Vaccine-induced thrombotic thrombocytopenia following coronavirus vaccine: A narrative review.

SHA, IU: Study concept or design. SHA, SW, TGS, NAQ and IU: Data collection, data analysis or interpretation, writing the paper. ZY: Critical revision of the article.

Not applicable.

None.

NA.

None.

VITT is a rare adverse effect of SARS-CoV-2 vaccination, and the benefits of COVID-19 vaccines continue to outweigh the rare side effects. However, while its incidence is low, there is undoubted an overwhelming need to discern the precise pathophysiology behind this syndrome to establish proper management protocols. Questions like why certain coronavirus vaccines carry a higher risk than others, why specific individuals develop thrombosis while others don't, higher prevalence in a particular gender and age group, and the impact of different interventions in such patients need to be investigated before a clear conclusion can be drawn. Lastly, future studies must take into consideration both pre-and post-vaccination investigations to discern the role of any underlying condition.

Not commissioned, externally peer-reviewed.

The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) cases were initially reported in Wuhan, China, towards the end of 2019. Following its extensive spread, the World Health Organization (WHO) declared COVID-19 a pandemic in March 2020 [ 1 ]. To the date, April 16, approximately 207 million confirmed cases have been reported, and 4.3 million deaths [ 2 ]. Coordinated global efforts led to the development of COVID-19 vaccines, followed by emergency use authorization within nine months of the pandemic [ 3 ]. These vaccines are now widely available for public administration [ 4 ]. The vaccines are safe and effective in preventing severe infection, hospitalization, and death [ 5 , 6 ]. To date, 4.4 billion vaccine doses have been administered [ 2 ]. The common adverse effects following COVID-19 vaccination are injection site pain and transient, self-limited systemic symptoms like headache, fever, myalgias, etc. [ 7 ]. Recently, a more severe adverse effect, thrombocytopenia with or without thrombosis, has been reported following SARS-CoV-2 vaccination. Thrombocytopenia is a medical condition characterized by platelets lower than 150,000/microliter and is associated with a risk of bleeding and thrombosis [ 8 ]. Such reports have raised concerns over the safety profile and hesitancy towards the available vaccines [ 9 ]. The term “Vaccine-Induced Thrombotic Thrombocytopenia” describes post-vaccination thrombocytopenia cases. VITT is characterized by thrombosis at unusual sites and thrombocytopenia following vaccination [ 9 ]. While VITT has been associated with both mRNA and viral vector vaccines, its prevalence is higher in viral vectored vaccines [ 7 ]. Following the incidence of 30 thromboembolism cases in March 2021, Oxford/AstraZeneca (AZD1222) was transiently suspended in numerous European countries [ 10 ]. Later the pharmacovigilance risk assessment committee ( PRAC ) of the European medical agency (EMA) reviewed all cases and declared thrombosis and thrombocytopenia as rare adverse effects of AZD1222. However, based on risk-benefit assessment, the vaccine was later declared safe for use [ 11 ]. Owing to a similar reason, in April 2021, Johnson & Johnson's Janssen (Ad26.CoV2·S) administration was also temporarily suspended [ 12 ]. Herein, we review the association between SARS-CoV-2 vaccines and VITT. This review evaluates the potential pathophysiology and clinical approach to diagnoses and management of VITT. The work has been reported in line with the PRISMA 2020 criteria [ 13 ]. Two authors (SHA, SW) dependently conducted a thorough literature search over PubMed and Clinicaltrials.gov from inception till August 16, 2021, without any language restriction. To achieve comprehensive results, search string comprised of keywords, “SARS-CoV-2 Vaccine”, “Coronavirus Vaccine,” “Corona Vaccine,” “COVID-19 Vaccine”, “thrombotic thrombocytopenic,” “Vaccine-Induced Thrombotic Thrombocytopenia,” “VITT,” “thrombocytopenia,” “reduced platelet count,” using BOOLEAN operators. Synonyms, related terms, and spelling variants were also engaged. All relevant case reports, case series, cohort studies, editorials, and correspondences were