Sex: M
Vaccine: COVID19
Symptoms: Factor VIII activity test, Full blood count, Haemodynamic test, Haemoglobin, Investigation
Clinical narrative: AHA; DVT; This is a literature report.     A 63-year-old male with medical history of hypertension, former tobacco use and hyperlipidemia presented one week after receiving the first dose of the Pfizer-BioNTech SARS-CoV-2 mRNA vaccine with a 3-day history of left lower extremity (LLE) swelling and pain. On presentation, he was hemodynamically stable. Physical examination was significant for tenderness at the calf of the LLE on palpation and passive range of motion. He also had 2+ pitting edema up to the left knee, and ecchymosis to the distal mid left thigh and posterior calf. Complete blood count revealed hemoglobin concentration of 11.9 g/dL, platelet count of 242x109/L, while activated partial thromboplastin time (APTT) was elevated to 68.0 seconds. Venous Doppler ultrasound showed acute DVT in the left popliteal vein, while CT of the LLE showed evidence of acute intermuscular fascial edema which was thought to be due to extravasation from interruption in flow by clot. He did not have personal or family history of hypercoagulability, no recent surgery, prolonged travel, immobilization or history of malignancy. Work up for malignancy with CT of the chest, abdomen and pelvis was negative. Given no prior personal or family history or risk factors for provoked DVT, patient's DVT was deemed unprovoked. The patient was admitted and started on heparin drip based on an assessment of unprovoked DVT and clinical suspicion of spontaneous gastrocnemius hematoma, with plan to monitor for compartmental syndrome (versus phlegm asia). By day 3, the patient had a supratherapeutic APTT of >400 seconds, as well as punctate ecchymoses from blood draw sites and progression of ecchymoses of posterior calf and posterior thigh of the LLE. The patient developed hypotension, necessitating intravenous fluid boluses. By day 4, he had developed multiple hematomas in the left upper and lower extremities, and acute posthemorrhagic anemia with hemoglobin concentration of 7.3 g/dL, necessitating transfusion of 1 unit of packed red blood cells (PRBC) that resulted in post-transfusion hemoglobin concentration of 8.8 g/dL. With further drop in hemoglobin, the decision was made to stop the heparin drip on day 4, as the initial lower extremity swelling was thought to be from a hematoma and the clot was likely due to stasis. A CT scan of the abdomen and pelvis did not show any hematoma. In addition, a repeat venous Doppler ultrasound of the bilateral lower extremities on day 5 was negative for DVT. An inferior vena cava (IVC) filter was subsequently placed on day 5. Despite discontinuing heparin, the patient continued to have markedly elevated APTT as shown: 68.0 seconds on Day 1; 119 seconds on  Day 2; >400 seconds on  Day 3; 133 seconds on  Day 4; 85.4 seconds on  Day 5; 85.5 seconds on  Day 6; 98.8 seconds on  Day 7; 96 seconds on  Day 8; 91.8 seconds on  Day 9; 75.7 seconds on  Day10; 78 seconds on  Day11; 72.5 seconds on  Day12. The patient had increasing swelling and ecchymoses of the left arm and developed a spontaneous hematoma of the right forearm. By days 5 through 7,he had developed hematomas in all four extremities and his hemoglobin concentration dropped to 6.5 g/dL, necessitating another PRBC transfusion. With multiple sites of hematoma and persistent blood loss and elevated APTT with recent vaccination, consideration was for bleeding disorders, disseminated intravascular coagulopathy (DIC) and autoimmune etiology and the possibility of vaccine induced coagulation disorder. Retrospective history for personal of family history of bleeding and autoimmune disorders was negative. Workup for DIC was negative. Von Willebrand Factor (vWF), antiphospholipid antibodies, lupus anticoagulant, TSH, anti-ds DNA, and hepatitis serology testing were negative. Results of the patient's mixing study, with partial correction of APTT: APTT initial patient: 103.2 seconds (reference range: 24.4-33.4 seconds); APTT pool plasma: 31.5 seconds; Immediate APTT 1:1 mixing: 43.0 seconds (reference range: less than 33.5);Incubated APTT 1:1 mixing: 56.5 seconds (reference range: 37.3 seconds).  Authors further obtained factor VIII assay, which was consistent with acquired factor VIII inhibitor (acquired hemophilia A): Factor VIII activity: less than 1; Factor VIII inhibitor EIA: positive; Factor VIII activity clotting: less than 1; Nijimegen assay: 69.6. Treatment with Factor Eight Inhibitor Bypassing Activity (FEIBA) at 100 units/kg every 12 hours was started immediately, and subsequently tapered and discontinued in three days upon resolution of active bleeding. To eliminate factor VIII inhibitor, immunosuppressive therapy was initiated with IV methylprednisolone 80 mg daily and cyclophosphamide 2 mg/kg daily. His hemoglobin concentration subsequently remained stable around 8.4-8.9 g/dL. On day 12, the patient felt much improvement in pain and swelling of extremities, and he was discharged home on oral prednisone and cyclophosphamide slow taper, with scheduled outpatient hematology follow-up in 1 week. The timeline from vaccine administration and development of symptoms to diagnosis and recovery was as followed: Vaccination Day 0: received first dose of Pfizer-BioNTech SARSCoV- 2 vaccine. Vaccination Day 4-7: developed progressively worsening LLE swelling, pain, and ecchymosis. Hospital Day 0-2: presented to hospital. DVT diagnosed, heparin drip started. Hospital Day 3-4: APTT >400 seconds, multiple hematomas, symptomatic anemia with Hgb of 7.3 g/dL, PRBC transfusion, heparin Stopped. Hospital Day 5-7: persistently elevated APTT, hematomas in all four extremities, IVC filter placed, additional PRBC transfusion for Hgb of 6.5 /dL. Hospital Day 6-11: additional work up with diagnosis of AHA, FEIBA and immunosuppressive therapy administered, no more bleeding, Hgb stable. Hospital Day 12-Office follow up at 1 week post-discharge: discharged home on oral prednisone and cyclophosphamide slow taper, Hgb of 12.5 g/dL at office follow-up. Repeat labs done in the outpatient office showed improved hemoglobin concentration to 12.5 g/dL, when his prednisone was tapered off, whereas cyclophosphamide was continued for a few more weeks. All procedures performed in this case report were in accordance with the ethical standards of the institutional and/or national research committees and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.    No follow-up attempts are needed. No further information is expected.; Sender's Comments: Based on the information available, a possible contributory role of the suspect product cannot be excluded for the reported events The impact of this report on the benefit/risk profile of the Pfizer product is evaluated as part of Pfizer procedures for safety evaluation, including the review and analysis of aggregate data for adverse events. Any safety concern identified as part of this review, as well as any appropriate action in response, will be promptly notified to regulatory authorities, Ethics Committees, and Investigators, as appropriate