Table 2. Characteristics of case series and observational studies included.
Abbreviations: CVST, cerebral venous sinus thrombosis; DVT, deep vein thrombosis; DIC, disseminated intravascular coagulation; IVIG, intravenous immunoglobulin; LMWH, low molecular weight heparin; HTN, hypertension; DM, diabetes mellitus; SAH, subarachnoid haemorrhage; MCA, middle cerebral artery; UFH, unfractionated Heparin; TIA, transient ischemic attack; ICA, internal carotid artery; PE, plasmapheresis/plasma exchange; CT, Computed tomography; NA, not available
N=total number of patients
| First Author | Published journal, date of publication | Study design, study setting | Study population | Total number of patients (n) with venous or arterial events | Sex female, n (%) | Age (years), mean ± SD or median (range) or median (IQR) | COVID-19 tests | Vaccine type, dose | Time period from vaccination to first symptoms (days) | Diagnosis | Comorbidities and risk factors | Blood investigations | Antiplatelet antibodies and platelet-activation assay | Previous exposure to heparin | Treatment received | Outcome |
| Wolf ME [14] | Journal of Clinical Medicine, 09 April 2021 | Case series, Germany | Patients treated by authors | 3 | 3 (100) | 22, 46, 36 | SARS-CoV-2-PCR -negative in all | AstraZeneca, all first dose | 4, 8, 7 | CVST (1); CVST with haemorrhage (2) | No | Thrombocytopenia (3); Elevated D-dimer (3); Thrombophilia panel negative (3) | Anti-PF4 antibodies – positive in all | NA | Endovascular rheolysis (3); Enoxaparin (3); Dabigatran (3); Danaparoid (2) | Improved (3) |
| Greinacher A [15] | The New England Journal of Medicine, 09 April 2021 | Case series, Germany and Austria | Patients in whom clinical data available by March 15, 2021 | 11 | 9 (82) | Median age – 36 (range, 22-49) | NA | AstraZeneca, first dose in one and others, NA | Range, 5-16 | CVST (9); Splanchnic vein thrombosis (3); Pulmonary embolism (3); Aortoiliac thrombus (1); Cerebral haemorrhage (1); DIC (5); Multiple (5); Others (1) | Pre-existing von Willebrand disease, anticardiolipin antibodies, and factor V Leiden (1); Chronic neurologic disease (1); Oral contraceptive use (1); Hormonal intrauterine device (2); NA (1) | Thrombocytopenia (11) | Anti-PF4 antibodies - positive in 9/9; PF4-dependent platelet-activation assay - positive in 9/9 | No | Heparin (5); No treatment (2); NA (2); apixaban (1) | Died (6); Recovering (4); Unknown (1) |
| Schultz NH [16] | The New England Journal of Medicine, 09 April 2021 | Brief report, Norway | Health care workers | 5 | 4 (80) | Median age – 39 (range, 32-54) | SARS-CoV-2 antibody test: nucleocapsid protein negative in all and spike protein positive in all | AstraZeneca, all dose | Range, 7 - 10 | CVST with haemorrhage (4); Splanchnic vein and abasivertebral veins thrombosis (1) | HTN, Hormone-replacement Therapy (1); Contraceptive pill (1); Contraceptive vaginal ring (1) | Thrombocytopenia (5); Elevated D-dimer (5) | Anti-PF4 antibodies – positive in all | No | Platelet transfusions (4); Steroids (4); IVIG (4); LMWH (4); Heparin (1) | Died (3); Full recovery (2) |
