止血障碍血栓形成

1、 Hypercoagulability Definition: Alteration in the hemostatic balance between blood fluidity and clot formation. This is due to genetic and acquired disorders which shift this balance toward excessive or inappropriate platelet aggregation and fibrin formation and predispose to thrombosis. Prethrombot

2、ic States 10 - inherited abnormalities resulting from mutations affecting the function of coagulant proteins and natural inhibitors 20 - acquired defects that either affect the endothelium, fluid flow or blood components. These defects are often superimposed on 10 defects Hypercoagulability: Prethro

3、mbotic States Virchow (1856) Abnormalities of blood vessels Abnormalities of fluid flow Abnormalities of blood components Blood Vessel Abnormalities Endothelial cell antithrombotic properties- PGI2, NO2, TFPI, PAI-1, heparans, thrombomodulin Genetic predisposition and acquired defects in these funct

4、ions increase the risk of arterial and venous thrombosis Role of dietary excesses, hypertension, diabetes mellitus, obesity, smoking, lipid abnormalities in atherosclerosis Atherosclerosis Endothelial injury and dysfunction LDL cholesterol oxidized LDL- foam cells Diabetes mellitus glycated LDL chol

5、esterol Smoking free radical production Hypertension smooth muscle proliferation Genetic alterations MTHFR mutations R. Ross. Atherosclerosis. NEJM 340:115-126, 1999 Atherosclerosis Site specific: Bifurcations Branching vessels Curvatures Decreased shear stress and increased turbulence Plaque format

6、ion and rupture Unstable plaque. R.Ross NEJM 340:115-126, 1999. Blood Flow Abnormalities Stasis is the underlying mechanism as the cause of venous or arterial thrombosis Conditions - immobilization, surgery, congestive heart failure, pregnancy, obesity. Increased blood viscosity RBCs - polycythemias

7、, sickle cells WBCs myeloproliferative disorders especially CML Platelets - primary thrombocytosis Paraproteins - Myeloma, Waldenstroms Macroglobulinemia Hypercoagualbility: Hereditary/Acquired Factor V Leiden Prothrombin 20210 Protein C Protein S Anti-thrombin III Dysfibrinogenemia Hyperhomocystein

8、emia PAI-I Platelet glycoprotein IIb/IIIa Factor V Leiden Mutation at position 506 rendering FV insensitive to degradation by activated protein C. Autosomal dominant; 5% Caucasian population. Heterozygote - 7x increased risk for venous thrombosis Homozygote - 80 x increased risk Often found in assoc

9、iation with other risk factors - protein C and S deficiencies Prothrombin 20210 Mutation Mutation results in increased synthesis of prothrombin resulting in elevated plasma levels of biochemically normal prothrombin Autosomal dominant; 1-2% of population Increased risk of venous thrombosis - 2x Prot

10、ein C Deficiency Autosomal dominant Mutation results in mild to severe deficiency; increase risk for venous thrombosis homozygote = purpura fulminans 0.2% of US population Acquired - DIC, liver disease, oral contraceptives, oral anticoagulant use Protein S Deficiency Autosomal dominant Increased ris

11、k of venous thrombosis Acquired deficiencies - DIC, liver disease. coumarin therapy, pregnancy (2nd and 3rd trimesters), estrogen replacement therapy, L-asparginase chemotherapy Hyperhomocysteinemia Increased levels are associated with increased risk of arterial and venous thrombosis. Multiple effec

12、ts on endothelial cells - decreased thrombomodulin, increased TF activity, inhibition of NO and TPA Hyperhomocysteinemia Primary - mutation of MTHFR gene Acquired - vitamin B12, B6 or folic acid deficiency, hypothyroidism, isoniazid, methotrexate, theophylline Hereditary Thrombophilia Consider if :

13、family history of thrombosis history of recurrent thrombosis thrombosis at a young age no acquired predisposing factors for thrombosis Malignancy Risk for thrombosis is multifactorial. Predominantly venous thrombosis - stasis, tumor invasion of vessels, chemotherapy effects superimposed on acquired

14、or primary defects in hemostasis. Distinct procoagulant (cysteine protease) found in many patients which can activate FX directly. Antiphospholipid Antibody Syndrome Autoimmune disorder, either primary or secondary, associated with an increased risk for arterial and venous thrombosis. Antibody is to

15、 cardiolipin in APA (ELISA assay); antibody is to beta 2 glycoprotein 1 and platelet phospholipids in patients with lupus anticoagulants (aPTT and/or PT). Thrombus Size, shape and morphology Mural thrombus Infected thrombus bacterial endocarditis Verrucous thrombus Libman-Sacks endocarditis Thrombus

16、 Natural history: Resolution Propagation Fragmentation/embolization Organization Resolution Propagation complete occlusion FFragmentation and Embolization Organization Fibroblast proliferation Organization Endothelial cell differentiation Resolution Organization - Rethrombosis Thrombus Clinical pres

17、entation: Arterial coronary, carotid and femoral Acute MI, Angina CVA, TIA Claudication Venous superficial veins, deep veins Thrombophlebitis, swollen, painful extremity Pulmonary embolus Atherosclerosis Endothelial injury and dysfunction LDL cholesterol oxidized LDL- foam cells Diabetes mellitus glycated LDL cholesterol Smoking free radical production Hypertension smooth muscle proliferation Genetic alterations MTHFR mutations Prothrombin 20210 Mutation Mutation results in increased synthesis of prothrombin resulting in elevated plasma levels of biochemically normal prothrombin