Thrombosis: Haemostasis in the Wrong Place

• What is thrombosis?

  The pathological formation of a blood clot (thrombus) within a blood vessel, obstructing blood flow.
• How does thrombosis occur?

  When haemostatic mechanisms are activated inappropriately in an uninjured vessel.
• What are the three key factors that contribute to thrombosis (Virchow’s Triad)?

  • Endothelial injury (damage to the blood vessel lining)
  • Abnormal blood flow (stasis or turbulence)
  • Hypercoagulability (increased tendency of blood to clot)

  
• How does endothelial injury contribute to thrombosis?

  Endothelial damage exposes subendothelial collagen and tissue factor, which:

  • Triggers platelet adhesion and activation
  • Initiates the coagulation cascade
  • Leads to thrombin generation and fibrin formation
• What are the common causes of endothelial injury contributing to thrombosis?

  • Atherosclerosis
  • Hypertension
  • Smoking
  • Infection
  • Trauma
• What role do platelets play in the initiation of a blood clot?

  • Adhere to exposed collagen and von Willebrand factor (vWF) at the injury site
  • Become activated, changing shape and releasing granules containing ADP, thromboxane A₂, and serotonin
  • Recruit additional platelets to form a platelet plug
• How does abnormal blood flow contribute to thrombosis?

  • Turbulent flow (e.g., in atherosclerosis) disrupts laminar blood flow, bringing platelets into contact with the vessel wall
  • Stasis (e.g., in deep vein thrombosis) prevents dilution of clotting factors and promotes platelet interaction with the endothelium
• What is hypercoagulability, and how does it initiate clot formation?

  Hypercoagulability is an increased tendency of blood to clot due to:

  • Genetic factors (e.g., Factor V Leiden mutation, prothrombin mutation)
  • Acquired factors (e.g., pregnancy, cancer, oral contraceptives, antiphospholipid syndrome)

  It leads to excessive activation of the coagulation cascade, increasing thrombin and fibrin formation.
• What is the role of tissue factor (TF) in initiating thrombosis?

  • Tissue Factor (TF) is exposed upon endothelial injury
  • It binds Factor VIIa, initiating the extrinsic coagulation pathway
  • Leads to rapid thrombin generation, which converts fibrinogen to fibrin, stabilising the clot
• What are the two main pathways that initiate the coagulation cascade?

  1. Extrinsic pathway (Tissue Factor pathway) – Initiated by TF-FVIIa complex
  2. Intrinsic pathway (Contact activation) – Initiated by Factor XII activation (minor role in vivo)

  Both converge at the common pathway, leading to thrombin and fibrin formation.
• What is thrombin, and why is it essential in thrombosis?

  Thrombin (Factor IIa) is a key enzyme that:

  • Converts fibrinogen into fibrin, forming a stable clot
  • Activates platelets to enhance clot formation
  • Amplifies the coagulation cascade by activating Factors V, VIII, and XI
• How does fibrin contribute to clot formation?

  • Fibrin is a fibrous protein formed from fibrinogen by thrombin
  • It creates a mesh that stabilises the platelet plug
  • Traps red blood cells and strengthens the clot
• What is the role of Factor XIII in clot formation?

  Factor XIII (fibrin-stabilising factor) cross-links fibrin strands, making the clot more resistant to mechanical and enzymatic breakdown.
• How does the body prevent excessive clot formation?

  The body regulates clot formation using:

  • Antithrombin III (inhibits thrombin and Factor Xa)
  • Protein C and S (degrade Factors Va and VIIIa)
  • Tissue Factor Pathway Inhibitor (TFPI) (inhibits TF-FVIIa complex)
• What is embolism?

  The blockage of a blood vessel by a substance (embolus) that has travelled from another part of the body. The embolus is often a dislodged thrombus but can also be fat, air, or amniotic fluid.
• What are the common causes of hypercoagulability contributing to thrombosis?

  • Genetic disorders
  • Cancer
  • Pregnancy
  • Oral contraceptives
• What are the common causes of stasis of blood flow contributing to thrombosis?

  • Prolonged immobility
  • Atrial fibrillation
  • Heart failure
• What are the main types of thrombosis?

  • Arterial thrombosis: forms in high-pressure arteries, often due to atherosclerosis; can cause heart attacks and strokes
  • Venous thrombosis: forms in low-pressure veins, often due to blood stasis; includes deep vein thrombosis (DVT) and pulmonary embolism (PE)
• What is deep vein thrombosis (DVT), and why is it dangerous?

  Deep vein thrombosis (DVT) is a thrombus formation in a deep vein, usually in the legs. It is dangerous because:

  • It can dislodge and travel to the lungs, causing a pulmonary embolism (PE).
  • It can lead to chronic venous insufficiency, causing swelling, pain, and ulcers.

  
• What is pulmonary embolism (PE), and what are its risks?

  Pulmonary embolism (PE) occurs when a thrombus from a deep vein (often from DVT) travels to the lungs, blocking a pulmonary artery. Risks include:

  • Severe hypoxia (oxygen deprivation)
  • Right heart failure due to increased pulmonary resistance
  • Sudden death if the embolus is large (massive PE)
• How does arterial thrombosis lead to heart attacks and strokes?

  • Coronary artery thrombosis can block blood flow to the heart, causing myocardial infarction (heart attack).
  • Cerebral artery thrombosis can block blood flow to the brain, causing ischemic stroke.
• What are some risk factors for thrombosis and embolism?