reviewed. Any discrepancies were resolved via discussion with a third reviewer (IU). The results of the literature search are shown in Fig. 1 . Following studies selection, two independent authors (TGS, NAQ) extracted all the relevant data into a table comprising of author's name, patient's age, and sex, past medical history, presenting complaint, laboratory findings, radiological findings, treatment interventions, and outcome. Any discrepancies were resolved by discussion with a third reviewer (IU). All significant findings are summarized in Table 1 . Fig. 1 Prisma flowchart. Fig. 1 Table 1 A tabulation of the outcomes of literature review of VITT following SARS-CoV-2 vaccination. Table 1 Author Sex and Age Past Medical history Presenting Complaint Vaccine administered Laboratory findings Radiological findings Intervention Outcome Al Maqbali et al. [ 55 ] 59 y/o Female Type 2 diabetes mellitus, osteoarthritis, and COVID-19 pneumonia in September 2020, OCP Sudden onset left leg pain 7 days after receiving her first dose. Pfizer-BioNTech mRNA Platelet = 182 × 10 9 /L D-dimer = 24 mg/L Bifurcation of the pulmonary trunk and main pulmonary arteries emboli extending to the lobar segmental and subsegmental branches Rivaroxaban 2 × 15 mg daily for 21 days, followed by rivaroxaban 20 mg daily for a total of 3 months Recovered Muir et al. [ 56 ] 48 y/o Male N/A 3 days history of malaise and abdominal pain Ad26.COV2. S vaccine (Johnson & Johnson/Janssen) Platelet = 13,000/mm 3 D-dimer = 117.5 mg/Liter Cerebral venous sinus thrombosis involving the right transverse and straight sinuses and extensive splanchnic vein thrombosis Argatroban & IVIG at a dose of 1 g/kg of ideal body weight Critically ill at the time of the report Sheikh et al. [ 57 ] 50 y/o Male N/A Headache, vertigo, and vision changes ChAdOx1 nCoV-19 (AstraZeneca) N/A Central venous sinus thrombosis (CVST) in transverse and sigmoid sinuses Desirudin, IVIG at 1 g/kg/hour and Prednisolone at 1 mg/kg daily Recovered Ramdeny et al. [ 58 ] 54 y/o Male Rare congenital limb malformation 7-day history of worsening headache, bruising and unilateral right calf swelling ChAdOx1 nCoV-19 (AstraZeneca) Platelet = 34. x 10 9 /L D-dimer = 6000 ng/mL Extensive cerebral venous sinus thrombosis Therapeutic IVIG and anticoagulation Recovered Bano et al. [ 49 ] 53 y/o Female N/A Worsening headache and weakness of the right arm and leg ChAdOx1 nCoV-19 (AstraZeneca) Platelet = 24 × 10⁹/L D-dimer = 5620 ng/mL Cerebral Venous sinus thrombosis Three units of platelets were transfused before urgent neurosurgical intervention Death Bano et al. [ 49 ] 61 y/o Female N/A 3-day history of progressive dyspnea, pain, and swelling in the right leg ChAdOx1 nCoV-19 (AstraZeneca) Platelet = 25 × 10⁹/L D-dimer = 9376 ng/mL Bilateral PE with right heart strain One unit of platelets, LMWH, was given twice. After which, anticoagulation was switched to treatment dose fondaparinux. Further platelet transfusion was withheld. The patient was treated with IVIG 1 g/kg single dose and pulsed dexamethasone 20 mg once daily for 4 days Recovered Wiedmann et al. [ 59 ] 42 y/o Female N/A Severe headaches, nausea, vomiting, fluctuating level of consciousness, and right-sided hemiparesis ChAdOx1 nCoV-19 (AstraZeneca) N/A Left transverse sinus and sigmoid sinus cerebral sinus vein thrombosis (CSVT) and cortical vein thrombosis IV methylprednisolone (1 mg/kg) daily and IVIG (1 g/kg) for 2 days Death Wiedmann et al. [ 59 ] 37 y/o Female N/A 2-day history of headaches, fever, transient numbness in the right foot, and right-sided visual disturbance ChAdOx1 nCoV-19 (AstraZeneca) N/A CSVT in the left transverse and sigmoid sinus and left occipital CSVT Urgent suboccipital craniectomy was performed and cerebellar herniation encountered during surgery Death Wiedmann et al. [ 59 ] 39 y/o Female N/A Abdominal pain and headaches ChAdOx1 nCoV-19 (AstraZeneca) Platelet = 119 × 10 9 /L Small cerebellar hemorrhage. CSVT in the inferior sagittal sinus, vein of Galen and straight, right transverse and sigmoid sinuses. Bilateral segmental pulmonary emboli, thrombosis in uterine veins. IVIG, steroids, warfarin Recovered Wiedmann et al. [ 59 ] 54 y/o female N/A Numbness of left-sided limbs 6 days post-vaccination, left-sided paralysis and facial nerve palsy. ChAdOx1 