| Scully M [17] | The New England Journal of Medicine, 16 April 2021 | Case series, United Kingdom | Patients referred | 23 | 14 (61) | Median age - 46 (range, 21-77) | SARS-CoV-2-PCR -negative in all | AstraZeneca, all first dose | Range, 6 - 24 | CVST (11); CVST with intracerebral haemorrhage (2); Pulmonary embolism (5); Splanchnic vein thrombosis (3); DVT (2); Multiple (7); SAH (1); Others (2); Bilateral adrenal haemorrhage (1); Ischemic stroke (MCA territory) (2); Acute myocardial infarction (1); Aortic thrombosis (1); Cerebral haemorrhage (1) | History of DVT (1); Combined oral contraceptive use (1) | Thrombocytopenia (22/22); Elevated D-dimer (21/21); Low fibrinogen levels (13); Lupus anticoagulant - positive (5/10); Anticardiolipin antibodies and anti–β2- glycoprotein 1b antibodies – negative (5/10) | Anti-PF4 antibodies -positive in 22 | No | NA | Died (7) |
| Mehta PR [18] | Brain, Behavior, and Immunity, 20 April 2021 | Case series, United Kingdom | Cases presented early during the vaccination programme | 2 | 0 (0) (Both male) | 32, 25 | SARS-CoV-2-PCR -negative | AstraZeneca, both first dose | 9, 6 | CVST with intracerebral haemorrhage and SAH (2) | Ex-smoker (1); Smoker (1); Primary sclerosing cholangitis and migraine (1) | Thrombocytopenia (2); Low fibrinogen levels (2); Factor V Leiden - heterozygous for the c.1601G > A (p. Arg534Gln) variant in one | Anti-PF4 antibodies -positive in 1/1 | NA | UFH (1); Platelet (1; Steroids (1); IVIG (1); Symptomatic (1) | Died (2) |
| Haakonsen HB [19] | The Journal of the Norwegian Medical Association, 28 April 2021 | Short case report, Norway | Health care professional | 2 | 1 (50) | 30s, 40s | NA | AstraZeneca, NA | 27, 29 | DVT (2) | Hypothyroidism (1) | Platelets and D-dimer normal | Anti-PF4 antibodies -negative in 1/1 | NA | Apixaban (1); Rivaroxaban (1) | NA |
| Tiede A [20] | Blood, 28 April 2021 | Brief report, Germany | Consecutive single-center cohort, between 8 March and 4 April 2021 | 5 | 5 (100) | 41, 67, 63, 61, 61 | SARS-CoV-2-PCR -negative in all | AstraZeneca, all first dose | Range, 5 - 11 | CVST with haemorrhage and thrombotic microangiopathy (1); TIA (1); Splanchnic vein thrombosis (1); Ischemic stroke with haemorrhagic transformation (MCA territory) (1); Multiple cortical infarctions and aortic arch thrombi (1) | NA | Thrombocytopenia (5); Elevated D-dimer (5) | Anti-PF4 antibodies – positive in all | No | UFH (1); Argatroban (4); Steroids (3); IVIG (3); Eculizumab (2); Alteplase (1) | Recovered (2); Recovering (3) |
| See I [21] | JAMA, 30 April 2021 | Case series, United States | Vaccine Adverse Event Reporting System (VAERS) to the CDC and FDA database from 02 March to 21 April 2021 | 12 | 12 (100) | 18 to younger than 60 years | SARS-CoV-2-PCR -negative in 10. SARS-CoV-2 antigen test - negative in 1. Not done in 1. | J&J/Janssen, all first dose | Range, 6 - 15 | CVST with intracerebral haemorrhage (7); CVST (5); SAH (1); Multiple (8); DVT (3); Splanchnic vein thrombosis (2); Pulmonary embolism (3) | High BMI (6); Hypothyroidism (1); Combined oral contraceptive use (1) | Thrombocytopenia (12); Elevated D-dimer (12); Thrombophilia panel -negative (11/11) | Anti-PF4 antibodies – positive in 11/11 | No | Heparin (6); Non-heparin Anticoagulant (10); IVIG (7); Steroids (3); Platelet (4) | Died (3); ICU (3); Still in hospital (2); Discharged (4) |
| Vayne C [22] | The New England Journal of Medicine, 19 May 2021 | Case series, France | Between 19 March and 01 April 2021 with suspected VITT | 9 | 7 (78) | Median age - 44 (range, 21-73) | NA | AstraZeneca, NA | Range, 9 - 18 | CSVT (6); Multiple (6); splanchnic vein thrombosis (4); DVT 2 ischemic stroke (1); Pulmonary embolism (2); Aortic thrombosis (1); No thrombosis (1) | NA | Thrombocytopenia (8); Elevated D-dimer (7/7); Low fibrinogen levels (5) | Anti-PF4 antibodies – positive in 7 | NA | NA | NA |
