Factor XIII Deficiency

Hemorrhagic diathesis is the clinical hallmark of FXIIID, but there is considerable variation in the severity of the disease. While some patients may suffer from life-threatening hemorrhages, others merely show an increased tendency to bleed upon provocation.

On the one hand, FXIIID-associated hemorrhagic diathesis may be apparent at birth and manifest as soft tissue hematoma or umbilical cord bleeding. On the other hand, FXIIID may be suspected in elder adults with an acute-onset tendency to bleed [1]. Regardless of the age of the patient, FXIIID may promote hemorrhages of the skin, which most commonly present as ecchymosis, mucosal hemorrhages such as bleeding gums, and subcutaneous hematomas [2]. Females in fertile age may suffer from menorrhagia and are often unable to carry a pregnancy to term [3]. Genitourinary and gastrointestinal bleedings leading to hematuria, melena, or hematochezia are not typical of FXIIID, but may occur occasionally [4]. Furthermore, FXIIID patients are at increased risks of life-threatening intracranial hemorrhages [5] [6]. It has been estimated that such hemorrhages occur in about a third of FXIIID patients [2]. They may also occur if the patient has shown only mild symptoms in the past [7].

Anamnestic and clinical data usually agree with hemophilia, but additional analyses are required to identify its cause. Coagulation studies are essential in the diagnosis of any bleeding disorder and may also serve as a starting point in FXIIID patients. In this context, platelet count, fibrinogen level, activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) are usually assessed. In FXIIID, all these values are within reference ranges, so the diagnosis of FXIIID requires a more specific approach [2].

FXIII activity can be quantified by the measurement of ammonia released during an in vitro transglutaminase reaction. This assay comprises the spectophotometric assessment of NAD(P)H levels, which negatively correlate with ammonia release [7]. In order to avoid an overestimation of FXIII activity, FXIIIA-independent ammonia release should be inhibited by means of plasma blanking with an irreversible FXIIIA inhibitor [2] [7]. Otherwise, the efficiency of the transglutaminase reaction involving FXIIIA may be evaluated indirectly by measuring the incorporation of labeled substrate amines into substrate proteins in consecutive reactions. Although this technique is very sensitive, it is also time-consuming and poorly available [7].

While the diagnosis of FXIII relies on the assessment of FXIII activity, the results of assays described so far don't allow for a distinction between deficiency subtypes. The latter requires antigen immunoassays and the determination of FXIII-A2B2, FXIII-A, and FXIII-B antigens. In the rare event of qualitative FXIIID, antigen assays yield normal results for the heterotetramer, for catalytic subunit A and carrier subunit B [1]. Quantitative alterations are found in most cases of FXIIID and allow for a distinction between FXIIID type 1 (deficiency of both subunits) and FXIIID type 2 (deficiency of catalytic subunit A). Sole deficiency of carrier subunit B is exceedingly rare, but reduces the plasma half-life of subunit A and does induce mild hemophilia [1].

However, antigen immunoassay results don't provide information as to the cause of FXIIID. Of course, the age of the patient and their medical history may suggest either inherited or acquired FXIIID, but it still recommended to carry out genetic studies and inhibitor assays to confirm the diagnosis and choose the correct treatment regimen. With regard to the former, sequencing of the whole coding region, the splice sites, and the promoter region should be carried out unless a targeted approach seems feasible: Due to founder effects, certain mutations are especially common among FXIIID patients in determined geographical areas and may first be looked for [7].

FXIIID patients require life-long therapy. Those with residual factor XIII activity <5% should regularly be administered plasma-derived virus-inactivated factor XIII concentrates or recombinant factor XIII to prevent life-threatening hemorrhages. In general, monthly to biweekly factor XIII replacement suffices to prevent bleeding episodes because this coagulation factor has an in vivo half-life of 11-14 days [2]. Because higher residual activity of factor XIII is associated with lower risks of such events, on-demand therapy does usually suffice for patients with factor XIII activity >5% [7]. If neither concentrates nor recombinant factor XIII are available to alleviate acute symptoms of FXIIID, fresh frozen plasma and cryoprecipitate constitute valuable alternatives [4].

Female FXIIID patients should be recommended close monitoring during pregnancy. The regular administration of factor XIII concentrates or recombinant factor XIII has been reported to prevent miscarriage and allows affected women to carry a pregnancy to term. While FXIIID outside of pregnancy aims at raising factor XIII activity to >5%, levels of >30% should be strived for in pregnant women [7]. Additional applications may be required during delivery and to avoid postpartum hemorrhages, though [8].

In preparation for surgery, factor XIII activity should be augmented to >50% [7].

First-line therapy of acquired FXIIID, an autoimmune disorder, also comprises the application of immunosuppressants [9]. To this end, corticosteroids like prednisolone are most frequently administered. They may be combined with cyclophosphamide. In case of an unsatisfactory response, the application of monoclonal antibody rituximab may be considered. Of note, recurrence after the discontinuation of immunosuppressive therapy is possible. While some patients achieve complete remission after a second round of immunosuppressive treatment, others require long-term immunosuppression.

Additional treatment options become available if acquired FXIIID can be related to an underlying disease. In general, this applies to about half of all patients diagnosed with acquired hemophilia [10].

An individual patient's prognosis depends on the severity of the disease, which is directly related to residual factor XIII activity [2]. It is important to note that the severity of hemophilia at a given point in time doesn't necessarily allow to deduce the overall severity of the disease. Patients are to be considered at high risk of future hemorrhages if residual factor XIII activity is <5% [7].

