Thrombosis: The warning sign for arteries – Part 1
While hemostatic plugs aid in containing plasma and blood, thrombi forming in the cardiovascular system can cause serious conditions such as ischaemic injury (constricted blood flow leading to iscahemia and later infarction) and thrombosis (lodging of thrombus in a distant blood vessel).
When the blood cells get injury, the hemostatic repair mechanism/thrombogenesis takes place. Virchow explained this process in 3 steps but two more are added for better understanding. They are,
- Endothelial injury
- Role of platelets
- Coagulation system
- Altered blood flow
The arterial wall being intact is essential for the wellbeing. Even a small injury cause vasoconstriction in smaller blood vessels to avoid blood loss. Endothelial injury is important as it majorly causes arterial thrombi and thrombi of the heart, especially in the left ventricle. Some of the risk factors of endothelial injury are,
- Injury due to myocardial infarction, prosthetic valves, etc.
- Ulcerated valves due to advanced atherosclerosis
- Hemodynamic stress
- Diabetes mellitus
- Arterial diseases
- Endogenous chemical agents (hypercholesterolaemia)
- Exogenous chemical agents (smoke)
Role of platelets:
Platelets come into play after endothelial injury.
Platelet adhesion – Platelets in circulation recognize the endothelial injury and adhere at the exposed sub-endothelial collagen by von Willebrand’s factor (primary aggregation). During early adhesion process, pseudopods are formed and the cytoplasmic organelles are shifted to the center of the cell.
Platelet release reaction – The platelets are released to the exterior by a release reaction. Two major types of platelets are released:
- Alpha granules contain fibrinogen, fibronectin, platelet derived growth factor, platelet factor 4 (an anti-heparin) and cationic proteins.
- Dense bodies contain ADP, ionic calcium, 5-HT (serotonin), histamine and epinephrine.
The phospholipid complex-platelet factor 3 gets activated.
Platelet aggregation –Following ADP’srelease, platelet aggregation takes place (secondary aggregation), resulting in the formation of a temporary hemostatic plug. The permanent hemostatic plug is formed by the action of thrombin, fibrin and thromboxane A2.
Role of coagulation system:
Coagulation mechanism is the conversion of plasma fibrinogen to a solid mass of fibrin. This process is involved in both hemostatic process and thrombus formation. The 3 major pathways in the process are explained below:
- In the intrinsic pathway, contact with abnormal surface leads to activation of factor XII and subsequently XI, IX, VIII and X, along with factor IV and platelet factor 3.
- In the extrinsic pathway, tissue damage leads to release of thromboplastin, which in contact with factor VII, activates factor X.
- The common pathway begins when both intrinsic and extrinsic pathways converge to activate factor X which forms a complex with factor Va and platelet factor 3, in the presence of calcium ions. This complex activates prothrombin (factor II) to thrombin (factor IIa) which, in turn, converts fibrinogen to fibrin. Initial monomeric fibrin is polymerized to form insoluble fibrin by activation of factor XIII.
The blood and the coagulation process are regulated by certain mechanisms. They are under,
- Protease inhibitors act on coagulation factors so as to prevent the formation of thrombin. Eg. Antithrombin III, protein C.
- Fibrinolytic system’s component plasmin is formed by the action of plasminogen activator on plasminogen present in normal plasma. Two types of plasminogen activators are tissue type derived from endothelial cells and leukocytes and urokinase-like, present in the plasma.
Alteration of blood flow:
Normally in the axial blood flow, blood cells and leucocytes are present in the fast-moving central stream, while platelets are present in the slow-moving laminar stream which is adjacent to the central stream. The most slow-moving, cell-free plasma flow in the peripheral stream, close to the endothelial layer.
Turbulence and statis disturb the normal blood flow. Turbulence injures the endothelium and allows deposition of platelets and fibrin. Stasis causes the blood cells including platelets to marginate to the periphery and form a pavement close to the endothelium. It increases the oxygen release from blood. Arterial and cardiac thrombi formation are facilitated by turbulence while venous thrombi are initiated by stasis.
Hypercoagubility of blood:
Hypercoagubility of blood is caused by increasing age, smoking, usage of oral contraceptives, obesity and smoking. It is explained as the basis of thrombosis in conditions such as nephrotic syndrome, cancer, extensive trauma, burns and during puerperium. It can occur due to the following changes in blood:
- Increase in coagulation factors
- Increase in platelet count and their adhesiveness
- Decrease in coagulation inhibitor levels
Primary and secondary factors favour thrombosis.
- Deficiency of antithrombin
- Deficiency of proteins C or S
- Defects in fibrinolysis
- Mutations in factor V
- Advanced age
- Prolonged bed rest
- Cigarette smoking
- Heart diseases
- Vascular diseases
- Hypercoagulable conditions
- Tissue damage
- Late pregnancy and puerperium
- Certain drugs
Thrombosis may occur in the heart, arteries, capillaries and veins. Their effects are different. Venous thrombi cause embolism while arterial thrombi cause ischaemia and infarction. Arterial thrombi tend to be white while the venous thrombi tend to be red and occlutive. Red thrombi are soft and gelatinous while white thrombi are pale and firm. The composition of thrombus is determined by the rate of flow of blood. Red thrombi resemble blood clots.
Origin of thrombi:
Thrombi may form in any chamber of the heart and the valve cusps but especially in the atrial appendages on the mitral and aortic valves called vegetations. Rarely, large round thrombus may form and obstruct the mitral valve and is called ball-valve thrombus. Agonal thrombi are formed shortly before death and may occur in either or both the ventricles.
FATE OF THROMBUS:
Thrombus activates the fibrinolytic system with constant release of plasmin which dissolves the thrombus, resulting in resolution. Lysis takes place in small venous thrombi. Fibrinolytic activity can be triggered by administering thrombolytic substances such as urokinase and streptokinase.
If the thrombus is not removed, organisation takes place. Phagocytic cells appear and phagocytose cell debris and fibrin
Fibrovascular granulation is formed by which the thrombus gets excluded from the vascular lumen and becomes part of the vessel wall. The new vascular channels in it may be able to re-establish the blood flow, called recanalisation. The fibrosed thrombus may undergo hyalinisation and calcification.
The thrombus may enlarge in size due to more and more deposition of particles from the flowing blood. It cause completely obstruct a vessel.
The infected thrombi and the thrombi in early stage may get detached and are released into the blood. They form emboli and cause ill effects.
- Cardiac thrombi – large thrombi in the heart may cause sudden death
- Arterial thrombi – may cause neurotic iscahemia
- Venous thrombi – may cause thromboembolism, oedema, poor wound healing, skin ulcer, painful thrombosed veins and painful white leg (phlegmasia alba dolens).
- Capillary thrombi – Microthrombi in microcirculation may give rise to disseminated intravascular coagulation (DIC).
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