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Etiology, pathogenesis & Morphology of thrombosis.pptx
- 1. ETIOLOGY, PATHOGENESIS & MORPHOLOGYOF THROMBOSIS DR. MANAHIL JAMIL
- 2. THROMBOSIS Thrombosis isthe formation of a thrombus inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thrombocytes) and fibrin to form a blood clot to prevent blood loss. A thrombus, also called a blood clot, is the final product of the blood coagulation step in hemostasis.
- 4. ETIOLOGY & PATHOGENESIS Theprimary abnormalities that lead to intravascular thrombosis are; 1. Endothelial injury next 2. Stasis or turbulent blood flow 3. Hypercoagulability The so-called “Virchow triad”
- 5. 1. ENDOTHELIAL INJURY This underlies thrombus formation in the heart and the arterial circulation, where the high rates of blood flow impede clot formation. Severe endothelial injury may trigger thrombosis by exposing vWF and tissue factor.
- 6. Inflammation andother noxious stimuli also promote thrombosis by shifting the pattern of gene expression in endothelium to one that is “prothrombotic.” This change is sometimes referred to as endothelial activation or dysfunction and can be produced by diverse exposures, including; 1. physical injury 2. infectious agents 3. abnormal blood flow 4. inflammatory mediators 5. metabolic abnormalities, such as hypercholesterolemia or homocystinemia 6. toxins absorbed from cigarette smoke.
- 7. MAJOR PROTHROMBOTIC ALTERATIONS: Procoagulant changes : Endothelial cells activated by cytokines downregulate the expression of thrombomodulin resulting in sustained activation of thrombin, which can in turn stimulate platelets and augment inflammation through PARs expressed on platelets and inflammatory cells inflamed endothelium also downregulates the expression of other anticoagulants, such as protein C and tissue factor protein inhibitor, changes that further promote a procoagulant state. Antifibrinolytic effects : Activated endothelial cells secrete plasminogen activator inhibitors (PAIs), which 1. limit fibrinolysis 2. and downregulate the expression of t-PA
- 10. II. ALTERNATIONS INNORMAL BLOOD FLOW Turbulence causes endothelial injury or dysfunction & countercurrents that contribute to local pockets of stasis. Stasis is a major contributor in the development of venous thrombi. Stasis and turbulence therefore: 1. Promote endothelial activation, enhancing procoagulant activity and leukocyte adhesion, in part through flow-induced changes in the expression of adhesion molecules and pro-inflammatory factors 2. Disrupt laminar flow and bring platelets into contact with the endothelium 3. Prevent washout and dilution of activated clotting factors by fresh flowing blood and the inflow of clotting factor inhibitors
- 12. III. HYPERCOAGULABILITY (THROMBOPHILIA) Hypercoagulability can be loosely defined as any disorder of the blood that predisposes to thrombosis. Can be divided into; 1. primary (genetic) 2. secondary (acquired) disorders
- 13. Primary (Genetic) Common Factor Vmutation (Arg to Glu substitution in amino acid residue 506 leading to resistance to activated protein C; factor V Leiden) Prothrombin mutation (G20210A noncoding sequence variant leading to increased prothrombin levels) Increased levels of factors VIII, IX, XI, or fibrinogen (genetics unknown) Rare Antithrombin III deficiency Protein C deficiency Protein S deficiency Very Rare Fibrinolysis defects Homozygous homocystinuria (deficiency of cystathione β-synthetase)
- 14. Secondary (Acquired) High Riskfor Thrombosis Prolonged bed rest or immobilization Myocardial infarction Atrial fibrillation Tissue injury (surgery, fracture, burn) Cancer Prosthetic cardiac valves Disseminated intravascular coagulation Heparin-induced thrombocytopenia Antiphospholipid antibody syndrome Lower Risk for Thrombosis Cardiomyopathy Nephrotic syndrome Hyperestrogenic states (pregnancy and postpartum) Oral contraceptive use Sickle cell anemia Smoking
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- 17. Thrombi arefocally attached to the underlying vascular surface, particularly at the point of initiation. From here, arterial thrombi tend to grow retrograde, while venous thrombi extend in the direction of blood flow; thus both propagate toward the heart. The propagating portion of a thrombus is often poorly attached and therefore prone to fragmentation and embolization. Thrombi often have grossly and microscopically apparent laminations called lines of Zahn, which are pale platelet and fibrin deposits alternating with darker red cell–rich layers. Such laminations signify that a thrombus has formed in flowing blood; their presence can therefore distinguish antemortem clots from the bland nonlaminated clots that occur postmortem
- 19. Mural thrombi: Thrombi occurring in heart chambers or in the aortic lumen. Abnormal myocardial contraction or endomyocardial injury promotes cardiac mural thrombosis Arterial thrombi : 1. frequently occlusive 2. consist of a friable meshwork of platelets, fibrin, red cells, and degenerating leukocytes Venous thrombosis (phlebothrombosis) : 1. Almost invariably occlusive 2. form in the sluggish venous circulation 3. contain more enmeshed red cells (red, or stasis, thrombi) 4. firm, are focally attached to the vessel wall, and contain lines of Zahn,
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- 24. Postmortem clots: 1. clots that form after death are gelatinous and have a dark red dependent portion where red cells have settled by gravity and a yellow “chicken fat” upper portion 2. not attached to the underlying vessel wall. Vegetations : 1. Thrombi on heart valves 2. Bloodborne bacteria or fungi can adhere to previously damaged valves or can directly cause valve damage; in either case, endothelial injury and disturbed blood flow can induce the formation of large thrombotic masses.
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- 26. If a patientsurvives the initial thrombosis, in the ensuing days to weeks thrombi undergo some combination of the following four events: Propagation : Thrombi accumulate additional platelets and fibrin (discussed earlier). Embolization : Thrombi dislodge and travel to other sites in the vasculature (discussed later). Dissolution : Dissolution is the result of fibrinolysis, which can lead to the rapid shrinkage and total disappearance of recent thrombi. Organization and recanalization : Older thrombi become organized by the ingrowth of endothelial cells, smooth muscle cells, and fibroblasts. Capillary channels eventually form that reestablish the continuity of the original lumen. Continued recanalization may convert a thrombus into a smaller mass of connective tissue that becomes incorporated into the vessel wall. Eventually, with remodeling and contraction of the mesenchymal elements, only a fibrous lump may remain to mark the original thrombus.