Pathophysiology Of Thrombogenesis

Pathophysiology

Since the protective haemostatic plug formed as a result of normal haemostasis is an example of thrombosis, it is essential to describe thrombogenesis in relation to the normal haemostatic mechanism.

Human beings possess an inbuilt system by which the blood remains in a fluid state normally and guards against the hazards of thrombosis and haemorrhage. However, injury to the blood vessel initiates haemostatic repair mechanism or thrombogenesis.

Read And Learn More Homeostasis

Virchow described three primary events which predispose to thrombus formation (Virchow’s triad): endothelial injury, altered blood flow, and hypercoagulability of blood. Two activation processes that follow these primary events are added to the triad—activation of platelets and of clotting system.  These events are discussed below.

1. Endothelial Injury:  The integrity of blood vessel wall is important for maintaining normal blood flow. An intact endothelium has the following functions:

• It protects the flowing blood from the thrombogenic influence of subendothelium.
• It elaborates a few anti-thrombotic factors (thrombosis inhibitory factors) as follows:
  • Heparin-like substance which accelerates the action of antithrombin III and inactivates some other clotting factors.
  • Thrombomodulin which converts thrombin into activator of protein C, an anticoagulant.
  • Inhibitors of platelet aggregation such as ADPase, PGI₂ (or prostacyclin).
  • Tissue plasminogen activator which accelerates fibrinolytic activity.
• It releases a few prothrombotic factors which have procoagulant properties (thrombosis favouring factors) as under:
  • Thromboplastin or tissue factor released from endothelial cells.
  • von Willebrand factor that causes adherence of platelets to the subendothelium.
  • Platelet activating factor which is activator and aggregator of platelets.
  • Inhibitor of plasminogen activator that suppresses fibrinolysis.

Vascular injury exposes the subendothelial extracellular matrix components (for example Collagen, elastin, fibronectin, laminin and glycosaminoglycans) which are thrombogenic and thus play important roles in initiating haemostasis as well as thrombosis . Injury to vessel wall also causes vasoconstriction of small blood vessels briefly so as to reduce the blood loss.

Endothelial injury is of major significance in the formation of arterial thrombi and thrombi of the heart, especially of the left ventricle. A number of factors and conditions may cause vascular injury and predispose to the formation of thrombi.

These are as under:

• Endocardial injury in myocardial infarction, myocarditis, cardiac surgery, prosthetic valves
• Ulcerated plaques in advanced atherosclerosis
• Haemodynamic stress in hypertension
• Arterial diseases
• Diabetes mellitus
• Endogenous chemical agents such as hypercholesterolaemia, endotoxins
• Exogenous chemical agents such as cigarette smoke

2. Role Of Platelets:

Following endothelial cell injury, platelets come to play a central role in normal haemostasis as well as in thrombosis. The sequence of events is as under :

 Platelet adhesion:

Glycoprotein Ib (GpIb) receptor on the platelets recognises the site of endothelial injury and the circulating platelets adhere to exposed subendothelial ECM (primary aggregation). von

• Willebrand’s factor (vWF), synthesised by the endothelial cells binds to GpIb and forms a firm adhesion of platelets with ECM. Thus, deficiency of vWF (as happens in von
• Willebrand’s disease) or absence of GpIb (as is seen in Bernard-Soulier disease) would result in defective platelet adhesion and cause abnormal bleeding.

Platelet release reaction:

Activated platelets then undergo release reaction by which the platelet granules are released to the exterior.

Two main types of platelet granules are released:

• Dense bodies Their release liberates ADP (adenosine diphosphate), ionic calcium, 5-HT (serotonin), histamine and epinephrine. The release of contents of dense bodies is more important since ADP is further an activator of platelets, and calcium is required in the coagulation cascade.
• Alpha granules Their release produces fibrinogen, fibronectin, platelet-derived growth factor (PDGF), platelet factor 4 (an antiheparin) and thrombospondin.

As a sequel to platelet activation and release reaction, the phospholipid complex-platelet factor 3 gets activated which plays important role in the intrinsic pathway of coagulation.

Platelet aggregation:

Following release of ADP, a potent platelet aggregating agent, aggregation of additional platelets takes place (secondary aggregation). This results in formation of temporary haemostatic plug. However, stable haemostatic plug is formed by the action of fibrin, thrombin and thromboxane A₂.

3. Role Of Coagulation:

System Coagulation mechanism is the conversion of the plasma fibrinogen into solid mass of fibrin. The coagulation system is involved in both haemostatic process and thrombus formation shows schematic representation of the cascade of intrinsic (blood) pathway, the extrinsic (tissue) pathway, and the common pathway leading to formation of fibrin polymers.

• In the intrinsic pathway: Contact with abnormal surface (for example, ECM in the subendothelium) leads to activation of factor XII and the sequential interactions of factors XI, IX, VIII and finally factor X, along with calcium ions (factor and platelet factor 3.
• In the extrinsic pathway: Tissue damage results in release of tissue factor or thromboplastin. Tissue factor on interaction with factor VII activates factor X.
• The common pathway:  Begins where both intrinsic and extrinsic pathways converge to activate factor X which forms a complex with factor Va and platelet factor 3, in the presence ofcalcium ions. This complex activates prothrombin (factor to thrombin (factor IIa) which, in turn, converts fibrinogen to fibrin.

