COVID-19 Adenoviral Vaccine-Induced Immune Thrombotic Thrombocytopenia

COVID-19 Adenoviral Vaccine-Induced Immune Thrombotic Thrombocytopenia: History

Please note this is an old version of this entry, which may differ significantly from the current revision.

Contributor:

Adenoviral-based vaccines such as ChadoX1 CoV-19 (AstraZeneca) and Ad26.COV2.S (J&J) were developed to prevent infection and reduce hospitalization or death in Coronavirus Disease 2019 (COVID-19) patients. These vaccines passed safety and efficacy trials with excellent neutralizing capabilities against SARS-CoV-2, very rare reports of acute thrombotic thrombocytopenic events following administration emerged in certain populations, which triggered a series of clinical investigations that gave rise to a novel phenomenon called vaccine-induced immune thrombotic thrombocytopenia (VITT).

thrombocytopenia
VITT
HIT
TTP
COVID-19

1. Introduction

The ChAdOx1 nCoV-19 (Vaxzervia^®) vaccine by AstraZeneca uses a simian-derived adenoviral vector encoding the codon-optimized full-length spike protein of SARS-CoV-2 ^[1]. Similarly, the Ad26.COV2.S vaccine (Janssen COVID-19) makes use of the Ad26 adenoviral vector to carry the spike protein gene and express it in cells bound by the non-replicating adenovirus ^[2]. Preliminary studies in millions of vaccinated individuals across various populations have shown significant vaccine efficacies for Vaxzervia^® (70.4%), in addition to its advantage of being cheaper and more accessible to developing countries, with an apparent increase in efficacy (90.0%) when given as a low-dose/standard-dose (LD/SD) two-dose regimen, according to pooled clinical trial results in the UK, South Africa, and Brazil ^[3]^[4]. This was shortly followed by the release of the Janssen COVID-19 vaccine by J&J, which was touted to be a more attractive and efficient option due to its one-dose regimen and excellent safety and efficacy profiles, preventing 66.1–66.9% of moderate or severe COVID-19 and up to 100% of hospitalizations compared with a placebo ^[5]^[6]. However, as surveillance reports in real-world studies would eventually reveal, very rare and unusual thrombotic thrombocytopenic complications in some populations taking the ChAdOx1 CoV-19 vaccine began to surface, stirring public health concerns. By March of 2021, many European countries issued decrees halting the administration of the said vaccine in favor of clinical investigation and research on vaccine efficacy against variants of concern and on reports of blood clotting events ^[7]^[8]. By April, several cases of cerebral venous sinus or splanchnic vein thromboses were reported by the European Medical Agency (EMA) through EudraVigilance, which led them to conclude that a very rare association between Vaxzevria^® vaccine exposure and the development of clotting disorders is present ^[9]. Subsequently, cases of thrombotic thrombocytopenia were also reported among patients vaccinated with Ad26.CoV2.S (Janssen), with anti-PF4 antibodies reportedly persistent for up to 5 months ^[9]^[10]^[11]. Current estimates show that the incidence of this novel and controversial phenomenon, later coined as vaccine-induced immune thrombotic thrombocytopenia (VITT), ranges from 1/26,500 to 1/127,300 persons and 1/518,181 persons vaccinated with the first and second doses of ChadOx1 nCoV-19, respectively. Meanwhile, the incidence of VITT is estimated to be at 1/263,000 persons vaccinated with a single dose of Ad26.COV2.S ^[12].

The phenomenon of VITT provides novel issues for patient care, vaccine development, and basic human physiology. Firstly, VITT remains a unique complication of adenoviral COVID-19 vaccines ^[13]. Secondly, the laboratory findings of VITT and spontaneous heparin-induced thrombocytopenia and thrombosis (HITT) are similar. They both show increased levels of anti-PF4 antibodies in the serum of patients with a thrombotic thrombocytopenic profile, warranting clarification and further investigation. Thirdly, VITT creates a new age risk group prone to developing the disease, which may lead to additional physical examination findings and management differences in patients suspected of having VITT.

The similarities between HITT and VITT lead to significant implications in patient disease and management and warrant a thorough investigation of their mechanisms for timely and effective treatment of the disease and its complications. However, little is known about VITT, and distinguishing it from the many syndromes of thrombotic thrombocytopenia can be difficult for inexperienced clinicians and researchers seeking to find treatment, despite the existence of recently published guidelines.