nCoV-19 (AstraZeneca) N/A CSVT in nearly all major venous sinuses Methylprednisolone (1 mg/kg) and IVIG (1 g/kg) for 2 days and decompressive hemicraniectomy Death Ruhe et al. [ 51 ] 84 y/o Female N/A Partial hemiplegia, scattered petechiae, and severe arterial hypertension. Pfizer-BioNTech mRNA Platelet count = 45 × 10 9 /L Multiple subacute emboli without vessel occlusion. Corticosteroid and plasma exchange therapy (PEX) with fresh frozen plasma. Rituximab at day 2 as second corticosteroid Recovering Gesseler et al. [ 60 ] 47 y/o Female N/A Progressive headache 7 days after the first dose ChAdOx1 nCoV-19 (AstraZeneca) Platelet = 9 × 10 9 /L D-dimer >35.2 mg/L Large-scale sinus thrombosis IVIg at 1 g/kg, Argatroban and corticosteroids. Platelet therapy was administered before the decompressive surgery. During operation, artificial hemostyptics and transfusions were done. Death Gesseler et al. [ 60 ] 50 y/o Female N/A Progressive headache 10 days after first dose ChAdOx1 nCoV-19 (AstraZeneca) Platelet = 24 × 10 9 /L D-dimer >35.2 mg/L Large-scale sinus thrombosis IVIg at 1 g/kg, Argatroban and corticosteroids. Platelet therapy was administered before the decompressive surgery. During operation, artificial hemostyptics and transfusions were done. Death Gesseler et al. [ 60 ] 44 y/o Female N/A Progressive headache 12 days after the first dose Ad26.COV2. S vaccine (Johnson & Johnson/Janssen) Platelet = 48 × 10 9 /L D-dimer >35.2 mg/L Large-scale sinus thrombosis IVIg at 1 g/kg, Argatroban and corticosteroids. Platelet therapy was administered before the decompressive surgery. During operation, artificial hemostyptics and transfusions were done. Death Patel et al. [ 15 ] 33 y/o Male N/A Back pain, hematuria, headache, and right lower leg pain for 1 week ChAdOx1 nCoV-19 (AstraZeneca) D-dimer >20 mg/L Anti-PF4 antibodies were positive PE in left pulmonary artery IV Argatroban, IVIG, and warfarin Recovered Patel et al. [ 15 ] 28 y/o Male N/A Back pain and lower limb weakness ChAdOx1 nCoV-19 (AstraZeneca) Elevated D-dimers and positive anti-PF4 antibodies Bilateral PEs and left proximal DVT IV Argatroban, IVIG, and warfarin Recovered Patel et al. [ 15 ] 61 y/o Male N/A Exertional dyspnea and pleuritic chest pain ChAdOx1 nCoV-19 (AstraZeneca) Elevated D-dimers and positive anti-PF4 antibodies Bilateral PEs IV Argatroban, IVIG, and warfarin Recovered Suresh et al. [ 17 ] 27 y/o Male N/A Intermittent headaches associated with eye floaters ChAdOx1 nCoV-19 (AstraZeneca) Platelets = 12 × 10 9 /L Anti -P4 antibodies were positive Cerebral venous sinus thrombosis. IVIg (1 g/kg) once a day, Dabigatran, Idarucizumab, Prednisolone once daily (1 mg/kg) with proton pump inhibitors cover Death Mehta et al. [ 16 ] 32 y/o Male N/A Thunderclap headache, subsequent left-sided incoordination, and hemiparesis ChAdOx1 vaccine (AZD1222, Vaxzevria) Platelets = 30 × 10 9 /L Superior sagittal sinus and cortical vein thrombosis No treatment since the condition continued to deteriorate Death Mehta et al. [ 16 ] 25 y/o Male Primary sclerosing cholangitis and migraines Photophobia, neck stiffness, visual disturbances, petechial rashes, and gum bleeding ChAdOx1 vaccine (AZD1222, Vaxzevria) Platelets = 19 × 10 9 /L Positive anti -P4 antibodies Superior sagittal sinus thrombosis with cortical veins involvement. Intravenous unfractionated heparin, platelet transfusions, IV dexamethasone, IVIG, and intravenous levetiracetam Death Xie et al. [ 50 ] 23 y/o N/A Chest pain and breathlessness N/A Platelets = 73 × 10 9 /L D-dimer = 17548 μg/L Pulmonary emboli, right ventricle thrombus, and splenic vein thrombus Apixaban, intubation, ventilation, plasma exchange, IV methylprednisolone, and heparin infusion Recovered Sørensen et al. [ 22 ] 33 y/o Female Migraine Headache and general malaise ChAdOx1 nCoV-19 (AstraZeneca) Platelets = 51 × 10 9 /L Anti-PF4 antibodies were positive Cerebral venous sinus thrombosis and portal vein thrombosis Tinzaparin, Fondaparinux Recovered Dias et al. [ 61 ] 47 y/o Female Iron deficiency anemia due to adenomyosis Headache, nausea, and photophobia Pfizer-BioNTech mRNA Platelets = 34000/mL Anti-PF4 antibodies were negative Thrombosis of superior sagittal, right lateral, transverse, sigmoid sinuses and jugular vein and left sigmoid sinus Acetazolamide, enoxaparin 