eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders

Factor XIII: Differential Diagnoses & Workup

Author: Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Coauthor(s): Elzbieta Klujszo, MD, Head of Department of Dermatology, Wojewodzki Szpital Zespolony, Kielce; 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; Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems
Contributor Information and Disclosures

Updated: Sep 26, 2007

Differential Diagnoses

Disseminated Intravascular Coagulation
Factor XI Deficiency
Dysfibrinogenemia
Glanzmann Thrombasthenia
Factor II
Menorrhagia
Factor IX
von Willebrand Disease
Factor V
Factor VII
Factor VIII

Other Problems to Be Considered

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 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.71

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.72

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.

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 a 2 PI cross-linking site.73,6,74 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.75

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.76

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+.73

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.77

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.78 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.79

Workup

Laboratory Studies

  • The following routine tests are the first step in the evaluation of any bleeding disorder: aPTT, PT, thrombin-clottable fibrinogen level, platelet counts, and bleeding time (the latter after ascertaining that the patient was not on antiplatelet drugs for at least the preceding 5 d). However, these tests cannot be used to screen for FXIII deficiency because the results would be within reference ranges in a patient with isolated severe FXIII deficiency.80
  • 5M urea solubility test: The next test performed is a qualitative screening test for severe FXIII deficiency that assesses clot solubility in 5M urea or 1% monochloroacetic acid. If the thrombin and Ca2+ -induced clot lyses within a few hours, severe FXIII deficiency is suggested provided fibrinogen levels are qualitatively and quantitatively within reference range. Excluding hypofibrinogenemia and dysfibrinogenemia is important, since these conditions cause false-positive results on the 5M urea solubility test. The thrombin-clottable fibrinogen test can be used to exclude hypofibrinogenemia and dysfibrinogenemia.
  • If the 5M urea solubility test demonstrates positive results, this finding should be confirmed by quantitating FXIII activity using a monodansylcadaverine or putrescine incorporation assay, which must be performed by laboratory personnel with expertise.
  • TEG is an old method used to assess clotting and lysis of fresh whole blood, and it has been used as an early tool in the initial evaluation, and as a simple laboratory test, of the mechanical strength (effect of FXIII) of fibrin sealants.81 However, TEG cannot supplant any of the qualitative or quantitative tests discussed in this section.
  • A new sensitive assay used to quantitate FXIII activity is based on monitoring the amount of ammonia (NH3) released by using glutamate dehydrogenase and nicotinamide adenine dinucleotide phosphate during the transamidation reaction (cross-linking) by FXIII.

    • Reportedly, this test is sensitive over a wide range of activities, from a low of 1 U/L (0.1%) to a high of 470 U/L (47%), with an impressive coefficient of variation (CV) of less than 8%, even at very low FXIII activity levels. Note that a low CV in the low range of FXIII activity is a desirable feature of assays of this enzyme.82
    • Compared to the cumbersome conventional quantitative amine incorporation assays, the new method appears to be simple, rapid, and reproducible not only in the assessment of inherited or acquired reductions of FXIII activity levels but also in the ability to measure increased FXIII activity levels resulting from certain mutations. The test fulfills the need for a simpler method to quantify FXIII activity.
    • The same group also has published results of a simple, quick (2 h), 1-step, enzyme-linked immunoassay (ELISA) to determine the presence of the plasma tetramer (A2 B2). Results demonstrated high sensitivity and low CVs within batches and in day-to-day variations.83
  • Another new and sensitive colorimetric assay based on incorporation of 5-(biotinamido) pentylamine into fibrin/fibrinogen was compared to a photometric method based on ammonia release and an ELISA of FXIII subunit A to quantitate FXIII activity. The test was shown to be sensitive to both reductions and increases in activity; the increases resulted from the FXIII Val34Leu mutation.68
  • In addition, a 2 PI and plasminogen activator inhibitor-1 assays should be performed to exclude abnormalities in the fibrinolytic pathway, which accelerate clot lysis.
  • Sodium dodecylsulfate polyacrylamide gel electrophoresis under reducing conditions has been used to assess the presence of cross-linked g or a chains of fibrin, which is a reflection of FXIII activity. The studies must be performed by laboratory personnel with special expertise.
  • If the presence of an inhibitor is suspected in a patient with a positive urea solubility test result, the next step is to repeat the urea solubility test with mixtures containing varying proportions of patient and normal plasma to differentiate between a deficiency or an inhibitor as the cause of a positive result. Since FXIII activity is present in serum, serum also may be substituted for plasma in the test.
  • Semiquantitation of the susceptibility of the fibrin clot to fibrinolysis can be obtained by adding iodine-125-labeled fibrinogen, tissue plasminogen activator, thrombin, and Ca2+ to the patient's plasma, with measurement of the time to 50% clot lysis. This method is useful in evaluating inhibitors but must be performed by laboratory personnel with special expertise.
  • See Lorand for a recent review of further details of the sequence of necessary testing to confirm the presence of a FXIII inhibitor.73
  • Acquired systemic disorders, including decompensated DIC and liver disease, require standard tests to confirm the diagnosis.
  • Caution is warranted in obtaining blood samples for any coagulation assays from heparinized central lines because of the effect of large amounts of heparin on any coagulation test that depends on thrombin generation.
  • Prenatal diagnosis
    • Use of several diagnostic procedures has been well established in the evaluation of patients with FVIII and factor IX (FIX) deficiencies. In one case report, a short tandem repeat marker that was closely linked to subunit A was used antenatally to identify the presence of a severe bleeding disorder in a subsequent pregnancy in a family in which an older sibling had severe FXIII deficiency.84
    • Chorionic villous sampling at approximately 10-12 weeks of gestation or amniocentesis at 16-20 weeks of gestation can be performed to obtain fetal cells for DNA analysis or for linkage studies. If DNA analysis cannot be performed, fetal blood obtained by fetoscopy at approximately 20 weeks of gestation can be used. In general, these procedures carry risks ranging from a low of approximately 0.5% maternal-fetal complications to a high of approximately 1-6% fetal death for fetoscopy.
    • Perform these procedures only after intense genetic and obstetric counseling of the parents.
  • Perform liver function tests; kidney function tests; HIV-1 and HIV-2 antigen and antibody tests; hepatitis A (HAV), hepatitis B (HBV), hepatitis C (HCV), hepatitis D, and hepatitis E antigen/antibody levels; and other tests as needed.
  • Assess a -fetoprotein levels and other tumor markers as needed in patients with chronic hepatitis.

