Successful treatment of thrombotic thrombocytopenia with cerebral sinus venous thrombosis following Ad26.COV2.S vaccination
Authors: Gemlyn George, Kenneth D. Friedman, Brian R. Curtis, Stuart E. Lind
Journal: American Journal of Hematology (2021)

A 40-year-old previously healthy Caucasian woman presented to her local urgent care with left-sided headache (worse with movement and associated with bouts of dizziness), left-sided neck pain and a sore throat that began 7 days after vaccination with the Ad26.COV2.S vaccine. Examination revealed enlarged tonsils (right greater than left) with a tonsillar exudate. She was prescribed amoxicillin-clavulanateand muscle relaxants. No blood work was done. Her headache persisted over the next 4 days. She presented to the University of Colorado Hospital 13 days following vaccination for evaluation after seeing reports of adverse events in patients receiving the same vaccine. Her symptoms at presentation included the headache and a sore throat. She had no history of antecedent illness before receiving Ad26.COV2.S vaccine, no history of thromboembolic disease (arterial or venous), autoimmune disease, and absence of use of estrogen-containing medication or smoking. She had no history of heparin exposure and had not been hospitalized since her childhood. Her BMI was 31 (height: 162 cm, weight: 81 kg), she had petechiae over the lateral aspect of both breasts. The physical exam otherwise was unremarkable. A CT venogram of the head and neck demonstrated the presence of an occlusive cerebral sinus venous thrombosis (CSVT) involving the left transverse sigmoid sinus and visualized internal jugular vein. There was no brain infarction. A CT angiogram of the chest demonstrated subsegmental filling defects in the right lung, involving the posterior basal segment and the superior segment of the right lower lobe. Ultrasound did not reveal venous thrombosis in the portal system or the lower extremities. On admission, she was thrombocytopenic with a platelet count of 20 000/mm3 (reference range: 150 000–400 000/mm3) with a normal hemoglobin, white blood and neutrophil count. The peripheral smear did not reveal schistocytes. The erythrocyte sedimentation rate was 26 mm/hr. She had an elevated D-dimer antigen level of 27 150 ng/ml fibrinogen equivalent units and a fibrinogen of 149 mg/dl (reference range: 150–400 mg/dl). She had normal baseline coagulation parameters (aPTT was 26.4 with a reference range of 23.8–36.2 s), haptoglobin and LDH. The transaminases were slightly elevated (AST 65 U/L, reference range 12–39 U/L and ALT 87 U/L, reference range 7–52 U/L with normal bilirubin, alkaline phosphatase and albumin. She was started on a direct thrombin inhibitor (bivalirudin) with an aPTT goal of 60–100, daily prednisone (1 mg/kg) and intravenous immune globulin (IVIG) dosed at 1 g/kg/day for 2 days. In our institution, ideal body weight is used for IVIG dosing, she received 60 g of IVIG for two consecutive days. The patient remained clinically stable with no additional signs or symptoms. By hospital day 6, the platelets had risen to 115 000/mm3, she was transitioned to and discharged on rivaroxaban. No platelet transfusions were administered. Upon follow up, 1 week later, her platelet count was 208 000/mm3 and she had no evidence of DIC. There were no neurological sequelae. An initial test for antibodies reacting with platelet factor 4 (PF4)-anion complexes, performed using a latex immunoturbidimetric assay (HemosIL HIT-Ab (PF4-H), was negative. Blood was sent to a reference lab (Versiti Blood Center of Wisconsin) and an ELISA assay for antibodies reacting with PF4-anion complexes was found to be strongly positive (OD = 2.14) with complete inhibition of reactivity following addition of a high concentration (100 IU/ml) of unfractionated heparin (UFH). A serotonin release assay (SRA) was positive with a low concentration of UFH (0.1 IU/ml), and negative in the presence of a high concentration of UFH (100 U/ml). The SRA was also positive in the absence of added heparin, similar to what has been reported in patients with auto-immune HIT (Table 1).1 In addition, the PF4 enhanced P-Selectin expression assay (PEA)2 was also strongly positive in the presence of UFH. The PEA reactivity was completely suppressed in the presence of a high concentration (100 IU/ml) of UFH. In summary, we report a case of cerebral sinus venous thrombosis (CSVT) with thrombocytopenia following vaccination with an adenovirus-based vaccine. Unlike the patients reported by Greinacher et al.3 and Schultz et al.4 our patient was vaccinated with Ad26.COV2.S, from Janssen, not the ChAdOx1 nCOV-19 AstraZeneca vaccine. Our patient is similar to the patient reported by Muir et al.5 insofar as the patient tested negative for heparin dependent antibodies with a commercial latex agglutination assay, but positive when an ELISA methodology assay was used. This point is of practical importance for providers seeing patients who may have this syndrome. The test methodology used to detect antibodies to PF4 anion complexes may not be routinely disclosed in the reports released to clinicians. Providers caring for patients suspected of having this syndrome should ensure that negative tests performed with assays other than an ELISA are followed up with ELISA assays performed by a reference laboratory. Our report differs from that of Muir et al.5 because we confirmed the presence of an autoantibody that activates platelets in the absence of heparin, as ascertained with two different assays, the SRA and the PEA. We also showed that this activity was suppressed in the presence of high dose heparin, a hallmark of HIT related antibodies. These functional tests were also positive in patients who received the ChAdOx1 nCoV-19 vaccine.3, 4 This report shows that functional platelet activation assays may be an acceptable alternative to ELISA testing, if more readily obtained. Dr Ken Friedman has consulted for Instrumentation Laboratory. The other authors declare no conflict of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.