INTRODUCTION — Vaccination is considered the most promising approach for ending or containing the coronavirus disease 2019 (COVID-19) pandemic. Available vaccines have proven highly safe and effective. (See "COVID-19: Vaccines".)
In late February of 2021, a prothrombotic syndrome was observed in a small number of individuals who received the ChAdOx1 CoV-19 vaccine (AstraZeneca, University of Oxford, and Serum Institute of India), an adenoviral vector-based vaccine. Subsequently, similar findings were observed in a small number of individuals who received the Ad26.COV2.S vaccine (Janssen; Johnson & Johnson), also based on an adenoviral vector. This syndrome has been designated vaccine-induced immune thrombotic thrombocytopenia (VITT). Other terminology is discussed below. (See 'Terminology' below.)
The exact incidence of VITT is unknown, but it appears to be rare. Despite the very low incidence, mass vaccination of many millions of individuals has resulted in several hundred patients developing VITT. Clinicians need to be aware of presenting features and appropriate evaluation and management, which continue to evolve.
TERMINOLOGY — Vaccine-induced immune thrombotic thrombocytopenia is the original name used for VITT in the publication describing the syndrome . This name describes the sequence of events that occur in the syndrome, with thrombosis often presenting before thrombocytopenia is appreciated. This is our preferred term for the syndrome.
Other names include:
●Vaccine-induced immune thrombocytopenia with thrombosis
●Thrombosis with thrombocytopenia syndrome (TTS)
●Vaccine-induced prothrombotic immune thrombocytopenia (VIPIT)
TTS is generally used as a more general descriptive name for a syndrome of thrombosis and thrombocytopenia of any cause following COVID-19 vaccination. Some individuals with TTS may have not been evaluated for anti-PF4 antibodies; some may have causes of thrombosis and thrombocytopenia other than VITT, such as antiphospholipid syndrome (APS), cancer-associated thrombosis and thrombocytopenia, disseminated intravascular coagulation (DIC), or thrombotic thrombocytopenic purpura (TTP) . In these other disorders, the temporal association of the syndrome with vaccination may be coincidental. (See 'Differential diagnosis' below.)
Some authors have used the term "pre-VITT" for thrombocytopenia, anti-PF4 antibodies, and symptoms of thrombosis such as severe headache with negative imaging following vaccination; in some cases, imaging subsequently became positive. We simply refer to this as VITT and treat accordingly. Possible explanations for initial negative imaging are presented below. (See 'Thrombosis' below.)
PATHOPHYSIOLOGY — VITT is caused by antibodies that recognize platelet factor 4 (PF4, also called CXCL4) bound to platelets. These antibodies are IgGs that activate platelets via low affinity platelet FcγIIa receptors (receptors on the platelet surface that bind the Fc portion of IgG). (See "The adaptive humoral immune response", section on 'Opsonic Fc receptors'.)
Ultimately, platelet activation (and possibly activation of other cells such as neutrophils) markedly stimulates the coagulation system and causes clinically significant thromboembolic complications. (See 'Mechanisms of thrombosis' below.)
Characteristics of VITT antibodies — VITT antibody characteristics include [1,3-5]:
●Recognize PF4 bound to platelets; the epitope on PF4 differs from the epitope recognized by heparin-induced thrombocytopenia (HIT) antibodies.
●Detectable in PF4/polyanion and PF4 enzyme-linked immunosorbent assay (ELISA) and in functional assays.
●Cause platelet activation.
●Not heparin dependent (not induced by heparin exposure; do not require heparin for detection in in vitro platelet activation assays). This is a major difference from HIT antibodies, which are typically heparin dependent. In vitro studies have documented that heparin suppressed binding of platelets and platelet aggregation with patient sera [6,7]. One study reported that generation of procoagulant markers in an in vitro assay was heparin-dependent, the clinical significance of which is unclear . Use of heparin to treat VITT is evolving. (See 'Anticoagulation' below.)
VITT antibodies bind to platelets via an eight amino acid region of PF4 on the platelet surface, located within the heparin binding site . VITT antibody binding is blocked by heparin. The amino acids bound by VITT antibodies overlap with but differ from the amino acids bound by HIT antibodies, and VITT antibody binding to platelets is stronger than HIT antibody binding.
