thromboplastin antecedent Hageman factor Fibrin-stabilizing factor Fletcher factor HMWK kininogen Factor I Factor II Factor III Factor IV Factor V Factor VII Factor VIII Factor IX Factor X Factor XI Factor XII Factor XIII Prekallikrein Fitzgerald factor Old version of coagulation pathway New version of coagulation pathway Natural coagulation inhibitors Important natural inhibitors are: Anti-thrombin (AT) ………(FXIa, IXa, Xa & IIa) Heparin cofactor II ……… Thrombin. Protein C (PC) and protein S (PS) both share in inhibiting of FV and FVIII. ▪TFPI NORMALLY – ANTIPLATELET PROPERTIES – ANTICOAGULANT PROPERTIES – FIBRINOLYTIC PROPERTIES IN INJURY – PRO-COAGULANT PROPERTIES Disorders of coagulation system BLEEDING THROMBOSIS Examples of bleeding manifestations Petechiae Conjunctival hemorrhage Purpura Ecchymosis Epistaxis Hematoma Petechiae is pinpoint flat round red spots caused by intradermal hemorrhage, less than 2 mm in diameter and do not blanch when pressed upon. Purpura is extravasation of RBC into skin and subcutaneous tissue, 0.2-10 mm. Ecchemosis is purpura > 10 mm. Hematoma: bleeding in the muscle. Hemarthrosis: bleeding in the joint. Hemoptesis, hematemesis, hematuria, conjunctival hemorrhage, epistaxis. Note that: Erythema: mean redness of skin due to increase blood flow blanch with pressure. Talengiectasia: dilated superficial capillaries blanch with pressure. Any simple bleeding may be a presentation to dangerous disorder. Investigations of bleeding tendency Sample use in investigation of coagulation: Preparation of citrated plasma by using special tube contain sodium citrate as anticoagulant mixed with proper amount of blood. Sample collected in EDTA tube cannot be use. Serum cannot be use. Investigations include: 1st line investigations (Basic screening tests ) 2nd line investigations Basic screening tests for bleeding disorders (1st line investigations for bleeding disorders) CBC (complete blood count) and blood film. BT (bleeding time). PT (prothrombin time). APTT (Activated Partial Thromboplastin Time). FNG (Fibrinogen assay). According to the result of 1st line investigation, the diagnosis made by 2nd line investigations of bleeding disorder like factor assay, PLT aggregometry and many other investigations. for a prolonged PT or aPTT , mixing study is done to distinguishes factor deficiency(will be corrected) from the presence of inhibitors. CBC and blood film examination: Assess platelet disorder. Assess hematological malignancy that cause bleeding disorder. Bleeding time or PFA100 (PLT function analyzer) : Prolonged in Patient with platelets disorders. Patient with blood vessel disorders. Prothrombin Time (PT): Prolonged in patient with extrinsic (factor VII) and common pathways coagulation factors defect (X, V,II,I). Activated Partial Thromboplastine Time (APTT): Prolonged in patient with intrinsic (Factor XII, XI, IX, VIII), and common pathways coagulation factors defect(X, V,II,I). Fibrinogen assay: Low FNG level in patient with defect in last stage of coagulation pathway mainly Fibrinogen. Classification of bleeding disorders Platelets disorders: reduction in PLT count(Thrombocytopenia) PLT dysfunction( thrombocytopathies). Coagulation factors disorders: inherited or acquired deficiency coagulation factors dysfunction. Vascular disorders: Inherited or acquired. And less frequently disorders in inhibitors and fibrinolytic system Platelet disorders superficial bleeding (skin and mucous membrane) and post-traumatic. Platelets disorders include thromocytopenias and thrombocytopathies (dysfunction). Causes of thrombocytopenia Reduced production of platelets: Congenital TCP or acquired TCP secondary to aplastic anemias , megaloplastic anemias , drugs, chemicals and viral infections(HIV..etc) Increased platelets destruction: autoimmune thrombocytopenic purpura (ITP). DIC,microangiopathic (HUS/TTP, pre-eclampsia, HELLP syndrome), Drugs(heparin,sulfa..) Sequestration and dilutional : hypersplenism. Autoimmune thrombocytopenic purpura (ITP) A relatively common hematological disorder, characterized by bleeding tendency due to immune thrombocytopenia, and could be classified into: Idiopathic thrombocytopenic purpura: a chronic autoimmune thrombocytopenia, usually in young adults, without precedent or associated illness. Secondary autoimmune thrombocytopenia: a chronic autoimmune thrombocytopenia associated with autoimmune disorders or malignancy. Acute post-viral autoimmune thrombocytopenia: acute usually selflimiting thrombocytopenic purpura, typically seen in children following acute viral infection or immunization. Clinically: usually with purpura overall the body sparing abdomen in acute or chronic pattern of presentation. Features of associated underlining disorders may present. Pathogenesis: Triggering factors induce autoAb production (usually IgG) against specific antigen on platelet which is removed by macrophage in the spleen. Spleen is considered as site of destruction and site of Ab production. Hematological findings: Blood picture showing isolated thrombocytopenia usually sever < 10 x109/L with many giant platelets. Findings of associated disease if present. Demonstration of platelets auto-antibodies but not specific. Important diagnostic test is clinical exclusion of other cause of thrombocytopenia and response to treatment with steroid. Bone marrow examination: usually normal cellularity with increased or normal number of megakaryocytes. BM examination is not necessary for diagnosis, it done to confirm the diagnosis and exclude serious diseases. Peripheral blood showing no platelets Peripheral blood showing giant platelets BM showing normal megakaryocytes Thrombocytopathies Characterize by superficial bleeding, prolonged bleeding time and usually with normal platelets count. Platelets dysfunction may occur at any phase of platelets function. Classification: Hereditary types: - Defect in adhesion (Bernard Soulier Syndrome) GP Ib - Defect in aggregation (Glanzmann’s thrombosthenia) GP IIB/IIIA - Defect in platelets granules (Storage pool disease) Acquired types: - Systemic disease as uremia, liver disease. - Antiplatelets drugs like aspirin, NSAID, dipyridamole, clopidogrel. - Hematological disease as myeloproliferative and hyperglobulinaemia. Detailed patient history and clinical examination combined with platelets function test (aggregometry) is mainstay of Dx. Coagulation factor disorders Main Inherited coagulation factor deficiency are: Hemophilia A Hemophilia B von Willebrand disease. Acquired coagulation factor deficiency: more common than inherited types, and usually associated with multiple clotting factor deficiency like: Liver disease Vitamin K deficiency DIC Coagulation inhibitors Hemophilia A (classic) Most common inherited coagulation defect, incidence is (1:5000) male birth X-linked recessive inherited disorder Positive family history , 20% of cases show new spontaneous mutation. Hemorrhage usually NOT spontaneous, target joint, IM injection… The defect is absence or reduce level of factor VIII. Female consider a carrier of hemophilia A and rarely be diseased. Gene of factor VIII located on long arm of chromosome X, with the gene of factor IX. Plasma half life of factor VIII is 8-12 hrs. Synthesis site; mainly from liver, and may be from other sites. Normal level of factor VIII in plasma is 50-150 U/dl, clinical significant occur when factor level < 30 U/dl. Classification of hemophilia Mild Moderate >5-49% 1-5% Bleeding with major surgery and trauma Excess bleed with minor surgery and trauma Severe