2. Clinical Manifestations, Diagnosis, and Treatment of HITT and VITT in Relation to Other Thrombotic Thrombocytopenic Syndromes

In many cases of thrombocytopenia, bleeding occurs due to a deficiency in circulating platelets, with clinical manifestations ranging from multiple petechiae or ecchymoses to spontaneous bleeding of the mucosa. In some cases, thrombocytopenia results from systemic factor activation that leads to a paradoxical increase in clot formation. This can be due to platelet activation by antiplatelet antibodies or by a defective von Willebrand factor (VWF), which result in aggregation and the inappropriate recruitment of other coagulation factors. A depletion of circulating platelets may then occur, which may explain paradoxical clotting in the setting of thrombocytopenia. Of the thrombocytopenic diseases known, paradoxical thrombosis occurs in heparin-induced thrombocytopenia (HIT), thrombotic thrombocytopenic purpura (TTP,) and hemolytic–uremic syndrome (HUS). Researchers briefly discuss each syndrome in terms of their physiopathology, clinical manifestations, diagnoses, and treatments, followed by their similarities and differences with those of VITT.

Heparin, or low-molecular-weight heparin (LMWH), which is normally given to patients requiring anticoagulation for prophylaxis or as a treatment for arterial or venous thromboembolism ^[14], acts by binding to the inhibitor antithrombin III to optimize its active site and increase its enzymatic activity ^[15]. In some cases, heparin binds to platelets and activates them, resulting in the release of platelet factor 4 (PF4) stored in its alpha granules, which are normally beneficial during vascular injury ^[16]^[17]. Unfortunately, PF4 can also be bound by heparin, and the PF4–heparin complex undergoes a conformational change to expose novel epitopes, which then lead to the formation of anti-PF4/heparin antibodies that are characteristic of HIT. The formed anti-PF4/heparin antibodies then bind the platelet’s FcγRIIa receptor, leading to further platelet activation ^[18]^[19], ultimately leading to platelet depletion and clotting, which are characteristics of heparin-induced thrombocytopenia with thrombosis (HITT).

Clinically, HIT does not lead to bleeding and thrombocytopenia is usually not severe ^[19], with deep vein thrombosis (DVT) being the most widely recognized manifestation, resulting in extremity gangrene, pulmonary embolism, or myocardial infarction in untreated cases ^[20]^[21]. This contrasts with the clinical manifestations of VITT, which include venous thrombosis of the CNS, adrenal, or splanchnic veins ^[22]. In addition, HIT is associated with exposure to low-molecular-weight heparin (LMWH) of unfractionated heparin (UFH), occurring within 5–14 days after exposure to heparin and is usually suspected using the 4T algorithm of (1) thrombocytopenia, (2) timing of decrease in platelet count, (3) thrombosis or localized skin reaction, and (4) non-evidence of other causes of thrombocytopenia. Although not all features may be present in a single patient, a score of 6–8 points suggest a high probability (about 50%) of diagnosing HIT, albeit with risks of overestimation in the ICU setting ^[19]. This phenomenon was formerly known as Type II HIT, where antibodies form against the PF4/heparin complex in autoimmune-mediated thrombotic thrombocytopenia. This was contrasted with Type I HIT, where heparin interacts directly with platelets, causing depletion via sequestration secondary to platelet clumping, which occurs within 48–72 h of heparin administration and does not involve an autoinflammatory reaction ^[23]. In contrast, a history of receiving an adenoviral vector-based vaccine for COVID-19 can prove to be essential information during history taking when considering a differential of HIT, such as VITT.

For confirmation, the presence of anti-PF4/heparin antibodies via ELISA or the ability of the patient serum to activate heparin–platelet solutions, called the platelet activation assay, typically supports the diagnosis with high specificity. In cases where a spontaneous HIT is suspected to occur, a platelet serotonin release assay (SRA) can be done in conjunction with or after performing an anti-PF4/heparin ELISA, which can support the diagnosis when peak serotonin release is greater than 80 percent at 0.1–0.3 U/mL heparin or greater than 50 percent in the absence of heparin exposure (0 IU/mL), in addition to at least two strongly positive PF4 enzyme immune assays (EIAs) and other characteristic features of HIT, such as inhibition at 100 IU/mL heparin or with Fc receptor-blocking antibodies in a patient who lacks a proximal history of heparin exposure ^[24].

