Factor XIII Deficiency Differential Diagnoses

Updated: Aug 01, 2019
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Perumal Thiagarajan, MD  more...
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DDx

Diagnostic Considerations

Other problems to be considered in the differential diagnosis include the following:

  • Factor XIII (FXIII) alloantibodies (which can be a cause of bleeding in patients with inherited severe FXIII deficiency who receive FXIII replacement)

  • Rare inherited afibrinogenemia or dyshypofibrinogenemias associated with a bleeding disorder

  • a2 -Plasmin inhibitor deficiency

  • Plasminogen activator inhibitor-1 deficiency

  • Hemophilia A or B (should be excluded, particularly in a male with delayed onset, recurrent bleeding after trauma or surgery, or with a joint bleed)

  • Bleeding in a patient with type III von Willebrand disease (may mimic hemophilic bleeding)

  • Inherited severe bleeding disorders affecting platelet function, eg, Glanzmann thrombasthenia

  • All other rare coagulation factor deficiencies (FII, FV, FVII, FX); all of these factor deficiencies are associated with abnormalities in routine screening coagulation tests (eg, activated partial thromboplastin time [aPTT], prothrombin time [PT]).

Acquired disorders

FXIII deficiency should be considered in patients with recurrent miscarriages and recurrent intracranial bleeding.

Any cause of disseminated intravascular coagulation (DIC) can lead to an acquired reduction in fibrinogen and FXIII.

Liver disease may result in decreased production of FXIII and fibrinogen (also can produce dysfibrinogenemia).

Cardiopulmonary bypass: Activation of hemostasis is an integral part of any cardiopulmonary bypass procedure. FXIII antigen levels and clot strength as measured by thromboelastography (TEG) were reduced in parallel with platelet count and fibrinogen levels after bypass; changes were secondary to increased thrombin generation. [86]

Malarial infections: Malaria affects a sizable population worldwide. Patients who are severely ill with falciparum malaria have activity levels of subunit A lower than 50%, with an increase during antiparasitic therapy. An inverse relationship has been found between FXIII levels, clinical severity of the disease, degree of parasitemia, and human neutrophil elastase levels. [87]

A significant reduction in FXIII subunit A levels has been found in patients with active Crohn disease, ulcerative colitis, and infectious colitis, without any change in the levels of the carrier protein (subunit B). A reduction in FXIII activity was associated with a concomitant increase in fibrinogen/fibrin split products correlating with inflammatory bowel disease activity during a yearlong follow-up study of patients with severe ulcerative colitis. The predictive value of such changes is yet to be confirmed in prospective clinical trials.

Reduced levels of FXIII have been reported in patients with scleroderma and Henoch-Schönlein purpura and in advanced malignancies. [88]

Following systemic thrombolytic therapy, severe reduction in the fibrinogen level (hypofibrinogenemia) also is associated with a dysfibrinogenemia. A specimen obtained from a patient who has systemic fibrinolytic effects may show a false-positive urea solubility test result because of an acquired abnormality in the substrate for FXIII (dyshypofibrinogenemia).

FXIII inhibitors

A wide variety of bleeding manifestations, which are not necessarily specific for an FXIII inhibitor, occur in patients with antibodies that inhibit FXIII function. Manifestations include persistent serious bleeding after trauma or surgery (including dental extractions); large hematomas over the extremities and abdominal wall; intramuscular, retroperitoneal, and intra-abdominal bleeding; gastrointestinal (GI) tract, urinary tract, and CNS bleeding; menorrhagia; prolonged postpartum hemorrhage; and spontaneous miscarriage.

Very few FXIII inhibitors have been reported thus far; they usually include immunoglobulin (Ig) G classes and may be monoclonal or polyclonal. Alloantibodies may arise in patients with deficiency who receive factor replacement or in patients who have received transfusions with blood products. Incidence of alloantibodies in patients with inherited FXIII deficiency appears to be approximately 1%, but a larger database is needed before the frequency is established with certainty.

