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 Table of Contents  
CASE REPORT
Year : 2023  |  Volume : 3  |  Issue : 1  |  Page : 51-53

Late presentation of factor XIII deficiency with recurrent muscle hematomas


Department of Pediatrics, MGM Medical College and LSK Hospital, Kishanganj, Bihar, India

Date of Submission09-Jul-2022
Date of Decision19-Jan-2023
Date of Acceptance30-Jan-2023
Date of Web Publication27-Feb-2023

Correspondence Address:
Dr. Sudesh Kumar
Room No. 3, I Block, MGM Medical College and LSK Hospital, Kishanganj - 855 107, Bihar
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ipcares.ipcares_169_22

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  Abstract 

Background: Plasma factor XIII is a proenzyme that gets activated in the final step of the coagulation cascade. Its physiological role is to stabilize clot formation by catalyzing the cross-linkage of fibrin. Factor XIII deficiency is a rare autosomal recessive disorder. Clinical Description: A 10-year-old boy presented with acute-onset swelling of the arm following a minor fall. There were no constitutional symptoms. There was a significant history of similar swellings 2 years earlier that had required surgery. The past and family history were otherwise noncontributory. The child was hemodynamically stable. Local signs suggested a hematoma or tumor. There was no pallor, icterus, petechiae, or ecchymosis. The remaining examination was normal. Provisional diagnoses included nonaccidental trauma or an underlying primary or secondary bleeding diatheses, tumor, or chronic osteomyelitis. Management: Soft-tissue ultrasonography showed a hematoma. The radiograph was normal. Hemograms, first-line tests for coagulopathy, infective biomarkers, and liver and kidney function tests were normal. There were no stigmata of neglect or physical/emotional abuse in the child. Since the clinical phenotype was of a bleeding disorder, but supportive investigations were inconclusive, we suspected factor XII deficiency. Specific levels showed zero activity. Fresh frozen plasma was administered due to the nonavailability of factor XIII. The hematoma was managed surgically. The child was discharged after genetic counseling and is receiving monthly cryoprecipitate. He is asymptomatic till now. Conclusion: Factor XIII deficiency should be suspected when there are clinical indicators of a bleeding diathesis, but supportive tests are not deranged.

Keywords: Bleeding diathesis, coagulopathy, cryoprecipitate, factor assay, fresh frozen plasma


How to cite this article:
Kumar S, Bhattacharya P, Kumari A. Late presentation of factor XIII deficiency with recurrent muscle hematomas. Indian Pediatr Case Rep 2023;3:51-3

How to cite this URL:
Kumar S, Bhattacharya P, Kumari A. Late presentation of factor XIII deficiency with recurrent muscle hematomas. Indian Pediatr Case Rep [serial online] 2023 [cited 2023 Mar 22];3:51-3. Available from: http://www.ipcares.org/text.asp?2023/3/1/51/370523

Factor XIII deficiency is a rare genetic, autosomal recessive disorder affecting one in 2–5 million live births.[1] Therefore, affected individuals often have a history of consanguinity. That is the reason why, although rare, it has been observed relatively more frequently in countries such as Iran, Pakistan, and India.[2] Plasma factor XIII is a proenzyme (composed of 2α and 2β subunits) that gets activated to XIII a by calcium and thrombin in the final step of the coagulation cascade. The physiological role of factor XIII is to stabilize the clot during the process of hemostasis by catalyzing the cross-linkage of fibrin. Thus, factor XIII plays an important role in wound healing and tissue repair.[3]

Factor XIII deficiency is clinically relevant because of the repertoire of its severity and bleeding manifestations. The incidence of intracranial hemorrhage is 20%–30%, significantly higher than that observed in any other bleeding disorder.[4] The myriad presentation of this deficiency includes lifelong bleeding diathesis such as delayed umbilical cord bleeding (56%), subcutaneous bleeding (57%), muscle hematomas (49%), prolonged postoperative bleeding (40%), intracranial hemorrhage (34%), and a high risk of miscarriage. The delayed bleeding (i.e., 12–36 h after trauma or surgery) is characteristic of factor XIII deficiency.[5],[6]

The key differentiating point of factor XIII deficiency from other congenital hemostatic factor deficiencies is that the typical coagulation screening tests and platelet function tests are normal in this disorder. We present a patient with recurrent bleeding and a normal coagulation profile in whom we suspected this deficiency and established the diagnosis based on a factor XIII assay.


