Patient Identification
Of 294 patients who were evaluated, 31 had been identified retrospectively once VITT had been recognized as a syndrome. A total of 57 patients were classified as being unlikely to have VITT because of three missing data points, unmet criteria, or both (50 patients) or because an alternative cause of the patient’s symptoms was likely (7 patients). The alternative causes were chronic disseminated intravascular coagulation from abdominal aortic aneurysm (in 3 patients) and metastatic cancer (in 4 patients). Of the remaining 237 patients who were considered to have suspected VITT, 17 were classified as having possible VITT; 50 were classified as having probable VITT because one of the criteria was not met (in most cases because of missing data) (Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org); and 170 were classified as having definite VITT. All the patients who were classified as having definite or probable VITT presented after the first vaccination with ChAdOx1 nCoV-19 (Fig. S2).
By the end of the study, approximately 16 million first doses of ChAdOx1 nCoV-19 had been administered to persons 50 years of age or older, and 8 million first doses had been administered to persons younger than 50 years of age. Thus, the approximate incidence of VITT was at least 1:100,000 among patients 50 years of age or older and at least 1:50,000 among patients in the younger group (<50 years of age).11
Baseline Characteristics of the Patients
Baseline Clinicopathological Features of the Patients with VITT. 
Baseline Distribution of Variables in Patients with Vaccine-Induced Immune Thrombocytopenia and Thrombosis (VITT).
Shown are the variables in patients with VITT, including those who did not survive.
The baseline characteristics and clinicopathological features of the 220 patients with definite or probable VITT are shown in Table 2. A total of 97% presented at 5 to 30 days after vaccination; the 3% of patients who presented between 30 and 48 days had isolated venous thromboembolism (deep-vein thrombosis or pulmonary embolism). The age at presentation ranged from 18 to 79 years, with a median of 48 years (interquartile range, 38 to 56). A total of 56% of the patients were younger than 50 years of age, and 85% were younger than 60 years of age. There were slightly more women (54%) than men. The median time from vaccination to presentation was 14 days (interquartile range, 10 to 16). Data on the patients’ age, days since vaccination, and baseline platelet count and fibrinogen and d-dimer levels are shown in Figure 1.
Medical History
Information about medical history was available for 165 of the 220 patients; 68 of these patients (41%) had no previous medical diagnoses. Of the 97 patients (59%) reported to have a past or current medical illness, no diagnoses or use of medications occurred at a frequency that would be unexpected in the general population. Conditions that were specifically examined were autoimmune disease, previous venous thromboembolism, prothrombotic disorders (including thrombophilia and antiphospholipid syndrome), cancer, and previous SARS-CoV-2 infection. Arterial risk factors and the use of hormonal preparations and anticoagulants were also assessed (Table S2). None of the patients had been exposed to heparin in the 3 months preceding their presentation with VITT, and 104 of the patients were not receiving any medication. In the 7 patients who were receiving oral anticoagulation therapy when they presented with VITT, the median d-dimer level was not significantly lower than that documented in the patients with definite VITT (23,850 FEU) or those with probable VITT (20,000 FEU).
Thrombocytopenia
The median baseline platelet count was 47,000 per cubic millimeter (range, 6,000 to 344,000). Eleven of the 220 patients (5%) presented with a normal platelet count (median, 175,000 per cubic millimeter; range, 153,000 to 344,000). All had positive anti-PF4 antibodies; in 9 of these patients, the platelet count subsequently decreased below the lower limit of the normal range (i.e., <150,000 per cubic millimeter). In 2 patients (<1%) the only available platelet counts were those measured at presentation; in 1 patient who presented with middle cerebral artery infarct, the platelet count was 153,000 per cubic millimeter, and in a patient with cerebral venous sinus thrombosis, the platelet count was 173,000 per cubic millimeter. Among 217 patients for whom data on platelet counts were available, the baseline platelet count was less than 30,000 per cubic millimeter at presentation in 56 patients (26%) and the nadir platelet count was less than 30,000 per cubic millimeter in 73 patients (34%).
In 6 patients, thrombocytopenia and all other criteria were met but thrombosis was not documented. Although these patients were classified as having probable, rather than definite, VITT, it is likely that the lack of thrombosis reflected the early recognition and treatment of VITT.
Anti-PF4 Antibodies
Anti-PF4 antibodies were present in 198 of 220 patients (90.0%) with definite or probable VITT. ELISA was not performed in 16 of 220 patients (7.3%) because they died before anti-PF4 antibody testing or had VITT that was diagnosed retrospectively before the recognition of involvement of anti-PF4 antibodies. The result was negative in 6 patients (2.7%). These patients met all other criteria for the diagnosis of VITT, including profound coagulation activation, and they received treatment for VITT. Optical densities were not correlated with disease severity (thrombosis at presentation or death) because different ELISA methods were used.
