Sex: M
Vaccine: FLUX
Symptoms: Antinuclear antibody negative, Antiphospholipid antibodies negative, Antithrombin III, Beta-2 glycoprotein antibody negative, Blood fibrinogen increased
Clinical narrative: Non-ST segment myocardial infarction/ST-segment elevation myocardial infarction following spontaneous vaccine-induced immune thrombotic thrombocytopenia; Acute onset, severe left-sided chest pressure; Acute onset, severe left-sided chest pressure that radiated to his left arm; Dyspnea; Diaphoresis; Acute onset chest pain/severe mid-sternal chest pain/recurrent chest pain; Sinus tachycardia; Right bundle branch block; Severely reduced left ventricular systolic function following spontaneous vaccine-induced immune thrombotic thrombocytopenia; Spontaneous vaccine-induced immune thrombotic thrombocytopenia; Headache that persisted; Thrombocytopenia; Proximal left anterior descending coronary artery thrombotic lesion; Multiple recurrent early stent thrombosis following spontaneous vaccine-induced immune thrombotic thrombocytopenia; Left ventricular thrombus; Initial information received on 20-Mar-2024 via physician regarding an unsolicited valid serious case issued from a literature article:   This case involves a 40-year-old male patient who experienced spontaneous vaccine-induced immune thrombotic thrombocytopenia (latency: unknown), non-ST segment myocardial infarction/ST-segment elevation myocardial infarction (latency: 1 day) and severely reduced left ventricular systolic function following spontaneous vaccine-induced immune thrombotic thrombocytopenia (latency: unknown) while receiving vaccine Influenza Vaccine (Quadrivalent).  The patient's past medical treatment(s) and family history were not provided.  The patient had a history of obesity (body mass index: 34.1 kg/m2) and hypertriglyceridemia.  The patient received COVID-19 vaccine (Pfizer) on 8 July 2022; 16 March 2021; 23 February 2021 and COVID-19 vaccine (Moderna) on 18 December 2021. Patient also received Influenza vaccine on 28 September 2015; 14 September 2018 and 17 October 2022.  On 19-Sep-2023, the patient received a  dose of suspect Quadrivalent Influenza Vaccine produced by unknown manufacturer lot number not reported via unknown route in unknown administration site.  On 20-Sep-2023, one day later, the patient presented to the hospital with acute onset, severe left-sided chest pressure (Chest discomfort), which awoke him from sleep, that radiated to his left arm (Limb discomfort). The discomfort was associated with dyspnea (Dyspnoea) and diaphoresis (Hyperhidrosis). One week prior, his daughter had developed upper respiratory tract infection symptoms, and the patient had developed a cough for 1 day followed by a headache that persisted (Headache) until presentation. The differential diagnosis for acute onset chest pain (Chest pain) with dyspnea and diaphoresis includes acute coronary syndrome, aortic dissection, pulmonary embolism, and pneumothorax. Investigations: A chest computed tomography scan with intravenous (IV) contrast was performed and was negative for pulmonary embolism, dissection, or pneumothorax. A 12-lead electrocardiograph (ECG) demonstrated nonspecific inferior lead ST-segment changes with sinus tachycardia, right bundle branch block (Bundle branch block right), and anteroseptal infarct. Laboratory work-up was notable for thrombocytopenia (114x10*3/uL (on day 0); baseline was 295x10*3/uL 4 months prior) and elevated troponin-I (1,613 (on day 0) > 1,870 > 3,751; normal < 86 pg/mL). A D-dimer level set 18 hours after admission was 3.56 ug/mL fibrinogen equivalent units (FEUs) (normal: < 0.51 ug/mL FEUs). Management: heparin infusion was initiated for non-ST segment myocardial infarction (Acute myocardial infarction). Cardiac catheterization identified an 80% proximal left anterior descending coronary artery (LAD) thrombotic lesion (Coronary artery thrombosis) with successful revascularization using a drug-eluting stent (everolimus-eluting stent); therapeutic activated clotting time (>250 seconds) was maintained during the procedure. Due to significant residual thrombus, the patient underwent rheolytic thrombectomy (Angiojet Thrombectomy System) and administration of a tirofiban bolus, followed by a 6-hour infusion. The stent appeared well-expanded postprocedure with mildly reduced apical LAD flow. Dual-antiplatelet therapy with aspirin and ticagrelor was initiated. Following 6-hour tirofiban infusion, the patient developed severe mid-sternal chest pain with diaphoresis and dyspnea. ECG demonstrated anterior ST-segment elevation. Emergent catheterization found multiple filling defects throughout his proximal LAD stent and native vessel distal to stent with slow apical LAD flow, i.e, shows stent thrombosis (ST) (Vascular stent thrombosis) with multiple thrombotic filling defects (on day 0). Intravascular ultrasound demonstrated adequate stent expansion with mural thrombus lining the entire surface of stent including distal nonstented portion. Aspiration thrombectomy of the stent and native vessel was performed, followed by LAD stent placement distal to previous stent. IV heparin and tirofiban bolus/infusion were administered followed by reloading of ticagrelor. On completing the 6-hour tirofiban infusion, the patient developed recurrent chest pain with anterior ST-segment elevation on ECG. Catheterization demonstrated recurrent ST; severely narrowed LAD stent lumen with angiographic suggestion of mural thrombus within previously placed stents and occluded mid-to-distal LAD at diagonal branch (day 1). IV heparin and tirofiban bolus/infusion were administered. After multiple thrombectomy attempts, the proximal-to-mid LAD stents appeared patent, but apical LAD had TIMI flow grade 0, likely from proximal thrombus embolization. Due to ongoing chest pressure and suboptimal distal LAD flow, an intra-aortic balloon pump (IABP) was placed with initiation of continuous heparin and 18-hour tirofiban infusions. Hematology was consulted and, despite the lack of heparin-exposure prior to the development of thrombocytopenia, recommended sending platelet  factor 4 antibody (PF4 Ab) to rule out spontaneous heparin-induced thrombocytopenia. PF4 Ab was positive with an optical density of 2.75 IU (day 1); heparin was discontinued and argatroban was initiated. On day 1 the platelets were 142x10*3/uL and troponin-I was 3205 pg/mL. On day 2, a serotonin release assay was sent and subsequently found to be negative (0 %), fibrinogen was 389 mg/dL (normal: 200-400 mg/dL), platelets were 144x10*3/uL and troponin I was 91.812 pg/mL. Within an hour of completing tirofiban infusion and starting argatroban, the patient developed severe chest pain with anterolateral ST-segment elevations on ECG. Repeat catheterization demonstrated shows recurrent ST with proximal LAD occlusion (abrupt cutoff at LAD stent origin) with partially successful thrombectomy and balloon angioplasty (day 3) followed by 10 mg intracoronary alteplase. Argatroban was switched to bivalirudin, and tirofiban bolus/infusion was administered. On day 3, platelets were 152x10*3/uL, troponin I was 30.069 pg/mL, anticardiolipin IgG, anticardiolipin IgM, anticardiolipin IgA and antinuclear antibodies (ANA IgG) were negative. At this time, the patient was transferred to the tertiary care center. At the medical center, echocardiogram demonstrated moderate to severely reduced left ventricular (LV) systolic function (Left ventricular dysfunction) (ejection fraction: 25%-30%) with LV thrombus (Cardiac ventricular thrombosis) (1.6 x 2.8 cm). He was switched from tirofiban to eptifibatide and continued on dual antiplatelet therapy and bivalirudin. Warfarin was initiated. IABP was weaned from 1:1 to 1:2 to 1:3 over several hours without symptomatic or hemodynamic change. After 72 hours and successful weaning of IABP, eptifibatide and bivalirudin were discontinued and IABP was removed 3 hours later. Patient remained asymptomatic for 1.5 hours following IABP removal, then developed severe chest pain and dyspnea refractory to nitroglycerin infusion with anterolateral ST-segment elevations on ECG. Emergent catheterization demonstrated recurrent ST; proximal LAD occlusion at origin of LAD stent (day 6). Partially successful rheolytic thrombectomy and angioplasty were performed with administration of intracoronary eptifibatide, but thrombus burden persisted in the mid-to-distal LAD. Following catheterization, bivalirudin and eptifibatide infusions were resumed, and warfarin was continued. A hypercoagulable evaluation laboratory panel was sent. On day 6, anticardiolipin IgG, anticardiolipin IgA, beta 2 glycoprotein IgM, beta 2 glycoprotein IgG, Beta 2 glycoprotein IgA, lupus anticoagulant, antinuclear antibodies (ANA IgG), neutrophil cytoplasmic antibodies, proteinase 3 antibody, myeloperoxidase antibody, factor V Leiden gene mutation polymerase chain reaction (PCR), factor II (prothrombin) gene mutation PCR all were negative. Anticardiolipin IgM was positive. Antithrombin III level was 116 % (normal: 75-135), protein C: 195 % (normal: 83-168), protein S: 218 % (normal: 84-134), complement C3: 170 mg/dL (normal: 88-165), complement C4: 32 mg/dL (normal: 14-44), eythrocyte sedimentation rate: 68 mm/h (normal: 0-15), C-reactive protein: 6.1 mg/dL (normal: < 1.0). Hematology was consulted and raised concern for spontaneous vaccine-induced immune thrombotic thrombocytopenia (SpVITT) (Thrombosis with thrombocytopenia syndrome) given that patient had: 1) an unusually aggressive series of arterial thromboses; 2) thrombocytopenia on presentation before administration of heparin; 3) an elevated PF4 Ab (optical density: 2.75) with negative serotonin release assay; and 4) an elevated D-dimer level.  