Ben Y. Reis, Ph.D. Boston Children’s Hospital Boston, MA Noa Dagan, M.D. Ran D. Balicer, M.D. Clalit Research Institute Tel Aviv, Israel rbalicer@ clalit . org . il and Others equally to this letter. letter at NEJM.org. Correspondence This letter was published on October 20, 2021, at NEJM.org. 1. Lopez Bernal J, Andrews N, Gower C, et al. Effectiveness of Covid-19 vaccines against the B.1.617.2 (Delta) variant. N Engl J Med 2021; 385: 585-94. 2. Puranik A, Lenehan PJ, Silvert E, et al. Comparison of two highly-effective mRNA vaccines for COVID-19 during periods of Alpha and Delta variant prevalence. August 21, 2021 (https:// www . medrxiv . org/ content/ 10 . 1101/ 2021 . 08 . 06 . 21261707v3). pre- print. 3. Herlihy R, Bamberg W, Burakoff A, et al. Rapid increase in circulation of the SARS-CoV-2 B.1.617.2 (Delta) variant — Mesa County, Colorado, April–June 2021. MMWR Morb Mortal Wkly Rep 2021; 70: 1084-7. 4. Frenck RW Jr, Klein NP, Kitchin N, et al. Safety, immunoge- nicity, and efficacy of the BNT162b2 Covid-19 vaccine in adoles- cents. N Engl J Med 2021; 385: 239-50. 5. Dagan N, Barda N, Kepten E, et al. BNT162b2 mRNA Cov- id-19 vaccine in a nationwide mass vaccination setting. N Engl J Med 2021; 384: 1412-23. Drs. Reis and Barda and Drs. Dagan and Balicer contributed A complete list of authors is available with the full text of this Supported by the Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute. Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. DOI: 10.1056/NEJMc2114290 Vaccine-Induced Thrombocytopenia with Severe Headache To the Editor: Vaccine-induced immune throm- botic thrombocytopenia (VITT), a serious adverse event after vaccination with ChAdOx1 nCoV-19 (AstraZeneca) or Ad26.COV2.S (Johnson & John- son–Janssen), is caused by platelet factor 4 (PF4)– dependent, platelet-activating antibodies.1-3 High- dose immune globulins and anticoagulation are the main treatments.4,5 In this report, we present evidence that vaccine-induced thrombocytopenia (VIT) without associated cerebral venous sinus thrombosis (CVST) or other thromboses and with severe headache as the heraldic symptom may precede VITT (“pre-VITT syndrome”). Eleven patients presented with severe head- ache in the absence of CVST 5 to 18 days after ChAdOx1 nCoV-19 vaccination. All the patients had thrombocytopenia, high d-dimer levels, and high levels of anti–PF4–heparin IgG antibodies. During follow-up, intracranial hemorrhage oc- curred in three patients (Patients 1, 2, and 3), with radiologic evidence of new CVST in Patients 2 and 3 (Fig. 1, and Table S1 in the Supplemen- tary Appendix, available with the full text of this letter at NEJM.org). Only two patients (Patients 2 and 4) were initially admitted with conditions that met the criteria for VITT; both patients had pulmonary embolism, and additional splanchnic vein thrombosis was present in Patient 2. In Patient 2, anticoagulation treatment had been initiated several days earlier for pulmonary em- bolism (without diagnosis of VITT) but was stopped after the onset of headache, shortly be- fore CVST developed. In two patients (Patients 1 and 3), peripheral thromboses were eventually identified during follow-up. Thrombotic compli- cations did not develop in seven of the patients (Patients 5 through 11); all but one of these pa- tients received high-dose immune globulin, gluco- corticoids, or therapeutic-dose anticoagulation within 5 days after headache onset. In contrast, in all four patients with subsequent thrombosis (Patients 1 through 4), therapeutic-dose antico- agulation either was not started until 6 to 9 days after headache onset or was stopped prema- turely before the development of CVST. Although the combination of thrombocytope- nia and severe headache due to CVST has been recognized as the typical presentation of VITT,1,2 the experience