For patients requiring anticoagulation for HIT, discontinuation of heparin and shifting to an alternative anticoagulant is warranted. To prevent thrombosis, a direct thrombin inhibitor (DTI) such as argatroban, an antithrombin pentasaccharide, such as fondaparinux, or the anti-Xa compound danaparoid may be used for antithrombosis, which are also given to VITT patients who require non-heparin anticoagulants. In the presence of thrombosis in HIT, patients can be treated with warfarin for 3 to 6 months, usually overlapped with a DTI or another antithrombin-binding compound such as fondaparinux to prevent venous gangrene ^[19]. In contrast, warfarin is contraindicated in VITT due to an increased risk of thrombosis or bleeding with no apparent benefit ^[25].

As opposed to HIT/T, thrombotic thrombocytopenic purpura (TTP) classically presents as a pentad in full-blown syndromes, characterized by microangiopathic hemolytic anemia, fever, thrombocytopenia, acute renal failure, and an altered mental status secondary to a seizure or stroke ^[26]. However, early detection in modern medicine has made it possible to no longer require the pentad in raising a high clinical suspicion for disease.

Of the cases of TTP, the acquired form is more common and occurs more frequently in women, which is typically described by the presence of autoantibodies against the metalloprotease ADAMTS13, an enzyme that cleaves the von Willebrand factor (VWF). In contrast, acquired cases are described by a mutation or deficiency in the activity of ADAMTS13, which occur less frequently and are usually detected in childhood. Both forms of TTP accumulate uncleaved VWFs, which then promote platelet aggregation and thrombosis. Clinically, an increased lactate dehydrogenase (LDH), indirect bilirubin, and reticulocyte counts are seen, among others. In terms of treatment, plasma exchange for at least two days remains the mainstay of treatment for TTP to normalize the platelet count and resolve the signs of hemolysis ^[26]. Although plasma exchange can also be beneficial in HIT, the concept of platelet transfusion can prove fatal in this syndrome, as new platelets can provide substrates that can further aggravate thrombosis ^[27]. Meanwhile, plasma exchange therapy remains to be an effective option for some patients with VITT.

A related, albeit less common, disease called hemolytic–uremic syndrome (HUS) can similarly present like TTP, with clinical findings such as acute renal failure (ARF), microangiopathic hemolytic fever, and thrombocytopenia preceded by diarrhea in typical cases caused by Shiga toxin-producing Escherichia coli. In atypical cases (aHUS), a mutation or autoantibody to factor H is more commonly seen, which prevents factor H-mediated inhibition of C3b and promotes the classical and alternative complement pathways in plasma-exposed cells ^[28]. As opposed to TTP and VITT, plasma exchange does not seem to affect the clinical outcomes of patients with HUS or aHUS, and treatment is primarily supportive, which may or may not include the anti-C5 antibody eculizumab ^[26].

As aforementioned earlier in this text, patients with VITT tend to present with neurologic signs (headache, visual disturbances, drowsiness), in addition to fever, mild bruising, and petechiae, as early as 4–28 days post-vaccination ^[20]. Similar to spontaneous HIT, antibodies against PF4 are produced without a proximal exposure to heparin, which current mechanisms suggest is a result of interactions between PF4 and vaccine constituents such as the adenoviral capsid and some non-assembled hexon proteins, promoted by pro-inflammatory molecules such as EDTA or possibly some trace human cell proteins ^[29]. Laboratory findings may include thrombocytopenia >15,000 cells/mm³ but which has been described to be as low as 7000 to 10,000 cells/mm³. In addition, elevated D-dimer levels by up to five times the upper normal limit are also seen, with a mild to moderate increase in variable international normalized ratios (INRs). More importantly, the presence of anti-PF4 antibodies as early as 7 to 10 days post-COVID-19 vaccination, to as late as 24 to 30 days in delayed presentations, is usually documented ^[27]^[30]. Although laboratory findings in VITT resemble that of disseminated intravascular coagulation (DIC), such as normal to decreased fibrinogen, elevated D-dimer levels, and moderate to severe thrombocytopenia, contrasting features include a predominance of thrombosis in VITT and a normal to mildly elevated PT/aPTT or INR ^[22]^[26]. To date, guidelines established by credible medical associations to formalize the diagnosis and management of VITT include those published by the National Institute for Health and Care Excellence (NICE) and the American Society of Hematology, which are summarized in Table 1 ^[31]^[32].