60 mg, and warfarin Recovered Dias et al. [ 61 ] 67 y/o Female Multiple cerebral cavernous malformations, hypertension, diabetes, dyslipidemia, viral myocarditis, and depression Right lower limb clonic movements, motor deficit, loss of consciousness, and headache Pfizer-BioNTech mRNA Platelets = 164000/mL Anti-PF4 antibodies were negative Thrombosis of high convexity cortical veins, superior sagittal, right transverse, and sigmoid sinus and jugular vein Levetiracetam 500 mg, enoxaparin 80 mg, dabigatran 150 mg Recovered Tiede et al. [ 18 ] 63 y/o Female N/A Headache, somnolence, dysphasia, right-sided hemiparesis, and arterial hypertension ChAdOx1 vaccine (AZD1222, Vaxzevria) Platelets = 27/nl D-dimer >35.2 mg/L Anti-PF4 antibodies were positive Left transverse and sigmoid sinus thrombosis, cerebral venous sinus thrombosis Heparin and eculizumab Recovering Tiede et al. [ 18 ] 67 y/o Female N/A Headache ChAdOx1 vaccine (AZD1222, Vaxzevria) Platelets = 40/nl D-dimer >35.2 mg/L Anti-PF4 antibodies were positive Aortic arch thrombi and cerebral arterial embolism Argatroban and IVIG Recovered Tiede et al. [ 18 ] 61 y/o Female N/A Fatigue ChAdOx1 vaccine (AZD1222, Vaxzevria) Platelets = 12/nl D-dimer >35.2 mg/L Anti-PF4 antibodies were positive Splanchnic vein thrombosis Argatroban, IVIG, alteplase, eculizumab Recovering Tiede et al. [ 18 ] 61 y/o Female N/A Headache, dysarthria, left-sided hemiplegia, conjugated gaze palsy ChAdOx1 vaccine (AZD1222, Vaxzevria) Platelets = 62/nl D-dimer> 35.2 mg/L Anti-PF4 antibodies were positive Right internal carotid and middle cerebral artery (M1) thrombosis and cerebral arterial thrombosis Argatroban and IVIG Recovering Guetl et al. [ 62 ] 50 y/o Female N/A Severe headache and severe back pain ChAdOx1 nCoV-19 (AstraZeneca) Platelets = 27 × 10 9 /L D-dimer >33 mg/L Anti-PF4 antibodies were negative Multifocal thrombus in the pelvic region and embolus in the posterior–basal right lower lobe IVIG, dexamethasone 40 mg, argatroban, and dabigatran Recovered Schultz et al. [ 46 ] 37 y/o Female Pollen allergy Headaches, fever, and visual disturbance ChAdOx1 nCoV-19 (AstraZeneca) Platelets = 22000 mm 3 D-dimer> 35 mg/L Thrombosis in the left transverse, left sigmoid sinuses, and cortical veins Dalteparin, platelets, and decompressive craniotomy Death Schultz et al. [ 46 ] 42 y/o Female Pollen allergy Headache and drowsiness ChAdOx1 nCoV-19 (AstraZeneca) Platelets = 14000 mm 3 Thrombosis in the left transverse left sigmoid sinuses and cortical veins Dalteparin, platelet transfusion, IVIg 1 g/kg, methylprednisolone 1 mg/kg, and hemicraniectomy Death Schultz et al. [ 46 ] 32 y/o Male Asthma Back pain ChAdOx1 nCoV-19 (AstraZeneca) Platelets = 10,000 mm 3 Thrombosis of portal vein branches IVIg 1 g/kg, prednisolone 1 mg/kg, dalteparin Recovered Schultz et al. [ 46 ] 39 y/o Female N/A Headache and abdominal pain ChAdOx1 nCoV-19 (AstraZeneca) Platelets = 70000 mm 3 Thrombosis of Inferior sagittal sinus, straight sinus, the vein of Galen, right transverse sinus, and right sigmoid sinus IVIg 1 g/kg, prednisolone 1 mg/kg, dalteparin, warfarin Recovered Schultz et al. [ 46 ] 54 y/o Female Hypertension Headache and hemiparesis ChAdOx1 nCoV-19 (AstraZeneca) Platelets = 19000 mm 3 Thrombosis of the cortical vein, superior sagittal vein, both transverse sinus and left sigmoid sinus IVIg 1 g/kg, methylprednisolone 1 mg/kg Death Malik et al. [ 63 ] 43 y/o Female Hyperlipidemia, anxiety, depression, obesity, obstructive sleep apnea, and gastroesophageal disease Headache, fever, body aches, chills, mild dyspnea, and light-headedness Ad26.COV2. S vaccine (Johnson & Johnson/Janssen) Platelets = 27 × 10 9 /L D-dimer = 35.2 mg/L Anti-PF4 antibodies were positive Pulmonary Embolism and Intracerebral thrombus IVIg, fondaparinux, fioricet and topiramate Recovered Garnier et al. [ 14 ] 26 y/o Female N/A Nausea and headache ChAdOx1 nCoV-19 (AstraZeneca) Anti-PF4 antibodies were positive Occlusion in middle cerebral artery Corticosteroids, anticoagulants, and plasma exchange N/A Abadi et al. [ 20 ] 30 y/o Female N/A Headache, neck pain, lower extremity pain, and weakness Ad26.COV2. S vaccine (Johnson & Johnson/Janssen) Platelets = 80 × 10 3 /μL Anti-PF4 antibodies were positive Acute deep vein thrombosis involving posterior tibialis and