Thrombosis: Haemostasis in the wrong place (Physiology)

♡ Varicose veins are swollen and enlarged veins that usually occur on the legs and feet

♡ They may be blue or dark purple, and are often lumpy, bulging or twisted in appearance

♡ Other symptoms include: aching, heavy and uncomfortable legs. Swollen feet and ankles

♡ Deep vein thrombosis (DVT) is a medical condition that occurs when a blood clot forms in a deep vein

♡ These clots usually develop in the lower leg, thigh, or pelvis, but they can also occur in the arm

♡ Coagulation plays a crucial role in preventing blood loss by forming clots to stop bleeding

♡ Interestingly, inflammation can activate coagulation, and in turn, coagulation can promote inflammation, making it an inflammatory response

♡ An MRI of the brain can show evidence of ischaemia, such as an infarct in a specific area like the left frontal lobe

♡ Ischaemia of the brain is often caused by an embolic stroke, which can originate from the carotid arteries or the heart

♡ The presence of an infarct in the left frontal lobe indicates ischaemia of the brain, likely caused by an embolic stroke

♡ This condition results in a region of neuronal cell death due to inadequate blood supply to the affected area

♡ Circulating fibrinogen remains inactive and does not form strands initially

♡ The process begins with primary aggregation and activation of platelets

♡ Secondary conversion of fibrinogen to fibrin is triggered by thrombin

♡ The clotting cascade aims to generate a large amount of thrombin

♡ Thrombin is essential for converting fibrinogen into fibrin, which forms strands crucial for clot formation

♡ Fibrin, produced through the clotting cascade, solidifies the agglutinated platelets to prevent blood loss

♡ It forms strands that reinforce the platelet plug, leading to the formation of a stable blood clot

♡ There is a constant balance between coagulation and fibrinolysis in the body.

♡ Anticoagulant and fibrinolytic agents constantly counteract coagulation triggered by tissue damage or inflammation

♡ Anticoagulants prevent thrombosis by inhibiting coagulation

♡ Endothelial cells express various factors that inhibit coagulation, such as nitric oxide and prostaglandin I2

♡ Antithrombin inhibits clotting when bound to heparan

♡ When endothelial cells are damaged or inflamed, they may favour coagulation

♡ Subendothelial cells release tissue factor or Von Willebrand factor, which initiates clotting

♡ Von Willebrand factor activates platelets, while tissue factor initiates clotting

♡ Fibrinolysis reverses thrombosis by breaking down the clot

♡ Plasmin, activated from plasminogen by Tissue Plasminogen Activator (tPA), breaks down the clot into smaller fragments.

♡ Arterial thrombosis primarily results from atheroma rupture or damage to the endothelium, as seen in conditions like myocardial infarction (MI) and stroke

♡ It typically forms platelet-rich 'white' thrombi and is mostly primary in nature

♡ Arterial thrombi may block downstream arteries, leading to tissue ischaemia or infarction

♡ Venous thrombosis often results from stasis or a hyper-coagulant state, such as deep vein thrombosis (DVT)

♡ It forms platelet-poor 'red' thrombi and is mostly secondary in nature (arises as a complication)

♡ Venous thrombi are prone to dislodgement and migration, potentially leading to pulmonary embolism when they reach the lungs

♡ Endothelial injury or dysfunction: Damage or impairment to the inner lining of blood vessels, which can be caused by factors such as inflammation, trauma, or turbulent blood flow

♡ Abnormal blood flow: Conditions that disrupt normal blood flow patterns, such as stasis (sluggish blood flow), turbulence, or changes in vascular anatomy

♡ Hypercoagulability: Increased tendency of the blood to clot, which can result from various factors including genetic predisposition, acquired conditions (e.g., cancer, pregnancy), or certain medications

♡ Squashes veins

♡ Acts as a pump to return blood to the heart

♡ Valves may not close successfully

♡ Blood flows in the wrong direction

♡ Blood pools in the legs

♡ Prevent backflow of blood

♡ Increases risk of stasis

♡ The affected organ becomes congested with fluid

♡ Increased pressure leads to more filtration

♡ The thrombosis might become dislodged and make its way back to the heart

♡ Thrombolysis occurs

♡ It moves to another location and blocks a vessel

♡ It becomes covered by endothelium

♡ It becomes recanalized and organized

♡ Recanalisation refers to the reopening or restoration of a previously blocked blood vessel, typically after the formation of a thrombus