  Clinical Description Top


A 10-year-old Muslim boy and resident of Bihar, presented in the pediatric outdoor department with complaints of gradually progressive swelling of his right arm for the last 2 months. The swelling was confined to the lateral aspect of the right arm and had appeared 24 h after a trivial fall. There was no history of the acute appearance of sudden paleness or a feeling of malaise. There was no history of fever, the appearance of rashes, jaundice, bleeding from any site, joint pains, or any other constitutional symptoms. There was a significant history of a similar type of swelling in the right and left thigh 2 years earlier, also after minor trauma, but which had been severe enough to require surgery at a higher center (articles were not available). The parents could not recall any history of prolonged bleeding in the neonatal period or after any minor injuries experienced in childhood. The child was second in the birth order of a consanguineous union. Family history was not contributory. There was no history of any siblings experiencing similar injuries in the past. They belonged to the low socioeconomic strata. The child had been developmentally normal and was presently studying in class 5 and was average in his studies. Immunization was complete for age.

On examination, the child was afebrile and hemodynamically stable, with a respiratory rate of 23/min, blood pressure of 100/70 mm Hg, and heart rate of 96/min. The body mass index was 16.2 kg/m2 General physical examination revealed a swelling that was approximately 12 cm × 10 cm in dimension, oval in shape, immobile, smooth surfaced, tense in consistency, nontender, with no signs of inflammation or discoloration of the overlying skin, and negative on transillumination test. These clinical signs were most likely indicative of a hematoma, though a tumor could not be excluded with conviction. There was no pallor, jaundice, petechiae, ecchymosis, other rashes, generalized lymphadenopathy, or evidence of injury elsewhere. The mucosa of the oral cavity was normal. Examination of the respiratory, cardiovascular, abdominal, and hematopoietic systems was normal.

On the basis of these clinical features, the main differential diagnoses kept were a hematoma secondary to nonaccidental trauma (possible physical abuse) or a hitherto unrecognized bleeding diathesis; a soft-tissue tumor; and less likely an infectious disease (that may have manifested with a mild fever that was overlooked by the parents) such as anicteric infectious or autoimmune hepatitis, dengue fever, or chronic recurrent multifocal osteomyelitis (CRMO).

Management and outcome

The soft-tissue ultrasound of the right arm showed a large hyperechoic lesion of size 12 cm × 10 cm with a solid internal portion. The X-ray of the arm showed no calcification and/or fracture of the bone. This indicated the presence of blood collection. Therefore, magnetic resonance imaging short tau inversion recovery images to look for CRMO were not required. The complete blood counts (hemoglobin 11.8 gm/dl, total leukocyte count 9400/mm3, differential leukocyte count P48%, L46%, E3%, M3%, and platelet count 2.2 lakh/mm3) and peripheral smear for abnormal cells and liver and kidney function tests were normal. In the bleeding panel, the bleeding time was 1 min 20 s, clotting time 4 min 30 s, prothrombin time (PT) 11.8 s, activated partial thromboplastin time (APTT) 28.8 s, and d-Dimer <500 ng/ml; all within normal limits. C-reactive protein levels (<6 mg/L) were normal. Hence, CRMO was ruled out on the basis of clinical features, the absence of increased inflammatory markers, and radiology findings. Thus, the differential diagnosis was narrowed down to nonaccidental trauma or bleeding diathesis. Since the other children were healthy, and there were no stigmata of neglect or physical/emotional abuse in the child, we proceeded with second-line investigations for a bleeding disorder.

Hypofibrinogenemia was ruled out by measuring fibrinogen level by clotting activity assay (electromechanical clot detection). This was 304 mg/dl, within the normal range of 200–400 mg/dl. Since all the other parameters were normal, we ordered the functional and qualitative test for factor XIII (clot dissolution with 5 M Urea). This showed absent factor XIII activity (0%) and confirmed factor XIII deficiency. Negative results of tests for rheumatoid factor, antinuclear antibody, and double-stranded DNA ruled out secondary causes of factor XIII deficiency. The final diagnosis kept was severe congenital factor XIII deficiency. Genetic studies could not be performed due to financial constraints. Other members of the family underwent a similar investigatory profile and were found to be unaffected.

