Triskaidekaphobia legitimized: Fatal Factor XIII deficiency
By Warren R. Heymann, MD, FAAD
April 12, 2023
Vol. 5, No. 15
I am not especially superstitious. The number 13 has never concerned me but acquired Factor XIII deficiency has now joined my ever-expanding pantheon of new complications to worry about.
The article entitled “Association of lethal acquired factor XIII deficiency and type 1 diabetes mellitus with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms with high levels of serum thymus and activation-regulated chemokine” got my attention. (1) Before dissecting the crux of the case, it is essential to review other pertinent issues in this manuscript.
What is serum thymus and activation-regulated chemokine (TARC)?
TARC/CCL17 is constitutively expressed in the thymus and is produced by dendritic cells, endothelial cells, keratinocytes, and fibroblasts. TARC is designated as a Th2-type chemokine because it binds to C-C chemokine receptor 4 and correlates with the number of circulating eosinophils. Serum TARC levels reflect the disease activity of atopic dermatitis, bullous pemphigoid, mycosis fungoides, generalized pustular psoriasis (not psoriasis vulgaris), and scabies. (2,3) TARC elevation is observed in the acute stage and flares of the drug-induced hypersensitivity syndrome; it has been proposed that monitoring serum TARC levels could be useful for determining when steroids may be tapered. (4)
How often does type I diabetes mellitus (DM) complicate DRESS syndrome?
Studying the sequelae in 145 patients with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS), Kano et al reported that the following newly developed diseases after recovery from DIHS/DRESS were observed: Graves’ disease (n = 2), Hashimoto’s disease (n = 3), painless thyroiditis (n = 2), fulminant type 1 diabetes mellitus (n = 5), and infectious diseases (n = 7). Sclerodermoid graft-versus-host disease-like lesions and systemic lupus erythematosus have also been reported as sequelae of DIHS/DRESS. (5) According to Perez et al, fulminant type I DM complicating DRESS is rarely reported. The authors state: “The mechanisms underlying the development of fulminant type 1 DM as a sequela of DRESS are complicated and not well understood. There seems to be an association with reactivation of herpes virus HHV-6, as well as a loss of suppressive function by T-regulatory cells, a type of immunosuppressant T-cell.” (6)
What is Factor XIII?
Factor XIII (FXIII) is a transglutaminase enzyme that is the last factor in the coagulation cascade. The plasma FXIII complex is composed of two subunits, FXIIIA and FXIIIB. It plays a significant role in hemostasis by cross-linking fibrin, thereby making clots denser, stiffer, and more stable. FXIII also functions in platelet-dependent clot retraction, wound healing, and tissue repair. (7,8)
What is Factor XIII deficiency?
Factor XIII deficiency is a bleeding disorder that may be congenital or acquired. Congenital FXIII deficiency is a rare autosomal recessive disorder manifested by spontaneous and delayed bleeding, such as umbilical and intracranial hemorrhage, abnormal wound healing, and scar formation. Acquired FXIII deficiency can be categorized as immune and non-immune mediated. Immune-mediated FXIII deficiency is due to the rare development of an autoantibody targeting FXIII epitopes. Associated disorders most often include systemic lupus erythematosus, rheumatoid arthritis, cancer (both solid tumors and lymphoproliferative malignancies), and medications (most notably isoniazid). Non-immune causes may be due to reduced FXIII synthesis (in patients with liver disease, leukemia, or on medications such as valproic acid or tocilizumab) and/or increased FXIII consumption (noted post-operatively, or with sepsis, disseminated intravascular coagulation, inflammatory bowel disease, or Henoch-Schönlein purpura). Most cases of acquired FXIII deficiency are not immune-mediated and are characteristically asymptomatic compared to immune-mediated FXIII deficiency which often presents with spontaneous or delayed post-operative bleeding. In those with spontaneous bleeding, 70% are subcutaneous and/or intramuscular. The leading cause of death in FXIII deficiency is intracranial hemorrhage. (8,9)
How is the diagnosis of Factor XIII deficiency confirmed?