Thrombosis and Thromboembolism
Sites of Disease in 220 Patients with Definite or Probable VITT.
Sites of disease (thrombosis or bleeding) that are not shown include the bowel and the pelvic, retinal, ophthalmic, and internal jugular veins.
The most common thrombotic site at presentation was the cerebral veins; this was at least one site of thrombosis in 110 of the 220 patients (50%) with definite or probable VITT. In 40 of these patients (36%), cerebral venous sinus thrombosis was complicated by secondary intracranial hemorrhage; in 2 patients, intracranial hemorrhage was reported in association with a cerebrovascular accident. Intracranial hemorrhage was more common in patients with lower platelet counts (median, 34,000 per cubic millimeter) than in those with higher platelet counts (median, 50,000 per cubic millimeter). The deep veins of the legs and the pulmonary arteries were the second most common sites and were affected in 82 of the 220 patients (37%) (40 cases of deep-vein thrombosis and 63 cases of pulmonary embolism; 21 patients had both). A total of 41 patients (19%) had splanchnic-vein thrombosis; this thrombosis most often affected the portal circulation (30 cases of portal-vein thrombosis and 22 cases of other splanchnic-vein thrombosis; 11 patients had both). Forty-seven patients (21%) had one or more arterial thrombotic events; aortic thrombosis or ischemic limb was seen in 26 patients (12%) and cardiac or cerebral arterial events were seen in 26 patients (12%), with 9 myocardial infarctions and 17 cerebrovascular accidents. In 64 of the 220 patients (29%) with definite or probable VITT, two or more vascular beds were involved (Table S3). The number of events according to disease site is shown in Figure 2. Thirty-one patients had isolated venous thromboembolism (all included pulmonary embolism except in 1 patient who had extensive superficial and deep-vein thromboses). No significant differences were noted among patients who presented with cerebral venous sinus thrombosis, those who presented with isolated venous thrombolism, and those who presented with arterial thrombosis with respect to age, platelet count (median and range), d-dimer level, fibrinogen level, or days since vaccination (Table S4).
Treatment
The forms of treatment used in patients classified as having definite or probable VITT are shown in Table S6. Intravenous immune globulin was used in 72% of the patients (at all platelet count levels) at a dose of 1 g per kilogram of body weight administered on day 1 of admission. In 11% of the patients, a second dose for ongoing or relapsed disease was administered.
A total of 17 patients with severe disease involving cerebral venous sinus thrombosis, thrombosis at multiple sites, or both underwent plasma exchange; this therapy was associated with 90% survival. Both patients who underwent plasma exchange and died had extensive intracranial hemorrhage at presentation. Octaplas (Octapharma) solvent detergent plasma was used; no allergic reactions, bleeding, hemodynamic compromise, or other complications were seen.
Systemic glucocorticoids were used in 26% of the patients and in 50% of those with a platelet count below 30,000 per cubic millimeter. Preparations included intravenous methylprednisolone, oral or intravenous dexamethasone, and oral prednisolone. Patients with a baseline platelet count of less than 30,000 per cubic millimeter were three times more likely to receive a platelet transfusion, typically in preparation for neurosurgery or for anticoagulation. In 15% of the patients with extensive cerebral venous sinus thrombosis with or without secondary intracranial hemorrhage, neurosurgery or thrombectomy was performed by interventional radiologists.
Anticoagulation was administered in 91% of the patients; non–heparin-based anticoagulation, including argatroban, fondaparinux, apixaban, and dabigatran, was used in 68%. Heparin was administered at some point during admission in 50 patients (23%). Its use was universal in the patients who presented before mid-March and received a diagnosis retrospectively, and it was administered to other patients before the diagnosis was considered and the anticoagulant was switched. Mortality among these patients was 20%, as compared with 16% among those receiving non–heparin-based anticoagulants.
Death
Clinical and Laboratory Features with Respect to Outcomes in Patients with VITT.
At the time of the data analysis, 170 of 220 patients with definite or probable VITT were alive and 49 had died (22%). Outcome survival data were unavailable for 1 patient. Clinical and laboratory features with respect to patient outcomes are shown in Table 3 and Table S5. In these 220 patients, the odds of death increased by a factor of 2.7 (95% CI, 1.4 to 5.2) among those with cerebral venous sinus thrombosis, by a factor of 1.7 (95% CI, 1.3 to 2.3) for every 50% decrease in the baseline platelet count, by a factor of 1.2 (95% CI, 1.0 to 1.3) for every increase of 10,000 FEU in the baseline d-dimer level, and by a factor of 1.7 (95% CI, 1.1 to 2.5) for every 50% decrease in the baseline fibrinogen level. Multivariate analysis identified the baseline platelet count and the presence of intracranial hemorrhage as being independently associated with death; the observed incidence of death was 73% among patients with both a platelet count below 30,000 per cubic millimeter and an intracranial hemorrhage.
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