popliteal veins, obstructive thrombosis in right transverse sinus extending to right sigmoid sinus and jugular bulb, pulmonary embolism Argatroban and Bivalirudin Recovered Agostino et al. [ 64 ] 54 y/o Female N/A Acute cerebrovascular accident ChAdOx1 nCoV-19 (AstraZeneca) Normal D-dimer Deep vein thrombosis, acute basilar thrombosis N/A Death Mauriello et al. [ 65 ] 48 y/o Female Penicillin allergy, episode of thrombocytopenia in 2016. Postmortem analysis indicated pre-existing thrombocytopenia Progressive headache, back pain, moderate right lower limb pain, and disseminated ecchymosis that required hospitalization on day 18 ChAdOx1 nCOV-19 AstraZeneca Platelets = 32000/μL D-dimer = 10 mg/mL Thrombo-embolic filling defects affecting the pulmonary artery, sigmoid transverse sinus thrombosis, right internal jugular vein thrombosis, right temporo-occipital intraparenchymal hemorrhage Initially low molecular weight heparin, anti-hypertensive, oral double (dabigatran 110 mg/die + rivaroxaban 30 mg/die) anticoagulants, IV methylprednisolone, dabigatran antagonist, and a decompressive craniectomy Death Wolf et al. [ 21 ] 22 y/o Female N/A Shivering, fever, and headaches for two days, with spontaneous resolution Day 4: New frontally accentuated headaches Day 7: A self-limited generalized epileptic seizure occurred. ChAdOx1 nCoV-19 (AstraZeneca) Platelets = 75000/Ul D-dimer = 2590 ng/mL Anti-PF4 antibodies were positive Superior sagittal sinus, left side transverse sinus, sigmoid sinus, and ascending cerebral veins thrombosis. Endovascular rheolysis, 2 × 1000 mg levetiracetam (PO) daily for three months, 2 × 80 mg enoxaparin sodium (SC) daily for ten days, followed by direct oral anticoagulation with 2 × 150 mg dabigatran PO daily for six months. Recovered Wolf et al. [ 21 ] 46 y/o Female N/A Severe headaches eight days after the first dose ChAdOx1 nCoV-19 (AstraZeneca) Platelets = 60,000/ul Anti-PF4 antibodies were positive Superior sagittal sinus, left-hand transverse sinus, sigmoid sinus thrombosis. Endovascular rheolysis in two separate sessions, 2 × 80 mg SC Enoxaparin for 2 days then changed to 3 × 750 mg Danaparoid Recovered Wolf et al. [ 21 ] 36 y/o Female N/A Severe headaches seven days after the first dose, three days of fever and headache, acute somnolence, and right-hand hemiparesis ChAdOx1 nCoV-19 (AstraZeneca) Platelets = 92000/ul Anti-PF4 antibodies were positive Straight sinus thrombosis, non-occlusive thrombus in the superior sagittal sinus 2250 IU danaparoid SC, endovascular rheolysis, 2 × 60 mg enoxaparin sodium SC daily for one week, followed by direct oral anticoagulation with 2 × 150 mg dabigatran PO daily for six months Recovered Bjørnstad-Tuveng et al. [ 19 ] Female in her 30s An uncomplicated birth 11 months prior with 1500 mL bleeding, mild preeclampsia treated with labetalol 100 mg. For the past 3 months, she used Duroferon 2 × 100 mg for iron deficiency and desloratadine 5 mg for allergies. Headache after 7 days of vaccination. This was followed by a worsening headache, slurred speech, and uncoordinated walking and movement. ChAdOx1 nCoV-19 (AstraZeneca) Platelets = 37 × 10 9 /L D-dimer > 7.0 mg/L Anti-PF4 antibodies were positive Postmortem examination revealed fresh small thrombi in the transverse sinus, frontal lobe, and pulmonary artery. 1 g of tranexamic acid intravenously, midazolam for seizure Death Tarawneh et al. [ 48 ] 22 y/o male N/A Petechia and gums bleeding 3 days post-vaccination Pfizer-BioNTech mRNA Platelets = 2 × 10 9 N/A Dexamethasone 40 mg daily for 4 days, platelet transfusion, and IVIG at 1 g/kg for 2 days Recovered N/A: Not Available, OCP: Oral contraceptives, IVIG: Intravenous Immunoglobulins, ITP: Immune thrombocytopenia, PE: Pulmonary embolism, CVST: Cerebral venous sinus thrombosis, IV: Intravenous, SC: Subcutaneous, PO: Per os LMWH: Low molecular weight heparin, DVT: Deep vein thrombosis. Prisma flowchart. A tabulation of the outcomes of literature review of VITT following SARS-CoV-2 vaccination. N/A: Not Available, OCP: Oral contraceptives, IVIG: Intravenous Immunoglobulins, ITP: Immune thrombocytopenia, PE: Pulmonary embolism, CVST: Cerebral venous sinus thrombosis, IV: Intravenous, SC: Subcutaneous, PO: Per os LMWH: Low molecular weight heparin, DVT: Deep vein thrombosis. The retrieved