Physiology, Coagulation Pathways

Function

The function of the coagulation pathway is to maintain hemostasis, which is the blockage of bleeding or hemorrhage. Primary hemostasis is an aggregation of platelets forming a plug at the damaged site of exposed endothelial cells. Secondary hemostasis encompasses the intrinsic and extrinsic pathways, which converge at a common point to form the common pathway. The common pathway activates fibrinogen, converting it into fibrin. These fibrin subunits have an affinity for each other and combine into fibrin strands that bind the platelets together, stabilizing the platelet plug.[4][5][6][7]

Mechanism

The mechanism by which coagulation allows for hemostasis is an intricate process involving a series of clotting factors. The intrinsic pathway comprises factors I, II, IX, X, XI, and XII, which are respectively named fibrinogen, prothrombin, Christmas factor, Stuart-Prower factor, plasma thromboplastin, and Hageman factor. The extrinsic pathway consists of factors I, II, VII, and X. Factor VII is called stable factor. The common pathway consists of factors I, II, V, VIII, and X. The factors circulate through the bloodstream as zymogens and are activated into serine proteases. These serine proteases act as a catalyst to cleave the next zymogen into more serine proteases and ultimately activate fibrinogen. The serine proteases among the clotting factors include factors II, VII, IX, X, XI, and XII, whereas factors V, VIII, and XIII are not classified as serine proteases. The intrinsic pathway is activated through exposed endothelial collagen, and the extrinsic pathway is activated through tissue factor released by endothelial cells after external damage.

Intrinsic Pathway

The intrinsic pathway is the longer pathway of secondary hemostasis. The pathway begins with the activation of factor XII (a zymogen, inactivated serine protease), which becomes factor XIIA (activated serine protease) after exposure to endothelial collagen. Endothelial collagen is only exposed when endothelial damage occurs. Factor XIIa acts as a catalyst to activate factor XI to XIa, which in turn activates factor IX to IXa. Factor IXa then catalyzes the conversion of factor X to Xa. This stepwise process is referred to as a cascade. Each activated factor triggers additional factors in subsequent steps. As the cascade progresses, the concentration of that factor increases in the blood. For example, the concentration of factor IX is more than that of factor XI. When factor II is activated by either the intrinsic or extrinsic pathway, it can reinforce the intrinsic pathway by giving positive feedback to factors V, VII, VIII, XI, and XIII. This amplification makes factor XII less critical; patients can clot well without factor XII. The intrinsic pathway is clinically assessed using the partial thromboplastin time (PTT).

Extrinsic Pathway

The extrinsic pathway is the shorter pathway of secondary hemostasis. Upon vascular injury, the endothelial cells release tissue factor and initiate the activation of factor VII to VIIa. Factor VIIa further activates factor X into factor Xa. At this stage, both the extrinsic and intrinsic pathways converge. The extrinsic pathway is clinically assessed using the prothrombin time (PT).

Common Pathway

The common pathway begins with the activation of factor X to factor Xa. The process of activating factor Xa is a complicated reaction mediated by a complex known as tenase. Tenase has 2 forms—extrinsic, consisting of factor VII, factor III (tissue factor), and Ca2⁺, or intrinsic, made up of cofactor factor VIII, factor IXA, a phospholipid, and Ca2⁺. Once activated, factor Xa converts factor II (prothrombin) to factor IIa (thrombin). In addition, factor Xa requires factor V as a cofactor to cleave prothrombin into thrombin. Factor IIa (thrombin) activates fibrinogen into fibrin. Thrombin also activates other factors in the intrinsic pathway (factor XI), cofactors V and VIII, and factor XIII. Fibrin subunits form fibrin strands, and factor XIII acts on fibrin strands to form a fibrin mesh. This mesh helps to stabilize the platelet plug.

