Sex: F
Vaccine: COVID19
Symptoms: Investigation, Light chain analysis, Lymphocyte count, Mean cell volume, Neurological examination
Clinical narrative: Thrombotic Thrombocytopenic Purpura Following Pfizer-BioNTech COVID-19 Vaccination; This is a literature report for the following literature source(s).  A 61-year-old female patient presented to the emergency department (ED) with complaints of malaise, lethargy, dyspnea on exertion, and jaundice, 22 days after receiving the third dose of the Pfizer-BioNTech COVID-19 mRNA vaccine. She started experiencing epigastric pain, nausea, and vomiting one week prior to presentation at the ED, 15 days after vaccination with the third dose of the vaccine. She also reported an episode of blood-streaked stools. She had no complaints of fever, gingival bleeding, epistaxis, altered mentation, dizziness, abdominal pain, diarrhea, or dysuria. She had received doses of the same vaccine prior and had no contraindications to the third dose. Her past medical history was significant for immunoglobin G (IgG) kappa light chain multiple myeloma (MM), heart failure with preserved ejection fraction (HFpEF), and neuropathy. With prior autologous stem cell transplant and carfilzomib therapy, multiple myeloma was in remission with pomalidomide, denosumab, and suppressive acyclovir. She was on torsemide and low-dose aspirin for her cardiovascular condition. There was no past medical or family history of any thrombotic events or autoimmune diseases. At presentation, she was alert, oriented, and cooperative. Her temperature was 36.8 Centigrade, pulse rate was 84 beats per minute, and blood pressure was 118/66 mm Hg. Her respiratory rate was 23 breaths per minute with oxygen saturation at 92% on ambient air and 98% on 2L/min of oxygen via nasal cannula. Her sclerae were icteric. Bipedal pitting edema was also noted. Systemic examination of the chest, abdomen, and nervous system were otherwise unremarkable. Electrocardiography showed normal sinus rhythm and cardiac troponins were not elevated. COVID-19 polymerase chain reaction (PCR) test showed a negative result. Her hematology and biochemistry profiles were significant for normocytic anemia, mild leukocytosis, severe thrombocytopenia, reduced haptoglobin and elevated bilirubin, transaminases, creatinine and lactate dehydrogenase (LDH). Her hematology and biochemistry profiles were as follows: ADAMTS13 activity assay (70-150): less than 5, notes: Day 3; ADAMTS13 activity assay (normal high range 12): 30 IU/ml, notes: Day 3; 7 IU/ml, notes: Day 5; 2 IU/ml, notes: Day 7; 2 IU/ml, notes: Day 10; ADAMTS13 activity assay (0-44): 78.57 %, notes: Day 3; 40.38 %, notes: Day 10; Alanine aminotransferase (normal high range 33): 34 IU/l, notes: Day 0; 84 IU/l, notes: Day 3; 24 IU/l, notes: Day 5; 10 IU/l, notes: Day 7; 18 IU/l, notes: Day 10; Aspartate aminotransferase (normal high range 31): 92 IU/l, notes: Day 0; 80 IU/l, notes: Day 3; 24 IU/l, notes: Day 5; 11 IU/l, notes: Day 7; 16 IU/l, notes: Day 10; Blood alkaline phosphatase (30-130): 74 IU/l, notes: Day 0; 96 IU/l, notes: Day 3; 15 IU/l, notes: Day 5; 13 IU/l, notes: Day 7; 18 IU/l, notes: Day 10; Blood bilirubin (normal high range 1.2): 6 g/l, notes: Day 0; 3.9 g/l, notes: Day 3; 1.5 g/l, notes: Day 5; 0.7 g/l, notes: Day 7; 0.6 g/l, notes: Day 10; Blood creatinine (0.70-1.20): 1.3 mg/dl, notes: Day 0; 1.2 mg/dl, notes: Day 3; 1.0 mg/dl, notes: Day 5; 0.8 mg/dl, notes: Day 7; 0.6 mg/dl, notes: Day 10; Blood lactate dehydrogenase (135-250): 239 IU/l, notes: Day 0; 200 IU/l, notes: Day 10; Blood urea (7-25): 42, notes: Day 0; 34, notes: Day 3; Fibrin D dimer (0.0-0.49): more than 4, notes: Day 3; Haemoglobin (12-15): 6.9 g/dl, notes: Day 0; 7.5 g/dl, notes: Day 3; 7.6 g/dl, notes: Day 5; 8.0 g/dl, notes: Day 7; 8.3 g/dl, notes: Day 10; Haptoglobin (36-195): less than 10, notes: Day 0; 43 g/l, notes: Day 10; International normalised ratio: 1.07, notes: Day 0; 1.14, notes: Day 3; 1.30, notes: Day 5; 1.23, notes: Day 7; 1.14, notes: Day 10; Lymphocyte count (1.1-4.8): 1.08, notes: Unit: per nL. Day 0; 3.41, notes: Unit: per nL. Day 3; 2.38, notes: Unit: per nL. Day 5; 2.03, notes: Unit: per nL. Day 7; 2.48, notes: Unit: per nL. Day 10; Mean cell volume (80-100): 90, notes: Unit: fL. Day 0; 95, notes: Unit: fL. Day 3; 90, notes: Unit: fL. Day 5; 96, notes: Unit: fL. Day 7; 98.5, notes: Unit: fL. Day 10; Neutrophil count (1.5-7.8): 