with these 11 patients suggests that VIT with severe headache, elevated d-dimer levels, and strongly positive results on anti–PF4– heparin IgG enzyme-linked immunosorbent as- say may precede VITT. Our findings have immediate implications for clinical practice: in this pre-VITT syndrome, severe headache may not develop as a symptom secondary to CVST but instead may precede CVST by several days, potentially in association with microthrombosis in smaller cortical veins. Consequently, patients who present with severe headache 5 to 20 days after adenovirus vector vaccination against coronavirus disease 2019 should undergo immediate testing for thrombo- cytopenia and d-dimer levels and, if available, n engl j med 385;22 nejm.org November 25, 2021 The New England Journal of Medicine Downloaded from nejm.org on October 4, 2022. For personal use only. No other uses without permission. Copyright © 2021 Massachusetts Medical Society. All rights reserved. T h e n e w e ng l a n d j o u r na l o f m e dic i n e 200,000 150,000 100,000 50,000 0 200,000 150,000 100,000 50,000 0 200,000 150,000 100,000 50,000 0 200,000 150,000 100,000 50,000 0 200,000 150,000 100,000 50,000 0 ) l µ r e p ( t n u o C t e l e t a l P 200,000 150,000 100,000 50,000 0 200,000 150,000 100,000 50,000 0 200,000 150,000 100,000 50,000 0 200,000 150,000 100,000 50,000 0 200,000 150,000 100,000 50,000 0 200,000 150,000 100,000 50,000 0 Vaccination: day −5 Patient 1 Vaccination: day −18 Immune globulin, dexamethasone Argatroban Patient 2 Immune globulin Argatroban Headache Headache Hospitalization mRS score, 2 H. mRS score, 6 0 5 10 15 20 25 40 0 5 10 15 20 25 Vaccination: day −6 Immune globulin Patient 3 Vaccination: day −14 Patient 4 Apixaban Headache Headache Dexamethasone, argatroban Enoxaparin Heparin Hospitalization Hospitalization mRS score, 0 0 5 10 15 20 25 40 0 5 10 15 20 25 Patient 5 Patient 6 mRS score, 3 Vaccination: day −9 Vaccination: day −11 Immune globulin, dexamethasone Apixaban Headache Immune globulin Argatroban Headache Hospitalization mRS score, 0 Hosp. mRS score, 0 0 5 10 15 20 25 40 0 5 10 15 20 25 Vaccination: day −6 Vaccination: day −8 Patient 7 Patient 8 0 5 10 15 20 25 40 0 5 10 15 20 25 Vaccination: day −7 Vaccination: day −8 Phenprocoumon (for atrial fibrillation) Headache Hosp. mRS score, 0 Patient 10 Apixaban (limited to 1 day because of drug exanthema) Immune globulin Apixaban Headache H. mRS score, 0 Patient 9 Immune globulin Argatroban Headache Hosp. mRS score, 0 Headache Hospitalization mRS score, 0 0 5 10 15 20 25 40 0 5 10 15 20 25 Vaccination: day −9 Rivaroxaban Patient 11 Headache Hosp. mRS score, 0 0 5 10 15 20 25 40 Days since Onset of Headache Days since Onset of Headache Onset of headache Headache Hospitalization Admission and discharge from local emergency department Surgical treatment Initiation of medical treatment Platelet count Platelet transfusion VIT without CVST (pre-VITT syndrome) VITT with cerebrovascular complication VITT with pulmonary embolism n engl j med 385;22 nejm.org November 25, 2021 The New England Journal of Medicine Downloaded from nejm.org on October 4, 2022. For personal use only. No other uses without permission. Copyright © 2021 Massachusetts Medical Society. All rights reserved. Correspondence Figure 1 (facing page). Clinical and Laboratory Data for Patients with VIT and Severe Headache (Pre-VITT Syndrome). Shown are the time courses of the manifestation of pre-VITT syndrome (defined by headache onset), hospital admission (including emergency department admission and discharge in Patients 1 and 2), platelet counts, and cerebrovascular complications (in Patients 1, 2, and 3), as well as medical and neurosurgical treatment (decompressive craniectomy). In each graph, the number of days since the on- set of headache is shown on the x axis and platelet