Chapter 23. Bleeding disorders associated with coagulopathy O bleeding platelet count, bleeding time, capillary fragility test: normal PT, aPTT: prolonged -> coagulation factor, fibrinogen deficiency O hereditary (hemophilia A, B, C, von Willebrand disease) vs acquired 01. Bleeding disorders associated with congenital coagulopathy 1. Hemophilia A O factor VIII deficiency (reduced amount or activity) O sex-linked recessive O the most common coagulopathy O severe hemophilia A: inversion mild-moderate hemophilia A: missense mutation

release of blood protease into the synovial space O clinical presentation: delayed and spontaneous nature of the bleeding - acute hemarthrosis release of blood protease into the synovial space -> cartilage destruction -> joint destruction - intramuscular hemorrhage - central nervous system bleeding: the most common cause of death O aPTT: prolonged O PT, bleeding time, thrombin clotting time (TCT): normal O specific coagulation factor assay for factor VIII (40%)

O von Willebrand disease: factor VIII activity (VIII:C) -> reduced 2. Hemophilia B O factor IX deficiency O sex-linked recessive O clinical presentation: identical to those of hemophilia A O aPTT: prolonged PT, thrombin clotting time, Bleeding time: normal specific factor assay for factor IX 3. Hemophilia C O factor XI deficiency (activated by thrombin) O autosomal recessive specific factor assay for factor XI

4. Von Willebrand disease O defect in vWF O heterogenous disorder O vWF: participates in primary hemostasis carrier protein for factor VIII (stability) exists as a series of oligomer (from dimer to oligomer) synthesized in endothelial cell (Weibel-Palade body), megakaryocyte N: VIII binding site M: collagen, GPIb-IX-V binding site (A domain) C: GPIIb-IIIa binding site (C1 domain) O clinical presentation: platelet-type bleeding O lab evaluation -bleeding time: prolonged (cf. platelet disorder, connective disorder) -Ristocetin cofactor activity (Ristocetin-induced platelet agglutination): 감소 restocetin -> structural change of vWF -> exposing A domain -> induce agglutination of platelet -plasma vWF antigen -Factor VIII activity (using aPTT) -Multimer analysis type I vWD: overall decreased but normal array of vWF multimers type II vWD: abnormal multimer pattern type III vWD: absence of all vWF multimers

5. 기타 유사혈우병 질환 (1) Factor XII, prekalikrein, HMWK O not associated with bleeding O aPTT: prolonged O because in vivo they do not participate in hemostasis (2) Factor II, X, V (in common pathway) O rare disorders O PT, aPTT: prolonged bleeding time, thrombin clotting time: normal O V deficiency: parahemophilia (3) Factor VII (in extrinsic pathway) O isolated prolonged PT aPTT, bleeding time, thrombin clotting time: normal (4) Disorders of fibrinogen O hereditary afibrinogenemia O hereditary hypofibrinogenemia O dysfibrinogenemia O PT, aPTT, thrombin clotting time: prolonged (5) Factor XIII deficiency O PT, aPTT, thrombin clotting time, platelet count, bleeding time: normal O Urea clot solubility test: shortened

02. Acquired coagulopathy and Bleeding disorders O cause: medication, underlying disease 1. Anticoagulant agents O Heparin: antithrombin III -> thrombin O warfarin (Coumadin): vitamin K antagonist -> II, X, IX, VII, protein C,S O Low-molecular weight heparin: Xa 2. DIC O cause bleeding (consumptional coagulopathy) or thrombosis (혈액순환장애) -> shock, acidosis O simultaneous presence of thrombin and plasmin O acute DIC: hemorrhagic condition chronic DIC: prothrombic condition O antithrombin III, alpha2-antiplasmin: decrease 3. Liver disease O liver: synthesize all coagulation proteins clears plasmin

4. Vitamin K deficiency O water insoluble O nutritionally depleted/ malabsorption (bile juice deficiency) O warfarin O antibiotics 5. Massive transfusion O dilution of plasma and platelet O increased concentrations of the anticoagulant sodium citrate 6. Uncommon acquired coagulation protein defects O dysfibrinogenemia O inhibitors (antibody) to coagulation factors O hypergammaglobulinemic states (coagulation inhibition) O malignancy: produce heparinoids 7. Uremia (요독증) O blood vessel damage O coagulation deficiency O platelet defects 8. Hyperfibrinolysis