DISORDERS OF HEMOSTASIS Dept.of Hematology ZhongShan Hospital,FuDan University Prof. JlAN-MIN XU General Considerations Disorders of hemostasis defects in platelet number or function problems in fibrin clot (coagulation) Bleeding due to platelet disorders is typically mucosal or dermatologic include epistaxis, gum bleeding, menorrhagia, gastrointestinal bleeding, purpura, and petechiae General Considerations Petechiae are seen almost exclusively in conditions of thrombocytopenia and not platelet dysfunction. Bleeding due to coagulopathy may occur as deep muscle hematomas as well as skin bleeding. Spontaneous hemarthroses are seen only in severe hemophilia. General Considerations Definition:  disorder of hemostasis spontaneous bleeding abnormal bleeding following trauma Machanism ：vessel wall defect thrombocytopenia, platelet disfunction coagulation disorder  Normal hemostasis and coagulation hemostasis: 1. Vessel wall ：（1）vessel spasm: reflex spasm S-HT↑slow down blood flow （2）subendothelial connective tissue ：encouraging platelet adhesion, activation,  aggregation （3）releasing TF, activating FⅫ：triggering intrinsic and extrinsic pathway  （4）pression of haematoma Normal hemostasis and coagulation 2. platelet ：（1）adhesion ：to subendothelial connective tissue by GPⅠb 、vWF （2）aggregation ：formation of platelet thrombus by GPⅡb/Ⅲa （3）release ：phosphatide-Arachidonic Acid -TXA2 further platelet activation and adhesion violent vessel spasm Normal hemostasis and coagulation coagulation: （1）Rearrangement of platelet membrane phosphatidate-PF3  （2）Tissue injury- TF release （3）Subendothelial connective tissue-Ⅻ-Ⅻa  triggering intrinsic and extrinsic pathway-white thrombus-red thrombus Normal hemostasis and coagulation coagulation ：nature: a cascade of enzymes activation not active before activated component: 12 coagulation factor:  11 in plasma (tissue factor)  protein ( exclude Ca++ )  code with Ⅰ、Ⅱ、Ⅲ、Ⅳetc. PK HMWK Normal hemostasis and coagulation 3.  course ：（1）thromboplatin  intrinsic: Ⅻ-Ⅻa——Ⅺ-Ⅺa-Ⅸ-  Ⅸa+Ⅷ+Ca+PF3  extrinsic: III-VII+Ca  Ⅹ-Ⅹa+Ⅴ+Ca+PF3 （2）thrombin ：prothrombinthromboplatin+Cathrombin Xa因子的核心作用Normal hemostasis and coagulation （3）fibrin ：fibrinogenthrombinfibrin monomer-polymerXIIIapolymer （4）function of thrombin ：coagulation ：activateⅠ、Ⅻ、strengthen Ⅷ、Ⅴplatelet ：aggregation, release fibrinolysis ：activate plasminogen Normal hemostasis and coagulation Anticoagulant system ：1.  anticoagulin ：（1）each coagulate factor and their complex has  its own inhibitor （2）important ：AT-Ⅲ：70% anticoagulant activity  serine proteinase inhibitor  Ⅱa. Ⅻa. Ⅺa. Ⅸa. DK Normal hemostasis and coagulation （3）protein C system ：PCTMAPC+PS  sterilize Va. VIIIa.  Inhibit PAI  Physiology and Pathology APCI Ⅹa,trypsinize ，TM+thrombin activator  sterilize Ⅴa ，Ⅷa  PC APC release plasminogen  Ca++ →fibrolysis Ca++ PS modulate the activation of c’acceleration inhibition APC ：Activated 	Protein C  Normal hemostasis and coagulation fibrinolysis ：plasminogenplasminogen activator plasmin  （PAI ）（a2-AP ）2. fibrinolysis ：fibrinogen→fragmentX →fragmentY →fragmentE ↘↘↘（FDP ）polypeptideABC fragmentD  fragmentD Abnormality 1. Vessel wall ：heredity ：Telangiectasis  aquired ：deficiency of Vit C 、Vit P  hypersensitivity ：anaphylactoid purpura  else ：Abnormality 2. Platelet ：（1）thrombocytopenia ：production ：AA, leukemia, infection, drug destruction ：ITP exhaust ：TTP 、HUS 、DIC  Abnormality  （2）thrombocythemia ：primary ：Primary hemorrhagic thrombocythemia secondary ：CML, splenectomy , infection trauma （3）function deficiency ：heredity ：thrombasthenia secondary ：drug, renal failure liver disease Abnormality  3. Coagulation ：（1）heredity ：hemophilia 、willabrand disease （2）aquired ：liver disease 、renal failure 、VitK deficiency 、DIC （3）anticoagulant agents ：Ⅷ、Ⅸ-Ab 、drug Diagnosis History and physical exam(PE): 1.history ：cause, sex 、heredity background  course 2.PE ：petechial bleeding (organ, muscle, joint cavity) Diagnosis Lab examination ：1.filter ：vessel, platelet: BT 、plt 、CRT coagulation ：CT 、APTT 、PT 、TT Diagnosis 2.particular: （1）platelet ：morphology ：bulk 、scatter 、gathering adhesion 、aggregation ：inducer ：Adr 、ADP 、collagen 、ristocetin  ↓thrombasthenia ↑thrombus disease Diagnosis （2）Coagulation ：APTT+CT ：VIII. IX. XI PTCT ：V. VII. X. II TT ：fibrinogen↓、anticoagulant agents Coagulant factor test ：quantity activation Prevention and Therapy 1. Prevention ：drug ：aspirin, persantin, indomethacin disease: liver disease ,renal failure heredity ：prevent traumer 、operation Prevention and Therapy 2. hemostasis ：（1）supplyment ：coagulant factor 、fresh  plasma 、blood 、platelet （2）drug ：vessel ：VitC 、VitP 、Carbazochrome 、Pred platelet ：Etamsylate 、Pred coagulation ：VitK 、prothrombin complex fibrinolysis ：EACA,PAMBA,Tranexamic Acid  （3）local ：oppression 、decrease movement * * Boneu et al. Sang Thrombose Vaisseaux . 1998;10:291-313. II VIIa 细胞的促凝血酶原激酶Ca2+ Xa XIa 内源性系统外源性系统X IX XIIIa  XI XII XIIa 溶解性纤维蛋白纤维蛋白原纤维蛋白（凝块）Xa Va  PL Ca2+ VII 凝血酶IIa IXa VIIIa  Ca2+ PL