Negative Feedback

To prevent over-coagulation, which causes widespread thrombosis, there are certain processes to keep the coagulation cascade in balance. As thrombin acts as a procoagulant, it also acts as negative feedback by activating plasminogen to plasmin and stimulating the production of antithrombin. Plasmin acts directly on the fibrin mesh and breaks it down. Antithrombin decreases the production of thrombin from prothrombin and decreases the amount of activated factor X.

Proteins C and S also act to prevent coagulation, mainly by inactivating factors V and VIII.

Protein Z is a vitamin K–dependent cofactor that inhibits factors Xa and XIa in conjunction with protein Z–dependent protease inhibitor.[8][9][10] This cofactor is associated with various gene polymorphisms and is synthesized in the liver. In addition, protein Z is linked to adverse pregnancy outcomes.

Organs Involved

The liver plays a crucial role in the coagulation process, as it is responsible for the formation of factors I, II, V, VII, VIII, IX, X, XI, XIII, and protein C and S. In addition, factor VIII is produced by the vascular endothelium.

Pathology to the liver can cause a lack of coagulation factors and lead to hemorrhage. A decrease in coagulation factors typically means severe liver damage. Factor VII has the shortest half-life, leading to elevated PT first in liver disease. The normal International Normalized Ratio (INR) is approximately 1.0. The INR is a standardized test that compares PT using the specific lab's substances, such as phospholipids and calcium tissue factors. This comparative study yields a standardized measure of clotting. Coagulopathy in liver disease is treated with fresh frozen plasma.

Pathophysiology

Generally, factor deficiencies are mostly autosomal recessive, except for factors VIII and IX, which are X-linked recessive. In contrast, anticoagulant deficiencies, such as factors Z, C, S, and antithrombin III, are primarily autosomal dominant.

Hemophilia A and B are more prevalent in White and Hispanic populations and are inherited in an X-linked recessive pattern. Hemophilia A involves a deficiency in factor VIII, whereas hemophilia B involves a deficiency in factor IX.[2][11][12][13][14]

Hemophilia C,  also known as Rosenthal syndrome, is most prevalent in Ashkenazi Jews and has an autosomal recessive mutation where there is a deficiency in factor XI.

Factor V Leiden is a genetic mutation more prevalent in individuals of European descent. Leiden is the city in the Netherlands where the malady was first found. This defect causes a state of hypercoagulability. The genetic mutation causes a defect in factor V such that protein C cannot inactivate it, allowing factor V to activate downstream factors continuously.

Deficiencies in proteins C and S can also lead to hypercoagulable states due to an inability to appropriately inhibit factors V and VIII, respectively. Protein S deficiency is reported to be more prevalent in Asian populations compared to Europeans.[15] African populations have been reported to have lower protein C and S levels compared to White populations.[16]   

Disseminated intravascular coagulation best demonstrates the continuum of coagulability.[17] With inception, various factors cause injury or inflammation of endothelial cells, leading to tissue factor release. Sepsis is the most common cause of disseminated intravascular coagulation (about 47% incidence), with mortality noted in the range from 20% to 50%. Tissue factor binds to factor VIIa, thereby activating platelets, leading to the readiness of other coagulation factors. Factors Xa and Va form a prothrombinase complex that produces more thrombin. Thrombin converts fibrinogen to fibrin, which is then cross-linked by factor XIII to form a stable, contractile mesh that binds to platelets via their GPIIb-IIIa links. Von Willebrand factor is an acute-phase reactant, also known as a phase-reactive protein, that increases in quantity during inflammation. Von Willebrand factor acts as an adhesive to bind platelets to an injured vessel and other platelets, forming the initial platelet plug. This platelet plug serves as a temporary measure and the first step in addressing a hemorrhage. Endothelial injury triggers the release of tissue plasminogen activator (t-PA), which, in the presence of inflammation, enhances plasmin activity and leads to hyperfibrinolysis. With the increased lytic activity, fibrinogen and fibrin are broken down into remnants, such as fragments D and E, whereas cross-linked residuals, known as D-dimers, are also formed. When lysis outstrips clotting factor production, hemorrhage can occur. 

