Abstract
Introduction: Acquired Factor XIII deficiency due to an antibody inhibitor (AIFXIII) is a rare but life-threatening bleeding disorder. Factor XIII is a fibrin stabilizing enzyme that crosslinks fibrin monomers. Deficiency of Factor XIII results in destabilization of formed clots within 24-48 hours, resulting in delayed hemorrhage. Because the standard coagulation tests are normal, the diagnosis of this disease requires a high degree of suspicion and specialized testing. We report a case of an 88-year-old female presenting with severe hemorrhage of unknown origin.
Goal: We aim to heighten the awareness amongst clinicians of the possibility of acquired FXIII deficiency when a patient presents with bleeding symptoms and normal routine coagulation tests.
Case: An 88-year-old female with a recent diagnosis of autoimmune hemolytic anemia (AIHA) on oral Prednisone developed left arm swelling, pain, and ecchymosis. She denied anticoagulation and history of abnormal bleeding. CT scan of the arm showed a biceps muscle hematoma measuring 17cm in length. On day 4, she developed hematoma on the contralateral forearm, which prompted bilateral fasciotomies and evacuation. Patient continued to have bleeding from her right forearm hematoma, requiring further exploration and evacuation of multiple clots.
Laboratory Tests: Her Hg dropped from 9.2 g/dl to 6.6 g/dl requiring RBC transfusions. Peripheral blood smear revealed features of chronic hemolysis. She had a normal coagulation profile including PT (11.1 sec), INR (1.05), PTT (24.4 sec), fibrinogen (295mg/dL) and normal platelet function assay. Her D-dimer was elevated at 371 ng/ml. She had a normal CRP (3.3mg/L), ANA antibody (<1:40) and ESR (23 mm/hr). SPEP showed hypoproteinemia without monoclonal bands. The patient's FVIII (307%), VWF ag (307%), VWF activity (369%), VWF collagen binding assay (412%) and alpha-2-antiplasmin (101%) were normal. Patient's Factor XIII levels were measured at 8%. We suspected this to be a case of AIFXIII. Testing for inhibitor with serial dilutions showed an antibody titer of 1:40.
Results: She was started on 100 mg/d of Cyclophosphamide and continued on 20mg of Prednisone. No further hematomas developed. Patient was discharged on day 29 with a close follow up. On day 66, patient had AIHA flare (Hg: 6.6g/dL) and was treated with PRBCs, Rituximab 375mg/m^2 for 4 infusions and prednisone 40mg daily. Her Factor XIII activity on day 68 was 12% and inhibitor titer 1:10. On day 98, patient developed large ecchymoses on the right knee, thigh and buttock. Her Factor XIII activity dropped to < 10% again and inhibitor titer went up to 1:20 on serial dilution. She was transfused with PRBCs and was started on IVIG at 1000 mg/kg X 5. Cyclophosphamide was stopped and Prednisone was decreased to 10mg daily. Her Factor XIII is still <10% but inhibitor titer is down to 1:10. Patient is not actively bleeding.
Discussion: There are less than 60 reported cases of AIFXIII in the literature. This is the first reported case presenting with warm antibody hemolytic anemia. Various treatments have been employed in the past for AIFXIII. It involves two strategies: hemostasis to treat acute bleeding symptoms and inhibitor eradication. Use of steroids and immunosuppressants such as Cyclophosphamide, Rituximab, and Cyclosporine has been prevalent in most of the cases to obtain inhibitor eradication. It is hard to define what combination of therapy works because most of the cases involve use of combination of these strategies and spontaneous remissions have also been seen. In this case, we suspect that patient presented with higher than expected factor XIII activity (8%) at the onset because she was already on immunosuppression for her AIHA for 2 months prior. She was refractory to first-line therapy with Rituximab and Cyclophosphamide in combination with steroids for complete inhibitor eradication. Second line therapy with IVIG was recently given and we are hopeful of a response.
Conclusion: AIFXIII is a rare but life-threatening bleeding disorder that should be suspected especially when elderly patients present with hemorrhage of unknown origin and normal screening coagulation studies. Characterization of the factor XIII activity and detection of antibodies should be undertaken promptly in order to provide the best anti-hemorrhagic and inhibitor eradication treatment.
Disclosures
No relevant conflicts of interest to declare.
An account of congenital rare bleeding disorders: a systematic study from a tertiary care centre in Eastern India