16.56, notes: Unit: per nL. Day 0; 12.41, notes: Unit: per nL. Day 3; 9.10, notes: Unit: per nL. Day 5; 8.3, notes: Unit: per nL. Day 7; 7.5, notes: Unit: per nL. Day 10; Platelet count: 150000 /mm3; Platelet count (150-350): 8, notes: Unit: per nL. Day 0; 12, notes: Unit: per nL. Day 1; 29, notes: Unit: per nL. Day 2; 49, notes: Unit: per nL. Day 3; 96, notes: Unit: per nL. Day 4; 120, notes: Unit: per nL. Day 5; 163, notes: Unit: per nL. Day 6; 216, notes: Unit: per nL. Day 7; 278, notes: Unit: per nL. Day 8; 304, notes: Unit: per nL. Day 9; 329, notes: Unit: per nL. Day 10; 378, notes: Unit: per nL. 6 month after follow-up; Red blood cell nucleated morphology present (0.00-0.01): 2.23, notes: Unit: per nL. Day 0; 2.74, notes: Unit: per nL. Day 3; 1.28, notes: Unit: per nL. Day 5; 0.18, notes: Unit: per nL. Day 7; 0.00, notes: Unit: per nL. Day 10; White blood cell count (4.5-11): 23.13, notes: Unit: per nL. Day 0; 18.63, notes: Unit: per nL. Day 3; 10.12, notes: Unit: per nL. Day 5; 12.76, notes: Unit: per nL. Day 7; 10.36, notes: Unit: per nL. Day 10. She was admitted for further evaluation and was transfused with packed red blood cells (RBCs) and platelets. Aspirin and pomalidomide were stopped. Oral torsemide (10 mg once daily) was continued to prevent volume overload given her history of HFpEF. Based on her presentation and blood reports, she qualified as high risk on the score and the suspicion for thrombotic thrombocytopenic syndromes, viz., TTP, VITT, and ITP were high on the list of differential diagnoses. She was started on plasmapheresis, methylprednisolone, and caplacizumab. In view of acute kidney injury, a temporary hemodialysis catheter was placed in the right internal jugular vein under sonographic and fluoroscopic guidance with no immediate complications. Her peripheral blood smear demonstrated normocytic anemia with moderate anisopoikilocytosis, numerous schistocytes and microspherocytes, and concomitant marked thrombocytopenia suggesting microangiopathic hemolytic anemia. Bone marrow aspirate and core biopsy, done to rule out relapse of MM, showed normocellular marrow with trilineage hematopoiesis with relative erythroid and megakaryocytic hyperplasia and no evidence of residual myeloma and negative for lymphoma and acute leukemia. Few scattered plasma cells were present that showed mixed phenotype with no monoclonal plasma cell population on flow cytometry. Luminal fibrin thrombi formation was appreciated in some small vessels. Her blood reports showed significantly reduced ADAMTS13 activity of <5% and high levels of ADAMTS13 inhibitor antibody at 30 U/mL. Her haptoglobin levels were also reduced. Test for HIV antibodies, hepatitis screening, and rapid plasma reagin was negative. Levels of antinuclear nuclear antibody, double-stranded DNA (dsDNA) antibodies, antineutrophil cytoplasmic antibodies (ANCA) IgG, rheumatoid factor, and PF-4/HIT (platelet factor-4/heparin-induced thrombocytopenia) antibodies were insignificant. Serum protein electrophoresis was within normal range. Thus, the diagnosis of TTP was confirmed. Transesophageal echocardiography (TEE) demonstrated grade I diastolic dysfunction with left ventricular ejection fraction at 60%. Abdominal ultrasonography (US) showed a normal appearance of the liver with status post cholecystectomy. She developed a progressively worsening headache and had a single episode of tonic-clonic seizure on the third day of admission that terminated with midazolam, possibly due to severe TTP. Rituximab was added to the treatment regimen. She was also started on levetiracetam for seizure prophylaxis. Her electroencephalogram was negative for further seizure activity. Computed tomography (CT) scan of the head without contrast was negative for any notable findings. On imaging, the chest radiograph was negative for any acute cardiopulmonary disease. CT scan of the chest with contrast showed mild cardiomegaly but no evidence of pulmonary embolus was noted. Doppler ultrasound study of veins of bilateral lower extremities was negative for any femoropopliteal or calf deep vein thrombosis. Her hospital stay was further complicated by a fever on the fifth day, possibly due to aspiration pneumonia and she underwent intubation and mechanical ventilation in the intensive care unit for airway protection. Piperacillin-tazobactam  (4.5 g intravenous six-hourly) was started empirically as per local