Table 1. Clinical features, diagnosis, and treatment of thrombotic thrombocytopenic syndromes.

	VITT	HITT	TTP	HUS/aHUS
Mechanism	- Adenoviral capsid interacts with PF4 - Non-assembled hexon proteins also interact with PF4 - Non-viral binding partners currently unclear - Leads to formation of anti-PF4 antibodies	- LMWH binds to platelets causing the release of PF4 - LMWH also binds to PF4, leading to anti-PF4/heparin antibody production - Leads to platelet aggregation and thrombosis - In heparin-independent HIT, anti-PF4 antibodies are formed	- Acquired: antibodies more commonly form against ADAMTS13 - Hereditary: mutation or deficiency in ADAMTS13 less common - Retains uncleaved Von Willebrand Factor (VWF) - Both promotes platelet aggregation and thrombosis	- Typical HUS: Shiga toxin-producing E. coli causes an immune response to factor H, promoting activation of C3b - Atypical HUS: mutations or autoantibodies to key factors (H, I) prevent C3b inhibition
Clinical manifestations	- Neurologic signs (headache, visual disturbances, drowsiness) - Bruising or petechiae with fever; less likely are signs and symptoms of DVT - Occurs 7–10 days after vaccination with ChAdOx1 nCoV-19 (AstraZeneca) or Ad26.COV2.S (Janssen) COVID-19 vaccines - Delayed detection usually up to 24 to 30 days post-vaccination	- 4T algorithm: thrombocytopenia without bleeding, timing within 5–14 days after heparin administration, thrombotic signs and symptoms (significant Wells score or signs of DVT, skin necrosis at heparin injection site), other causes of thrombocytopenia excluded	- Characteristic pentad: jaundice or pale conjunctiva (microangiopathic hemolytic anemia), purpura or ecchymoses (thrombocytopenia), renal failure, neurologic findings (headache, dizziness, seizures, visual disturbances), fever - May develop some but not all clinical signs; pentad not required for diagnosis	- Microangiopathic hemolytic anemia - Thrombosis resulting in acute renal failure, seizure, or stroke - Signs of uremia, bruising, petechiae, or ecchymoses (thrombocytopenia) - Fever, usually preceded by hemorrhagic diarrhea in typical HUS - Can be difficult to distinguish from TTP in atypical cases
Diagnosis	- COVID-19 vaccination 5–30 days (NICE) or 4–42 days (ASH) prior to symptom onset - Any arterial or venous thrombosis - Thrombocytopenia (<150 × 10⁹/L) - Presence of anti-PF4 antibodies via ELISA - Elevated D-dimer (>2000–4000 µg/L FEU/DDU) and normal to decreased fibrinogen (>2–4 g/L) - Additional features: normal to mildly elevated PT/aPTT and INR - PF4 antibody testing (confirmatory assay)	- HIT/HITT is a clinical diagnosis. Supporting lab findings include mild to moderate thrombocytopenia (<20,000/mm³), normal PT/aPTT and INR, anti-PF4/heparin antibodies via ELISA, positive platelet activation (serotonin release) assay, 5–14 days after exposure to heparin in classical HIT - Thrombotic thrombocytopenia without heparin exposure, strong SRA > 50% at 0IU/mL heparin, strong positivity in at least two PF4 enzyme immune assays in spontaneous HIT	- Thrombocytopenia - Normal PT/aPTT, INR - Increased LDH, indirect bilirubin, and reticulocyte counts - Decreased hematocrit - Deficiency in ADAMTS13 activity (<10%) and presence of anti-ADAMTS13 antibodies	- Thrombocytopenia, - Normal PT/aPTT, INR - Normal to decreased ADAMTS13 activity - Reduced eGFR - BUN: CREA > 20 or azotemia with or without uremic signs and symptoms
Treatment	- Non-heparin anticoagulants (argatroban, fondaparinux, danaparoid) - IVIG - Case-to-case use of glucocorticoids - Plasma exchange therapy	- Discontinuation of heparin or shift to non-heparin anticoagulation (argatroban, danaparoid) - Warfarin overlapped with direct thrombin inhibitors after resolution of thrombocytopenia	- Plasma exchange therapy, rituximab, or caplacizumab - Immunomodulatory therapies: cyclophosphamide, vincristine - Splenectomy	- Supportive only; plasma exchange therapy does not affect clinical outcomes - Eculizumab in patients vaccinated against meningococcemia
Complications	- Venous thrombosis in the central venous sinus (most common) - Thrombosis of splanchnic or adrenal veins - DVT (less common) - Arterial thrombosis also occurs and uncommonly leads to stroke or MI	- Commonly progresses to HITT if left untreated, manifesting as deep vein thrombosis with possible pulmonary embolism or MI - Extremity ischemia or gangrene may lead to amputation	- Thrombotic microangiopathy results in renal failure, retinopathies, seizures, or stroke - Petechiae or ecchymoses in the skin are also seen	- Thrombotic microangiopathy results in renal failure, retinopathies, seizures, or stroke - Petechiae or ecchymoses in the skin are also seen

