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5.1 Haemostasis and Clotting vs Bleeding
Haemostasis and Clotting vs Bleeding
Learning Outcomes
Be able to:
Describe haemostasis and the normal clotting mechanism.
Be able to define the different terms related to coagulation disorders, the drugs and strategies for prevention and treatment of thrombosis and the clinical use of antiplatelet, anticoagulant and thrombolytic drugs for common thrombotic presentations.
Introduction
The tight balance between blood clotting and bleeding is always maintained in the body under normal physiological conditions. The body must be able to keep blood fluid enough to circulate without clotting easily but also have the ability to clot in response to tissue injury. Haemostasis is the process by which the body halts or reduces bleeding from damaged blood vessels and is a crucial survival mechanism for organisms in potentially dangerous environments. Primary haemostasis involves the formation of temporary platelet plugs whilst secondary haemostasis simultaneously initiates the coagulation cascade to strengthen and stabilise the plug with fibrin. Then as part of wound healing, fibrinolysis occurs, which is where the clot is dissolved once blood vessel integrity has been restored. Therefore, the balance between blood clotting (thrombosis) and bleeding (haemorrhage) is maintained by the formation of platelet plugs, the clotting cascade and fibrinolysis. We will discuss these processes in more detail now.
Haemostasis and the Coagulation Cascade
Haemostasis (derived from “hem-”, which means “blood”, and “-stasis”, which means “to stop”) is the process by which the body halts or reduces bleeding from damaged blood vessels. It involves multiple interactions between the vessel wall, platelets and coagulation factors. Blood is normally separated from the activators of haemostasis by the endothelial cells in the vessel wall. However, physical trauma to the vascular system (i.e., puncture or cut) initiates the 3 main stages of haemostasis. These are:
Vascular spasms and vasoconstriction to reduce blood flow from the site of injury,
Formation of an unstable temporary platelet plug to seal the leaking small arteries and veins (primary haemostasis), and,
Coagulation via the clotting cascade which produces fibrin that stabilises and strengthens the plug, or clot (secondary haemostasis).
The process of platelet aggregation (primary haemostasis) is explored in further detail below:
Adhesion: Trauma to a blood vessel exposes collagen and von Willebrand Factor (vWF). Circulating inactivated platelets are attracted to the collagen and vWF and attach to the collagen and vWF via receptors on the platelet.
Activation: The activated platelet releases prothrombotic molecules – ADP which binds to its own receptors P2Y1 and P2Y12 and causes platelets to stick together and thromboxane A2 which recruits more platelets and increases the platelet plug.
Aggregation: The combination causes aggregation of platelets and some red blood cells to form a platelet plug (primary haemostasis). This step also causes the simultaneous initiation of the clotting cascade. Watch the video below and then read on to learn about the clotting cascade (secondary haemostasis).
📺 Watch the following short video on platelet activation and thrombus formation (2:07 minutes)
Blood coagulation, via the clotting cascade, refers to the process where liquid blood transforms into a clot. The clotting cascade involves a complex sequence of enzymatic reactions and various coagulation “factors”. These factors exist in the blood as inactive precursors (zymogens) of proteolytic enzymes and cofactors. They become activated through proteolysis, with their active forms designated by the suffix “a.” Key factors in this cascade, including XIIa, XIa, Xa, IXa, and thrombin (Factor IIa), are serine proteases. A small amount of an activated factor can catalyze the production of a larger quantity of the next factor, thus amplifying the process in a cascading manner.
The coagulation process consists of two interrelated pathways (intrinsic and extrinsic systems).
Extrinsic system: Initiated by activation of clotting Factor VII by a tissue factor released from damaged cells which activates Factor X. It is called ‘extrinsic’ as it involves components from outside the blood
Intrinsic system: Factor XII is activated by ‘contact’ with the injured surface and initiates a series of reactions leading to the activation of Factor X. It is called ‘intrinsic’ as it involves components present within the blood.
Under physiological conditions, both pathways operate as a single, unified system in vivo. Both pathways result in activation of Factor X to Xa, which converts prothrombin to thrombin (Factor IIa). This thrombin then acts through several positive feedback loops (on Va, VIIIa, and platelets) to amplify and propagate the process, resulting in the production of more thrombin. Thrombin catalyses the conversion of soluble fibrinogen to insoluble fibrin. Fibrin binds specifically to activated platelets via glycoprotein IIb/IIIa, contributing to platelet aggregation in the platelet plug. Furthermore, thrombin also activates clotting Factor XIII which allows fibrin molecules to crosslink and form a meshwork that traps platelets and red blood cells in the platelet plug, resulting in a robust and insoluble clot.