FXIIID is either an inherited disorder or an acquired autoimmune disease:

• The former is inherited in an autosomal recessive pattern and is caused by germline mutations in genes F13A1 and F13B, which encode for subunits A and B of FXIII, respectively. More than 150 mutations in F13A1 and about 15 mutations in F13 B have been reported to date [1] [8]. FXIIID patients may be homozygous or compound heterozygous for pathogenic mutations in genes F13A1 and F13B [8]. Of note, heterozygous carriers may show mild clinical symptoms if their residual factor XIII activity is <30% [1] [2].
• The etiology of acquired FXIIID is still poorly understood. It is triggered by the production of autoantibodies directed against either subunit of FXIIID and frequently occurs concomitantly to malignant neoplasms, infectious diseases, additional autoimmune disorders, drug intake or pregnancy [1] [10]. Autoantibody production may also be provoked by factor XIII administration to treat the congenital form of the disease [2]. However, this side effect has rarely been reported in FXIIID patients [7].

The global incidence of FXIIID is 1 per 2 to 3 million inhabitants, rendering FXIIID the rarest of all rare bleeding disorders [2]. However, higher incidence rates have been observed in areas where consanguineous marriage is common [2]. This especially applies to Iran [11]. Inherited FXIIID is a congenital condition and severe disease is associated with symptoms apparent at birth. By contrast, acquired FXIIID is typically diagnosed in the elder adult. The individual risk of developing this variant of FXIIID increases with age.

A complex network of reactions favoring or inhibiting the formation of blood clots is the basis of hemostasis. Primary hemostasis is achieved via the interaction of platelets with each other and with vessel wall components, and results in the formation of a weak platelet plug. This plug is stabilized during secondary hemostasis, which is initiated by activated thrombocytes or upon endothelial damage. Secondary hemostasis involves a cascade of enzyme activation events that may either follow the intrinsic or extrinsic pathway. Both eventually result in the conversion of prothrombin to thrombin. Thrombin, in turn, is required for fibrinogen cleavage and thus for the production of fibrin, but also catalyzes the calcium-dependent activation of factor XIII to factor XIIIA.

For fibrin to build a resistant fibrin net able to stabilize the weak platelet plug, polymer formation is required and mediated by factor XIIIA. In detail, factor XIII establishes crosslinks between glutamine and lysine residues of the α- and γ-chains of donor and acceptor fibrin monomers. This final step in the common pathway of coagulation isn't taken in individuals suffering from FXIIID.

No recommendations can be given to prevent the formation of autoantibodies directed against factor XIII. By contrast, genetic counseling is a valuable tool to reduce the incidence of congenital FXIIID. If the mutation underlying FXIIID in a certain family is known, prenatal diagnosis becomes feasible. In fact, tests for FXIIID have been part of prenatal diagnosis programs in regions with particularly high incidence rates [11].

Factor XIII, also referred to as fibrin-stabilizing factor, is a zymogen implicated in the common pathway of coagulation, the final steps of blood clotting preceded by both the intrinsic and extrinsic cascades. The common pathway of coagulation includes the activation of factor XIII to factor XIIIA, an enzyme required for the formation of a fibrin net that stabilizes the thrombus. Accordingly, FXIIID patients present with hemorrhagic diathesis. The disease may be congenital or acquired as an autoimmune disease, and manifests at birth or in the elder adult, depending on its etiology. Factor XIII replacement is the mainstay of therapy and may be carried out in a regular manner to prevent life-threatening hemorrhages in patients with very low residual factor XIII activity, or may only be necessary to mitigate bleeding episodes. FXIIID patients who have access to such therapies have a good prognosis, but FXIIID left untreated is associated with a high risk of intracranial bleedings that may entail severe disability or death.

Factor XIII is part of the complex system of reactions favoring or inhibiting the formation of blood clots. In a whole, it may be referred to as the hemostatic network. It assures that blood clots form where it is necessary, while excess thrombus formation is avoided. Patients suffering from factor XIII deficiency (FXIIID) have a tendency to bleed because blood clots cannot be sufficiently stabilized in the absence of this coagulation factor. This so-called hemorrhagic diathesis may manifest as umbilical cord bleeding, soft tissue hematoma, hemorrhages of the skin, and bleeding gums. Women suffering from FXIIID may experience heavy menstrual flow and may be unable to carry a pregnancy to term. Furthermore, FXIIID is associated with an increased risk of life-threatening intracranial hemorrhages.

The disease may be congenital or acquired as an autoimmune disease. Both are very rare disorders, with inherited FXIIID being somewhat more common in areas where consanguineous marriage is practiced. About a third of all FXIIID patients live in Iran. Patients suffering from congenital FXIIID may present symptoms at birth. Autoimmune FXIIID is usually diagnosed in the elder adult. In both cases, treatment relies on the replacement of factor XIII, which may be done administering plasma-derived virus-inactivated factor XIII concentrates, recombinant factor XIII, or - if the former are not available - fresh frozen plasma or cryoprecipitate. In severe cases, during pregnancy, and in preparation for surgery, monthly to biweekly treatment is required. Otherwise, on-demand therapy may suffice. Patients diagnosed with autoimmune FXIIID may additionally be administered immunosuppressants. These drugs diminish the production of antibodies against factor XIII and thereby alleviate the symptoms of FXIIID.

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