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Corresponding author at: Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, 3-39-15, Showa, Maebashi 371-8511, Japan.
Vaccine-induced immune thrombotic thrombocytopenia (VITT) is defined as thrombosis after inoculation of adenovirus vector vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). VITT rarely occurs with messenger RNA vaccines, and the use of heparin for VITT is also controversial. A 74-year-old female patient with no risk factors for thrombosis was brought to our hospital after loss of consciousness. Nine days before admission, she had received the third vaccine against SARS-CoV-2 (mRNA1273, Moderna). Immediately after transport, cardiopulmonary arrest occurred, prompting extracorporeal membrane oxygenation (ECMO). Pulmonary angiography showed translucent images of both pulmonary arteries, resulting in the diagnosis of acute pulmonary thromboembolism. Unfractionated heparin was administered, but D-dimer subsequently became negative. Pulmonary thrombosis remained in large volume, indicating that heparin was ineffective. Treatment was shifted to anticoagulant therapy using argatroban, which increased D-dimer level and improved respiratory status. The patient was successfully weaned from ECMO and ventilator. Anti-platelet factor 4 antibody examined after treatment initiation showed negative results; however, VITT was considered as an underlying condition because of the time of onset after vaccination, the ineffectiveness of heparin, and the absence of other causes of thrombosis. In case heparin is not effective, argatroban can be an alternative therapy against thrombosis.
Learning objective
During the coronavirus disease 2019 pandemic, treatment with vaccine against severe acute respiratory syndrome coronavirus 2 has been widely performed. Vaccine-induced immune thrombotic thrombocytopenia is the most common thrombosis after adenovirus vector vaccines. However, thrombosis can also occur after messenger RNA vaccination. Though commonly used for thrombosis, heparin may be ineffective. Non-heparin anticoagulants should be considered.
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) and became a pandemic in 2020. As treatment and prevention, many people have been vaccinated worldwide. However, cases of vaccine-induced immune thrombotic thrombocytopenia (VITT), characterized by both thrombocytopenia and thrombosis, have been reported after vaccination against SARS-CoV-2 [
], the majority of which were in individuals inoculated with adenoviral vector vaccines, such as ChAdOx1 (AstraZeneca) and Ad25.COV2.S (Johnson & Johnson/Janssen), but rarely in those with messenger RNA (mRNA) vaccine. An early study suggested the use of non-heparin anticoagulants due to their similarity to autoimmune heparin-induced thrombocytopenia (HIT). In contrast, meta-analyses found no apparent difference in mortality between heparin and non-heparin anticoagulants [
]. The use of heparin as anticoagulant therapy for VITT is controversial.
Herein, we report a case of acute pulmonary thromboembolism after vaccination, which was considered to be VITT caused by mRNA vaccine, mRNA1273 (Moderna). In this case, heparin was clinically ineffective and argatroban was successful.
Case report
A 74-year-old woman felt dizziness, fell, and became unconscious at home one morning. When the emergency medical team arrived, the patient was pale, cold sweating, and hypoxic. She was transported to our hospital with assisted ventilation.
She was independent in her usual daily activities but had history of hypertension, dyslipidemia, and hypothyroidism. She did not have history of thrombosis or previous heparin exposure, smoking, or alcohol drinking; moreover, there was no family history of thrombosis. Eight months previously, she received two doses of mRNA vaccine against SARS-Cov-2, BNT162b2 (Pfizer-BioNTech), and 9 days before the incident, one dose of mRNA1273 (Moderna) vaccine.
Vital signs showed tachycardia of 113/min and tachypnea of 40/min, and hypoxemia with SpO2 85 % under assisted ventilation. Blood pressure was 104/87 mm Hg. Body mass index was 21.8 kg/m2. The level of consciousness was Glasgow coma scale E3V4M6, and a contusion wound caused by the fall was found on the occipital region. There were no abnormal findings in the chest and abdominal regions, and there was no swelling, edema, or skin rash on the extremities. Blood tests showed elevated D-dimer, but antithrombin-III, protein C, protein S, lupus anticoagulant, and SARS-CoV-2 antigen were negative (Table 1). Transthoracic echocardiography showed an enlarged right ventricle and flattened intraventricular septum (Fig. 1A ).