In terms of treatment, current management algorithms for VITT are similar to HIT: administration of a non-heparin anticoagulant to address thrombosis (argatroban, fondaparinux, danaparoid), plasma exchange therapy to deplete the plasma of the pathologic anti-PF4 antibodies and to address the thrombocytopenia and hypofibrinogenemia, use of glucocorticoids, and IV immunoglobulin G (IVIG) to compete with the anti-PF4 antibodies to block platelet activation, which is usually given to patients with autoimmune or heparin-independent HIT at a dose of 1 g/kg for at least two days ^[27]^[33]. Similarly, anecdotal reports of managing patients with VITT have shown that administration of LMWH (0.1–0.3 U/mL up to 100 U/mL) combined with endovascular recanalization of the venous sinuses in CVST can normalize platelet counts and improve patient survivability ^[28]^[34]. However, due to the lack of robust and high-quality evidence on the benefit of LMWH, interim recommendations suggest against heparin administration in patients with suspected or confirmed VITT ^[35]. It is important to note that treatment can be started prior to confirmation of ELISA and SRA results if there is a high clinical suspicion of VITT (severe symptoms, thrombocytopenia, positive imaging, elevated D-dimer levels five times the upper normal limit) ^[36]. For more information on the approach to treating patients with VITT, the reader is referred to current guidelines and recommendations ^[25]^[36].