  • Immobility – e.g., long flights, bed rest, hospitalization
  • Surgery & trauma – increases endothelial damage and clotting risk
  • Cancer – tumors can produce pro-coagulant factors
  • Hormonal factors – pregnancy, oral contraceptives, HRT
  • Genetic disorders – Factor V Leiden mutation, protein C or S deficiency
  • Obesity & smoking – contribute to inflammation and endothelial damage
• How can thrombosis and embolism be prevented?

  • Anticoagulants (e.g., heparin, warfarin, DOACs) – prevent clot formation
  • Compression stockings – prevent venous stasis
  • Early mobilisation – after surgery or prolonged bed rest
  • Lifestyle changes – stop smoking, control weight, stay active
• What are the three main stages of blood clotting?

  • Vascular spasm – Immediate vasoconstriction of the damaged vessel to reduce blood flow.
  • Platelet plug formation – Platelets adhere to the damaged vessel, become activated, and aggregate to form a temporary plug.
  • Coagulation cascade – A series of enzymatic reactions lead to fibrin clot formation, stabilising the platelet plug.
• What triggers platelet activation in thrombosis?

  • Exposure of subendothelial collagen and von Willebrand factor (vWF).
  • Binding of platelets to vWF via glycoprotein Ib (GpIb) receptors.
  • Platelets release ADP, thromboxane A₂ (TXA₂), and serotonin, enhancing aggregation and vasoconstriction.
  • Activation of glycoprotein IIb/IIIa (GpIIb/IIIa), allowing platelets to bind fibrinogen and form a plug.
• What is the coagulation cascade, and how is it involved in thrombosis?

  The coagulation cascade is a series of enzymatic reactions that convert fibrinogen into fibrin to stabilize a clot. It consists of:

  • Intrinsic pathway (contact activation) – Initiated by exposed collagen and platelets (Factor XII activation).
  • Extrinsic pathway (tissue factor pathway) – Initiated by tissue factor (TF) released from damaged endothelial cells.
  • Both pathways converge at the common pathway, leading to thrombin activation, which converts fibrinogen to fibrin.
• What is the role of thrombin in thrombosis?

  Thrombin (Factor IIa) is a key enzyme in the coagulation cascade that:

  • Converts fibrinogen into fibrin, forming a stable clot.
  • Activates platelets, amplifying clot formation.
  • Activates Factors V, VIII, and XIII to enhance coagulation.
  • Can contribute to excessive clot formation in thrombosis.
• What is fibrin, and how does it stabilize a clot?

  Fibrin is an insoluble protein formed from fibrinogen by thrombin. It:

  • Forms a mesh-like structure that traps platelets and red blood cells.
  • Strengthens the initial platelet plug.
  • Is cross-linked by Factor XIIIa, making the clot more stable.
• How is the coagulation cascade regulated to prevent excessive clotting?

  • Antithrombin III – Inhibits thrombin and Factors Xa, IXa, and XIa.
  • Protein C and Protein S – Inactivate Factors Va and VIIIa.
  • Tissue factor pathway inhibitor (TFPI) – Inhibits the tissue factor-Factor VIIa complex.
  • Plasmin – Breaks down fibrin to dissolve clots (fibrinolysis).
• What is fibrinolysis, and how does it affect thrombosis?

  Fibrinolysis is the breakdown of fibrin clots to prevent excessive thrombosis. It involves:

  • Plasminogen being converted to plasmin by tissue plasminogen activator (tPA) or urokinase.
  • Plasmin degrading fibrin into fibrin degradation products (FDPs), including D-dimer (a clinical marker for clot breakdown).
  • Plasminogen activator inhibitors (PAIs) regulating this process.
• What happens if the regulation of clotting fails in thrombosis?

  • Excessive clot formation leads to thromboembolic diseases such as deep vein thrombosis (DVT), pulmonary embolism (PE), and stroke.
  • Defective clot breakdown results in persistent thrombi, increasing the risk of ischemia and tissue damage.
  • Hypercoagulability states (e.g., Factor V Leiden mutation, antiphospholipid syndrome) increase the risk of spontaneous thrombosis.
• Which major clotting factors play a role in thrombosis?

  • Tissue Factor (TF): Triggers the extrinsic coagulation pathway.
  • Thrombin (Factor IIa): Converts fibrinogen to fibrin, stabilizing the clot.
  • Fibrinogen (Factor I): Precursor of fibrin, essential for clot formation.
  • Factor Xa: A key enzyme in the coagulation cascade that activates thrombin.
• Which major inhibitors regulate clotting to prevent excessive thrombosis?

  • Antithrombin (AT): Inhibits thrombin and Factor Xa.
  • Protein C and Protein S: Inactivate Factors Va and VIIIa, slowing clot formation.
  • Tissue Factor Pathway Inhibitor (TFPI): Inhibits the Tissue Factor–Factor VIIa complex.
• What is the key enzyme responsible for fibrinolysis?

  Plasmin, which degrades fibrin into fibrin degradation products (FDPs), including D-dimer.
• How is plasmin activated?

  Plasminogen is converted to plasmin by:

  • Tissue Plasminogen Activator (tPA) (released by endothelial cells)
  • Urokinase-type Plasminogen Activator (uPA)
• What inhibits fibrinolysis to prevent excessive clot breakdown?

  • Plasminogen Activator Inhibitor-1 (PAI-1): Inhibits tPA and uPA, preventing plasmin activation.
  • α2-Antiplasmin: Directly inhibits plasmin activity.
• What happens if fibrinolysis is impaired?

  Excessive clotting can occur, leading to thrombotic disorders such as deep vein thrombosis (DVT) or pulmonary embolism (PE).
• How is fibrinolysis measured clinically?

  D-dimer test detects fibrin degradation products, indicating active fibrinolysis and possible thrombosis.