The patient was treated with 2 doses of IV immunoglobulin (IVIG) for suspected SpVITT. Following IVIG administration, the patient's platelet count increased from 254,000 (on day 6) to 456,000 (on day 9) over 3 days. A repeat PF4 enzyme-linked immunoadsorbent assay had a titer of 2.92 (on day 9) (Zymutest HIA Elisa). Hypercoagulability evaluation showed no evidence of inherited or acquired hypercoagulable syndrome. Once the patient's international normalized ratio level reached 3.9, the eptifibatide infusion was discontinued followed by discontinuation of the bivalirudin 24 hours later. The patient remained asymptomatic over the subsequent days and was successfully discharged home on aspirin, ticagrelor, and warfarin. Echocardiogram on discharge demonstrated improved LV systolic function (ejection fraction: 35%) and resolving LV thrombus (1.6 x 0.4 cm). Discharge ECG showed sinus tachycardia, anteroseptal infarct, and persistent ST-segment elevations in leads V1-V3. During followup, three months after initial presentation, the patient has had no new episodes of thrombosis or cardiac event under guideline-directed medical therapy. He was actively participating in cardiac rehabilitation with minimal exertional symptoms.  Author stated that, VITT has been associated with development of venous and/or arterial thrombi between 4 and 42 days of vaccination. The 5 criteria for "definitive VITT" include: 1) COVID vaccine 4-42 days prior to symptom onset; 2) any venous or arterial thrombosis; 3) thrombocytopenia (platelet count <150 x 109/L); 4) positive PF4 Ab enzyme-linked immunoadsorbent assay; and 5) markedly elevated D-dimer (>4,000 FEU or equivalent). SpVITT appears to have an identical presentation with the exception of vaccine exposure. This patient had symptoms consistent with a viral infection approximately 1 week prior to his presentation, which might well have served as the inciting event. The influenza vaccine that he received might have exacerbated the development of SpVITT through its proinflammatory effects, but they do not think the time course of its delivery nor of previous COVID-19 vaccinations is consistent with these being the primary cause of his prothrombotic course. This patient had both clinical and laboratory criteria that support a diagnosis of SpVITT (thrombocytopenia associated with a strongly positive anti-PF4 enzyme-linked immunoadsorbent assay, negative serotonin release assay, multiple arterial thrombi, and very high D-dimer level). A limitation of this study is that they did not definitely establish presence of VITT-like antibodies (unfortunately, no residual patient serum/plasma was available for referral to a specialty anti-PF4 laboratory). However, the clinical course following the patient IVIG treatment (including rebound in platelet count) is highly suggestive of SpVITT as the correct diagnosis. The patient was treated with 2 doses of IVIG with improvement in his platelet counts and no recurrent thrombi despite weaning of IV anticoagulation.  Action taken: Not applicable.  Corrective treatment: Heparin, tirofiban, aspirin, ticagrelor, argatroban, alteplase, bivalirudin, eptifibatide, warfarin for acute myocardial infarction and thrombosis with thrombocytopenia syndrome. Nitroglycerin, revascularization using a drug-eluting stent, angioplasty, intra-aortic balloon pump for acute myocardial infarction. IV immunoglobulin, rheolytic thrombectomy, aspiration thrombectomy of the stent for thrombosis with thrombocytopenia syndrome. Not Reported for Left ventricular dysfunction.   Outcome: Recovering for all the events.  Seriousness criteria: Hospitalization for all the events. Medically significant for acute myocardial infarction and thrombosis with thrombocytopenia syndrome.  Reporter's causality: Related for all the events.; Sender's Comments: Sanofi company comment dated 20-Mar-2024: This case involves a 40-year-old male patient who experienced spontaneous vaccine-induced immune thrombotic thrombocytopenia (latency: unknown), non-ST segment myocardial infarction/ST-segment elevation myocardial infarction (latency: 1 day) and severely reduced left ventricular systolic function following spontaneous vaccine-induced immune thrombotic thrombocytopenia (latency: unknown) while receiving vaccine Influenza Vaccine (Quadrivalent). Based on information received the causal role of Vaccine cannot be excluded due to compatible temporal relationship of ADR to the Vaccine. Further information regarding time to onset, concurrent condition during vaccination, tolerance, allergic history, laboratory investigations excluding alternative etiologies for the reported event are needed to fully assess this case. Based upon the reported information, the role of vaccine cannot be assessed.