Figure 5.1.2: The coagulation cascade: sites of action of anticoagulant drugs. Oral anticoagulants that inhibit vitamin K synthesis interfere with post-translational g-carboxylation of factors II, VII, IX and X (shown in blue boxes); LMWHs, low-molecular-weight heparins; PL, negatively charged PL supplied by activated platelets. [Source: Rang & Dale’s Pharmacology, 10th Ed, 2023]
The cellular receptor for Factor VII is known as ’tissue Factor.’ When Ca²⁺ is present, this interaction triggers an active site transition, leading to the swift autocatalytic conversion of Factor VII into its active form, VIIa. The tissue Factor–VIIa complex subsequently activates Factors IX and X. During platelet activation, acidic phospholipids (PLs), particularly phosphatidylserine, are exposed on the outer membranes of platelets, functioning as surface catalysts that facilitate the activation of various clotting Factors by bringing them together in functional complexes. Platelets also secrete coagulation Factors, such as Factor Va and fibrinogen, contributing further to the clotting process. Sustained coagulation relies on the continued production of Factor Xa through the IXa–VIIIa–Ca²⁺–PL complex, as the tissue Factor–VIIa complex is quickly neutralized in plasma by tissue Factor pathway inhibitor and antithrombin III. Factor Xa, in conjunction with Ca²⁺, PL, and Factor Va, converts prothrombin into thrombin, which is the key enzyme in the coagulation cascade. The intrinsic (contact) pathway begins when Factor XII (Hageman Factor) attaches to a negatively charged surface, eventually merging with the in vivo pathway at the point of Factor X activation. Although the initial part of this pathway is not essential for in vivo blood coagulation, both pathways are interconnected, and various positive feedback mechanisms further enhance the coagulation process. Thrombin (Factor IIa) enzymatically cleaves fibrinogen, producing fragments that polymerise to form fibrin. It also activates Factor XIII, a fibrinoligase, which strengthens fibrin-to-fibrin links, thereby stabilising the coagulum. In addition to coagulation, thrombin also causes platelet aggregation, stimulates cell proliferation and modulates smooth muscle contraction. Paradoxically, it can inhibit as well as promote coagulation.
📺 Watch the videoon formation of a thrombus in real time.(0.59 sec)
📺 Watch the following overview of coagulation. It provides reference to platelet plug formation and the process by which the clotting cascade strengthens the clot. (2:44 minutes)
Keeping Coagulation in Check
As expected this accelerating enzyme cascade has to be controlled otherwise all the blood in the body would coagulate within minutes of the initiation of the cascade. Fibrinolysis is the opposite process to coagulation and helps to restore vascular patency and also occurs in response to vascular damage. The presence of fibrin activates by the fibrinolytic system to break down fibrin and reverse the coagulation.
Blood coagulation is also controlled by enzyme inhibitors such as antithrombin III. Antithrombin III neutralises all of the serum proteases in the cascade (serum proteases = Factors XIIa, XIa, Xa, IXa and thrombin which is also known as Factor IIa).
Additionally, the vascular endothelium actively prevents the extension of a thrombus. Endothelial cells convert arachidonic acid to prostacyclin via cyclooxygenase-1 or 2 (COX-1 or COX-2) and prostacyclin synthase. Prostacyclin inhibits platelet function by increasing intracellular cAMP levels. Nitric Oxide diffuses into platelets and affects a variety of intracellular mediators which changes the conformation of the glycoprotein IIb/IIIa receptor which decreases the ability of platelets to aggregate.
Inactive plasma protein (plasminogen from the liver) is converted by plasminogen activators (Factor XIa, XIIa, Kalikrein) to plasmin (a serine protease). Plasmin breaks fibrinogen and fibrin into fragments X,Y,D and E collectively known as fibrin (and fibrinogen) degradation products. Most important plasminogen activator is tissue-type plasminogen activator (t-PA) – present in vascular endothelium. t-PA release is stimulated by thrombin.
Thrombosis
A thrombosis refers to the abnormal formation of a haemostatic plug (or clot) within blood vessels without the presence of bleeding. This is essentially “haemostasis in the wrong place”. Over a century ago, Rudolph Virchow identified three factors that predispose individuals to thrombosis. This is known as “Virchow’s triad”. It encompasses damage to the vessel wall (such as when an atheromatous plaque ruptures or erodes), altered blood flow (as seen in the left atrial appendage during atrial fibrillation or in leg veins during prolonged immobility), and increased blood coagulability (which may occur in the later stages of pregnancy or with certain oral contraceptive use).
