<p> L:5 …Coagulation Hemorrhagic Disorders… & Physiology</p><p>:I. Coagulation Physiology :Overview When a blood vessel wall is ruptured, platelets adhere to the exposed subendothelium and become activated, beginning the process of aggregation. The platelet plug thus formed provides a surface on which certain coagulation factors can become activated and initiate the coagulation cascade. This complex series of reactions ultimately results in the formation of a fibrin clot to seal the .vessel until new cell growth can replace the damaged tissue</p><p>:Coagulation factor :Biochemical nature - 1 Most of them are glycoproteins that normally exist in inactive, pre-enzymatic forms which called "zymogens". These must undergo activation to serine proteases in order to participate in coagulation. Several cofactors, like calcium .ion(Ca²+) and phospholipids also contribute to coagulation :Nomenclature - 2 .By roman numeral: V, X. In addition of "a": Xa indicates activation :Sites of biosynthesis- 3 :a)Hepatic synthesis liver is the 1ry site except for von Willebrand factor(vWF),also Factor VIII .which is tightly bound to vWF :b)Extrahepatic synthesis Megakaryocytes(synthesis of vWf, fibrinogen, factor V and XIII), macrophages(synthesis of factors V, VII, IX and X), and endothelial .(cells(synthesis of vWf :Requreiment for vitamin K- 4 The activities of prothrombin(factor II) and factors VII, IX and X require the .binding of Ca²+ by the γ-carboxy residues in these factors The γ-carboxylation of these glutamic acids is a posttranslational event that depends on vitamin K. In the absence of vitamin K, these factors are formed, but .[they are inactive. [i.e. Vit K dependent factors=II, VII,IX, X</p><p>:Coagulation cascade :Overview - The coagulation cascade is the serial activation of coagulant factor zymogens to their active enzymatic forms. Each enzyme catalyze the conversion of the next zymogen in the series to its active enzymatic form and so on until thrombin converts fibrinogen to fibrin. Fibrin monomers rapidly polymerize to fibrin </p><p> http://medicineunitedgroup.tripod.com 1 Dr.Ashwag B. Alshareif strands, and the resultant clot is further stabilized by the cross-linking action of .factor XIII The coagulation cascade can be initiated and proceed along either the extrinsic pathway(system) or the intrinsic pathway. The two systems coverage at the activation of facto X, and the final sequence of events-the common pathway-is .the same for both systems</p><p> http://medicineunitedgroup.tripod.com 2 Dr.Ashwag B. Alshareif :II-Tests of the coagulation system PT APTT TT Measure Extrinsic and Intrinsic and Thrombin- common common fibrinogen pathway. pathway except .reaction Monitor oral factor XIII anticoagulant monitor .((e.g.warfarin parenteral anticoagulant .((e.g. Heparin Method Phospholipid + Phospholipid + Thrombin + platelets platelet platelet poorplasma and poorplasma + poorplasma and Ca initiate activated agent the time of fibrin .coagulation such as kaolin strand is clotting then .measured . initiated by Ca</p><p>.N.B. PT = Prothrombin time .APTT = Activated partial thromboplastin time .TT = Thrombin time :Other screening test .By quantitative fibrinogen or screening test for factor XIII</p><p>:III-Congenital hemorrhagic disorders</p><p>.(Hemophilia A (factor VII deficiency* .(Hemophilia B (factor IX deficiency*</p><p>.