Mild factor XIII deficiency and concurrent hypofibrinogenemia: effect of pregnancy.

Factor XIII (FXIII) deficiency is a rare bleeding disorder. Patients with mild congenital FXIII deficiency tend to be asymptomatic, but may demonstrate significant bleeding symptoms with surgery, trauma, and pregnancy. Postpartum hemorrhage has been described in mild FXIII deficiency. We present a case of mild FXIII deficiency and concurrent hypofibrinogenemia manifested by recurrent postpartum hemorrhage, menorrhagia, and miscarriage. Mutational analysis identified a previously unreported heterozygous mutation of the FXIIIA subunit (p.Trp315Arg). No mutation was noted in the fibrinogen gene. FXIII levels decreased approximately 50% from nonpregnant levels to their nadir during labor, whereas fibrinogen levels rose approximately 1.5-fold from decreased nonpregnant levels to their peak at the time of labor. This case illustrates the course of mild FXIII and fibrinogen deficiencies during pregnancy, labor, and postpartum, and raises possible management options for prevention of antepartum and postpartum hemorrhage in women with these deficiencies.

Coagulation factor XIII: a multifunctional transglutaminase with clinical potential in a range of conditions.

Coagulation factor XIII (FXIII), a plasma transglutaminase, is best known as the final enzyme in the coagulation cascade, where it is responsible for cross-linking of fibrin. However, a growing body of evidence has demonstrated that FXIII targets a wide range of additional substrates that have important roles in health and disease. These include antifibrinolytic proteins, with cross-linking of α2-antiplasmin to fibrin, and potentially fibrinogen, being the principal mechanism(s) whereby plasmin-mediated clot degradation is minimised. FXIII also acts on endothelial cell VEGFR-2 and αvß3 integrin, which ultimately leads to downregulation of the antiangiogenic protein thrombospondin-1, promoting angiogenesis and neovascularisation. Under infectious disease conditions, FXIII cross-links bacterial surface proteins to fibrinogen, resulting in immobilisation and killing, while during wound healing, FXIII induces cross-linking of the provisional matrix. The latter process has been shown to influence the interaction of leukocytes with the provisional extracellular matrix and promote wound healing. Through these actions, there are good rationales for evaluating the therapeutic potential of FXIII in diseases in which tissue repair is dysregulated or perturbed, including systemic sclerosis (scleroderma), invasive bacterial infections, and tissue repair, for instance healing of venous leg ulcers or myocardial injuries. Adequate levels of FXIII are also required in patients undergoing surgery to prevent or treat perioperative bleeding, and its augmentation in patients with/at risk for perioperative bleeding may also have potential clinical benefit. While there are preclinical and/or clinical data to support the use of FXIII in a range of settings, further clinical evaluation in these underexplored applications is warranted.

Surgical wound healing in bleeding disorders.

Animal experiments have shown that a number of bleeding disorders may affect wound healing (WH), including haemophilia B, deficiency of factor XIII and abnormalities of fibrinogen. Therefore, normal healing requires adequate haemostatic function for the appropriate time frame (up to 4 weeks in the clean and uncontaminated wound). Many factors may affect WH, including impaired haemostasis, diabetes, poor nutrition, insufficient oxygenation, infection, smoking, alcoholism, old age, stress and obesity. The gold standard for the correct care of surgical wounds in patients with bleeding disorders includes wound dressing and comprehensive standard care (haemostasis, nutritional support, treatment of co-morbidities, offloading, reperfusion therapy and compression). Although complications of surgical wounds healing in patients with bleeding disorders are uncommon, a low level of the deficient factor for an insufficient period of time could cause WH complications such as haematomas, infection, and skin necrosis and dehiscence. Clinical experience and animal experiments appear to indicate that, to get a satisfactory healing of surgical wounds and avoid potential complications of WH, a good level of haemostasis is necessary for 2-3 weeks after surgery. However, many treaters would regard this recommendation at odds with (i.e. more aggressive than) current standards. Unfortunately no additional clinical evidence for this recommendation can be provided.

Factor XIII deficiency related recurrent spontaneous intracerebral hemorrhage: a case and literature review.

Spontaneous intracerebral hemorrhage (ICH) in young adults under 50 years of age is an uncommon occurrence associated with considerable morbidity and mortality. The differential diagnosis of ICH in this population differs from that of older individuals and includes vascular, toxic, inflammatory, oncologic, infectious and hematologic conditions. We present a case based observation of a spontaneous and recurrent ICH in a 25-year-old female secondary to undetected Factor XIII (FXIII) deficiency with no prior associated stigmata of hematologic disturbance admitted to a tertiary care neuroscience intensive care unit (NICU). Our patient was admitted after spontaneous development of left thalamic hemorrhage with ventricular extension. Initial management included external drain placement (EVD) and fresh frozen plasma administration. Diagnostic evaluation was unrevealing including CT angiography, magnetic resonance imaging (MRI) with venography, conventional cerebral angiogram, and hematologic and rheumatologic screens. Our patient recovered but represented 6 months later with five foci of spontaneous ICH. She underwent vascular, infectious, oncologic, hematologic, and rheumatologic evaluations. She expired secondary to ICH expansion with uncal herniation. The results of our investigation revealed markedly diminished FXIII activity. The pathophysiology, diagnosis and treatment of this disease are reviewed. FXIII deficiency should be considered in a case of cryptogenic ICH presenting with multifocal, recurrent ICH and a normal coagulation profile. Early diagnosis and initiation of factor replacement therapy offer the best strategies to reduce the morbidities associated with this disease.