Case series suggest that VITT antibodies are often transient:
●A series of 65 individuals with serologically confirmed VITT that repeated functional assays over time found the functional assays became negative in 48 (74 percent), at a median of 15.5 weeks (range, 5 to 28 weeks) . ELISA assay titers declined but were less likely to become negative (only 14 [22 percent] were negative by a median of 25 weeks). Of 29 individuals who subsequently received an mRNA COVID-19 vaccine (most were still receiving anticoagulation for the initial VITT episode), none developed new thromboses or increases in ELISA titer; two had mild thrombocytopenia with declining ELISA titers and no recurrence of platelet-activating antibodies.
●A series of 35 individuals with serologically confirmed VITT that repeated functional assays over time found the assays became negative by 11 weeks in 23 of the 35 (66 percent) and after 12 weeks in 14 of 15 evaluable individuals (93 percent) . ELISA assay titers also declined but did not become negative in most cases. Five individuals subsequently received an mRNA vaccine as their second dose of COVID-19 vaccine while continuing to receive anticoagulation for VITT, and none had recurrent symptoms of VITT.
These data support the safety of giving an mRNA vaccine if/when needed as a second dose or booster dose. The safety of receiving another dose of an adenoviral vaccine is unknown. However, the persistence of VITT antibodies for long periods of time in some individuals ("long VITT") provide a rationale for avoiding future use of adenoviral vectored COVID-19 vaccines in individuals who have had an episode of VITT [11,12]. (See 'Prevention (common questions)' below.)
Mechanisms/triggers of antibody formation — The mechanism(s) by which the implicated vaccines trigger development of new antibodies (and/or immune stimulation of preexisting antibodies) is under investigation. An evolving model suggests a two-hit process in which the vaccine stimulates neoantigen formation (first hit) along with a systemic inflammatory response (second hit), which together lead to production of anti-PF4 antibodies . Vaccine components that could bind to PF4 and alter its conformation, generating a neoantigen, may include virus proteins, proteins from the HEK3 cell line, and free DNA [1,3]. Preliminary studies suggest that a complex of adenoviral hexon proteins bound to PF4 may be responsible [13,14].
●PF4 is a positively-charged tetrameric protein; the positive charge usually causes PF4 molecules to repel each other, but in the presence of negatively charged (polyanionic) molecules such as heparin, pentosan polysulfate (a rarely used medication), or endogenous polyphosphates, PF4 may form higher order structures that act as neoantigens [15,16]. DNA and RNA also have polyanionic properties and may create a neoantigen when bound to PF4 [17,18].
●Hexon is the major adenoviral surface protein. The complex between PF4 and hexon appears to be mediated by electrostatic interactions [13,14]. (See "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection", section on 'Virion structure'.)
●An inflammatory co-signal has been proposed to further stimulate the immune response. EDTA (used as a preservative) can increase capillary permeability and may contribute [3,13].
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein antigens in the vaccine do not appear to be a source of molecular mimicry. There is no antibody cross-reactivity with the SARS-CoV-2 spike protein, and development of COVID-19 following recovery from VITT does not appear to re-trigger VITT antibodies or clinical recurrence of VITT [19,20].
Mechanisms of thrombosis — Anti-PF4 antibodies cause "pancellular" activation, meaning that, besides activating platelets and coagulation reactions, the antibodies activate monocytes (leading to tissue factor expression), neutrophils (leading to NETosis), and endothelial cells (leading to tissue factor expression) . Activation of these other cell types further contributes to high thrombosis risk.
Thrombosis in VITT can occur in typical sites of venous thromboembolism such as pulmonary embolism or deep vein thrombosis (DVT) in the leg ; however, a distinctive feature of the syndrome is thrombosis in unusual sites including the splanchnic (splenic, portal, mesenteric) veins, adrenal veins (risk for adrenal failure), and the cerebral and ophthalmic veins. Arterial thrombosis including ischemic stroke (often, middle cerebral artery) and peripheral arterial occlusion has also occurred, often in individuals with venous thrombosis. (See 'Thrombosis' below.)
The pathophysiologic explanation for these unusual sites of thrombosis is unknown. The distribution is similar to that seen with other unusual thrombophilias such as paroxysmal nocturnal hemoglobinuria (PNH) and thromboembolic complications associated with a JAK2 mutation. Autopsy studies in individuals who have died of VITT have demonstrated catastrophic venous thrombosis involving multiple large and small vessels .