The most important consideration is to recognize bleeding in the context of normal, standard coagulation laboratory tests. Prothrombin time, INR, and activated partial thromboplastin time are usually normal as factor XIII is not included in the formation of the fibrin. (8) A quantitative functional FXIII activity assay is the first-line screening test. If FXIII activity is decreased, the subtype of deficiency should be established through the measurement of FXIII-A, FXIII-B and/or FXIII-A2B2 antigen concentrations. (9) I strongly recommend a consultation with a hematologist to help navigate ordering these tests that (I assume) are seldomly ordered by dermatologists.
How is immune-mediated Factor XIII deficiency managed?
Immediate control of hemorrhage by using FXIII concentrates or FXIII-containing blood products is essential. Immunosuppressive therapy with corticosteroids, rituximab, IVIG, cyclosporin, or cyclophosphamide may all be considered; plasma exchange has been valuable but does not decrease autoantibody synthesis. (8) The patient referred to in the case that piqued my curiosity was a 52-year-old woman with DIHS/DRESS due to salazosulfapyridine prescribed for rheumatoid arthritis. Her course was complicated by development of type I diabetes complicated by ketoacidosis, subcutaneous hematomas, and a fatal cerebral hemorrhage. (1)
If dermatologists encounter Factor XIII deficiency, it is likely to be in the context of autoimmunity. The disorder is potentially fatal, so rapid recognition of the disorder is essential, in those patients exhibiting unexplained hemorrhages. To my knowledge, I have not yet encountered this complication of autoimmunity — knock on wood.
Point to Remember: Acquired Factor XIII deficiency should be considered in patients with autoimmune diseases presenting with hemorrhagic complications that are otherwise unexplained by standard coagulation studies.
Our expert’s viewpoint
Tulin Budak-Alpdogan, MD
Professor of Medicine, Department of Hematology Oncology
Cooper University Hospital
Factor XIII has two subunits, Factor XIIIA, and Factor XIIIB, which stabilize clots by cross-linking fibrin and making it dense and stiff. (10) Factor XIII deficiency not only causes a severe bleeding diathesis but it also impairs wound healing and tissue repair, leading to abnormal scar formation.
Congenital Factor XIII deficiency is a rare disorder, with an estimated frequency of one in 2-5 million live births. Acquired Factor XIII deficiency occurs in association with consumption or decreased production of Factor XIII, or is related to the production of autoantibodies against Factor XIII. (9) Acquired Factor XIII deficiency has been reported in a variety of systemic conditions, including severe liver disease, inflammatory bowel disease, Henoch-Schonlein purpura, lupus, scleroderma, rheumatoid arthritis, myeloid leukemias, monoclonal gammopathy of unknown significance (MGUS), sepsis, and surgery. It has also been linked to several medications including isoniazid, tocilizumab, and valproic acid.
Diagnosing acquired Factor XIII deficiency requires a high index of suspicion. (8) Standard coagulation profiles including the prothrombin time (PT) and partial thromboplastin time (PTT) are typically not prolonged in cases of Factor XIII deficiency. A clot solubility test usually suggests the diagnosis, but this testing is neither sensitive nor specific. Multiple conditions such as hypofibrinogenemia, dysfibrinogenemia, and high pepsinogen can yield a false positive clot solubility test. Quantitative assays/functional activity assays for Factor XIII activity are recommended as first-line screening tests when Factor XIII deficiency is suspected. When Factor XIII deficiency is proven with this screening assay, immunological assays are useful to distinguish Factor XIII subunits A and B, and to evaluate for Factor XIII A2B2 complex. These assays are very useful to identify congenital Factor XIII deficiency types, and subsequent genetic analysis can be used to confirm the specific gene alteration. However, for acquired Factor XIII deficiencies, autoantibodies should be evaluated with either neutralizing autoantibodies against Factor XIII subunit A using mixing studies, or an ELISA to evaluate for non-neutralizing inhibitors.
Factor XIII deficiency related bleeding can be treated with infusions of plasma components. The half-life of Factor XIII is about 6-19 days, which is rather long in comparison to the half-lives of other factors in the coagulation cascade. Cryoprecipitate is the most commonly available plasma product that contains approximately 20%-30% of the original Factor XIII of plasma. (11) One bag of cryoprecipitate per every 10-20 kg of body weight should be infused to provide adequate Factor XIII levels. The FDA has approved the first recombinant Factor XIII-A subunit for clinical use in 2013, but this has been only tested in the setting of congenital Factor XIII deficiency. (12)
Kawai R, Suzuki S, Tanaka A, Yamazaki M, Inoue T, Katagiri K. Association of lethal acquired factor XIII deficiency and type 1 diabetes mellitus with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms with high levels of serum thymus and activation-regulated chemokine. J Dermatol. 2021 Jul;48(7):e341-e342. doi: 10.1111/1346-8138.15918. Epub 2021 May 8. PMID: 33963600.