(Clinical features: (according to factor level The severity of the clinical manifestation is directly related to the degree of .factor deficiency :a-Mild disease factor level > 0.05U/ml. Usually are asymptomatic except when stressed by .trauma or surgery :b-Moderate disease factor levels b/w 0.02 and 0.05 U/ml. Often are asymptomatic, but occasionally bleeding can occur without a defined trauma, may be soft tissue bleeding or .hemarthrosis :c-Sever disease</p><p> http://medicineunitedgroup.tripod.com 3 Dr.Ashwag B. Alshareif factor level < 0.01 U/ml. Spontaneous bleeding, most commonly hemarthrosis - .in large joints soft tissue bleeding can result in nerve compression syndromes, and CNS - .bleeding</p><p>.S.test: APTT prolonged, PT unaffected :Diagnosis .S.F.A: Factor VIII and factor IX assay .N.B. S.test = Screening test .S.F.A. = Specific Factor Assay Gene for factors VIII and IX reside on X chromosome so called "X-linked" so, - male only affected "XY" but female are carriers "XX". We can see ♀ with ."hemophilia when associate ♂ marry carrier ♀ or in 45x "turner syndrome</p><p>:Therapy :a-Pharmacologic therapy :(for hemophilia A only(has no effect on Hemophilia B .desompression release body stores of factor VIII :b-Replacement therapy ."FFP "Fresh frozen plasma- .(Cryoprecipitate (FFP at 4˚C- .(Factor concentrates (plasma pooled from thousands of donors-</p><p>:*von Willebrand's disease* .The most common inherited bleeding disorders- .It lie on Chromosome 12- .It always associated with prolonged bleeding time- :Clinical features .Mucous membrane bleeding- Epistaxis and monrrohgeia or coma- .Bruising and bleeding are usually unless induced by trauma- .Spontaneous bleeding occur only with sever disease-</p><p>:IV-Acquired Hemorrhagic Disorders</p><p>.Include 2 disease: Vit K deficiency & liver disease :A-Vitamin K deficiency .Vit K dependent factor: II, VII, IX, X, beside protein C & S .When Vit K absent these factor form but in inactive form</p><p>:Etiology .a- Dietary deficiency especially with chronically ill</p><p> http://medicineunitedgroup.tripod.com 4 Dr.Ashwag B. Alshareif b- Malabsorption Because vitamin K is fat-soluble, its absorption depends on biliary and pancreatic secretions. Cholestasis result in malabsorption of vitamin .K .c-Antibiotic therapy as broad-spectrum antibiotic d-Vitamin K antagonists: Oral anticoagulants(e.g. warfarin) act by interfering .with the reduction of vitamin K .e-Hemorrahgic disease of the newborn :Clinical features Patients may present with sever bruising or excessive bleeding following a .surgical procedure :Diagnosis .Both the PT and PTT are prolonged :Therapy .a-Parental vitamin K therapy .b-FFP in sever cases</p><p>:B-Liver disease :Etiology a-Decreased synthesis of coagulation factors all factors except vWF are made .by hepatocytes .b-Cholestatic liver disease can cause vitamin K deficiency .c-Functionally abnormal fibrinogens in sever liver disease d-Clearance of activated coagulation factors from the blood by the liver also is impaired in sever liver disease, and the result may be disseminated .(intravascular coagulation(DIC</p><p>:Clinical features Gastrointestinal bleeding is common in pt with liver disease and often originates .(from complicating coincident lesions(e.g. esophageal varices</p><p>:Diagnosis PT is most commonly prolonged-1 there is abnormalities of all the coagulation screening tests can occur and -2 .thrombocytopenia :Therapy .a-Trial of parenteral vitamin K therapy if the cause is Vit K deficiency .b-Replacement therapy by: FFP</p><p> http://medicineunitedgroup.tripod.com 5 Dr.Ashwag B. Alshareif Coagulation Regulation and Hypercoagulable… …States</p><p>:I. Control Mechanism In Coagulation Seen after coagulation is initiated, several regulatory mechanisms are activated, which ultimately inhibit coagulation. If left unchecked, the autoamplification .mechanisms of coagulation would result in generalized thrombosis :Naturally occurring anticoagulants :(Antithrombin III (AT III-1 AT III is a plasma protein that acts as a serine protease inhibitors. It can inhibit .