Factor XIII concentrate could not be procured. Hence, we managed the child by initial transfusion of fresh frozen plasma (FFP). Surgical drainage was performed by the surgical department within a week of this. The posttransfusion and postoperative periods were uneventful. After parental counseling, the child was discharged with the plan to administer cryoprecipitate (1 unit/10 kg per transfusion) every month. At the 3-month follow-up visit, the child was doing well, exhibited a healthy local site, and had no recurrence of bleed.


  Discussion Top


Coagulation factors and platelets are essential requirements for the maintenance of optimal hemostasis in the body. Factor XIII, also known as the fibrin stabilizing factor, is involved in the last step of the coagulation cascade. It stabilizes the clot by cross-linking the fibrin mesh.[7] Factor XIII deficiency is a rare bleeding disease which may either be congenital or acquired. Congenital cases are present at the time of birth and inheritance is autosomal recessive. Acquired causes of factor XIII deficiency are chronic liver disease, chronic kidney disease, inflammatory bowel disease, and autoimmune conditions such as systemic lupus erythematosus, rheumatoid arthritis, and myeloid leukemia. These were all excluded in this case by history, examination, and/or investigations.

Factor XIII deficiency can present in many ways. Almost 80% of patients present with umbilical cord bleeding.[8] Other presentations are recurrent mucosal bleeding, ecchymosis, hemarthrosis, muscle hematoma, and intracranial bleeding.[9] The diagnosis of factor XIII is often overlooked initially, leading to the sudden late onset of fatal life-threatening complications being the initial presentation. Our case presented with a late presentation of recurrent muscle hematoma following trivial trauma. We were unable to elicit any significant history of prolonged umbilical bleeding, ecchymosis, hematomas, or any mucosal bleeding in early childhood from the parents who appeared to be reliable.

The diagnosis of factor XIII is confirmed by documenting decreased plasma levels of the factor with normal PT and APTT values. Genetic mutation studies are confirmatory for diagnosis, but are expensive, and not easily available at many places. Genetic counseling of affected families after confirmatory diagnosis may be offered with the possibility of prenatal diagnosis. Specific management is replacement therapy with factor XIII concentrate. In case of unavailability (as in this case), which is often the situation in low- and middle-income countries, FFP or cryoprecipitates can be used. These blood products are not used in many high-income countries due to the increased risk of viral infection and hypersensitivity reactions. Lifelong intervention to prevent or minimize recurrent bleeding comprises factor XIII replacement at intervals of 3–4 weeks. Due to nonavailability, we had to manage with monthly transfusions of cryoprecipitate. In female patients who have attained menarche, supportive therapy with oral contraceptive pills and antifibrinolytic drugs may be prescribed in cases of excessive menstrual blood loss.



Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Odame JE, Chan AK, Wu JK, et al. Factor XIII deficiency management: A review of the literature. Blood Coagul Fibrinolysis 2014;25:199-205.  Back to cited text no. 1
    
2.
Dorgalaleh A, Alavi SE, Tabibian S, et al. Diagnosis, clinical manifestations and management of rare bleeding disorders in Iran. Hematology 2017;22:224-30.  Back to cited text no. 2
    
3.
Hsieh L, Nugent D. Factor XIII deficiency. Haemophilia 2008;14:1190-200.  Back to cited text no. 3
    
4.
Peyvandi F, Palla R, Menegatti M, et al. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: Results from the European network of rare bleeding disorders. J Thromb Haemost 2012;10:615-21.  Back to cited text no. 4
    
5.
Schroeder V, Kohler HP. Factor XIII deficiency: An update. Semin Thromb Hemost 2013;39:632-41.  Back to cited text no. 5
    
6.
Fadoo Z, Merchant Q, Rehman KA. New developments in the management of congenital Factor XIII deficiency. J Blood Med 2013;4:65-73.  Back to cited text no. 6
    
7.
Chaudhry R, Usama SM, Babiker HM. Physiology, coagulation pathways. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482253/. [Last updated on 2022 Aug 29].  Back to cited text no. 7
    
8.
Vahid Golpayegani M, Behnia H, Akhgar Araghi M, et al. Factor XIII deficiency, review of the literature and report of a case. J Compr Ped 2016;7:e30303.  Back to cited text no. 8
    
9.
Pelcovits A, Schiffman F, Niroula R. Factor XIII deficiency: A review of clinical presentation and management. Hematol Oncol Clin North Am 2021;35:1171-80.  Back to cited text no. 9
    




 

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