Autoantibodies may be idiopathic, secondary to drugs or autoimmune diseases. Many reported FXIII antibodies were believed to be secondary to long-term ingestion of certain drugs. The most commonly implicated drug is INH, which functions as a lysine analog and acts as a false substrate for FXIII. Other drugs that have been reported to induce antibodies include penicillin (allergy), procainamide, and phenytoin sodium.

Antibodies to FXIII may inhibit any of several functions, including activation of FXIII to FXIIIa and transamidating function of FXIIIa. Antibodies may bind to fibrin, preventing it from binding to FXIIIa, or antibodies may bind to the fibrin-binding site on FXIIIa, thus blocking its ability to bind to fibrin. Antibodies may inhibit other functions, such occurs at the a2 PI cross-linking site. [11, 89, 90] Both plasma and platelet zymogens and their active enzymes may be the target of the antibody. All studied inhibitors neutralize plasma cross-linking activity of FXIII, and most also inhibit in vitro amine incorporation tests. Many inhibitors specific for subunit A also are associated with a reduction in the antigenic amount of subunit B, although the inhibitor is not directed against subunit B. Currently, the reasons for this are not clear.

Patients with acquired FXIII inhibitors usually are older and present with a new onset of a bleeding disorder, similar to the mode of presentation of patients with acquired factor VIII (FVIII) inhibitors. The mortality rate is high, and to date, almost one half of reported patients have died despite the use of several modalities of therapy. The remainder of patients improved over time, similar to the pattern of spontaneous disappearance of acquired FVIII inhibitors.

Case reports highlighting inhibitor features

An acquired IgG antibody isolated from the plasma of a female with systemic lupus erythematosus inhibited the activities of both plasma FXIII (tetramer) and platelet FXIII (dimer). Immunoelectrophoretically, no subunit A was detected in the patient's plasma or platelets, but the level of plasma subunit B was within reference range. [91]

In an 80-year-old woman with an acquired bleeding disorder, an acquired IgG-l monoclonal antibody was detected using TEG and clot solubility tests. This acquired IgG-l monoclonal antibody selectively inhibited FXIIIa transamidation but did not inhibit thrombin-induced activation of FXIII. [92]

An IgG antibody detected in a 62-year-old man using solubility of the patient's clot in 5M urea was associated with low reference range levels demonstrated by a putrescine casein incorporation assay (62%); however, on sodium dodecyl sulphate gel electrophoresis, none of the a chains and only two thirds of the g chains of fibrin became cross-linked. This IgG antibody recognized the plasma tetramer and inhibited virtually all a-chain and two thirds of g-chain cross-linking of fibrin, with a 100-fold greater affinity for the thrombin-activated forms of FXIII. A previously unreported effect of the antibody was seen, ie, the antibody induced an enzymatically active configuration in thrombin-activated FXIII, even in the absence of Ca2+. [89]

A patient with Waldenström macroglobulinemia who was taking INH for tuberculosis developed an IgG antibody that was detected via a positive 5M urea solubility test result and low incorporation of monodansyl cadaverine into casein. [93]

Another case report raises a concern as to whether a patient with psoriasis had an acquired FXIII inhibitor. Normalization of generalized bleeding and poor wound healing with improvement in joint mobility followed correction of a 19% activity of FXIII with replacement therapy. [94] In inherited severe FXIII deficiency, a minimal rise of FXIII activity to approximately the 3-5% range usually is sufficient to control bleeding. The higher FXIII activity of 19%, in this patient with psoriasis and bleeding, is reminiscent of the finding of residual FVIII coagulant activity in the plasma of patients with acquired FVIII inhibitors who also have bleeding out of proportion to the detectable residual FVIII activity. A summary by Lorand of the salient features of several patients with FXIII inhibitors is available. [95]

Differential Diagnoses