studies comprise data of 44 patients (32 females, 11 males, 1 not defined) with a mean age of 44.9 ± 14.3 years. The following figure ( Fig. 2 ) depicts the geographical distribution of the reported cases around the globe, with the majority of cases arising in Europe. Based on these and future reporting, we can predict the potential spatial spread, geographical locations that may be more susceptible than others and this may help us establish links between different genetic and environmental factors, predisposing an individual to such consequences of vaccines. Fig. 2 Geographical distribution of the reported cases. Fig. 2 Geographical distribution of the reported cases. The exact pathophysiology behind VITT is unclear. As shown in Table 1 , most of the cases presented with thrombocytopenia, elevated D-dimer, and positive titers of IgG antibodies against platelet factor 4 (PF-4) [ [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] ]. Based on these findings, this syndrome is closely related to heparin-induced thrombocytopenia (HIT), a medical condition characterized by thrombocytopenia, and the presence of antibodies against the Heparin-PF4 complex [ 23 ]. HIT, an autoimmune reaction to heparin, involves the generation of IgG antibodies against the Heparin-PF4 complex. The Fc portion of these antibodies adheres to the complex, binds to the FcYRIIa receptors [ 24 ], and initiates platelets activation via intracellular signaling involving spleen tyrosine kinase [ 25 ]. This results in the release of microparticles and a procoagulant state [ 26 , 27 ]. Furthermore, clearance of activated and antibody-bound platelets by the reticuloendothelial system culminates in thrombocytopenia [ 28 ]. A prerequisite in the diagnosis of HIT includes a known recent exposure to heparin. A condition labeled “Autoimmune Heparin-Induced Thrombocytopenia (aHIT)” manifests with clinical and laboratory findings without any prior use of heparin [ 29 ]. Based on this resemblance, a comparison has been drawn between VITT and variants of aHIT [ 30 ], and hence, we may assume that a similar mechanism follows post-vaccination. However, the mechanism behind the generation of these antibodies is yet to be elucidated. In HIT, the electrostatic interaction between positively charged PF4 and negatively charged heparin culminates in the formation of the Heparin-PF4 complex [ 31 ]. This phenomenon has also been observed with other negatively charged molecules like numerous polyphosphates [ 32 ], Polyvinyl phosphonate [ 33 ], nucleic acids [ 34 ], etc. According to Visentin et al. [ 33 ], numerous negatively charged molecules, spaced about 0.5 nm apart along the molecular backbone and of sufficient length, can form complexes with PF4 while being detectable by the antibodies. Hence, components of vaccines can be expected to play a crucial role in the generation of PF4-polyanions complex and antibodies against them. Moreover, environmental factors and genetic predisposition can exacerbate clinical presentation. For example, specific genotypes encoding FcRIIA have been associated with an increased risk of thrombosis in individuals with anti-PF4-polyanion antibodies [ 24 ]. Another postulated mechanism involves cross-reactivity of anti -SARS-CoV-2 spike protein antibodies that generates following SARS-CoV-2 vaccination with PF4. This may be attributable to molecular mimicry, a phenomenon whereby a certain degree of resemblance exists between the pathogens and the host's antigens [ 35 ]. Kanduc et al. [ 36 ] report massive homogeneity between the SARS-CoV-2 spike glycoprotein and human proteins, thus further strengthening this hypothesis. This structural resemblance can also explain the findings of thrombocytopenia [ 37 ] and anti-PF4 antibodies [ 38 ] in certain SARS-CoV-2 patients. However, the currently available literature suggests no evidence of cross-reactivity [ 38 , 39 ]. Zhang et al. [ 40 ] investigated the findings of thrombosis and thrombocytopenia in SARS-CoV-2 patients. They reported spike protein's ability to stimulate platelet activation and thrombus formation via the Mitogen-activated protein kinase (MAPK) pathway. Based on the findings [ 40 ], the generation of spike protein following vaccination can also play a pivotal role in inducing thrombocytopenia and thrombosis