Hemostasis, coagulation cascade, bleeding disorders, hematologic abnormalities, anemia, anemia of chronic disease, iron deficiency anemia, thalassemia

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Department
Biomedical Science
Course
BMS 460
Professor
D.Rao Veeramachaneni
Semester
Fall

Description
30 September 2° Hemostasis Anti-thrombotic role of endothelial cell Release of t-PA triggers fibrinolysis Release of thrombomodulin blocks coagulation cascade Checks and balances Polymerization fibrin and platelet aggregates form a solid, permanent plug to prevent any further hemorrhage. Once activated, the coagulation cascade must be restricted to the local site of vascular injury to prevent clotting of the entire vascular tree. At this stage, counter-regulatory mechanisms (e.g., tissue plasminogen activator [t-PA]) are set into motion to limit the hemostatic plug to the site of injury. Fibrinolytic cascade modulates the size of the final clot Endothelial cells secrete tissue plasminogen activator (t-PA), which is most active when bound to fibrin. t-PA converts plasminogen (a circulating zymogen secreted by liver) into active plasmin, which breaks down fibrin and interferes with polymerization. The resulting fibrin degradation products also act as anticoagulants. Other PAs include urokinase (plasma and tissues) and streptokinase (bacterial infections). Freely circulating plasmin is inactivated by alpah 2plasmin inhibitor Coagulation Cascade Initial step is formation of platelet plug to stop bleeding from damaged vessel Platelet plug is reinforced by fibrin clot Then, fibrin clot is stabilized by activated factor XIIIa, which cross-links fibrin strands Fibrin clot may occur via either intrinsic or extrinsic pathway (or both), though in vivo it occurs via a hybrid model Coagulation factors in intrinsic or extrinsic pathway assemble on surface of activated platelets, which are usually at vascular injury site I: fibrinogen II: prothrombin III: tissue thromboplastin (tissue factor and phospholipid) IV: ionized calcium V: occasionally called labile factor or proaccelerin VI: unassigned VII: occasionally called stable factor or proconuertin VIII: antihemophilic factor (Hemophilia A) IX: plasma thromboplastin component, Christmas factor (Hemophilia B) X: occasionally called Stuart-Prower factor XI: occasionally called plasma thromboplastin antecedent (Hemophilia C) XII: Hageman factor XIII: fibrin-stabilizing factor Note: “a” after factor # indicates “activated” All of these activating steps involve serine proteases which require Ca ions This is why citrate and EDTA work as anticoagulants Intrinsic pathway Activated by endothelial injury in blood vessel XII (Hageman factor) → XIIa XIIa acts on XI → XIa XIa acts on IX → IXa IXa complexes with VIII → VIIIa 2+ VIIIa, with Ca , acts on X → Xa Extrinsic pathway Activated by tissue and platelet injury III (tissue thromboplastin) → IIIa IIIa complexes with VII → VIIa 2+ VIIa, with Ca , acts on X → Xa Common pathway Xa complexes with V V with platelet phospholipid (platelet factor III) acts on prothrombin activator Heparin blocks sequence after this point Prothrombin → thrombin Vitamin K required for synthesis of prothrombin Oral anticoagulants (warfarins) block synthesis of prothrombin Antithrombin III and protein C block Heparin blocks sequence after this point Fibrinogen → fibrin Plasmin blocks With XIII, insoluble fibrin clot forms Plasmin blocks Platelets aggregate ASA blocks platelet aggregation Thrombolytics (TPA) or “clot-busters”, e.g., streptokinase, block Summary Effective circulation requires a balance between the ability to form clots to repair vascular injury and the need to maintain blood flow through vessels Accomplished by tightly regulated interaction of the vascular wall (particularly the endothelium), platelets, and the coagulation cascade Endothelial cells exert both pro- and anti-coagulant actions. While endothelium normally limits (inhibits) blood clotting, when injured they can also become prothrombic, with activites that affected platelets, coagulation proteins, and the fibrinolytic system. Injured endothelial cells release or expose tissue factor III, called thromboplastin, which triggers activation of the coagulation cascade (extrinsic pathway). Coagulation occurs via the sequential enzymatic conversion of a cascade of circulating and locally synthesized proteins. Tissue factor elaborated at sites of injury is the most important initiator of the coagulation cascade; at the final stage of coagulation, thrombin converts fibrinogen into insoluble fibrin, which helps to form the definitive hemostatic plug. Coagulation is normally constrained to sites of vascular injury by Limiting enzymatic activation to phospholipid complexes provided by activated platelets Natural anticoagulants elaborated at sites of endothelial injury or during activation of the coagulation cascade Induction of fibrinolytic pathways involving plasmin through the activities of various plasminogen activators (PAs) Role of thrombin in hemostasis and cellular activation Thrombin plays a critical role in generating cross-linked fibrin (by cleaving fibrinogen to fibrin, and by activating factor XIII), as well as activating several other coagulation factors. Through protease-activated receptors, thrombin also modulates several cellular activities. It directly induces platelet aggregation and thromboxane (TxA2) production, and activates endothelial cells to express adhesion molecules, and a variety of fibrinolytic (t-PA), vasoactive (NO, PGI2), and cytokine mediators (e.g., PDGF) Thrombin mediates additional anticoagulant activities including via thrombomodulin Thrombin also directly activates leukocytes Bleeding Disorders Defective primary hemostasis Quantitative deficiency of platelets Decreased production Bone marrow failure: iatrogenic – chemotherapy; replacement by malignancy; aplastic anemia Ineffective hematopoiesis: myelodysplastic syndromes Selective impairment of platelet production: drug-induced – alcohol, cytotoxic drugs; infections – HIV Nutritional deficiencies – 12, folate Decreased peripheral survival Acute idiopathic thrombocytopenic purpura – disease of childhood Qualitative deficiency of platelets Platelets circulate in normal numbers, but defective in one or more of the 5 functions – adhesion, activation, release reaction, recruitment, aggregation – most commonly the latter two Inherited (primary; rare) Bernard-Soulier Syndrome, Glanzmann Thrombasthenia Acquired (secondary) Ingestion of aspirin and other anti-inflammatory drugs Uremia due to accumulation of organic acids in renal failure Plateletpheresis The process of apheresis involves removal of whole blood from a patient or donor. Within an instrument that is essentially designed as a centrifuge, the components of whole blood are separated. One of the separated portions is then withdrawn and the remaining components are re-transfused into the patient or donor. Defective secondary hemostasis Cascade factor deficiencies Inherited (recessive) Deficiency disease states – hemophilia – have been reported for the following coagulation factors Hemophilia A – Factor VIII (rare) Hemophilia B – Factor IX (rare) Hemophilia C – Factor XI (exceedingly rare) Acquired Warfarin (Coumadin) coagulopathy Warfarin inhibits production of II, VII, IX and X by liver 3 million patients in US are on warfarin; 1 – 4%/year have major bleeding episodes – hemorrhages in skin, soft tissues, urinary and GI tracts Heparin coagulopathy Heparin is a potent inhibitor of thrombin 10 – 20% patients receiving unfractionated heparin have a significant bleeding complication with ~2 – 4% of these being intracranial Unfractionated heparin is a heterogeneous mixture of oligosaccharides isolated from pig intestine and bovine lung; each lot of he
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