[Factor XIII in man: a review]. / Der Faktor XIII des Menschen: eine Ubersicht.

Activated by calcium and thrombin, factor XIII (FXIIIa) cross-links fibrin, thus increasing the stability of the fibrin clot. Furthermore, the hemostatic and reparative function of factor XIIIa is mediated by cross-linking other proteins like alpha(2)-plasmin-inhibitor, fibronectin, and collagen. The FXIII Val34Leu polymorphism plays a role in athero- and thrombogenesis. FXIII deficiency is an autosomal recessive disorder. The most common symptom is the bleeding tendency of the umbilical cord some days after birth. The diagnosis is confirmed by a solubility clot test in urea (5 mol/l) and then differentiated with an incorporation assay and immuno-electrophoresis. The bleeding tendency typically becomes obvious when FXIIIa activity is <1-2%. Severe bleeding episodes, however, may even occur with FXIIIa activities of 30-50%, especially in heterozygous persons. The sometimes life-threatening bleeding tendency of the inherited FXIII deficiency can be treated with FXIII concentrates. Acquired FXIII deficiency occurs in several internal diseases and after major surgery. The clinical significance is not completely clear. Moreover, FXIII is applied locally as a component of fibrin glues.

[Clinical course and management of severe congenital factor XIII deficiency]. / Krankheitsbild und Behandlung des schweren homozygoten Faktor-XIII-Mangels.

Severe homozygous factor XIII deficiency was first described in Switzerland, in 1961. At present 14 patients are known here. Nine are of Swiss origin, the others are immigrants from eastern Europe. A 27-year-old woman with many haemorrhages during childhood immigrated to Switzerland and went through four episodes of haemorrhagic corpus luteum cyst rupture with life-threatening blood loss into the abdomen and three haemorrhages into the retroperitoneal muscles causing sensomotoric palsies, before the diagnosis was established. A monthly prophylactic replacement therapy of 500 IE factor XIII concentrate was started. Since then no signs of haemorrhage occurred. For the last trimester of pregnancy treatment intervals were shortened and dosage increased. Haemorrhage from the umbilical cord for weeks, subcutaneous haematomas, intracranial haemorrhage, muscle haemorrhage and wound bleeding with impaired wound healing as well as tendency to marked scar formation are characteristic for severe homozygous factor XIII deficiency. Without replacement therapy women suffer from obligate abortion. Diagnosis is made by the solubility of fibrin clots in urea (5 mol/l) or monochloroacetic acid (1-2%). For confirmation and monitoring of replacement therapy a quantitative incorporation assay is used. Replacement therapy is necessary in case of haemorrhage, injury, and surgery. Because of the high risk of intracranial haemorrhage prophylaxis is strongly recommended.

Rare inherited coagulation disorders in India.

Twenty four cases with rare coagulation disorders were diagnosed over a 4 year period. These included 8 patients with factor X deficiency, 7 with factor XIII deficiency, 4 each with fibrinogen and factor VII deficiency and 1 with factor V deficiency. All these patients had presented with bleeding manifestations. Two patients with factor X deficiency showed interesting clinical presentations, one patient had recurrent deep vein thrombosis and another patient had a pseudotumor of the thigh.

[Blood coagulation factor XIII and fibrin stabilization (author's transl)]. / Blutgerinnungsfaktor XIII und Fibrinstabilisierung

Coagulation factor XIII (fibrin stabilizing factor, FSF) is detectable in plasma, platelets, placenta and various tissues. In the activated form FSF has the enzymatic properties of a transglutaminase and is capable of stabilizing fibrin by inducing covalent bondings between fibrin monomers. In patients with congenital factor XIII deficiency or acquired immune inhibitors of fibrin stabilization a severe bleeding tendency is evident. There is not yet enough information available concerning the significance of reduced FSF-activity as cofactor in hemorrhagic diathesis and wound healing disturbances in various disease states. There are some indications from experimental studies that there might be an influence of FSF on tumor growth and metastasis as well as arteriosclerosis. The quantitation of the enzyme by radiological and immunological techniques yield reproducible results. Fibrin in its stabilized or non stabilized form can be discriminated in polyacrylamide gel electrophoresis after reduction of fibrin clots.