Arterial thrombi are often linked with atherosclerosis and consist mainly of platelets in a fibrin matrix, known as a white thrombus. These thrombi can disrupt blood flow, potentially leading to tissue damage or infarction downstream. Venous thrombi, on the other hand, consist of a small white head and a larger red tail, similar in composition to a blood clot, and are known as red thrombi. These thrombi can detach and travel through the bloodstream as emboli. Venous emboli frequently lodge in the pulmonary arteries, causing pulmonary embolism, whereas emboli from the left heart or carotid arteries may obstruct blood flow in the brain or other organs, leading to severe outcomes like stroke or death.
Figure 5.1.1: The main events in the formation of an arterial thrombus. Exposure of acidic PLs during platelet activation provides a surface on which factors IXa and VIIa interact with factor X; factor Xa then interacts with factor II. Activation of factor XII also initiates the fibrinolytic pathway. (A similar series of events occurs when there is vascular damage, leading to haemostasis.). PAF: Platelet-activating factor; TXA 2: thromboxane A2. [Source: Rang & Dale’s Pharmacology, 10th Ed, 2023].
Drug Therapy
Drug therapy plays a key role in managing haemostasis and thrombosis. In cases where haemostasis is impaired—such as in haemophilia or after excessive anticoagulant use—medications that promote blood clotting, such as antifibrinolytic and haemostatic drugs, are necessary. On the other hand, treating or preventing thrombosis and thromboembolism is critical given the prevalence and severity of these conditions. Drugs used for these purposes can influence haemostasis and thrombosis through three main mechanisms:
Altering blood coagulation (fibrin formation),
Modifying platelet function, and,
Enhancing fibrin removal (fibrinolysis).
📺 Watch the following overview of haemostasis, platelet aggregation, coagulation cascade, thombosis and anti-coagulants.
In summary
Haemostasis is a vital process that prevents excessive bleeding through platelet activation and fibrin formation, crucial for maintaining vascular integrity.
Platelets are activated through contact with vWF and collagen. They release prothrombotic molecules to recruit more platelets and cause aggregation forming a platelet plug.
As part of this process, the clotting cascade is initiated. The intrinsic and extrinsic pathways meet to produce Factor Xa. Factor Xa converts prothrombin to thrombin. Thrombin converts soluble fibrinogen to insoluble fibrin.
Fibrin binds specifically to activated platelets via glycoprotein IIb/IIIa, contributing to platelet aggregation.
Fibrin subunits come together to form fibrin strands, and Factor XIII acts on fibrin strands to form a fibrin mesh. This mesh helps to stabilise and strengthen the platelet plug to form an insoluble clot.
Thrombosis, characterized by abnormal clot formation within blood vessels, poses significant health risks and is influenced by Virchow’s triad: endothelial damage, altered blood flow, and increased coagulability.
Arterial thrombi primarily consist of platelets and fibrin, while venous thrombi include a mix of fibrin and trapped blood cells, with both capable of causing severe complications like embolism. Arterial thrombosis is often related to ruptured atherosclerotic plaques, high blood pressure, and turbulent blood flow. Venous thrombosis typically occurs in areas of diminished blood flow or stasis; influenced by inherited conditions, immobility, surgeries, cancers, pregnancy, and hormone therapy.
Drug therapies targeting haemostasis and thrombosis management focus on altering blood coagulation, modifying platelet function, or enhancing fibrinolysis.
The coagulation cascade, involving enzymatic activation of clotting factors and feedback loops, culminates in fibrin formation catalyzed by thrombin, regulated by antithrombin III and endothelial mechanisms.
Understanding these processes and their pharmacological interventions is critical for effectively managing bleeding disorders and preventing thrombotic events.
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Figure 5.1.1: The main events in the formation of an arterial thrombus. Exposure of acidic PLs during platelet activation provides a surface on which factors IXa and VIIa interact with factor X; factor Xa then interacts with factor II. Activation of factor XII also initiates the fibrinolytic pathway. (A similar series of events occurs when there is vascular damage, leading to haemostasis.). PAF: Platelet-activating factor; TXA 2: thromboxane A2. [Source: Rang & Dale’s Pharmacology, 10th Ed, 2023].