Similarity to spontaneous HIT — VITT belongs to a spectrum of platelet-activating anti-PF4/heparin disorders, which also include :
●Classic HIT – In classic heparin-induced thrombocytopenia (HIT), individuals develop thrombocytopenia, often with thrombosis, beginning 5 to 10 days after an immunizing heparin (unfractionated or low molecular weight heparin) exposure (the first day of immunizing heparin exposure is considered day 0). The antibodies are heparin dependent, meaning that the platelet count falls while the individual is receiving heparin and typically recovers within four to five days after stopping heparin exposure. Classic HIT occurs in <0.1 to 5 percent of individuals exposed to heparin, with the highest incidences associated with tissue trauma (surgery) and exposure to unfractionated rather than low molecular weight heparin for at least a week. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Pathophysiology'.)
●Autoimmune HIT (aHIT) – Autoimmune HIT represents a small portion of patients with HIT who have atypical presentations, some of which are summarized in the table (table 1). Although the platelet count usually begins to fall within the 5- to 10-day window after starting heparin exposure, the platelet count decrease may occur (or progress) after stopping heparin (delayed-onset HIT), or the thrombocytopenia may persist for days to weeks after stopping heparin (persisting or refractory HIT). The sole heparin exposure may have been heparin flushes (heparin-flush HIT) or fondaparinux (fondaparinux-associated HIT). These patients have a mix of antibodies that are heparin-dependent and heparin-independent. For heparin-independent antibodies, heparin is not required to produce a strongly positive result in a functional assay such as the serotonin-release assay (SRA) . (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Terminology and HIT variants'.)
●Spontaneous HIT – Spontaneous HIT (also called spontaneous HIT syndrome) is a type of HIT in which there is no known preceding heparin exposure to explain the clinical and serologic picture. Three distinct subtypes are recognized:
•Following orthopedic surgery (usually total knee replacement).
•In medical patients, usually following a viral or bacterial infection, although occasionally no preceding trigger is identified.
•In association with a monoclonal gammopathy in which the IgG has anti-PF4 platelet-activating properties .
Of these related syndromes, VITT most strongly resembles spontaneous HIT, triggered by an adenoviral vectored COVID-19 vaccine.
The key feature that distinguishes VITT (and other HIT/aHIT disorders) from immune thrombocytopenia (ITP) is that antiplatelet antibodies in VITT activate platelets, causing thrombosis, whereas antiplatelet antibodies in ITP do not.(See 'Differential diagnosis' below.)
Implicated vaccines — Two adenoviral vector-based vaccines have been implicated in causing VITT:
●ChAdOx1 nCoV-19 (AstraZeneca, University of Oxford, and Serum Institute of India)
●Ad26.COV2.S (Janssen; Johnson & Johnson)
●Data are limited for the Gam-COVID-Vac/Sputnik V (Gamaleya Institute) vaccine, but a few cases have been reported .
Other adenoviral vaccines have been administered to large numbers of individuals without reported cases of VITT. Examples include Ad5-based COVID-19 vaccine (CanSino Biologics) and Ad26.ZEBOV-GP (recombinant) Ebola vaccine (Janssen Biologics). It is unknown whether this represents a biologic difference in vaccine safety due to different vaccine constituents or a difference in reporting. (See "COVID-19: Vaccines", section on 'Other vaccines'.)
A case of possible VITT related to the mRNA-1273 (Moderna) vaccine has been published, although the individual may have had another autoimmune or spontaneous HIT syndrome [26,27]. A publication from the Vaccine Adverse Event Reporting System (VAERS) at the Centers for Disease Control and Prevention (CDC) and the US Food and Drug Administration (FDA) identified three cases of thrombosis with thrombocytopenia in recipients of mRNA-1273 from among over 350 million vaccine recipients . The three affected individuals had a positive serologic test for anti-PF4 antibodies; one had an indeterminant functional assay and one did not have functional assay testing. The authors concluded that these events likely represented background rates of clinical findings or a non-VITT etiology and that the data did not support an association of VITT with mRNA vaccines. VITT has not been reported after the other mRNA-based vaccine, BNT162b2 (Pfizer-BioNTech). Population-based studies involving millions of individuals vaccinated with BNT162b2 have not observed increased risks of thrombosis [29-31].
