Chapter 22. Bleeding trait and disorders O bleeding trait: spontaneous bleeding, bruising, purpura O cause: vessel defect, platelet defect, coagulation defect, fibrinolysis defect

01. Bleeding disorders associated with vessel defects O capillary fragility test: positive, bleeding time: prolonged Prothrombin Time(PT), activated partial thromboplastin Time(aPTT):normal 1. 혈관벽 이상에 의한 자반병 (purpura) O scurvy, ACTH/Adrenal Cortex Hormone, Cushing’s syndrome -> vitamin C deficiency -> proline to hydroxyproline X -> normal collagen production X -> vessel defect O Ehlers-Danlos syndrome, Marfan syndrome, Osler disease -> 선천성 혈관형성 이상 2. 혈관염에 의한 자반병 O 혈관의 염증성 변화로 출혈을 일으키는 질환 O anaphylactoid purpura (Schonlein-Henoch purpura, 알레르기성 자반병 ) 3. 이상 단백혈증을 동반하는 자반병 O macroglobulinemia, multiple myloma, cryoglobulinemia O hyperviscosity syndrome (HVS) -> 혈액순환장애

O ecchymoses: >1cm (bruising) purpura: cm petechiae: cm O hematoma: a localized collection of blood outside the blood vessels. Usually in liquid form within the tissue O Ehlers-Danlos: collagen synthesis defect, Marfan’s syndrome: fibrillin-1 defect, connective tissue defect Osler disease: abnormal blood vessel formation O Schonlein-Henoch purpura: skin disease, palpable purpura systemic vasculitis, IgA immune complex deposition O cryoglobulinemia: proteins that become insoluble at reduced temp. O Fanconi anemia: bone marrow failure O copper deficiency: myelodysplasia

4. Atherosclerosis -> coronary artery disease (CAD) (1) cause: hyperlipidemia, hypertension, smoking, diabetes mellitus (2) Endothelial injury (increased permeability) accumulation of lipoprotein (LDL) monocyte recruitment ->macrophage->foam cell smooth muscle cell (SMC) recruitment SMC proliferation and ECM production lipid accumulation -> atheroma or plaque formation platelet adhesion 5. Thrombosis (1)Endothelial dysfunction O cause: toxin, hypertension, inflammation, metabolic products (2) Stasis or turbulence O Normal blood flow is laminar O endothelium damage * Ulcerated atherosclerotic plaque, aneurysm, hyperviscosity syndrome (3) hypercoagulability O factor V Leiden (cannot be cleaved by protein C) O increased prothrombin synthesis O inhibition of antithrombin, thrombomodulin (by homocysteine)

02. Bleeding disorders associated with abnormal platelets O capillary fragility test: positive, bleeding time: prolonged clot retraction: prolonged, PT, aPTT: normal O platelet count: 100,000/ul 이하 시 1. 혈소판 감소를 동반하는 질환 (thrombocytopenia) (1) 혈소판 생성저하

(2) 혈소판 파괴의 항진 (immune-mediated) * immune thrombocytopenic purpura (ITP) O autoAb against platelet antigen -> platelet destruction in RES (Fc receptor) O secondary to SLE O bone marrow: normal * heparin-induced thrombocytopenia O heparin/Platelet Factor4 complex -> Ab generation -> Ab-Ag complex bind to platelet FcgammaRII -> platelet activation -> platelet thrombus formation -> thrombocytopenia

(3) 혈소판파괴의 항진 (Nonimmune-mediated) O disseminated intravescular coagulation increased consumption excess of thrombin, plasmin cause bleeding and thrombosis confirmatory tests: D-dimer, FDP, fibrin monomer test O thrombotic thrombocytopenic purpura (TTP) endothelial damage -> abnormal release of large vWF molecules from Weibel-palade bodies (vWF processing enzyme ADAMTS-13) increased adhesion and aggregation of platelet little consumption of coagulation factors O hemolytic uremic syndrome (HUS) thrombotic microangiopathies (similar to TTP) renal failure, hemolytic anemia, thrombocytopenia shiga toxin-producing E. Coli -> endothelial damage -> platelet activation(thrombocytopenia) -> glomerular damage -> renal failure -> inactivating ADAMTS 13 -> large vWF (4) Hypersplenism

04. Disorders associated with thrombocytosis O normal range: 150, ,000/ul thrombocytosis: above 5(7)00,000/ul O primary thrombocytosis independent of growth factor not function normally thrombosis and bleeding (hemorrhagic thrombocythemia) O secondary thrombocytosis rarely have symptoms of thrombosis the most common cause: iron deficiency iron -> inhibit thrombopoietin 표 22-4 참조

05. Disorders associated with dysfunctional platelet O platelet count: normal, function: abnormal O bleeding time: prolonged 1. Congenital platelet disorders O intrinsic vs extrinsic (1) Disorders of adhesion O von Willebrand disease (extrinsic): defect in vWF Ristocetin cofactor assay: abnormal, platelet aggregation assay: abnormal O Bernard-Soulier syndrome (intrinsic): defect in GP Ib-IX-V thrombocytopenia, large platelet Ristocetin cofactor assay: normal, platelet aggregation assay: abnormal O Ehlers-Danlos syndrome (extrinsic): defect in connective tissue (collagen synthesis defect) (2) Disorders of aggregation O afibrinogenemia (extrinsic) O Galnzmann thrombasthenia (intrinsic): defect in GP IIb-IIIa O bleeding time, clot retraction time: prolonged

(3) Disorders of activation (secretion) O storage pool deficiency lack the normal storage granule alpha-SPD (alpha-granule deficiency), delta-SPD (dense granule deficiency) congenital vs acquired (partial degranulated, spent platelet) O defect in platelet stimulus-response coupling pathway cannot be mobilized to release defect in signal transduction pathway cyclooxygenase -> reduced thromboxane A2 (aspirin) (4) Disorders of platelet procoagulant activities O Scott syndrome defect in expression of acidic phospholipid (phosphatidylserine) on platelet surface -> decreased factor IXa, Xa binding

2. Acquired platelet disorder (1)Uremia ( 요독증 ) (2) Myeloproliferative disorder O thrombotic or hemorrhagic symptom O essential thrombocytosis 거핵구의 암성 증식 -> 혈소판증가, 기능저하 -> 출혈, 혈전형성 (3) Myelodysplastic disorders and acute leukemia abnormal maturation -> abnormal morphologically and metabolically (4) Dysproteinemia increased Ig -> increased viscosity -> interfere with fibrin polymerization -> nonspecifically coat platelet -> interfere with binding of agonists (5) Cardiopulmonary bypass: partially activated (6) Antiplatelet antibody partial activation, interfere with binding of vWF, fibrinogen (7) Liver disease: cannot clear FDP -> inhibit binding of fibrinogen (8) Various drugs