Kawasaki Y, Kamata M, Shimizu T, Nagata M, Fukaya S, Hayashi K, Fukuyasu A, Tanaka T, Ishikawa T, Ohnishi T, Tada Y. Thymus and activation-regulated chemokine (TARC) in patients with psoriasis: Increased serum TARC levels in patients with generalized pustular psoriasis. J Dermatol. 2020 Oct;47(10):1149-1156. doi: 10.1111/1346-8138.15511. Epub 2020 Jul 16. PMID: 32677127.
Arakawa Y, Tamagawa-Mineoka R, Masuda K, Katoh N. Serum thymus and activation-regulated chemokine levels before and after treatment for pruritic scabies. J Eur Acad Dermatol Venereol. 2020 Dec;34(12):e817-e818. doi: 10.1111/jdv.16698. Epub 2020 Jun 30. PMID: 32484992.
Kanatani Y, Miyagawa F, Ogawa K, Arima A, Asada H. Parallel changes in serum thymus and activation-regulated chemokine levels in response to flare-ups in drug-induced hypersensitivity syndrome. J Dermatol. 2020 Nov;47(11):e417-e419. doi: 10.1111/1346-8138.15548. Epub 2020 Aug 12. PMID: 32789941.
Kano Y, Tohyama M, Aihara M, Matsukura S, Watanabe H, Sueki H, Iijima M, Morita E, Niihara H, Asada H, Kabashima K, Azukizawa H, Hashizume H, Nagao K, Takahashi H, Abe R, Sotozono C, Kurosawa M, Aoyama Y, Chu CY, Chung WH, Shiohara T. Sequelae in 145 patients with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms: survey conducted by the Asian Research Committee on Severe Cutaneous Adverse Reactions (ASCAR). J Dermatol. 2015 Mar;42(3):276-82. doi: 10.1111/1346-8138.12770. Epub 2015 Jan 27. PMID: 25623158.
Perez P, Sze W, Lozeau D, Avichal D, Miller J. Development of Fulminant Type 1 Diabetes Mellitus in a Patient with DRESS Syndrome. Case Rep Endocrinol. 2020 Aug 30;2020:9018147. doi: 10.1155/2020/9018147. PMID: 32908723; PMCID: PMC7477587.
Alshehri FSM, Whyte CS, Mutch NJ. Factor XIII-A: An Indispensable "Factor" in Haemostasis and Wound Healing. Int J Mol Sci. 2021 Mar 17;22(6):3055. doi: 10.3390/ijms22063055. PMID: 33802692; PMCID: PMC8002558
Mangla A, Hamad H, Kumar A. Factor XIII Deficiency. 2021 Apr 6. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan–. PMID: 32491399.
Yan MTS, Rydz N, Goodyear D, Sholzberg M. Acquired factor XIII deficiency: A review. Transfus Apher Sci. 2018 Dec;57(6):724-730. doi: 10.1016/j.transci.2018.10.013. Epub 2018 Oct 30. PMID: 30446212.
Muszbek L, Bereczky Z, Bagoly Z, Komáromi I, Katona É. Factor XIII: a coagulation factor with multiple plasmatic and cellular functions. Physiol Rev. 2011 Jul;91(3):931-72.
Caudill JS, Nichols WL, Plumhoff EA, Schulte SL, Winters JL, Gastineau DA, Rodriguez V. Comparison of coagulation factor XIII content and concentration in cryoprecipitate and fresh-frozen plasma. Transfusion. 2009 Apr;49(4):765-70.
Carcao M, Altisent C, Castaman G, Fukutake K, Kerlin BA, Kessler C, Lassila R, Nugent D, Oldenburg J, Garly ML, Rosholm A, Inbal A. Recombinant FXIII (rFXIII-A2) Prophylaxis Prevents Bleeding and Allows for Surgery in Patients with Congenital FXIII A-Subunit Deficiency. Thromb Haemost. 2018 Mar;118(3):451-460
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