Cases of possible VITT with other (non-COVID-19) vaccines may be reported . However, identification of thrombocytopenia and thrombosis with anti-PF4 antibodies after a commonly administered vaccine should not be interpreted to show causality; these rare occurrences could easily be consistent with the background rate of spontaneous heparin-induced thrombocytopenia (spontaneous HIT) in the general population. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Terminology and HIT variants'.)
Incidence and risk factors — The incidence of VITT is unknown but it appears to be exceedingly rare. Most reports have described a small number of cases among tens of millions of vaccinated individuals [1,33]. The highest incidence was reported from Norway, in which five cases were reported from among approximately 130,000 individuals vaccinated with ChAdOx1 nCoV-19, suggesting an incidence of 1 in 26,000 . A January 2022 report from the VAERS surveillance system to the CDC and FDA identified 54 cases of thrombosis with thrombocytopenia (in some cases, anti-PF4 antibodies were not tested) from among over 14 million recipients of Ad26.COV2.S, for an incidence of 3.8 per million (approximately 1 in 263,000) . Pharmacovigilance for these outcomes has been thorough, suggesting that case ascertainment is high. (See 'Implicated vaccines' above.)
Risk factors for VITT are unknown. Female sex and younger age were proposed as possible risk factors based on initial reports, but these associations may be skewed by the demographics of early vaccinated populations:
●Sex – Initial reports suggested a female predominance, with female sex accounting for 9 of 11 cases in one series and 4 of 5 cases in another [1,4]. However, this may have reflected the demographics of the first wave of individuals to receive the vaccine (young female health care workers). In a series of 220 definite and probable cases from the United Kingdom, there was no sex preponderance . In three of the first cases from Canada, two were males, and all were over the age of 60 years; this was during the period when the ChAdOx1 nCoV-19 (AstraZeneca) vaccine was being avoided in younger women . In the December 2021 report from the ACIP, rates were similar between males and females in most age brackets, with the exception of females ages 30 to 49 years, in whom rates were higher . (See 'Implicated vaccines' above.)
If there is a true female predominance, this would be consistent with the epidemiology of the related syndrome of heparin-induced thrombocytopenia, which affects females slightly more than males (approximately 60 to 65 percent females) . It would also be consistent with the incidence of other immune disorders, for which there is often a female preponderance and a propensity for younger ages. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Incidence and risk factors'.)
●Age – Initial reports appeared to suggest that individuals with VITT were younger (<55 or 60 years); however, this may reflect the age of the initially vaccinated populations. Cases in individuals >60 years are emerging [34,35].
Overview of clinical presentation — VITT strongly mimics autoimmune heparin-induced thrombocytopenia (aHIT), with typical clinical features noted below. (See 'Thrombocytopenia' below and 'Thrombosis' below and 'Coagulation abnormalities/DIC' below.)
The syndrome likely begins in a narrow window 5 to 10 days post-vaccination, leading to identification of cases typically between 5 to 30 days post-vaccination (potentially later, especially when VITT presents with thrombosis in certain locations such as deep vein thrombosis [DVT] or pulmonary embolism [as opposed to cerebral venous thrombosis, which tends to present earlier], or if there is a delay in recognizing the symptoms and/or in seeking medical attention) [26,38].
Several reports have also described a general flu-like syndrome in the same 5- to 10-day window or at the time of presentation with thrombosis, possibly suggesting an enhanced inflammatory response [1,39,40]. As awareness of the syndrome has increased, less-typical presentations have emerged such as thrombosis without thrombocytopenia or thrombocytopenia without thrombosis.
In a series of 220 patients with definite or probable VITT, the following features were noted :
●Age – Median 48 years, range 18 to 79 years.
●Sex – 55 percent female, 45 percent male.
●Time since vaccination – Median 14 days; range 5 to 48 days.
●Site(s) of thrombosis – Cerebral veins (including intracranial hemorrhage), deep veins of the leg, pulmonary arteries, and splanchnic vessels. Over half had thrombosis in multiple sites.
●Platelet count – Median 47,000/microL, range 6000 to 344,000/microL.
●Fibrinogen – Median 2.2 g/L (220 mg/dL), range 0.3 to 4.4 mg/dL.
●D-dimer – Median 24,000 fibrin equivalent units (FEU; equivalent to 12,000 ng/mL), range 5000 to 80,000 FEU.
