Michele Romoli, MD, PhD, FEBN – Neurology and Stroke Unit, Bufalini Hospital, Cesena, Italy

Diana Aguiar de Sousa, MD, PhD, Stroke Center, Lisbon Central University Hospital, Lisboa; Instituto de Medicina Molecular; Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal

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Cerebral venous thrombosis (CVT) is a less common type of stroke, happening approximately in 1.5:100’000 adults1. A surge of interest in CVT has developed over the last years, particularly in relation to the recent pandemic. As COVID-19 spread through nations, and vaccination campaigns rolled out worldwide, reports on CVT during infection or after immunization have accumulated2,3. Several factors can contribute to CVT, including oral contraception, pregnancy or hormonal treatments, thrombophilia, cancer and several medications. Often CVT can be a first manifestation of a systemic condition. Examples of this type of situation can be when CVT develops as part of an autoimmune-mediated thrombocytopenia, as for heparin-induced thrombocytopenia (HIT)4 or as part of a vaccine-induced thrombocytopenia (VITT), with thrombosis happening also at other uncommon sites3,5.

After heparin exposure, heparin-induced thrombocytopenia (HIT) can develop, with a concrete risk of developing thrombosis at both arterial and venous sites4,6. HIT, either in classical and autoimmune form, is not just a drug-induced thrombocytopenia, as it is based on an autoimmune process, which also justifies the timing of onset, usually 5 days after heparin exposure. In classical  HIT, antibodies form against platelet factor 4 (PF4), a tetramer that has an heparin-binding site but also heparin-independent binding sites for other antigens7. In HIT, heparin-dependent antibodies against PF4 form PF4/heparin/IgG immune complexes. This leads to moderate platelet consumption and thrombin formation, with a prothrombotic state. Such mechanism differs from other drug-induced thrombocytopenia (e.g., vancomycin), which usually have a steep decrease in platelet count, due to direct platelet clearance (disruption). Is CVT common in HIT? Based on a recent systematic review, CVT develops in 1.6% of people with HIT4. Despite being uncommon, HIT-related CVT carries a 82% rate of hemorrhagic lesions and has a 33% mortality, which is higher compared to CVT without HIT, but also compared to HIT alone4. Management is based on withdrawing heparin, as this promotes the formation of PF4/heparin/IgG complexes, and use of non-heparinoid anticoagulants, including vitamin-K antagonists or direct oral anticoagulants4.  As a delay in identification translates into less accurate management, early suspicion is crucial.

VITT develops in relation to heparin-independent antibodies, although also with formation of PF4/IgG complexes leading to platelet consumption, clearance and pancellular activation7. VITT represents a very rare adverse effect of adenovirus-based SARS-CoV2 vaccines that may occur in the first 30 days after vaccination with ChAdOx1 nCov-198, especially in younger age groups9. Thrombocytopenia can be severe, and thrombosis can happen at unusual sites, including the splanchnic vein. CVT is critically more frequent in VITT compared to HIT, a further point suggesting that main or secondary pathophysiological mechanisms differ4. VITT diagnostic criteria also include low platelet count (<150 × 109/L), elevated plasma D-dimer levels (>0.5 mg/L), and positive test for anti-PF4 (platelet factor 4) antibodies8,10. Management has to focus on immediate immunomodulation, including intravenous immunoglobulin (1 mg/kg/d for 2 days) and/or plasma exchange. Anticoagulation can be started directly with non-heparinoids, although it is currently not clear whether heparin has a deleterious effect11,  and platelet transfusion should be avoided unless for treating a life-threatening bleeding or before surgery10.

Despite sharing an autoimmune mechanism, VITT and HIT differ for thrombotic complications and mortality. Despite the rarity of this syndrome, CVT is critically more frequent in VITT compared to HIT4. Efforts should be made to adhere to treatment recommendations, as this might improve survival12.

References

  1. Coutinho JM, Zuurbier SM, Aramideh M, et al. The Incidence of Cerebral Venous Thrombosis. Stroke 2012; 43: 3375–3377.
  2. Baldini T, Asioli GM, Romoli M, et al. Cerebral venous thrombosis and severe acute respiratory syndrome coronavirus-2 infection: A systematic review and meta-analysis. Eur J Neurol. Epub ahead of print 2021. DOI: 10.1111/ene.14727.
  3. See I, Su JR, Lale A, et al. US Case Reports of Cerebral Venous Sinus Thrombosis with Thrombocytopenia after Ad26.COV2.S Vaccination, March 2 to April 21, 2021. JAMA – J Am Med Assoc 2021; 325: 2448–2456.
  4. Aguiar de Sousa D, Romoli M, Sánchez Van Kammen M, et al. Cerebral Venous Thrombosis in Patients With Heparin-Induced Thrombocytopenia a Systematic Review. Stroke 2022; 53: 1892–1903.
  5. Schultz NH, Sørvoll IH, Michelsen AE, et al. Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination. N Engl J Med 2021; 384: 2124–2130.
  6. Warkentin TE. Think of HIT. Hematol Am Soc Hematol Educ Progr 2006; 408–414.
  7. Warkentin TE. Platelet-activating anti-PF4 disorders: An overview. Semin Hematol 2022; 59: 59–71.
  8. Pavord S, Scully M, Hunt BJ, et al. Clinical Features of Vaccine-Induced Immune Thrombocytopenia and Thrombosis. N Engl J Med 2021; 1–10.
  9. Krzywicka K, Van De Munckhof A, Van Kammen MS, et al. Age-Stratified Risk of Cerebral Venous Sinus Thrombosis after SARS-CoV-2 Vaccination. Neurology 2022; 98: E759–E768.
  10. Ferro JM, Sousa DA de, Coutinho JM, et al. European stroke organization interim expert opinion on cerebral venous thrombosis occurring after SARS-CoV-2 vaccination. Eur Stroke J 2021; 6: CXVI–CXXI.
  11. Singh A, Toma F, Uzun G, et al. The interaction between anti-PF4 antibodies and anticoagulants in vaccine-induced thrombotic thrombocytopenia. Blood 2022; 139: 3430–3438.
  12. Scutelnic A, Krzywicka K, Mbroh J, et al. Management of cerebral venous thrombosis due to adenoviral COVID-19 vaccination This article is protected by copyright . All rights reserved . DOI: 10.1002/ana.26431.