Pathogenesis of throbosis and fate of thrombus md pathology exam question give robbins based answer
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"Thrombosis"[MeSH Terms]
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Robbins pathology thrombosis pathogenesis fate thrombus Virchow triad organization recanalization
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Pathogenesis of Thrombosis and Fate of Thrombus
Definition
Thrombosis is the formation of a solid mass of blood constituents, called a thrombus, within the intact cardiovascular system during life. It is the pathological counterpart of normal hemostasis.
The pathogenesis is explained by Virchow triad:
- Endothelial injury or endothelial dysfunction
- Abnormal blood flow: stasis or turbulence
- Hypercoagulability of blood
Robbins & Kumar Basic Pathology, pp. 66-68.
Pathogenesis of thrombosis: Virchow triad
1. Endothelial injury or dysfunction
This is particularly important in arterial and cardiac thrombosis, where rapid blood flow normally prevents clot formation.
Mechanism
Endothelial injury causes:
- Exposure of subendothelial collagen and von Willebrand factor (vWF), causing platelet adhesion and activation.
- Exposure or expression of tissue factor, which activates the coagulation cascade.
- Loss of endothelial anticoagulant activity.
- Reduced fibrinolysis.
Activated or dysfunctional endothelium becomes prothrombotic by:
- Increased expression of tissue factor
- Decreased thrombomodulin, endothelial protein C receptor, and tissue factor pathway inhibitor
- Increased plasminogen activator inhibitor (PAI), which inhibits fibrinolysis
Causes
- Atherosclerosis
- Hypertension
- Vasculitis and inflammation
- Myocardial infarction
- Trauma
- Cigarette smoking
- Hypercholesterolemia
- Homocystinemia
- Toxins and infections
Examples: Rupture of an atherosclerotic plaque causes arterial thrombosis; endocardial damage after myocardial infarction predisposes to mural thrombus.
2. Abnormal blood flow: stasis and turbulence
A. Stasis
Stasis is especially important in venous thrombosis.
It promotes thrombus formation by:
- Bringing platelets and leukocytes into closer contact with endothelium
- Preventing washout of activated clotting factors
- Reducing inflow of anticoagulant factors
- Causing endothelial activation and hypoxia
Causes of stasis
- Prolonged bed rest or immobilization
- Congestive cardiac failure
- Varicose veins
- Atrial fibrillation
- Venous obstruction or compression
- Pregnancy
- Dilated cardiac chambers
B. Turbulence
Turbulence is more important in arterial and cardiac thrombosis.
It promotes thrombosis by:
- Causing endothelial injury or dysfunction
- Creating local pockets of stasis and countercurrents
- Disrupting normal laminar blood flow
Causes of turbulence
- Atherosclerotic plaques
- Aneurysms
- Abnormal cardiac valves
- Atrial fibrillation
- Ventricular aneurysm following myocardial infarction
3. Hypercoagulability
Hypercoagulability means an increased tendency of blood to clot because of abnormalities in coagulation factors or anticoagulant pathways. It is an important cause of venous thrombosis.
It may be inherited or acquired.
A. Primary or inherited hypercoagulability
| Condition | Mechanism |
|---|---|
| Factor V Leiden mutation | Factor V becomes resistant to inactivation by activated protein C |
| Prothrombin gene mutation | Increased prothrombin synthesis |
| Antithrombin deficiency | Reduced inhibition of thrombin and other coagulation factors |
| Protein C deficiency | Failure to inactivate factors Va and VIIIa |
| Protein S deficiency | Impaired activity of protein C |
| Hyperhomocystinemia | Endothelial injury and prothrombotic effect |
B. Secondary or acquired hypercoagulability
- Prolonged immobilization or bed rest
- Major surgery and trauma
- Malignancy, especially mucin-secreting adenocarcinomas
- Pregnancy and puerperium
- Oral contraceptive pills or estrogen therapy
- Antiphospholipid antibody syndrome
- Heparin-induced thrombocytopenia
- Disseminated intravascular coagulation
- Nephrotic syndrome
- Increasing age
- Obesity and smoking
Clinical correlation: Malignancy can produce migratory thrombophlebitis, called Trousseau syndrome.
Fate of thrombus
After formation, a thrombus may undergo one or more of the following four outcomes:
1. Propagation
The thrombus enlarges by further deposition of:
- Platelets
- Fibrin
This may progressively occlude the vessel lumen and increases the chance of embolization.
2. Embolization
Part or all of the thrombus may detach and travel through the circulation as an embolus.
- Venous thrombi usually embolize to the lungs, causing pulmonary embolism.
- Left-sided cardiac or arterial thrombi can produce systemic emboli, commonly involving the brain, kidneys, spleen, and lower limbs.
3. Dissolution
A recently formed thrombus may be removed by activation of the fibrinolytic system, mainly through plasmin-mediated breakdown of fibrin.
- Fresh thrombi may completely dissolve.
- Older thrombi are resistant to lysis because fibrin becomes extensively polymerized and organized.
- This explains why thrombolytic treatment is more effective when given early.
4. Organization and recanalization
Older thrombi undergo organization:
- Endothelial cells, smooth muscle cells, and fibroblasts grow into the thrombus.
- The thrombus is converted into fibrous tissue and becomes incorporated into the vessel wall.
- New capillary channels may form through the thrombus.
This formation of new vascular channels is called recanalization. It may restore some blood flow, but the original lumen is generally not completely restored.
Other possible late changes
- An organized thrombus may become calcified, producing a phlebolith, especially in veins.
- It may become infected, producing septic thrombophlebitis.
Conclusion for exam
Thrombosis results from one or more components of Virchow triad: endothelial injury, abnormal blood flow, and hypercoagulability. A thrombus may propagate, embolize, dissolve, or undergo organization with recanalization. Thrombosis causes disease either by local vascular occlusion and ischemic infarction or by embolic obstruction at a distant site.
Source: Robbins & Kumar Basic Pathology, “Thrombosis” and “Fates of Thrombi,” pp. 66-68.
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