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Factor XIII Deficiency Differential Diagnoses

  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Perumal Thiagarajan, MD  more...
 
Updated: Jun 17, 2016
 
 

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
  • a 2 -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.[84]

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.[85]

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.[86]

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.[10, 87, 88] 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.[89]

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.[90]

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+.[87]

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.[91]

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.[92] 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.[93]

Differential Diagnoses

 
 
Contributor Information and Disclosures
Author

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School; Visiting Professor, Rutgers University School of Public Affairs and Administration

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, New York Academy of Medicine, American Academy of Dermatology, American College of Physicians, Sigma Xi

Disclosure: Nothing to disclose.

Coauthor(s)

Pere Gascon, MD, PhD Professor and Director, Division of Medical Oncology, Institute of Hematology and Medical Oncology, IDIBAPS, University of Barcelona Faculty of Medicine, Spain

Pere Gascon, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, New York Academy of Medicine, New York Academy of Sciences, Sigma Xi

Disclosure: Nothing to disclose.

Elzbieta Klujszo, MD Head of Department of Dermatology, Wojewodzki Szpital Zespolony, Kielce

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Ronald A Sacher, MB, BCh, FRCPC, DTM&H Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MB, BCh, FRCPC, DTM&H is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society on Thrombosis and Haemostasis, Royal College of Physicians and Surgeons of Canada, American Clinical and Climatological Association, International Society of Blood Transfusion

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: GSK Pharmaceuticals,Alexion,Johnson & Johnson Talecris,,Grifols<br/>Received honoraria from all the above companies for speaking and teaching.

Chief Editor

Perumal Thiagarajan, MD Professor, Department of Pathology and Medicine, Baylor College of Medicine; Director, Transfusion Medicine and Hematology Laboratory, Michael E DeBakey Veterans Affairs Medical Center

Perumal Thiagarajan, MD is a member of the following medical societies: American College of Physicians, American Society for Clinical Investigation, Association of American Physicians, American Society for Biochemistry and Molecular Biology, American Heart Association, American Society of Hematology, Royal College of Physicians

Disclosure: Nothing to disclose.

Additional Contributors

Paul Schick, MD Emeritus Professor, Department of Internal Medicine, Jefferson Medical College of Thomas Jefferson University; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital

Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Society of Hematology

Disclosure: Nothing to disclose.

Acknowledgements

Rajalaxmi McKenna, MD, FACP Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems

Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis

Disclosure: Nothing to disclose.

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Coagulation reactions leading to thrombin generation and activation of factor XIII.
Final steps in clot formation (from article: Factor XIII).
Activation of factor XIII and generation of insoluble cross-linked fibrin. Adapted from Lorand L. Ann N Y Acad Sci. 2001;936:291-311.
Postulated interaction between factor XIII and thrombin-activatable fibrinolytic inhibitor.
Cell surfaced–directed hemostasis. Initially, a small amount of thrombin is generated on the surface of the tissue factor–bearing (TF-bearing) cell. Following amplification, the second burst generates a larger amount of thrombin, leading to fibrin (clot) formation (from article: Factor XIII). Adapted from Hoffman and Monroe. Thromb Haemost. 2001;85(6):958-65.
Gene, messenger RNA, and protein for subunit A of factor XIII. Adapted from Reitsma PH. In: Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Lippincott Williams & Wilkins; 2001:59-87 and from Roberts HR, Monroe DM III, Hoffman M. In: Williams Hematology. McGraw-Hill Professional; 2001:1409-34.
Table. Some Features of the A and B Chains of Factor XIII
Properties A Chain B Chain
Plasma FXIII Has 2 A chains Has 2 B chains
Plasma level Approximately 15 mg/mL Approximately 21 mg/mL
Chains are free in plasma No. All bound to B chain and present as an A2 B2 tetramer Yes. Excess B chain present in plasma as a B2 dimer
Chain contains the catalytic site Yes No
Chain is the carrier protein No Yes
Chain acts as a brake on FXIII activation No Yes
Cellular FXIII Has 2 A chains (A2 dimer) Has no B chains
Mutations can lead to decreased FXIII activity Yes Yes
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