| Althaus K [23] | Haematologica, 20 May 2021 | Case series, Germany | Multicenter study between 01 February and 06 April 2021 | 8 | 5 (63) | Median age -41.5 (range, 24 - 53) | NA | AstraZeneca, NA | Range, 6 - 20 | CVST (3); CVST with haemorrhage (2); Multiple (3); Pulmonary embolism (3); DVT (1) | Contraception (1); No (7) | Thrombocytopenia (8); Elevated D-dimer (5/5); Low fibrinogen levels (3/5); Factor V Leiden – heterozygous (1) | Anti-PF4 antibodies – positive in all; Platelet activation assay – positive in 8/8 | NA | Endovascular rheolysis (1); Anticoagulation (5); IVIG (4); Non-heparin anticoagulation (4) | Died (3) |
| Pomara C [24] | Haematologica, 20 May 2021 | Case series, Italy | Patients admitted | 2 | 1 (50) | 50, 37 | SARS-CoV-2 molecular test – negative in both | AstraZeneca, NA | 10, 10 | Splanchnic vein thrombosis (1); CVST with intracerebral haemorrhage (1) | No | Thrombocytopenia (2); Elevated D-dimer (2); Low fibrinogen levels (2) | Anti-PF4 antibodies – positive in all | NA | Nadroparin (1); Platelet (1); Neurosurgical intervention (1) | Died (2) |
| Dias L [25] | Journal of Stroke and Cerebrovascular Diseases, 25 May 2021 | Case series, Portugal | Cases admitted | 2 | 2 (100) | 47, 67 | SARS-CoV-2-PCR -negative in both | Pfizer/BioNTech, first dose in one patient and second dose in another patient | 6, 3 | CVST with SAH (1); CVST (1) | Iron-deficiency anaemia due to adenomyosis (1); Combined oral contraceptives use (1); History of multiple cerebral cavernous malformations, hypertension, diabetes, dyslipidaemia, viral myocarditis, and depression (1) | Platelet normal (2); Low protein S (1); CT - probable renal cell carcinoma (1) | Anti-PF4 antibodies – negative in both (but checked 2 months and 20 days respectively post event) | NA | Enoxaparin (2); Warfarin (1); Dabigatran (1) | Discharged (2) |
| Bourguignon A [26] | The New England Journal of Medicine, 09 June 2021 | Brief report, Canada | First patients with thrombotic complications in Canada | 3 | 1 (33) | 63, 69, 72 | NA | AstraZeneca, NA | 18, 12, 7 | Multiple (3); Pulmonary embolism (2); DVT (2); CVST (1); Ischemic stroke (MCA territory and ICA thrombus); (1) Splanchnic vein thrombosis (1) | Non–insulin-dependent DM, HTN, obstructive sleep apnoea and recently diagnosed prostate cancer (1) | Thrombocytopenia (3); Elevated D-dimer (3); Low fibrinogen levels (3) | Anti-PF4 antibodies – positive in all | History of heparin exposure 9 months back in one patient. No exposure in others | UFH (1); Tinzaparin (1); Fondaparinux (2); Rivaroxaban (1); Argatroban (1); PE (1); IVIG (3) | Still in hospital (1); Recovering (1); Discharged (1) |
| Pawlowski C [27] | Journal of Stroke and Cerebrovascular Diseases, 16 June 2021 | Retrospective cohort, United States | People vaccinated in the Mayo Clinic hospital system between 01 January 2017 and 15 March 2021 and underwent at least one SARS-CoV-2 PCR test | 3 | 2 (67) | All with CVST age ≥ 65 | NA | Pfizer/BioNTech, all first dose | Within 30 days of vaccination | CVST (3) | Localized cancer (1); Heart disease (2); IBD, peptic ulcer disease, rheumatic disease, and renal disease (1) | NA | NA | NA | NA | NA |