Most cases occur after the first dose of the vaccine, although VITT can occur after the second dose of a two-dose vaccine. (See 'Second dose (for two-dose vaccines) or booster dose' below.)
Thrombocytopenia — Thrombocytopenia may be suspected based on the presence of petechiae or mucosal bleeding, or it may be an incidental finding. (See 'Bleeding' below.)
The typical platelet count range of patients with definite VITT is between 10,000 and 100,000/microL, with a median platelet count of 20,000 to 25,000/microL . Some individuals with VITT may have mild thrombocytopenia or a platelet count outside this range . Examples include an individual with early VITT and a decreasing platelet count or an individual with a higher baseline platelet count for whom a count of 120,000/microL may represent a significant decrease.
Thrombosis — Thrombosis has been the presenting feature in most of the initial reported cases of VITT [1,4,33,41]. Both venous and arterial thromboses have been described. Cerebral venous thrombosis (CVT; also called cerebral venous sinus thrombosis [CVST] and dural sinus thrombosis [DST]), which may present as intracerebral hemorrhage, appears to be the most common site of thrombosis in some series [33,42,43]. Often thrombi are present at multiple sites, frequently with thrombosis in unusual locations. However, inability to document thrombosis in an individual with other features that strongly suggest VITT is not a reason to avoid treatment for VITT.
Symptoms of thrombosis include severe pain (severe, unremitting headache, backache, abdominal pain, chest pain) as well as typical symptoms of deep vein thrombosis (DVT) or pulmonary embolism, as summarized in the table (table 2).
Locations of thrombosis include the following, in decreasing order of frequency:
•Splanchnic vein thrombosis (includes mesenteric vein, portal vein, splenic vein, hepatic vein)
•Adrenal vein thrombosis, which may present as adrenal hemorrhage. If bilateral, the patient is at risk for acute adrenal failure
•Pulmonary embolism and DVT (DVT is less common)
•Other unusual sites such as the ophthalmic vein 
Observational data from case reporting suggest that CVT accounts for 25 to 60 percent of thromboses in patients who developed VITT after receiving the ChAdOx1 nCoV-19 vaccine (AstraZeneca) [33,42,43]. CVT has also been reported following the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) .
Clinical features of CVT include those related to intracranial hypertension (headache), focal findings and seizures, and encephalopathic changes (mental status changes, coma), as discussed separately. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis", section on 'Clinical aspects'.)
Some individuals have presented with CVT symptoms (severe headache) and initially had negative imaging, suggesting that imaging findings may lag behind clinical symptoms. Microthrombosis may be responsible for symptoms with negative imaging, although this explanation remains speculative. One case series described 11 patients with high suspicion for VITT and CVT (timing relative to adenoviral vaccination, severe headache, thrombocytopenia, high D-dimer, positive PF4 antibody testing) in whom initial brain imaging was negative . Regardless of the explanation for this phenomenon, an individual with strongly suspected VITT requires treatment (including full-dose anticoagulation) and continued evaluation, even if initial imaging findings do not document thrombosis. (See 'Management' below.)
•Ischemic stroke, especially middle cerebral artery territory
•Acute limb ischemia
●Sudden death – Sudden death (diagnosis of VITT established post-mortem) may reflect any number of thrombotic complications including coronary thrombosis, pulmonary embolism, or intracerebral hemorrhage .
Coagulation abnormalities/DIC — Individuals with VITT have a high frequency of overt, decompensated disseminated intravascular coagulation (DIC), which manifests the following abnormalities:
●Moderate to severe thrombocytopenia, or a significant decrease from the individual's baseline platelet count (see 'Thrombocytopenia' above)
●Elevated D-dimer (often greatly elevated, >10 mg/L [>10,000 ng/mL])
●Decreased fibrinogen (approximately half have a fibrinogen level below the normal range; many of the remainder are in low-normal range)
●Normal or mildly increased prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (aPTT)
Elevations in D-dimer are very nonspecific and may reflect ongoing thrombosis, chronic inflammatory states, and/or DIC. (See "Clinical use of coagulation tests", section on 'Fibrin D-dimer'.)
A DIC-like picture appears to be more common with autoimmune HIT syndromes such as VITT than with classic HIT. (See 'Pathophysiology' above.)