COVID best exemplifies the initial onset of severe pneumonia or acute respiratory distress syndrome, followed closely by a terminal coagulopathic phase known as disseminated intravascular coagulation.[18][19] The viral infection triggers a massive inflammatory response, often referred to as a cytokine storm. Interleukin-6 is released within the storm, concurrent with other infectious and tissue injury, and consequently causes a decrease in protein S, a hypergammaglobulinemia, and disseminated intravascular coagulation. With the fibrin and platelet deposition of progressive disseminated intravascular coagulation, there is an increased risk of hemorrhage, as the factors and thrombocytes themselves are consumed faster than they are replaced. Similarly, the fibrin is cross-linked by factor XIII, and as the strands are broken, these adhered sections become the characteristic D-dimers. The increase in D-dimer concentration has been advocated as a means to monitor the disease severity and mortality risk; however, this opinion is debated. Although many diseases with disseminated intravascular coagulation display vascular thrombi, in COVID, the presence of micro- and macrovascular thrombi is accentuated. Autopsy findings reveal not only interstitial damage and edema but also significant pulmonary thrombosis. In COVID, there are additional clotting issues in the other organs, with an overall multi-organ failure. With such widespread thromboses, many patients can succumb to the hemorrhage of a consumptive coagulopathy. 

Clinical Significance

PT and PTT evaluate the time it takes for the extrinsic and intrinsic pathways to take effect, respectively. Mixing studies are performed to determine whether a PT or PTT is elevated due to a factor deficiency or a factor inhibitor (antibodies to specific factors). In a mixing study, the patient's plasma is mixed with a control plasma. If the mixed plasma PT and PTT normalize, the PT and PTT prolongation is due to a factor deficiency. If they do not normalize, the prolongation is due to a factor inhibitor. An example of an inhibitor is lupus anticoagulant.

Vitamin K deficiency can lead to elevated PT and PTT and may present as hemarthrosis, intramuscular bleeding, or gastrointestinal bleeding. Vitamin K deficiency is commonly observed in newborns due to the lack of gut colonization by bacteria and may also occur in conditions associated with malabsorption, such as cystic fibrosis, celiac disease, and Crohn disease.

Heparin is an anticoagulant used in hospital settings for deep venous thrombosis prophylaxis. Heparin binds to and activates antithrombin, which then inactivates thrombin and factor Xa.

Warfarin is used for long-term anticoagulation therapy in patients with atrial fibrillation to prevent thrombus formation in the left atrium. This anticoagulant acts by inhibiting epoxide reductase. Epoxide reductase is a critical component in coagulation factor production because it helps recycle vitamin K. Without vitamin K, more coagulation factors cannot be produced by the liver. 

New oral anticoagulants offer significant advantages as alternatives to warfarin therapy. The group has 2 categories—direct thrombin inhibitors, such as dabigatran, and direct factor Xa inhibitors, such as rivaroxaban, apixaban, and exoxaban.[20] As a group, these medications are effective with a lower bleeding risk compared to warfarin.[21] Although conflicting opinion exists, it is generally believed that concurrent therapy with a proton pump inhibitor is appropriate to decrease the risk of gastric bleeding, particularly in situations where the patients may be predisposed.[22][23][24][25] As new oral anticoagulants are renally excreted, their use in patients with renal impairment often raises significant concerns. A common clinical scenario, particularly in nursing facilities, involves an older patient with renal insufficiency who becomes acutely ill while on one of these agents. As the patient begins to feel unwell, oral intake often declines significantly, leading to dehydration and further deterioration of renal function with a subsequent increase in the new oral anticoagulant concentration. Ultimately, because of this, there is an increase in the risk of hemorrhage. Although these agents do not require routine monitoring like warfarin, careful attention to renal function remains essential throughout therapy.