| Fan BE [28] | American Journal of Hematology, 16 June 2021 | Case series, Singapore | Multicenter | 3 | 2 (67) | 54, 62, 60 | NA | Pfizer/BioNTech, all second dose | 1, 9, 8 | CVST with haemorrhage (3); SAH (2); Multiple (1); Pulmonary embolism (1); Others (1) | Dyslipidaemia (2); DM (1); HTN (2); Family history of unprovoked pulmonary embolism (1) | Platelet normal (2); Thrombophilia panel negative (2); Low anti-thrombin III (1) | Anti-PF4 antibodies – negative in 1/1; Heparin induced platelet aggregation – negative in 2/2 | NA | UFH (2); LMWH (3); Warfarin (2) | Recovering (2); Recovered and discharged (1) |
| Esba LCA [29] | Expert Review Of Vaccines, 17 June 2021 | Case series, Saudi Arabia | Hospital’s internal electronic safety reporting system from December 2020 to 13 April 2021 | 5 | 2 (40) | 27, 38, 40, 61, 61 | NA | AstraZeneca Pfizer/BioNTech (first dose in one patient and second in two patients, NA in others) | Both CVST - 14 Cardiac arrest - same day Pulmonary embolism - 9, 6 | CVST (2); Cardiac arrest (1); Pulmonary embolism (2) | DM (2); HTN (2); COPD (1); Heart failure (1); Dyslipidaemia (1); Smoking (2); NA (1) | Thrombocytopenia (2/4) | HIT screen - negative in 1/1 | NA | No treatment (1); Enoxaparin (4); Heparin (1); Apixaban (2) | Discharged (3); Died (1); Still in hospital (1) |
| Gattringer T [30] | Stroke & Vascular Neurology, 08 July 2021 | Case series, Austria | Patients admitted | 2 | 2 (100) | 39, 24 | SARS-CoV-2-PCR -negative in 1 and positive in 1 | AstraZeneca, both first dose | 6, 8 | CVST (1); CVST with haemorrhage (1) | No (2) | Thrombocytopenia (2); Elevated D-dimer (2); Low fibrinogen levels (2); Thrombophilia panel negative (2) | Anti-PF4 antibodies – positive in both | NA | Danaparoid (1); Argatroban (2); Dabigatran (2); Steroids (2); IVIG (2) | Discharged (2) |
| Bano F [31] | BMJ Case Reports, 13 July 2021 | Case series, United Kingdom | All patients presented over a period of 5 days to a single center | 3 | 2 (67) | 61, 53, 55 | SARS-CoV-2-PCR -negative in all | AstraZeneca, all first dose | 13, 11, 8 | CVST with haemorrhage (2); Pulmonary embolism (1) | Asthma, HTN, high BMI, hormone replacement therapy and indapamide intake (1); Fibromyalgia (1); No (1) | Thrombocytopenia (3); Elevated D-dimer (3); Low fibrinogen levels (3) | Anti-PF4 antibodies – positive in all; Platelet functional assay - positive in 1/3 | No | LMWH (1); Fondaparinux (1); Argatroban (1); Platelet (3); Cryoprecipitate (1); IVIG (1); Steroids (2); Neurosurgical intervention (1) | Recovered and discharged (1); Died (2) |
| Schulz JB [32] | Annals of Neurology, 19 July 2021 | Retrospective survey, Germany | Web-based questionnaire emailed to neurology department of hospitals, data collection closed on 14 April 2021 | 59 | 44/58 (76) | Mean age (SD) - 46.7 (17.1); (of total 62 cerebrovascular events); Median - 46 (range, 20-89) | NA | AstraZeneca Pfizer/BioNTech (56 with first dose and 3 with second dose) | Range, 1 - 25 in CVST patients | Total cerebrovascular events (62); Total vascular events (59); CVST (45); Ischemic stroke (9); Haemorrhagic stroke (4); Others (7) | Smoking (6/52); Obese (3/59); Previous thrombosis event (1/59) | Thrombocytopenia (In 26/43 CVST and 3/9 ischemic stroke patients); Elevated D-dimer (In 23/33 CVST and 3/4 ischemic stroke patients) | Anti-PF4 antibodies – positive in 22/31 CVST patients and 5/5 ischemic stroke patients | NA | IVIG, steroids, heparin, other anticoagulants | Died (11) |