via spike protein-ACE2 interaction-induced platelets activation. However, it remains unanswered if similar interactions can be observed post-vaccination with vector or mRNA vaccines. Moreover, some evidence [ 41 ] reveals potential interactions between adenovirus particles and circulating platelets leading to platelet activation and aggregation. The possibility of such interactions in the case of viral vector-based vaccines cannot be ruled out and requires further investigation. Furthermore, as shown in Table 1 , the findings of negative anti-PF4 antibodies in selective cases indicate involvement of a non-HIT like mechanism hence strengthening the above suggested hypothesis. Future research should focus on potential interactions between spike proteins and platelets and the phenomenon of cross-reactivity. Another intriguing aspect of the higher prevalence of VITT among individuals vaccinated with viral vector-based vaccines needs to be investigated in the search for potential links. Development of thrombosis in selective individuals and incidence of rare site thrombosis like cerebral venous sinuses deserve equal attention for the exact pathophysiology to be elucidated. Lastly, the development of anti-PF4 antibodies only in certain VITT patients can also provide important clues in determining the pathogenesis. Following the escalation in reported thrombocytopenia and thrombosis cases post COVID-19 vaccination, the American Society of Hematology (ASH) reviewed all the reported cases and laid specific ground rules to diagnose this novel presentation. As per the ASH [ 42 ], cases meeting the following criteria can be identified as VITT: a) Symptom onset 4–42 days post SARS-CoV-2 vaccination b) Any venous or arterial thrombosis (often cerebral or abdominal) c) Thrombocytopenia d) Antibodies to platelet factor 4 (PF4) identified by enzyme-linked immunosorbent test (ELISA) e) Markedly elevated D-dimer (>4 times upper limit of normal) Symptom onset 4–42 days post SARS-CoV-2 vaccination Any venous or arterial thrombosis (often cerebral or abdominal) Thrombocytopenia Antibodies to platelet factor 4 (PF4) identified by enzyme-linked immunosorbent test (ELISA) Markedly elevated D-dimer (>4 times upper limit of normal) Individuals presenting with the complaints of severe headache, visual changes, abdominal pain, nausea, vomiting, back pain, shortness of breath, leg pain or swelling, petechiae, easy bruising, or bleeding, 4–42 days post-vaccination, must be evaluated critically for the condition mentioned above. Laboratory investigations, including CBC with platelet count, PF4 ELISA, d-dimer, fibrinogen, and imaging techniques for thrombosis, can play a crucial role in timely diagnosis and management [ 42 ]. Currently, numerous potential pharmacological therapies are being evaluated in the line of management for VITT. The outcomes range from being propitious to contraindicated or variable in different individuals. Briefed below are specific interventions being employed to overcome VITT. The currently available evidence acknowledges IVIG as a potential treatment depicting remarkable success. Hence it is now incorporated into the treatment regimen. A potential explanation for this involves the Fcγ receptor blockade by the antibodies. The recommended dose in VITT is 1–2 g/kg of the person's body weight. However, ideally, the administered IVIG should be the ones collected before the pandemic. The plausible explanation being vaccine response deterioration due to COVID-19 antibodies present in the donated IGs [ 43 ]. There has been growing evidence of their efficacy in patients with VITT [ 44 ]. In some instances, preliminary trials to validate its effectiveness and progressive clinical worsening in some instances [ 45 ] have raised suspicions over its use regarding heparin. Therefore, the American society of hematology (ASH) suggests avoiding the use of heparin unless VITT has been ruled out or another condition diagnosed [ 42 ]. The drug of choice is direct oral anticoagulants (dabigatran, apixaban, rivaroxaban, edoxaban, and fondaparinux) or parenteral direct thrombin inhibitors (e.g., bivalirudin and argatroban). The absolute contraindication following anti-coagulation therapy includes a high risk of bleeding. Hence strict clinical monitoring is crucial