This entry is adapted from the peer-reviewed paper 10.3390/hematolrep14040050

References

Van Doremalen, N.; Lambe, T.; Spencer, A.; Belij-Rammerstorfer, S.; Purushotham, J.N.; Port, J.R.; Avanzato, V.A.; Bushmaker, T.; Flaxman, A.; Ulaszewska, M.; et al. ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques. Nature 2020, 586, 578–582.
Bos, R.; Rutten, L.; van der Lubbe, J.E.M.; Bakkers, M.J.G.; Hardenberg, G.; Wegmann, F.; Zuijdgeest, D.; de Wilde, A.H.; Koornneef, A.; Verwilligen, A.; et al. Ad26 vector-based COVID-19 vaccine encoding a perfusion-stabilized SARS-CoV-2 spike immunogen induces potent humoral and cellular immune responses. NPJ Vaccines 2020, 5, 91.
Knoll, M.D.; Wonodi, C. Oxford-AstraZeneca COVID-19 vaccine efficacy. Lancet 2021, 397, 72–74.
Voysey, M.; Clemens, S.A.C.; Madhi, S.A.; Weckx, L.Y.; Folegatti, P.M.; Aley, P.K.; Angus, B.; Baillie, V.L.; Barnabas, S.L.; Bhorat, Q.E.; et al. Safety and efficacy of the ChadOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: An interim analysis of four randomized controlled trials in Brazil, South Africa, and the UK. Lancet 2021, 397, 99–111.
Livingston, E.H.; Malani, P.N.; Creech, C.B. The Johnson & Johnson Vaccine for COVID-19. JAMA 2021, 325, 1575.
Sadoff, J.; Struyf, F.; Douoguih, M. A plain language summary of how well the single-dose Janssen vaccine works and how safe it is. Future Virol. 2021, 16, 725–739.
Mahase, E. COVID-19: WHO says rollout of AstraZeneca vaccine should continue, as Europe divides over safety. BMJ 2021, 372, n728.
Vallée, A.; Chan-Hew-Wai, A.; Bonan, B.; Lesprit, P.; Parquin, F.; Catherinot, É.; Choucair, J.; Billard, D.; Amiel-Taieb, C.; Camps, É.; et al. Oxford-AstraZeneca COVID-19 vaccine: Need of a reasoned and effective vaccine campaign. Public Health 2021, 196, 135–137.
Douxfils, J.; Favresse, J.; Dogné, J.; Lecompte, T.; Susen, S.; Cordonnier, C.; Lebreton, A.; Gosselin, R.; Sié, P.; Pernod, G.; et al. Hypotheses behind the very rare cases of thrombosis with thrombocytopenia syndrome after SARS-CoV-2 vaccination. Thromb. Res. 2021, 203, 163–171.
Kennedy, V.E.; Wong, C.C.; Hong, J.M.; Peng, T.; Brondfield, S.; Reilly, L.M.; Cornett, P.; Leavitt, A.D. VITT following Ad26.COV2.S vaccination presenting without radiographically demonstrable thrombosis. Blood Adv. 2021, 5, 4662–4665.
Kanack, A.J.; Singh, B.; George, G.; Gundabolu, K.; Koepsell, S.A.; Abou-Ismail, M.Y.; Moser, K.A.; Smock, K.J.; Green, D.; Major, A.; et al. Persistence of Ad26.COV2.S-associated vaccine-induced immune thrombotic thrombocytopenia (VITT) and specific detection of VITT antibodies. Am. J. Hematol. 2022, 97, 519–526.
Pai, M. Epidemiology of VITT. Semin. Hematol. 2022, 59, 72–75.
Lacy, J.; Pavord, S.; Brown, K.E. VITT and Second Doses of COVID-19 Vaccine. N. Engl. J. Med. 2021, 386, 95.
Ockelford, P. Heparin 1986. Indications and effective use. Drugs 1986, 31, 81–92.
Weitz, J.I. Antiplatelet, anticoagulant, and fibrinolytic drugs. In Harrison’s Principles of Internal Medicine, 20th ed.; Jameson, J.L., Fauci, A.S., Kasper, D.L., Hauser, S.L., Longo, D.L., Loscalzo, J., Eds.; McGrawHill Education: New York, NY, USA, 2018; Available online: https://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=192018816 (accessed on 24 May 2021).
Qiao, J.; Al-Tamimi, M.; Baker, R.I.; Andrews, R.K.; Gardiner, E.E. The platelet Fc receptor, FcγRIIa. Immunol. Rev. 2015, 268, 241–252.
Sachais, B.S.; Higazi, A.A.-R.; Cines, D.B.; Poncz, M.; Kowalska, M.A. Interactions of platelet factor 4 with the vessel wall. Semin. Thromb. Hemost. 2004, 30, 351–358.
Maharaj, S.; Chang, S. Anti-PF4/heparin antibodies are increased in hospitalized patients with bacterial sepsis. Thromb. Res. 2018, 171, 111–113.