epidemiology and susceptibility patterns and continued for seven days. She was extubated on the seventh day as she regained normal levels of consciousness. She had no further episodes of seizures or focal neurological deficits. Plasmapheresis was discontinued once platelet counts moved above 150000/uL. She was discharged on oral 40 mg prednisone with a plan to taper the dose by 10 mg/week and prophylactic sulfamethoxazole-trimethoprim and proton pump inhibitors. She was advised to continue daily caplicizumab (11 mg/day subcutaneous injections) and weekly rituximab (375 mg/m2 infusions) as an outpatient for four weeks. She fared well on her follow-up and her platelet count was found to be within normal range (378/nL) on her most recent outpatient visit, 6 months following the discharge. The patient presented with thrombocytopenia and hemolytic anemia and developed acute kidney injury and neurologic manifestations during her hospital stay, consistent with the classically described demographic and clinical profile. Definitive diagnosis is based on decreased ADAMTS13 activity levels (< 10% of normal activity), but empiric treatment should be started before ADAMTS13 activity levels are available, based on high clinical suspicion for TTP or increased likelihood of severe ADAMTS13 deficiency based on score or PLASMIC scores. Mortality is 90% without treatment, but survival rates range anywhere from 60% to 90% with prompt treatment. Traditionally treatment is based on plasma exchange and corticosteroids with the inclusion of rituximab and caplacizumab in refractory cases. However, the health authority recommends early initiation of caplacizumab. A similar therapeutic strategy was employed for the patient with early initiation of caplacizumab and the addition of rituximab to achieve an adequate response. The first case of vaccine-induced TTP was reported in 1960, involving the typhoid vaccine. Since then, other cases of TTP have been reported involving influenza, pneumococcal, H1N1, and rabies vaccines among others. De novo TTP as well as relapse of both congenital and acquired TTP in remission have also been reported with COVID-19 vaccines, with the former variety being more common. The authors report a de novo case of acquired TTP. COVID-19 mRNA vaccines can trigger TTP in patients with a history of TTP in remission by providing a 'second hit' and aggravating ADAMTS13 deficiency. The causal relationship between acquired TTP and COVID-19 vaccination is primarily supported by temporal correlations rather than by identifying cross-reactive epitopes between antigens in these vaccines and ADAMTS13, an avenue for further research. The diagnosis of TTP due to the Pfizer-BioNTech COVID-19 mRNA vaccine was made in the patient after ruling out all the other inciting factors known to secondarily provoke TTP. The reduced levels of ADAMTS13 activity along with high levels of ADAMTS13 antibodies confirmed acquired TTP and the absence of PF4-HIT antibodies ruled out VITT. The authors reported a case of TTP following Pfizer-BioNTech COVID-19 mRNA vaccine administration, to raise awareness of this rare albeit serious complication and to highlight the importance of early initiation of therapy. Post-vaccination TTP should be distinguished from VITT, another serious complication of COVID-19 vaccination, by ADAMTS13 activity and antibody levels and PF4-HIT antibody assays, since both are managed differently. Plasma exchange in conjunction with steroids is the mainstay treatment for TTP. Early initiation of caplacizumab and rituximab should be considered with inadequate response. While the benefits of COVID-19 vaccination far outweigh the risks, the possibility of TTP as an adverse effect is to be acknowledged. Further research is needed to evaluate the relationship between COVID-19 vaccines and TTP including comparative epitope profiling of COVID-19 vaccine antigens and ADAMTS-13, and identification of predictive parameters for the development of TTP after COVID-19 vaccination.; Sender's Comments: A possibly contributory role of BNT162B2 in triggering the onset of Thrombotic Thrombocytopenic Purpura cannot be fully excluded, considering the temporal relationship.  More immunological and biomolecular evidence would be needed to explore the plausible physiopathologic mechanism between the vaccination and the event occurrence.  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