♡ Higher risk of pulmonary embolism

♡ Higher risk of post-thrombotic syndrome (pain, swelling, maybe even ulcers)

♡ Rarely causes pulmonary embolism

♡ Rarely causes post-thrombotic syndrome

♡ Inflammation along with damage to the venous valves from the thrombus itself

♡ Valvular incompetence combined with persistent venous obstruction inducing a rupture of small superficial veins, subcutaneous hemorrhage, and an increase of tissue permeability

♡ Symptoms include pain, swelling, discoloration, and even ulceration

♡ The dislodged thrombus travels back to the right side of the heart

♡ From the right side of the heart, it passes into the pulmonary circulation

♡ Pulmonary embolism occurs when the thrombus blocks one of the pulmonary arteries

♡ Damage to the vessel endothelium exposes underlying subendothelial cells

Damaged endothelium exposes Von Willebrand factor on subendothelial cells, which activates platelets

Circulating Von Willebrand factor may bind to exposed subendothelial cells

Activated endothelial cells can also express Von Willebrand factor

Von Willebrand factor

Fibrinogen receptor (GPIIb/IIIa)

Thromboxane A2 (TxA2)

Adenosine diphosphate (ADP)

Platelets can also be activated by thrombin, collagen, and many other mediators

-Activated platelets release Thromboxane A2 (TxA2) and Adenosine diphosphate (ADP).

-TxA2 and ADP induce receptors for fibrinogen (GPIIb/IIIa) on adjacent platelets.

-These receptors bind to receptors on adjacent platelets and increase the expression of the glycoprotein complex GPIIb/IIIa.

Platelet aggregation is the process by which platelets clump together to form a blood clot.

Fibrinogen acts as a tether, holding platelets together, which is aggregation.

Fibrinogen, the soluble precursor to fibrin, is present in the circulation and facilitates platelet aggregation.

♡ Once a clump of platelets aggregate, they form a negatively charged surface, which is required for coagulation

♡ Coagulation involves the conversion of fibrinogen to fibrin and then crosslinking of the fibrin clot

♡ Exposure of Tissue Factor (TF) expressing cells during injury allows the complex formation of TF with coagulation factor VII

♡ Charged phospholipids (PL) are also required for coagulation

♡ The purpose is to produce activated factor ten (Xa), which is a protease that catalyzes the conversion of prothrombin (II) to thrombin (IIa)

♡ Thrombin (IIa) is a protease that cleaves fibrinogen into fibrin, which is important for blood clot formation

♡ Fibrinogen contributes to blood clotting by binding to the GpIIb/IIIa surface membrane receptor on activated platelets, facilitating platelet aggregation and the formation of bridges between them

♡ Fibrin forms long polymers that hold activated platelets together in a blood clot

♡ Once there is enough thrombin present, factor thirteen (XIII) is activated and causes cross-linking of fibrin, which further stabilizes the clot

♡ The extrinsic pathway begins in the vessel wall when damaged endothelial cells release Tissue Factor (TF)

♡ Tissue Factor combines with calcium on the negatively charged platelet surface and activates factor VII

♡ The Vlla-tissue factor complex can be quickly inactivated by antithrombin (AT) in vivo

♡ The intrinsic pathway begins in the bloodstream and is activated when blood is exposed to collagen or other damaged surfaces

♡ The Activation of factor XII (also known as Hageman factor), which is part of the intrinsic pathway. Factor XII activation initiates a cascade of reactions leading to the formation of a blood clot

♡ Defects in the factors of the extrinsic pathway have far larger physiological effects than mutations in the enzymes of the intrinsic pathway

Tissue plasminogen activator (tpA) is a serine protease found on endothelial cells.

It catalyzes the activation of circulating plasminogen into plasmin

♡ Plasmin catalyzes the breakdown of cross-linked fibrin clot into fragments called D-dimers.

Antithrombin (AT) is a small protein molecule made by the liver that circulates in the plasma.

Heparan expressed by endothelial cells binds to AT, causing a conformational change that activates AT.

The activated AT then inactivates thrombin, factor Xa, factor VII, and other components of the clotting cascade.

♡ Thrombolytic agents like tissue plasminogen activator and related compounds are used to treat strokes and myocardial infarctions by promoting the breakdown of blood clots