Imaging Studies

  • MRI, CT scan, and ultrasound have been used to localize, quantify, and serially monitor the location and response of bleeding to specific therapy.
  • Perform other imaging tests as needed to diagnose associated diseases.

Other Tests

  • Perform ECGs as needed.

Procedures

  • Diagnostic amniocentesis, chorionic villous sampling, or fetoscopy may be performed during pregnancy. Perform other routine procedures when indicated. Perform arthrocentesis only when infection is suggested. Any invasive procedure requires the appropriate factor replacement.
  • When indicated, perform other procedures, such as colonoscopy, in persons without hemophilia. Evaluate persistent GI tract bleeding without an apparent cause using endoscopy and colonoscopy to exclude underlying lesions. Persistent genitourinary tract bleeding requires evaluation for nephrolithiasis, tumors, or obstruction. If a biopsy is needed, patients require replacement therapy prior to and following the procedure until the biopsy site has healed.
  • Invasive lifesaving procedures should be performed in patients with inhibitors only in concert with appropriate treatment.

More on Factor XIII

Overview: Factor XIII
Differential Diagnoses & Workup: Factor XIII
Treatment & Medication: Factor XIII
Follow-up: Factor XIII
Multimedia: Factor XIII
References
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Further Reading

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Keywords

plasma transglutaminase, fibrin stabilizing factor, transligase, factor XIII deficiency, fibrin stabilizing factor deficiency, FXIII, FXIII deficiency, rFXIII, FXIIIa, hemophilia, bleeding diathesis, autosomal blood disorder, blood disorder, congenital hemorrhagic diathesis, coagulation disorder, tissue transglutaminase, thrombin

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Contributor Information and Disclosures

Author

Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Coauthor(s)

Elzbieta Klujszo, MD, Head of Department of Dermatology, Wojewodzki Szpital Zespolony, Kielce
Disclosure: Nothing to disclose.

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 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, and Sigma Xi
Disclosure: Nothing to disclose.

Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, 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.

Medical Editor

Paul Schick, MD, Emeritus Professor, Department of Internal Medicine, Thomas Jefferson University Medical College; Research Professor, Department of Internal Medicine, Drexel University College of Medicine
Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Hematology, International Society on Thrombosis and Haemostasis, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Ronald A Sacher, MD, Director of the Hoxworth Blood Center, Professor, Departments of Internal Medicine and Pathology, University of Cincinnati Medical Center
Ronald A Sacher, MD is a member of the following medical societies: American Society of Hematology
Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membership

CME Editor

Rebecca J Schmidt, DO, FACP, FASN, Clinical Associate Professor of Medicine, West Virginia School of Osteopathic Medicine; Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine
Rebecca J Schmidt, DO, FACP, FASN is a member of the following medical societies: American College of Osteopathic Internists, American College of Physicians, American Medical Association, American Society of Nephrology, International Society of Nephrology, National Kidney Foundation, Renal Physicians Association, and West Virginia State Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

 
 
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