Fig. 1Transthoracic echocardiography (A), pulmonary arteriography (B), and thoracic contrast-enhanced computed tomography on admission (C) and on day 70 (D). Short-axis images of transthoracic echocardiography taken during systole (upper panel) and diastole (lower panel) (A) showing an enlarged right ventricle (RV), flattened intraventricular septum and compressed left ventricle (LV). Pulmonary angiography (B) shows translucent images suggestive of thrombi in the upper and lower lobar branches of the right pulmonary artery and the lower lobar branch of the left pulmonary artery (arrows). Contrast-enhanced computed tomography scan of the chest on admission (C) shows contrast defects, indicating thrombi in the right pulmonary artery trunk, upper and lower lobar branches, and lower lobar branch of the left pulmonary artery (arrows). Contrast-enhanced computed tomography scan on day 70 (D) shows shrinkage of the contrast defect (arrows).
Shortly after arrival, the patient went into cardiopulmonary arrest (pulseless electrical activity); subsequently, veno-arterial extracorporeal membrane oxygenation (VA ECMO) and ventilator management were started emergently. Pulmonary arteriography and contrast-enhanced computed tomography (CT) showed thrombi in both pulmonary arteries (Fig. 1B and C). Acute pulmonary thromboembolism was diagnosed, and intravenous unfractionated heparin was started. No thrombus was found in deep veins, and the mean pulmonary artery pressure was 45 mm Hg (reference range: 10–20 mm Hg). On day 2, massive retroperitoneal hematoma developed, and transfusions of concentrated red blood cells, concentrated platelets, and fresh-frozen plasma were administered daily. However, although circulation was minimally maintained using noradrenaline and dobutamine, a massive pleural effusion and pulmonary edema appeared. On day 9, the circuit connection was switched to veno-arterial-venous (VAV) ECMO, and then on day 10, to veno-venous (VV) ECMO.
Platelet counts dropped below 100,000/μl after admission. D-dimer increased from 9.0 μg/ml on admission to 30 μg/ml on day 2 and then decreased toward almost negative on day 10. However, contrast-enhanced CT showed that a large amount of pulmonary artery thrombi remained, and the mean pulmonary artery pressure was 50 mm Hg, making ECMO withdrawal difficult. Heparin dose was adjusted to 1.5–2 times the baseline activated partial thromboplastin time (APTT). The patient was clinically considered to have a poor response to heparin; thus, the anticoagulant was shifted to argatroban starting on day 13; argatroban dose was also adjusted to 1.5–2 times the baseline APTT. On day 13, platelet factor (PF) 4/heparin antibody—called HIT antibody—was negative based on the latex-aggregation assay results. However, after changing to argatroban, D-dimer was re-elevated, respiratory status improved, and the mean pulmonary artery pressure reached 28 mm Hg. The patient was successfully weaned from ECMO on day 18 and ventilator on day 24 (Fig. 2). On day 28, using the enzyme-linked immunosorbent assay (ELISA), the anti-PF4 antibody level was 0.396 (cut-off value, 0.400).
Fig. 2Clinical course from admission to day 50. The patient was started on unfractionated heparin with extracorporeal membrane oxygenation (ECMO), ventilator, noradrenaline, and dobutamine for acute pulmonary thromboembolism. Platelet counts were severely decreased after admission, requiring platelet transfusions. D-dimer was elevated immediately after admission but decreased soon thereafter. On day 13, heparin was shifted to argatroban, which re-elevated D-dimer as well as improved respiratory and circulatory condition. The patient was successfully weaned from ECMO, ventilator, noradrenaline, and dobutamine. Heparin and argatroban doses were adjusted to achieve 1.5–2 times the baseline activated partial thromboplastin time.
During the treatment course, severe jaundice and liver damage appeared, and hepatoprotective drugs, such as monoammonium glycyrrhizate and ursodeoxycholic acid, were administered. Renal failure was also observed in the acute phase, which required continuous hemodiafiltration and hemodialysis. The liver and renal function gradually improved. After discontinuation of sedatives, the patient continued to have poor arousal, and brain magnetic resonance imaging showed multiple cerebral infarctions due to circulatory instability at the acute phase, but no evidence of cerebral venous thrombosis. The patient's level of consciousness gradually improved. Although there was no evidence of thromboembolism in the fundus, Candida endophthalmitis was present, and long-term treatment with fosfluconazole was prescribed. On day 58 when she was able to take medication orally, the anticoagulant was shifted from argatroban to edoxaban. On day 70, contrast-enhanced CT showed a reduction in pulmonary artery thrombi, but a small amount remained (Fig. 1D). On day 133, the patient was transferred to another hospital for rehabilitation.
