1st June 2023

Coagulation overview

Coagulation pathway

The coagulation pathway consists of a series of reactions, which lead to homeostasis, the blockage of bleeding or haemorrhage. The coagulation cascade is made up of various clotting factors and the liver is the key organ involved in coagulation, being the site of synthesis of the clotting factors. Haemostasis can be primary or secondary. In primary haemostasis, at the site of endothelial damage, the aggregation of platelets form a plug. Secondary haemostasis involves the intrinsic and extrinsic pathways. These both diverge to form the common pathway and lead to fibrin becoming activated; these fibrin units combine and stabilise the platelet plug.
The two pathways, the intrinsic and extrinsic pathways, both converge to activate factor X. This then leads to the common pathway in which activated factor X, in combination with factor V, platelet membrane phospholipids and Ca2+ ions convert prothrombin to thrombin (activated factor II), which in turn results in the activation of fibrin (activated factor I). The fibrin subunits then combine to form a stable fibrin clot.

Regulations of Clotting

Proteins C and S act to prevent coagulation, as these proteins mainly act to inactivate factors V and VIII.

Clotting cascade.

Image Source: Wikimedia Commons (2012). Classical blood coagulation pathway, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Classical_blood_coagulation_pathway.png (Accessed on: 10 January 2023).

Coagulation screen

The coagulation screen includes laboratory tests to assess haemostasis. Measured tests include PT, APTT, INR (from PT), bleeding time and fibrinogen.

The bleeding time can be measured, which demonstrates the function of the platelets. Platelet disorders, including von Willebrand’s disease, ITP, TTP and any cause of thrombocytopenia, can prolong the bleeding time.

Prothrombin time (PT) and activated prothrombin time (APTT) measure the timing of the extrinsic and intrinsic pathways, respectively.  A variety of conditions can affect the PT (extrinsic pathway), including liver disease, warfarin therapy, other causes of vitamin K deficiency and disseminated intravascular coagulation (DIC). The INR can be calculated by using the patient’s PT and the INR is commonly measured and monitored whilst patients are receiving warfarin therapy to aid with warfarin dose adjustments. The APTT can be affected by Haemophilia A and B, von Willebrand’s disease and acquired haemophilia.

In the labs, mixing studies can be performed by mixing the patient’s plasma with control plasma. These studies can be used to determine whether the PT or APTT is prolonged because of a factor deficiency (for example Haemophilia A, B) or because of the presence of a factor inhibitor (for example lupus anticoagulant). If after mixing the patient’s plasma with control plasma, the PT/APTT normalises, then the prolongation is due to a factor deficiency. If the PT/APTT remain prolonged, the prolongation is due to a factor inhibitor such as a lupus anticoagulant.

Thrombin converts fibrinogen to fibrin to produce a fibrin-based clot. As fibrinogen is an acute phase protein, elevated levels can indicate systemic inflammation, various cancers and tissue injury. Low fibrinogen levels can be seen in an inherited condition, whereby the body is unable to effectively produce fibrinogen. Low fibrinogen levels can be seen in liver disease, malnutrition, and disseminated intravascular coagulation (DIC).