Virginia Research Day 2021

ACQUIRED HEMOPHILIA A WITH A POSSIBLE GENETIC COMPONENT Linsey Atchison, DO; Akintunde Akinleye, MD Sovah Health Internal Medicine Residency Program, Danville, VA

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Clinical Course : Patient was admitted for acute blood loss anemia and workup. When Factor VIII Activity was found to be < 1, she was treated with high dose prednisone, fresh frozen plasma ( FFP), Vitamin K, recombinant factor VIIA, and was transferred to University of Virginia (UVA) for Factor Eight Inhibitor Bypass Activity Therapy (FEIBA). Genetic testing found a 50% ASXL1 c.1898A>G (p.H633R) missense mutation at the genomic position chr20: g.31022413A>G. The high factor VIII inhibitor titer level and continued bleeding necessitated prednisone, cyclophosphamide, antihemophilic factor, anti-inhibitor coagulant complex (FEIBA), rituximab, 7 units of RBCs, and 3 units of FFP Discussion: Acquired Hemophilia A (AHA), a very rare form of hemophilia, is estimated to affect approximately 1- 4/1,000,000 people yearly. Most cases are thought to be idiopathic, but several conditions and medications have can be catalysts for acquiring it. Among acquired factor inhibitors, Factor VIII is the most common. They usually present with severe bleeding in cutaneous, deep tissue, and multifocal sites. This case presents a possible, previously unidentified contributing factor: ASXL1 gene mutations.

Background: Acquired Hemophilia A (AHA) is a rare spontaneous bleeding disorder caused by the production of autoantibodies to clotting factor VIII. It can cause life-threatening bleeding with soft tissue bleeding being the most common. While this rare condition has been associated with pregnancy, autoimmune diseases and various medications, most are classified ‘idiopathic’. Chief Complaint & History : 59-year-old Caucasian female presented with acute, progressively worsening, non-traumatic right upper arm and bilateral leg bruising. She was found to have diffuse hematoma formation and a rapidly dropping hemoglobin. Past Medical History: Hypertension, COPD, gout, reflux esophagitis, chronic kidney disease, coronary artery disease, pulmonary embolism previously on apixaban, tobacco/polysubstance abuse. Previous Admission (6 weeks prior): Possible pulmonary embolism and started on apixaban. Previous Admission (1 week prior): Hypopharyngeal hematoma, warranting discontinuation of anticoagulation therapy. Medications : Allopurinol, amlodipine, ferrous sulfate, metoprolol tartrate, omeprazole, prednisone, acetominophen (Apixaban stop 1 week prior) Allergies: No known drug allergies Review of Systems : Sore throat, bilateral leg and foot pain with swelling in feet, sore leg muscles, right upper arm and left posterior leg bruising, and diffuse, firm, painful nodules on bilateral legs. Social History: Lives at home with family, no difficulties with activities of daily living. Smokes 2-3 cigarettes per day for 40 years, drinks 1-2 beers per week, and uses cocaine 1-2 times per month. Family History : Hypertension, no history of cancer or blood disorders

Vital Signs: T: 98.8 F; P: 104; BP: 126/71; RR 18; Oxygen sat 99% on room air Pertinent Physical Findings : Mild peripheral edema. Large, firm, tender nodules on right proximal inner thigh and left proximal posterior-lateral thigh/buttock. Large tender hematoma on right upper, medial arm.

Pertinent Diagnostic Studies: Hgb: 8.5 (10-11), aPTT: >200 Figure 1: Right Upper Extremity CT Scan: Red arrows –Hematoma Blue arrows – Ecchymosis

Figure 2: Right Lower Extremity CT Scan: Stranding in superior medial popliteal fossa (ecchymosis)

1:1 Mix aPTT: 51, 1:1 Mix aPTT, incubated: 85, Lupus anticoagulant aPTT: 109.3, Lupus AC 1:1 Mix aPTT: 98.2 Factor VIII Activity: <1, Porcine Factor VIII Inhibitor: 12.0 Factor VIII Inhibitor Titer: 448 → 461 → 653 *High ASXL1 c.1898A>G missense variant Right arm and Lower legs Duplex Ultrasound were normal; while CT scans of the same had subcutaneous fat stranding along posterior arm with medial blood collection superficial to right deltoid (Figure 1) & subcutaneous fat stranding in the medial aspect and within the superior medial popliteal fossa (Figure 2).

Conclusion: This case of Acquired Hemophilia A brings to light a possible new discovery of a previously unknown ASXL1 gene mutation. While ASXL1 mutations are most often identified in myelodysplastic syndromes and myeloid malignancies, this case could spark new research into ASXL1 mutations as a possible genetic factor associated with the development of AHA.

References: (1) www.UpToDate.com - Approach to the adult with a suspected bleeding disorder (2) https://www.stepwards.com/?page_id=866 (coagulation cascade diagram)

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