Discussion
In this case, the mRNA vaccine may have caused VITT, which is generally believed to occur with adenoviral vector vaccines, and heparin, which has been controversial for VITT, was not effective and argatroban was extremely effective.
Adenovirus vector vaccines and mRNA vaccines have been developed against SARS-Cov-2. Thrombosis after vaccination against SARS-Cov-2, particularly adenovirus vector vaccines, is known as VITT and mostly occurs in the 5–10 days after vaccination. The types of thrombosis include cerebral venous thrombosis, pulmonary thromboembolism, and other systemic thrombosis. The involvement of antibodies against PF4 contributes to the pathogenesis of VITT [
]. Generally, the diagnosis of VITT is confirmed by a history of COVID-19 vaccination within 20 days, thrombosis with thrombocytopenia, positive anti-PF4 antibody, and positive functional platelet activation testing. If anti-PF4 antibody and functional platelet activation test is positive, VITT is confirmed. If anti-PF4 antibody is negative, VITT is considered unlikely [
Recommendations for the clinical and laboratory diagnosis of VITT against COVID-19: communication from the ISTH SSC subcommittee on platelet immunology.
]. The sensitivity of the anti-PF4 antibody measured by ELISA is 70.6 %–94.1 % and specificity is 77.8 %–100 %. However, negative anti-PF4 antibodies cannot rule out VITT [
In this case, the patient developed fatal pulmonary thromboembolism 9 days after mRNA1273 inoculation. Anti-PF4 antibody measured on day 28 was borderline negative. The diagnosis of VITT is “unlikely,” but clinically unlikely to be anything other than vaccine-related thrombosis. Therefore, the diagnosis of VITT can be acceptable, considering the time of onset after vaccination, the sudden onset of pulmonary thrombosis, the ineffectiveness of heparin, and the absence of other causes of thrombosis.
Other differential diagnoses are idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, malignancies, hematological cancers, spontaneous HIT, and unprovoked pulmonary thromboembolism. Antiphospholipid and HIT antibodies were negative, and there were no signs of hemolytic anemia, no malignancy or lymphadenopathy on CT scan, or other findings indicative of the above-mentioned diseases. Spontaneous HIT without a history of heparin exposure and subsequent thrombocytopenic thrombosis were negative due to negative HIT antibodies, which are highly sensitive [
In the present case, with APTT-adjusted heparin, D-dimer became negative, while a large amount of pulmonary thrombi remained. After switching to argatroban, D-dimer level was re-elevated and clinical improvement was achieved, thereby indicating that heparin was ineffective and argatroban was effective. This findings of this case support the initial report and recommendation that heparin was not effective and that the non-heparin anticoagulant argatroban was a better choice.
The patient's vital signs deteriorated rapidly, and heparin administration and extracorporeal circulation were started as emergency treatment. Although vaccination history was later determined and the possibility of VITT considered, heparin was continued as the first-line treatment. In particular, no immunoglobulin therapy shown to be effective against VITT was administered to the patient [
]. In addition, due to hemorrhagic complications, such as retroperitoneal hematoma, we decided to transfuse platelets, which are not supposed to be used for VITT, to maintain extracorporeal circulation. Furthermore, the possibility of chronic pulmonary thromboembolic pulmonary hypertension was considered owing to high pulmonary artery pressure, but there was no previous history of shortness of breath or abnormalities on electrocardiogram scan.
In summary, this case suggests that VITT, which is generally believed to be caused by adenoviral vector vaccines, may have been caused by mRNA vaccine. Further understanding of the mechanism of VITT and its treatment is needed.
Patient permission/consent statement
Written consent was obtained to report the patient's medical condition.
Conflict of interest
The authors declare that there is no conflict of interest.
Acknowledgments
The authors would like to thank Dr Atsushi Yasumoto, Hokkaido University, and Dr Eriko Morishita, Kanazawa University, for their help in measuring anti-PF4 antibody. The measurement of anti-PF4 antibody (ELISA) was supported by Japan Agency for Medical Research and Development (AMED) under Grant Numbers JP20ek0210154. The authors would like to thank Enago (www.enago.jp) for the English language review.
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Recommendations for the clinical and laboratory diagnosis of VITT against COVID-19: communication from the ISTH SSC subcommittee on platelet immunology.
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