Initial monomeric fibrin is polymerised to form insoluble fibrin by activation of factor XIII.

Regulation of coagulation system:

Normally, the blood is kept in fluid state and the coagulation system is kept in check by controlling mechanisms. These are as under:

• Protease inhibitors:  These act on coagulation factors so as to oppose the formation of thrombin for example ,Antithrombin III, protein C, C1 inactivator, α₁-Antitrypsin, α₂-Macroglobulin.
• Fibrinolytic system: Plasmin, a potent fibrinolytic enzyme, is formed by the action of plasminogen activator on plasminogen present in the normal plasma. Two types of plasminogen activators (PA) are identified:
  • Tissue-type PA derived from endothelial cells and leucocytes.
  • Urokinase-like PA present in the plasma.

Plasmin so formed acts on fibrin to destroy the clot and produces fibrin split products (FSP).

4. Alteration Of Blood Flow:

Turbulence means unequal flow while stasis means slowing

• Normally, there is axial flow of blood in which the most rapidly-moving central stream consists of leucocytes and red cells. The platelets are present in the slow-moving laminar stream adjacent to the central stream while the peripheral stream consists of most slow-moving cell-free plasma close to endothelial layer.
• Turbulence and stasis occur in thrombosis in which the normal axial flow of blood is disturbed. When blood slows down, the blood cells including platelets marginate to the periphery and form a kind of pavement close to endothelium (margination and pavementing).
• While stasis allows a higher release of oxygen from the blood, turbulence may actually injure the endothelium resulting in deposition of platelets and fibrin.
• Formation of arterial and cardiac thrombi is facilitated by turbulence in the blood flow, while stasis initiates the venous thrombi even without evidence of endothelial injury.

5. Hypercoagulability (Thrombophilia):

Thrombophilia or hypercoagulable states are a group of conditions having increased risk or predisposition to develop venous thrombosis. These conditions may be hereditary (or primary) or acquired (or secondary) causes

However, in a given case of thrombosis, several factors are generally present simultaneously.

Causes of thrombophilia (hypercoagulable states):

Inherited (Primary) Factors:

• Deficiency of antithrombin III
• Deficiency of protein C
• Deficiency of protein S
• Mutation in factor V Leiden
• Defects in fibrinolysis (dysfibrinogenaemia, plasminogen disorders)
• Increased levels of coagulations factors (II and VIII)
• Homocystinuria
• Dysfibrinogenaemia

Acquired (Secondary) Factors:

• Risk factors:
  • Advancing age
  • Prolonged bed-rest
  • Prolonged immobilisation (for example In plaster cast, long-distance travel)
  • Cigarette smoking
  • Obesity
• Predisposing clinical conditions:
  • Heart diseases (for example, Myocardial infarction, CHF, rheumatic mitral stenosis, cardiomyopathy)
  • Vascular diseases (for example, Atherosclerosis, Aneurysms of the aorta and other vessels, Varicosities of leg veins)
  • Hypercoagulable conditions (for example, Polycythaemia, Myeloproliferative disorders, TTP, DIC, Nephrotic syndrome, Disseminated cancers)
  • Shock
  • Tissue damage for example Trauma, fractures, burns, major surgery on bones, abdomen or brain.
  • Late pregnancy and puerperium
  • Certain drugs (for example Anaesthetic agents, oral contraceptives, hormonal replacement therapy).
• Antiphospholipid antibody (APLA) syndrome:
  • Lupus anticoagulant antibody
  • Anti-cardiolipin antibody

Hereditary (Primary) factors:

These include deficiency or mutation of some factors as under:

• Deficiency of antithrombin III It is inherited as autosomal dominant disorder having less than 50% antithrombin III. The condition is associated with recurrent episodes of venous thrombosis.
• Deficiency of protein C and S Both these are autosomal dominant disorders having either a reduced amount of protein C or S, or both, or their functional defect. Clinically, both conditions are associated with a life long risk of thrombosis of deep leg veins.
• Mutation in factor V Leiden This is also an autosomal dominant disorder in which the mutation lies in the replacement of arginine by glycine at position 506. It is the most common cause
  of thrombophilia.
• Defects in fibrinolysis These include a few rare inherited disorders such as dysfibrinogenaemia and plasminogen disorders.
• Increased levels of coagulations factors (II and VIII). Elevated level of prothrombin and factor VIII due to genetic mutation may predispose to thrombosis.

Secondary (acquired) factors:

As listed thrombosis is favoured by certain risk factors, some predisposing clinical conditions and antiphospholipid antibody (APLA) syndrome.

There are 2 types of APLA:

1. Lupus anticoagulant antibody and anti-cardiolipin antibody.
2. Presence of either of the two APLA predisposes an individual to recurrent thrombosis: Venous in the former and arterial in the latter type.

Other features include spontaneous abortions, transient ischaemic attacks, thrombocytopenia, elevation of activated partial thromboplastin time and multi-organ involvement. Patients of SLE may often coexpress lupus anticoagulants.