Physiology, Factor XIII


Article Author:
Daniel Malkhassian


Article Editor:
Sandeep Sharma


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Updated:
2/4/2019 9:02:49 PM

Introduction

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.[1] 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[2]. 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.

Cellular

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.[3] 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.[4]

Function

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.[3] FXIII also works on A2-antiplasmin to also cross-link it to fibrin, further strengthening antifibrinolytic properties.[5]

Mechanism

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.[6]

Related Testing

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.[7]

First line detection of Factor XIII activity is obtainable by ammonia release assay, or a quantitative functional factor XIII assay.[6] Diagnosis can be confirmed by a clot solubility test in urea later differentiated with an incorporation assay and immune-electrophoresis.[8] 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.

Pathophysiology

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.[9] Autoantibodies have been identified as inhibitors to cross-link formation of fibrin monomers.[10] 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.[11]

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.[12] The prevalence of congenital FXIII deficiency in the general population is currently 1 per 2 million people.

Clinical Significance

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.[13] 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.[14] 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.[15] 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.[5]


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Physiology, Factor XIII - Questions

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Where does the clotting protein that cross-links newly formed fibrin threads in clots originate from?



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A newborn boy, born to a couple who recently immigrated from southeastern Iran, presents with delayed umbilical stump bleeding. Family history shows a rare hematological disease on both sides of the family. The parents state that the condition is very common among people in their village. What is the common pattern of inheritance for the most likely congenital blood disease?



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An unrelenting intracranial hemorrhage is confirmed by imaging and workup points in the direction of factor XIII deficiency. What pathway of homeostasis is directly interrupted by this clotting factor deficiency?



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Physiology, Factor XIII - References

References

Mitchell JL,Mutch NJ, Let's cross-link: diverse functions of the promiscuous cellular transglutaminase factor XIII-A. Journal of thrombosis and haemostasis : JTH. 2019 Jan;     [PubMed]
Dorgalaleh A,Tabibian S,Shams M,Majid G,Naderi M,Casini A,Tavasoli B,Gheidishiran M,Daneshi M,Safa M, A Unique Factor XIII Mutation in Southeastern Iran with an Unexpectedly High Prevalence: Khash Factor XIII. Seminars in thrombosis and hemostasis. 2019 Jan 10;     [PubMed]
Muszbek L,Katona É,Kerényi A, Assessment of Factor XIII. Methods in molecular biology (Clifton, N.J.). 2017;     [PubMed]
Durda MA,Wolberg AS,Kerlin BA, State of the art in factor XIII laboratory assessment. Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis. 2018 Dec;     [PubMed]
Dufner GS,Marbet GA, [Factor XIII in man: a review]. Hamostaseologie. 2002 Feb;     [PubMed]
Menegatti M,Peyvandi F, Treatment of rare factor deficiencies other than hemophilia. Blood. 2018 Dec 17;     [PubMed]
Yan MTS,Rydz N,Goodyear D,Sholzberg M, Acquired factor XIII deficiency: A review. Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis. 2018 Dec;     [PubMed]
Franchini M,Frattini F,Crestani S,Bonfanti C, Acquired FXIII inhibitors: a systematic review. Journal of thrombosis and thrombolysis. 2013 Jul;     [PubMed]
Ichinose A, Autoimmune acquired factor XIII deficiency due to anti-factor XIII/13 antibodies: A summary of 93 patients. Blood reviews. 2017 Jan;     [PubMed]
Komáromi I,Bagoly Z,Muszbek L, Factor XIII: novel structural and functional aspects. Journal of thrombosis and haemostasis : JTH. 2011 Jan;     [PubMed]
Jain S,Acharya SS, Management of rare coagulation disorders in 2018. Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis. 2018 Dec;     [PubMed]
Dorgalaleh A,Alavi SE,Tabibian S,Soori S,Moradi E,Bamedi T,Asadi M,Jalalvand M,Shamsizadeh M, Diagnosis, clinical manifestations and management of rare bleeding disorders in Iran. Hematology (Amsterdam, Netherlands). 2017 May;     [PubMed]
Hayward CPM, How I investigate for bleeding disorders. International journal of laboratory hematology. 2018 May;     [PubMed]
Shi DY,Wang SJ, Advances of Coagulation Factor XIII. Chinese medical journal. 2017 Jan 20;     [PubMed]
Tahlan A,Ahluwalia J, Factor XIII: congenital deficiency factor XIII, acquired deficiency, factor XIII A-subunit, and factor XIII B-subunit. Archives of pathology     [PubMed]

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