Coagulation Disorders

ability to maintain blood in a fluid state and prevent loss from sites of vascular damage.

• 1. vascular wall
• 2. platelets
• 3. coagulation proteins

vascular injury exposes subendothelial collagen, resulting in platelet activation. this is followed by activation of coagulation proteins to create a more stable meshwork to seal off the damaged site.

platelet response to vascular injury

• 1. adhesion
• 2. activation
• 3. aggregation

adhesion of platelets to the damaged endothelial site by activation of surface membrane receptor (glycoprotein Ib/IX) and adhesive protein (vW factor).

platelets are activated by binding to vWF causing release of 2nd messenger within platelets, to change shape from discoid to spherical, that causes secretion of cytoplasmic ADP in turn activating glycoprotein IIb/IIIa receptor and contraction of the platelet mediated through actin fibers.

release of cytoplasmic ADP causes activation of adjacent platelets and platelet-platelet binding mediated by fibrinogen and gpIIb/IIIa receptor.

• fibrin clot formation.
• coagulation proteins generate thrombin which converts fibrinogen to fibrin which adds stability to the clot after fibrin monomers are cross-linked by Factor XIII

• 1. kallikrein activates F-XII
• 2. F-XIIa activates F-XI
• 3. F-XIa activates F-IX

sequence of activation of F-VII by tissue factor

• 1. activation of X to Xa
• 2. conversion of prothrombin II to thrombin
• 3. conversion of fibrinogen to fibrin monomers

fibrin monomers polymerize and are made more stable by cross-linking by F-XIII

regulation of platelets

• 1. serine protease inhibitors
• 2. protein C system
• 3. fibrinolysis

best know SERPIN: antithrombin, which is activated by heparin to bind with thrombin which inhibits thrombin from participating in the generation of fibrin monomers. antithrombin can also inactivate Factor X.

• regulates major cofactors of the coagulation cascade: F-Va, VIIIa.
• activated protein C (APC) is the major effector enzyme, protein S is a major cofactor.

• - limits generation of a fibrin clot.
• - in the presence of fibrin, tissue plasminogen activator (TPA) can activate plasminogen to plasmin. plasmin breaks down cross-linked fibrin monomers.
• - TPA is therapeutic in recent myocardial infarcts.
• - uncontrolled activation of plasmin can lead to bleeding complications.

• balance in favor of procoagulation: thrombosis
• favor of regulation: bleeding disorders

• 1. prothrombin time (PT)
• 2. partial thromboplastin time (PTT)
• 3. platelet count
• 4. bleeding time

• - measurement of time needed for plasma to form a clot in the presence of added tissue thromboplastin (to initiate the extrinsic coag. cascade) and calcium ions.
• - prolonged PT: decreases or abnormalities in F-VII, X, V, II and/or fibrinogen.
• - measures degree of anticoagulation in patients receiving oral anticoagulants

• - measurement of the time needed for plasma to form a clot in presence of added kaolin (to activate contact-dependent F-XII), cephalin and calcium.
• - accesses the intrinsic coag. cascade.
• - Prolonged PTT: decrease/abnormality of F-XII, XI, IX, VIII, V, X, II and fibrinogen.
• - measure degree of anticoagulation in patients receiving heparin

• normal range: 150-400k/uL.
• decrease in number: thrombocytopenia
• increase in platelets: thrombocytosis and thrombocythemia

• platelet problem: mucosal bleeding
• coagulation problem: deep tissue hematomas
• regulatory problem: screening tests are normal

mucocutaneous bleeding, prolonged bleeding time, thrombocytopenia

soft tissue bleeding, prolonged PT and/or PTT and/or thrombin time

soft tissue bleeding, normal screening tests

• 1. von Willebrand's syndrome
• 2. hemophilia a
• 3. hemophilia b

• - autosomal dominant with decreased or abnormal vWF.
• - Type I: decreased amounts of vWF
• - Type II: abnormal vWF
• - Type III: absence of vWF
• - Lab tests: prolonged bleeding time, prolonged PTT, decreased vWF/F-VII

• - desmopressin: releases vWF from endothelial cells
• - antifibrinlytic agents
• - F-VIII concentrates containing vWF
• - cryoprecipitate for severe cases

• - this complex is involved in both hemophilia A and vWs.
• - it is composed of vWF and factor VIII procoagulant. both are produced by different genes on different chromosomes.
• - vWF functions both as a carrier molecule for F-VIII and as a glue between damaged endothelials and platelets (1 hemostasis)
• - Factor VIII procoagulant is released from vWF after clot formation and participates in generation of F-X (2 hemostasis)
• - synthesized in the liver

• - sex-linked recessive disorder due to decreased production of F-VIII
• - clinical hallmark: soft-tissue bleeding
• - lab: normal bleeding time, prolonged PTT, decreased VIII, normal vWF, normal IX

F-VIII concentrates, desmopressin, fibrinolytic inhibitors

• sex-linked recessive disorder due to decreased production of F-IX
• lab results include normal bleeding time, prolonged PTT, normal VIII/vWF and decreased IX

F-XII deficiency and contact factor deficiencies

platelet disorder and F-XIII deficiency (able to form a fibrin plug but it is unstable to due lack of cross-linking from F-XIII)

• 1. thrombocytopenia
• 2. idiopathic thromocytopenia purpura (ITP)
• 3. thrombotic thrombocytopenic purpura (TTP)
• 4. disseminated intravascular coagulation (DIC)

• - decrease in platelet count (<100k/uL)
• - <20k results in spontaneous bleeding

immune mediated destruction of platelets

acute disorder with unknown cause causing intravascular platelet activation with formation of platelet-rich microthrombi.

uncontrolled activation of the hemostatic system. there is both systemic thrombin formation and systemic plasmin formation. coagulation factors are activated and consumed faster than they can be produced resulting in bleeding and microvascular thrombi.