key: cord-0717091-o0kvmgqb authors: Arepally, GM; Ortel, TL title: Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT): What We Know and Don't Know date: 2021-06-03 journal: Blood DOI: 10.1182/blood.2021012152 sha: bad3913eb83e7670a536a992be439584f36abfc5 doc_id: 717091 cord_uid: o0kvmgqb Development of vaccines to fight COVID19has been a remarkable medical achievement. However, this global immunization effort has been complicated by arare vaccine-related outcome characterized by thrombocytopenia and thrombosisin association with platelet-activating anti-platelet factor 4 antibodies.In this Spotlight article, we will discuss the recently described complication of vaccine-induced immune thrombotic thrombocytopenia (VITT)occurring in response to certain COVID19 vaccines. Although information about this clinical condition is rapidly evolving, we will summarize our current understanding of VITT. Development of vaccines to fight COVID19 has been a remarkable medical achievement. However, this global immunization effort has been complicated by a rare vaccine-related outcome characterized by thrombocytopenia and thrombosis in association with platelet-activating anti-platelet factor 4 antibodies. In this Spotlight article, we will discuss the recently described complication of vaccineinduced immune thrombotic thrombocytopenia (VITT) occurring in response to certain COVID19 vaccines. Although information about this clinical condition is rapidly evolving, we will summarize our current understanding of VITT. The global effort to curb the spread of the COVID19 infection has been remarkable for its speed and efficacy. Within one year of the arrival of SARS-CoV-2 virus on the world stage, pharmaceutical companies developed and delivered vaccines that have dramatically reduced the burden of COVID19 disease. In the United Kingdom (UK), one dose of commercially approved vaccines effectively reduced hospitalization and death by >80% 1 while in the United States (US) hospitalization rates from COVID19 were reduced by 67% and 94% with single and dual vaccination, respectively. 2 In late February 2021, initial descriptions of a safety signal emerged with the adenoviral-based (ChAdOx1-S) COVID19 vaccine distributed by Astra Zeneca(AZ). 3, 4 These reports detailed otherwise healthy individuals developing complications of thrombocytopenia and thrombosis in atypical locations (cerebral and/or splanchnic veins) within weeks of receiving the vaccination. By mid-April 2021, similar complications were described with another adenoviral-based vector (recombinant Ad26.COV2.S) distributed by Johnson & Johnson (J&J). 5, 6 This syndrome has been variably referred to as vaccineinduced immune thrombotic thrombocytopenia (VITT), or thrombosis with thrombocytopenia syndrome (TTS). For this article, we will use the more specific term VITT, given the temporal relationship of disease with COVID19 vaccination. Although descriptions of VITT are recent (less than three months as of this publication), published case reports/case series are relatively few, and research is limited, there is coalescing knowledge about the epidemiology, pathogenesis, diagnosis, and management of this syndrome. In this Spotlight article, we will review what is currently known and unknown about VITT. We know that VITT is a safety signal from adenoviral-based vectors. What made this safety signal discernible was the concurrent presentation of thrombocytopenia and thrombosis, a rare occurrence in the general population and those immunized with non-adenoviral based SARS-CoV-2 vaccines. As of 5/12/21, the estimated incidence of VITT is ~7-10 cases per million individuals with the AZ vaccine (~309 cases reported out of 32.9 million doses given in the United Kingdom) 7 and ~3.2 per million (or 28 cases out of 8.7 million doses administered in the US) for the J&J vaccine 5 (See Table 1 ). The reported rates for the J&J vaccine likely underestimate the true incidence of disease, given the shorter period of J&J vaccine availability (emergency use authorization granted in the US on 2/27/21) and delays in reporting of the syndrome. The epidemiology of VITT must be considered in the context of similar complications in the general population. The annual incidence of isolated thrombocytopenia, such as immune thrombocytopenia (ITP), or isolated cerebral vein thrombosis (CVT) is higher than that reported for VITT, but when adjusted for the two-week time frame characteristic of VITT presentations, corresponding rates are lower than that of VITT. ITP in the general population occurs in 16-39 cases per million (or 0.61-1.5 cases per million in any 2-week period), 8, 9 while isolated CVT is reported in 13-20 cases per million (0.5-0.77 cases per million in any 2-week period). 10, 11 While there are no formal studies of thrombocytopenia in association with CVT, other well-known thrombotic thrombocytopenic syndromes, such as thrombotic thrombocytopenic purpura and/or atypical hemolytic uremic syndrome, occur at a frequency of 11.3 cases per million (or 0.43 cases per million in any 2-week period). Hematologic complications of either isolated ITP or CVT occurring in the wake of COVID19 vaccination also appear to be lower than reported rates of VITT. Complications of ITP for the two messenger ribonucleic acid( mRNA)-based vaccines have been estimated to occur in 0.8-1 cases per million, based on reporting to the Vaccine Adverse Event Reporting System (VAERS), 12 while isolated CVT after vaccination with BioNTech/Pfizer is ~4 cases per million (2 of 489,871). 