after initiating oral anticoagulants. Most cases of VITT described steroids as a clinically effective treatment option. However, further data is needed to move past the anecdotal evidence. The above data and prediction are based on their successfully reported usage in our included cases and recently, by Schultz et al. [ 46 ], where the combined IVIG and steroids were supported. This therapy is only indicated in significant bleeding. Goel et al. [ 47 ] reported a five times increase in mortality of patients infused with platelets following thrombocytopenia. In our included studies, eight reportedly administered platelet infusion. Following Goel et al. [ 47 , 48 ], only two patients survived [ 49 ]. Plasma exchange was used in three cases. Two out of the three patients survived [ 50 , 51 ]. Relevant details by Garnier et al. were unavailable [ 14 ]. Plasma exchange is used in refractory VITT [ 52 ]. Clinically, there is insufficient data to evaluate whether plasma exchange can be administered safely in VITT. Plasma exchange is not a standard treatment option in HIT [ 42 ]. Extrapolating this to VITT, we may assume similar effects on patients with VITT. However, more data is required to draw any conclusion. Plasma exchange is not a standard treatment option in HIT [ 42 ]. Extrapolating this to VITT, we may assume similar effects on patients with VITT. However, more data is required to draw any conclusion. Aspirin or other anti-platelets are currently contra-indicated in VITT due to increased risk of bleeding. Smith et al. [ 53 ] suggested a possible prophylactic role of antiplatelets in VITT. This highlights the need for more work in this area. Rituximab is not recommended currently due to its longer response time (6–8 weeks) [ 42 ]. Moreover, this drug's mechanism of action can be explained via its downregulation of CD-20 B-cells. This can potentially lead to the inactivation of antibodies against COVID-19, hence rendering the vaccine administration useless. The following regimen is per the American Society of Hematology (ASH) [ 42 ], International Society on Thrombosis and Haemostasis (ISTH) [ 54 ], and National Institute for Health and Care Excellence (NICE) in the United Kingdom: 1. Start IVIG. 2. The ISTH guidelines recommend administering steroids if a patient's platelet count is less than 50 × 109/L. 3. Platelet infusion and plasma exchange should not be considered initially. 4. Based on their history and previous clinical profile, patients shall be started an anticoagulant (non-heparin). Vitamin K antagonists should be avoided while the platelet count is low. Moreover, direct thrombin inhibitors should be avoided in pregnant women. DOACs and fondaparinux are suitable for noncritically ill patients. 5. For patients having less than 50 × 103/μL and severe risk of bleeding, IV direct thrombin inhibitors can be used. This will lead to a shorter half-life and rapid action. 6. Fibrinogen levels should be strictly monitored and kept in range (>1.5 g/L) 7. If platelet count remains less than 30 × 109/L despite intravenous immunoglobulin and steroid treatment or fibrinogen level is less than 1 g/L, plasma exchange can be considered after an opinion with hematologists. Start IVIG. The ISTH guidelines recommend administering steroids if a patient's platelet count is less than 50 × 109/L. Platelet infusion and plasma exchange should not be considered initially. Based on their history and previous clinical profile, patients shall be started an anticoagulant (non-heparin). Vitamin K antagonists should be avoided while the platelet count is low. Moreover, direct thrombin inhibitors should be avoided in pregnant women. DOACs and fondaparinux are suitable for noncritically ill patients. For patients having less than 50 × 103/μL and severe risk of bleeding, IV direct thrombin inhibitors can be used. This will lead to a shorter half-life and rapid action. Fibrinogen levels should be strictly monitored and kept in range (>1.5 g/L) If platelet count remains less than 30 × 109/L despite intravenous immunoglobulin and steroid treatment or fibrinogen level is less than 1 g/L, plasma exchange can be considered after an opinion with hematologists.

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The authors declare that there is no conflict of interests.