Factor XIII, also known by the name fibrin stabilizing factor, is a key clotting factor in the coagulation cascade known for stabilizing the formation of a blood clot. After clot formation, there is a subsequent breakdown and recurrent bleed with deficiency. The plasma form of Factor XIII is a protein heterodimer of A and B subunits expressed by bone marrow and mesenchymal lineage cells remarkable for transglutaminase function- catalyzing cross-linkage peptide reactions. Rare deficiency of the transglutaminase enzymatic properties, responsible for crosslinking fibrin mesh, causes life-threatening issues of clot stability and homeostasis. Though extremely rare in occurrence, congenital disorders of Factor XIII are associated with high rates of morbidity and mortality, particularly in the Khash region of Southeastern Iran, passed on autosomal recessively. Acquired Factor XIII deficiency is attributed mainly to immune or idiopathic causes. Umbilical cord bleeding in neonates often points to Factor XIII deficiency, while brain hemorrhages are the most common overall cause of death in this blood disorder. Common symptoms of deficiency include bruising, hematomas, muscle bleeds and delayed post-surgical bleeds. Factor XIII plays a vital role in normal homeostasis, but research is discovering that the factor may play a large part in many other processes.
Factor XIII (FXIII), is a heterotetrameric proenzyme converted by thrombin with calcium to a transglutaminase that catalyzes intertwining between fibrin monomers, and between a2-antiplasmin and fibrin during the coagulation cascade. FXIII has a plasmatic form, and a cellular form carried inside platelet alpha granules. The cellular form consists of identical FXIII-A dimers, distinctive for their catalytic transglutaminase domain. While the cellular form of FXIII is a dimeric, and part of the transglutaminase family, the plasma form is a tetramer FXIII-A and FXIIIB subunits. FXIII-A is made of a sandwich domain, a catalytic domain, an activation peptide, and two-barrel domains. FXIII-B's defining characteristic is its ten repetitive sushi domains. It is the plasma forms FXIII-B component that attaches to fibrinogen. For the plasma forms activation, thrombin cleaves off the activation peptide of FXIIIA, with circulating calcium ions. FXIII-B detaches, and the FXIII-A becomes the active transglutaminase involved in fibrin crosslinking and clot stabilization.
FXIII forms gamma-glutamyl-lysyl amide crosslinking of fibrin, stabilizing the insoluble clot against shear stress. As a result, it achieves further protection from clot degradation in the coagulation cascade. FXIII also works on A2-antiplasmin to also cross-link it to fibrin, further strengthening antifibrinolytic properties.
Homeostasis is the body’s way of preventing blood loss, broken down into three main stages: vasoconstriction, platelet plug formation, and blood clotting. Within a clot, fibrin mesh strengthening occurs with the aid of Factor XIII, mainly by keeping the platelet plug together. Both the intrinsic pathway and extrinsic pathways of the coagulation cascade feed into the common pathway. The common pathway involves thrombin-catalyzed cleavage of fibrinogen into fibrin, forming a mesh that strengthens the platelet plug. Subsequently, Factor XIII covalently bonds to fibrin to further support fibrin's interaction with the platelets to prevent dissolution of the clot. Clot retraction, which usually occurs a day after the initial clot formation, involves disruption of Factor XIII crosslinks and fibrinolysis.
Testing for low FXIII levels can be warranted when general hematology labs show no abnormality of PT, PTT, INR and bleeding time in the presence of hemorrhage, hematomas and/or delayed bleeding. These findings would indicate more of a workup for a defect in clot stabilization or fibrinolysis, particularly after trauma or surgical procedures.
First line detection of Factor XIII activity is obtainable by ammonia release assay, or a quantitative functional factor XIII assay. Diagnosis can be confirmed by a clot solubility test in urea later differentiated with an incorporation assay and immune-electrophoresis. Other tests include quantitative factor XIII activity assays, factor XIII specific assays, and genetic testing. Without prophylactic treatment, hemorrhagic diathesis from Factor XIII deficiency can cause mortality.
There are two common forms of FXIII deficiency: acquired and congenital.
Acquired FXIII deficiency
Causes of acquired FXIII deficiency include immune-mediated inhibition, non-immune FXIII heightened consumption or lack of synthesis. Acquired deficiency is attributed to idiopathic causes, autoimmune diseases, and malignant conditions. Autoantibodies have been identified as inhibitors to cross-link formation of fibrin monomers. The most common cause of fatality is a hemorrhage, often intracranially. Due to the rarity of acquired FXIII deficiencies, there is a lack of extensive literature and analytical information. As research moves forward, there have been reports of acquired deficiency in several medical conditions such as strokes, IBD, liver cirrhosis, and disseminated intravascular coagulation. Low factor levels in these medical conditions have been known to drop by 20% to 70%, with consumption of FXIII or decreased synthesis.
Congenital FXIII deficiency
Rare bleeding disorders are mostly inherited autosomal recessively. Iran, a middle eastern nation with remote areas of high incidences of consanguinity, has a phenomenally high rate of rare bleeding disorders (RBD), especially Factor XIII. While factor activity measurements are useful for other RBD, clot solubility is necessary for FXIII deficiency diagnostics. As aforementioned, severe, life-threatening bleeding is often the characteristic clinical presentation. The prevalence of congenital FXIII deficiency in the general population is currently 1 per 2 million people.
Common clinical signs for coagulation factor deficiencies clinically include mucosal bleeding, bleeding pre and post medical procedures, and hemorrhagic diathesis. More severe signs include intracranial bleeding and hemarthroses, fairly specific to low levels of Factor XIII and Factor X, and afibrinogenemia. With the current advancement of treatment for rare factor deficiencies, acute presentation of FXIII-related hemorrhage treatment includes administration of FXIII concentrates to arrest blood loss, then giving prednisolone and cyclophosphamide to combat anti FXIII antibodies. Long term prophylaxis includes platelet-derived and/or recombinant FXIII along with cryoprecipitate. The plasma half-life for FXIII is between 11 to 14 days, and so regular administration of blood products is often necessary for long term care. Women with FXIII deficiency can experience recurrent miscarriages and menorrhagia, while in men fertility can be affected.
For FXIII, other biological functions are under consideration beyond a "fibrin stabilizing factor." The transglutaminase activity of FXIII has been attributed to wound healing, embryo and uterus interactions, angiogenesis and bone extracellular matrix stabilization.
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