13 There is also persuasive epidemiologic data on VITT to suggest a class effect among vaccines. The two We have preliminary insights into VITT pathogenesis. Published reports indicate that VITT is: 1) an immune complication resembling a variant of autoimmune heparin-induced thrombocytopenia (aHIT), 2) unlikely a byproduct of COVID19 infection and 3) independent of anti-SARS-CoV2 protective immunity. Demonstration of circulating anti-PF4 antibodies in conjunction with thrombocytopenia and thrombosis suggest that VITT is a clinical variant of aHIT. [3] [4] [5] [6] 14, 15 Anti-platelet factor 4 (PF4) antibodies are the hallmark of HIT, a thrombotic disorder caused by the anticoagulant drug heparin. Spontaneous HIT, a rare manifestation of HIT, occurs without prior heparin exposure and in most cases, is precipitated by recent infection and/or orthopedic surgery. 16 While disease manifestations in HIT are caused by antibodies directed to ultra-large complexes of PF4 bound to heparin or polyanions, such as glycosaminoglyans, polyphosphate, deoxyribonucleic acid, [17] [18] [19] [20] [21] aHIT is associated with anti-PF4 antibodies whose functional effects are largely independent of heparin or polyanions. 16 Pathogenic anti-PF4/heparin antibodies cross-link FcRIIA on platelets, monocytes and neutrophils to initiate procoagulant cellular responses that generate a profound hypercoagulable state. 22 Thrombotic risk in HIT and/or aHIT is strongly correlated with high levels of circulating anti-PF4 antibodies, as detected by immunoassays and/or functional assays of platelet activation. [23] [24] [25] It is also clear from recent data that VITT is not an aberrant clinical manifestation of COVID19 infection. While COVID19 is recognized as a hypercoagulable disorder, complications of CVT with or without thrombocytopenia are uncommon in the wake of infection. In a recent study of ~500,000 patients with documented COVID19, 20 patients developed CVT (0.004%), while thrombocytopenia with CVT was noted in only 1 patient. 13 As well, most VITT patients do not have active COVID19 infection as documented by negative SARS-CoV-2 RNA testing at time of disease presentation. 3, 4, 14, 15, 26 The immune responses to SARS-CoV-2 proteins and PF4, as seen in COVID19 and VITT patients, respectively, are also non-overlapping. While high levels of anti-PF4 antibodies are present in nearly all patients with VITT, 3, 4, 6, 14, 15, 26 anti-PF4 antibodies are found at the expected prevalence (~8-12%) in hospitalized patients with COVID19, who are likely exposed to heparin during treatment. 27, 28 There are also no significant differences in the incidence of anti-PF4 antibodies in COVID19 patients with and without thrombosis to support a pathogenic role for anti-PF4 antibodies. 27 Finally, serologic studies do not show antigen cross reactivity between anti-SARS-CoV-2 and anti-PF4 antibodies, signifying that anti-PF4 antibodies are unlikely a by-product of anti-SARS-CoV-2 immunity. 27 We recognize that VITT is a clinically distinctive syndrome with 1) a propensity for cerebral and/or splanchnic vein thromboses 2) laboratory features showing consumptive coagulopathy in association with anti-PF4 seropositivity and 3) poor outcomes. To date, the largest number of cases with VITT seen in association with the AZ (n= 242) and J&J (n=15) have been reported by the Medicines and Health Care Products Regulatory Agency in the UK and CDC in the US, respectively (See Table 1 ). 5, 7 While initial reports indicated disease predisposition in younger females, 3,4,14,15 a larger data set from the UK 7 suggest a more modest age and gender imbalance. Disease incidence appears to be lower among individuals over the age of 70 (18% with AZ and none with J&J) with a slight female predominance (1.4:1, F:M for AZ; see Table 1 ). Published case series do not show any consistent association with medical co-morbidities, including use of oral contraceptive pills, hormonal therapy, cardiovascular disease or thrombophilia. 3, 4, 14, 15 The majority of subjects present after one dose of vaccine, often within weeks of immunization. [3] [4] [5] 7, 14, 15 Presenting symptoms are reflective of underlying thrombosis and include headaches, nausea, vomiting and/or abdominal pain. CVT is the most common site of thrombosis in reported series and occurs in 38-80% of reported cases, [3] [4] [5] [6] [7] 14, 15 followed by involvement of the splanchnic bed (portal, spleen and/or mesenteric veins). These atypical sites of thrombosis in VITT stand in distinction to in HIT and aHIT, where thromboses occur in more typical locations, such as deep venous thrombosis, pulmonary embolism and/or arterial thromboses. [29] [30] [31] [32] The laboratory features of VITT indicate a consumptive coagulopathy (thrombocytopenia, low fibrinogen and elevated D-dimer), which is only seen in the most severe cases of HIT 33 . When performed, tests for acquired thrombophilias such as anti-phospholipid antibodies, paroxysmal nocturnal hemoglobinuria, ADAMTS13 deficiency and myeloproliferative neoplasms are usually normal. [3] [4] [5] 7, 14, 15 Circulating anti-PF4/heparin antibodies are detectable in most patients using enzyme-linked immunosorbent assays (ELISA), but not by latex immunoturbidometric assays (LIAs) a technique that relies on competitive inhibition with latex particles coated with a monoclonal HIT-like monoclonal antibody. 