Konkle, B.A. Disorders of platelets and vessel wall. In Harrison’s Principles of Internal Medicine, 20th ed.; Jameson, J.L., Fauci, A.S., Kasper, D.L., Hauser, S.L., Longo, D.L., Loscalzo, J., Eds.; McGrawHill Education: New York, NY, USA, 2018; Available online: https://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=192018598 (accessed on 24 May 2021).
Murphy, K.D.; Galla, D.H.; Vaughn, C.J.; McCrohan, G.; Garrisi, W.J. Heparin-induced thrombocytopenia and thrombosis syndrome. Radiographics 1998, 18, 111–120.
Wannamaker, E.; Kondo, K.; Johnson, D.T. Heparin-induced thrombocytopenia and thrombosis: Preventing your thrombolysis practice from taking a HITT. Semin. Intervent. Radiol. 2017, 34, 409–414.
Warkentin, T.E.; Cuker, A. COVID-19: Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT). UpToDate 2021. Available online: https://www.uptodate.com/contents/covid-19-vaccine-induced-immune-thrombotic-thrombocytopenia-vitt (accessed on 26 May 2021).
Chong, B.H. Heparin-induced thrombocytopenia. Aust. N. Z. J. Med. 1992, 22, 145–152.
Warkentin, T.E.; Basciano, P.A.; Knopman, J.; Bernstein, R.A. Spontaneous heparin-induced thrombocytopenia syndrome: 2 new cases and a proposal for defining this disorder. Blood 2014, 123, 3651–3654.
Rizk, J.G.; Gupta, A.; Sardar, P.; Henry, B.M.; Lewin, J.C.; Lippi, G.; Lavie, C.J. Clinical Characteristics and Pharmacological Management of COVID-19 Vaccine-Induced Immune Thrombotic Thrombocytopenia with Cerebral Venous Sinus Thrombosis: A Review. JAMA Cardiol. 2021, 6, 1451–1460.
Konkle, B.A. Bleeding and thrombosis. In Harrison’s Principles of Internal Medicine, 20th ed.; Jameson, J.L., Fauci, A.S., Kasper, D.L., Hauser, S.L., Longo, D.L., Loscalzo, J., Eds.; McGrawHill Education: New York, NY, USA, 2018; Available online: https://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=192014303 (accessed on 24 May 2021).
Scully, M.; Singh, D.; Lown, R.; Poles, A.; Solomon, T.; Levi, M.; Goldblatt, D.; Kotoucek, P.; Thomas, W.; Lester, W. Pathologic antibodies to platelet factor 4 after ChAdOx1 nCoV-19 vaccination. N. Engl. J. Med. 2021, 384, 2202–2211.
Jokiranta, T.S. HUS and atypical HUS. Blood 2017, 129, 2847–2856.
Greinacher, A.; Schönborn, L.; Siegerist, F.; Steil, L.; Palankar, R.; Handtke, S.; Reder, A.; Thiele, T.; Aurich, K.; Methling, K.; et al. Pathogenesis of vaccine-induced immune thrombotic thrombocytopenia (VITT). Sem. Hematol. 2022, 59, 97–107.
Schultz, N.H.; Sørvoll, I.H.; Michelsen, A.E.; Munthe, L.A.; Lund-Johansen, F.; Ahlen, M.T.; Wiedmann, M.; Aamodt, A.-H.; Skattør, T.H.; Tjønnfjord, G.E.; et al. Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination. N. Engl. J. Med. 2021, 384, 2124–2130.
Pavord, S.; Hunt, B.J.; Horner, D.; Bewley, S.; Karpusheff, J. Vaccine induced immune thrombocytopenia and thrombosis: Summary of NICE guideline. BMJ 2021, 375, 2195.
Bussel, J.B.; Connors, J.M.; Cines, D.B.; Dunbar, C.E.; Michaelis, L.C.; Kreuziger, L.B.; Lee, A.Y.Y.; Pabinger-Fasching, I. Vaccine-induced Immune Thrombotic Thrombocytopenia. Am. Soc. Hematol. 2022, 9, e73–e80.
Warkentin, T.E. High-dose intravenous immunoglobulin for the treatment and prevention of heparin-induced thrombocytopenia: A review. Expert Rev. Hematol 2019, 12, 685–698.
Wolf, M.E.; Luz, B.; Niehaus, L.; Bhogal, P.; Bäzner, H.; Henkes, H. Thrombocytopenia and Intracranial Venous Sinus Thrombosis after “COVID-19 Vaccine AstraZeneca” Exposure. J. Clin. Med. 2021, 10, 1599.
Kantarcioglu, B.; Iqbal, O.; Walenga, J.M.; Lewis, B.; Lewis, J.; Carter, C.A.; Singh, M.; Lievano, F.; Tafur, A.; Ramacciotti, E.; et al. An Update on the Pathogenesis of COVID-19 and the Reportedly Rare Thrombotic Events Following Vaccination. Clin. Appl. Thromb. Hemost. 2021, 27, 10760296211021498.
Alam, W. COVID-19 vaccine-induced immune thrombotic thrombocytopenia: A review of the potential mechanisms and proposed management. Sci. Prog. 2021, 104, 368504211025927.

© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.