(many serine protease enzyme (e.g. thrombin, factor Xa, IX, and XIa Heparin increase its action with 1000-fold. By binding of heparin or heparin like substances (e.g. heparin sulfate) to AT III make complex inactive serious .protease</p><p>:Protein C-2 Is the inactive precursor form of the anticoagulant, protein Ca, which is a serine- protease that acts on specific clotting factors in the presence of the cofactor .protein S. Both protein C and protein S are vitamin K-dependent For activation of protein C it requires thrombin and thrombomodulin, a protein - .receptor found on the surface of endothelial cells .It inactivate factors Va, VIIIa- It enhance fibrinolysis by preventing the degradation of plasminogen activator - .by its inhibitors .Protein C inhibitors inactivate protein C-</p><p>:Fibrinolytic system The body's system for dissolution of clots has similarities to the coagulation mechanism. In this system, the inactive precursor plasminogen is converted to .plasmin, a serine protease with specific fibrinolytic activity</p><p> http://medicineunitedgroup.tripod.com 6 Dr.Ashwag B. Alshareif :Activation - :There are three mechanism of activation .a)Intrinsic activation: related to intrinsic system b)Extrinsic activation: 1-tissue plasminogen activator (t-PA): synthesized .in endothelial cells .Urikinase: normally found in urine-2 :c)Exogenous(therapeutic) activation .streptokinase- .t-PA and Urokinase- :Sites of action- Plasmin acts primarily on fibrin → fibrinogen also degrade(fibrinolysis and - .(fibrinogenolysis Plasmin is inactivated when the protein α2-antiplasmin, binds to the active site - .of the light chain of Plasmin, forming a one-to-one complex</p><p>II-Thrombotic disorders :(Thrombophilia) :A-Congenital thrombotic disorders .AT III deficiency(1 :Clinical features* Thrombosis: lower extremities the most common site. In some pt is seen during .pregnancy or after surgery .Protein C deficiency(2 .Protein S deficiency(3</p><p>:B-Acquired Thrombotic disorders. Thromboembolic disease :Risk factors- .a-Abnormal blood flow .Congenital: sickle cell disease-1 .Acquired: Congestive heart failure, Obesity, Smoking, and Hyperviscosity-2 :b-Abnormal vasculature .Congental: Hyperlipidemia-1 Acquired: ATS(atherosclerosis), Hyperlipidemia, Diabetes Mellitus, and -2 .Estrogen therapy :c-Abnormal coagulation .Congental: AT III deficiency, Protein C deficiency, and Protein S deficiency-1 .Acquired: Malignancy, Nephrotic syndrome, Trauma, Lupus anticoagulant-2</p><p> http://medicineunitedgroup.tripod.com 7 Dr.Ashwag B. Alshareif :Clinical manifestations- .((a-Venous thrombosis can be superficial or deep venous thrombosis((DVT .b-Pulmonary embolism .c-Arterial thrombosis like coronary, cerebral and mesenteric :Therapy- :Anticoagulants-1 .a-Heparin use in treatment for acute thrombotic events Mechanism of action: Heparin binds to AT III, markedly enhancing its - .ability to inactive serine proteases, especially thrombin .(Monitoring: using the partial thromboplastin time(PTT - .Adverse effects. Bleeding and Heparin-induced thrombocytopenia- </p><p>.b-Warfarin is used for long-term therapy Mechanism of action: Warfarin inhibits the reduction of oxidized - vitamin K, causing relative vitamin K deficiency; thus, its anticoagulants effect depends on depletion of functionally normal .(vitamin K-dependent factors(i.e. II,VII, IX, and X Administration and monitoring: Warfarin usually is begun while a pt is - receiving heparin, with about a 3-day overlap of therapies. It .(monitoring by prothrombin time(PT .Adverse effects: Bleeding and Warfarin-induced necrosis - </p><p>:Thrombolytic agents-2 .a-Streptokinase .b-Urokinase .c-t-PA</p><p>:III-Thrombohemorrhagic Disorders :(A-Disseminated intravascular coagulation (DIC</p><p> http://medicineunitedgroup.tripod.com 8 Dr.Ashwag B. Alshareif :Therapy- .For bleeding: FFP, platelets, red cells- .Thrombosis: Heparin-</p><p>.(B-Thrombotic thrombocytopenic Purpura(TTP .C-Heparin thrombocytopenia</p><p> http://medicineunitedgroup.tripod.com 9 Dr.Ashwag B. Alshareif</p>