14, 15, 34 While most reports demonstrate a strong correlation of anti-PF4 seropositivity with functional assays of platelet activation, 3,4,14 one recent case series of J&J vaccine subjects indicate low rates of positivity in functional assays (only 1/9 VITT subjects had platelet activating antibodies). 15 Clinicians should be aware that functional studies may yield false negative results in VITT, as standard platelet activation assays for detection of HITT antibodies, such as the serotonin release assay, rely on low (0.1 -1 U/ml) and high (10-100 U/ml) doses of heparin to demonstrate heparin-dependent activity. VITT antibodies show PF4dependent activity and may lose reactivity in the presence of heparin. 27 Ideally, functional assays for VITT antibodies should be performed in the presence and absence of added PF4. VITT is a morbid complication associated with high fatality rates. Where reported, cerebral hemorrhage complicates thrombosis in 26%-80% of published case series 3, 4, 14, 15 and is the leading cause of death. Case fatality in patients with VITT is ~20% (Table 1) , likely due to delayed recognition of clinical symptoms and signs by affected individuals and/or providers. It is too early to understand the long-term outcomes in those recovering from CVT and/or splanchnic vein thromboses. We have sufficient evidence in the form of shared clinical and laboratory features between VITT and aHIT to approach the management of VITT as a HIT-like syndrome. In the published case series, treatment with UFH or LMWH and/or platelet transfusions may have contributed to disease progression, 4,14 while treatment with non-heparin anticoagulants and IVIG was often associated with recovery. Based on these reports and established protocols for treatment of HIT, we recommend the following approach to the management of VITT patients (See If imaging studies reveal thrombosis, we recommend hospitalization, initiation of treatment with nonheparin anticoagulants and avoidance of platelet transfusions. A significant proportion of these patients also have intracerebral hemorrhage, however, which can complicate initial management. Although current neurosurgical guidelines recommend anticoagulation in those with intracranial hemorrhage, 36, 37 anticoagulation decisions in this setting should be individualized and occur in collaboration with neurological or neurosurgical specialists. Adjunctive therapies for management of severe VITT thromboses include treatments used for refractory HITT, such as IVIG, 38,39 plasma exchange, 40,41 and mechanical thrombectomy. 42, 43 For bleeding complications, we suggest IVIG and/or prednisone to improve platelet counts and cryoprecipitate and/or FFP for correction of coagulopathy. Case reports also indicate that patients may present with thrombocytopenia, coagulopathy and anti-PF4 antibody positivity, but without thrombosis, 44 in which case, patients should be managed similarly as patients with thrombosis using non-heparin anticoagulants until platelet counts and coagulopathy resolve. Once patients recover, we recommend continuing oral anticoagulation for a minimum of three months. For additional guidance on diagnosis and management, the reader is referred to recent guidelines based on expert opinion from the American Society of Hematology, 45 International Society on Thrombosis and Haemostasis, 46 We concede that the knowledgebase informing this review is currently limited, emerging data may shift our current understanding and there remain many more unknowns than knowns. We still do not have clarity on the incidence of disease and impact of age, gender and race, as surveillance systems are passive, and many cases are likely unreported. Whether the class effects and differences seen in VITT incidence associated with AZ and J&J vaccines are related to the DNA cargo, contaminants, the adenovirus vector itself is also unknown at this time. A number of questions remain about PF4's causative role in the immune response and identification of biomarkers and/or genetic susceptilibity that could portend thrombotic risk. Finally, there remain uncertainties regarding management and longterm outcomes-how long should patients be treated with anticoagulation, are future adenoviral-based vaccines or therapies contraindicated, should VITT patients avoid heparin in their future? Despite these unknowns, our knowledge of this disease has progressed at a remarkable pace. With increased disease awareness and recognition of this syndrome by providers and the public, alike, future cases should help refine our clinical understanding and improve clinical outcomes. 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Safety of heparin use Successful treatment of vaccine-induced prothrombotic immune thrombocytopenia (VIPIT) Thrombosis with Thrombocytopenia Syndrome (also termed Vaccine-induced Thrombotic Thrombocytopenia) Recommendations for the clinical and laboratory diagnosis of VITT against COVID-19: Communication from the ISTH SSC Subcommittee on Platelet Immunology Guidance from the Expert Haematology Panel (EHP) on Covid-19 Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT) GMA serves as a consultant for Astra Zeneca and Novartis. TLO has no relevant conflicts to disclose. GMA and TLO wrote and reviewed the manuscript.