counts on the y axis. Outcomes were assessed with the modified Rankin scale (mRS); scores on the scale range from 0 to 6, with higher scores indicating greater disability (0 indicates no symptoms, and 6 indicates death). CVST denotes cerebral venous sinus thrombosis, VIT vaccine-induced thrombocytopenia, and VITT vaccine-induced immune thrombotic thrombocytopenia. testing for anti–PF4–heparin IgG antibodies. When these antibodies are present at high titers, patients are at imminent risk for CVST, and it is likely that this condition can be prevented with immediate treatment, such as with intravenous immune globulin. The decision to initiate thera- peutic-dose anticoagulation is a difficult one; the risk of emerging thrombosis, including CVST, has to be balanced against the risk of intracra- nial hemorrhage on an individual basis (e.g., with consideration of platelet count and fibrino- gen levels). Farid Salih, M.D. Charité-Universitätsmedizin Berlin Berlin, Germany farid.salih@charite.de Linda Schönborn, M.D. Universitätsmedizin Greifswald Greifswald, Germany Siegfried Kohler, M.D. Christiana Franke, M.D. Martin Möckel, M.D. Thomas Dörner, M.D. Hans C. Bauknecht, M.D. Christian Pille, M.D. Jan A. Graw, M.D. Charité-Universitätsmedizin Berlin Berlin, Germany Angelika Alonso, M.D. University Hospital of Mannheim Mannheim, Germany Johann Pelz, M.D. University Hospital of Leipzig Leipzig, Germany Hauke Schneider, M.D. Antonios Bayas, M.D. Monika Christ, M.D. University Hospital of Augsburg Augsburg, Germany Joji B. Kuramatsu, M.D. University Hospital of Erlangen Erlangen, Germany Thomas Thiele, M.D. Andreas Greinacher, M.D. Universitätsmedizin Greifswald Greifswald, Germany andreas.greinacher@med.uni-greifswald.de Matthias Endres, M.D. Charité-Universitätsmedizin Berlin Berlin, Germany matthias.endres@charite.de Profs. Greinacher and Endres contributed equally to this letter. Supported by Deutsche Forschungsgemeinschaft project number 374031971–TRR 240 (to Prof. Greinacher) and EXC- 2049–390688087 NeuroCure under the German Excellence Strategy (to Prof. Endres) and by the Domagk-Programm of the Universitätsmedizin Greifswald (to Dr. Schönborn). Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. This letter was published on September 15, 2021, at NEJM.org. 1. Long B, Bridwell R, Gottlieb M. Thrombosis with thrombo- cytopenia syndrome associated with COVID-19 vaccines. Am J Emerg Med 2021; 49: 58-61. 2. Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S. Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination. N Engl J Med 2021; 384: 2092-101. 3. Scully M, Singh D, Lown R, et al. Pathologic antibodies to platelet factor 4 after ChAdOx1 nCoV-19 vaccination. N Engl J Med 2021; 384: 2202-11. 4. Bussel JB, Connors JM, Cines DB, et al. Thrombosis with thrombocytopenia syndrome (also termed vaccine-induced thrombotic thrombocytopenia), version 1.6. American Society of Hematology, August 12, 2021 (https://www . hematology . org/ covid - 19/ vaccine - induced - immune - thrombotic - thrombocytopenia). 5. Bourguignon A, Arnold DM, Warkentin TE, et al. Adjunct immune globulin for vaccine-induced thrombotic thrombocyto- penia. N Engl J Med 2021; 385: 720-8. DOI: 10.1056/NEJMc2112974 Efpeglenatide and Heart and Kidney Outcomes in Type 2 Diabetes To the Editor: In the AMPLITUDE-O trial, Ger- stein et al. (Sept. 2 issue)1 found a lower risk of cardiovascular events among participants with type 2 diabetes who received a weekly injection of efpeglenatide than among those who received placebo. This trial confirms the interest in gluca- n engl j med 385;22 nejm.org November 25, 2021 The New England Journal of Medicine Downloaded from nejm.org on October 4, 2022. For personal use only. No other uses without permission. Copyright © 2021 Massachusetts Medical Society. All rights reserved.