Often bleeding predominates in acute DIC, whereas in VITT, thrombosis predominates. However, bleeding complications have been reported in VITT, especially intracerebral bleeding (usually in association with cerebral thrombosis and subsequent hemorrhage). (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Clinical manifestations' and 'Bleeding' below.)
Bleeding — Clinically serious bleeding has been described in some individuals, especially those with cerebral venous thrombosis (CVT) who subsequently developed intracranial bleeding while receiving anticoagulation with a heparin product [1,4]. Hemorrhage is a frequent manifestation of CVT in the absence of anticoagulation (due to venous congestion) and it is not clear what role, if any, the use of anticoagulation or the exposure to heparin had in these bleeding manifestations. Antithrombotic agents are used in CVT, even in individuals with hemorrhage. (See 'Anticoagulation' below.)
Isolated thrombocytopenia (without thrombosis) and hemorrhage have also been reported; this individual also had a very high D-dimer .
Minor bleeding (bruising) and petechiae are also common.
When to suspect — VITT may be suspected in an individual who develops symptoms of thrombosis or thrombocytopenia during an appropriate time frame following one of the implicated vaccines, as illustrated in the algorithm (algorithm 1). For these reasons, clinicians should ask about recent vaccination status (whether the individual was recently vaccinated, number of days post-vaccination, and specific vaccine received).
The mnemonic VITT can be used to codify these key features:
●Interval (5 to 30 days post-vaccine)
●Thrombosis (usually the event that draws attention to VITT)
●Thrombocytopenia (usually recognized when a complete blood count [CBC] is drawn to investigate thrombosis; less often, can be incidentally detected)
In classic heparin-induced thrombocytopenia (HIT), the 4Ts score is used to estimate the pretest probability of HIT and determine the appropriateness of HIT antibody testing (see "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on '4 Ts score'). An adapted score (table 3) may help identify key features of the syndrome and the appropriateness of initiating therapy while awaiting the results of platelet factor 4 (PF4) antibody testing. This score has not been validated for diagnosing VITT.
Symptoms of thrombosis depend on the location, as summarized in the table (table 2). CVT may be more common in females.
Symptoms related to thrombocytopenia such as bruising and petechiae are common. More serious bleeding has generally occurred after anticoagulation was initiated.
Routine testing of platelet counts following COVID-19 vaccination is not suggested due to the rarity of the syndrome. D-dimer testing should not be performed for screening given its lack of specificity.
In preliminary reports of VITT, testing for SARS-CoV-2 infection was performed and was uniformly found to be negative [1,4,33]. Testing for infection is reasonable to exclude the possibility of a COVID-19 hypercoagulable state or other systemic infection, especially since recently vaccinated individuals may have not yet developed protective immunity. However, treatment of VITT should not be delayed while awaiting results of this testing.
Laboratory testing — Diagnosis of VITT requires consideration of clinical and laboratory features. Laboratory testing for VITT includes the following:
●CBC – A complete blood count (CBC) with platelet count to document thrombocytopenia and compare platelet counts over time. The degree of thrombocytopenia (or decrease from the individual's baseline) is helpful in estimating the likelihood of VITT. No specific abnormalities are seen on the peripheral blood smear; patients usually do not have platelet clumps, schistocytes, nucleated red blood cells (normoblasts), a marked left-shift, or other immature cells.
●Coagulation testing – Testing the prothrombin time (PT) and activated partial thromboplastin time (aPTT) is standard before starting anticoagulation. The fibrinogen and D-dimer help assess the presence of disseminated intravascular coagulation (DIC) and may be used in estimating the likelihood of VITT. Hypofibrinogenemia with bleeding (rare in VITT) may help determine the need for administering a source of fibrinogen. (See 'Minimize platelet transfusions' below.)
•PT and aPTT
•Fibrinogen and D-dimer
●PF4 antibody testing – Positive testing is confirmatory; details are discussed below. (See 'PF4 assays' below.)
However, a positive anti-PF4 antibody test alone (without thrombocytopenia or thrombosis) is not sufficient to make the diagnosis.
•In a series of 492 health care workers who were vaccinated with the ChAdOx1 nCoV-19 (AZD1222; AstraZeneca) vaccine, six had positive anti-PF4 antibody testing and were clinically well with normal platelet counts . Their sera did not cause platelet activation in an in vitro functional assay.
•Another study tested sera from 281 vaccinated individuals vaccinated with one of two vaccines and found anti-PF4 antibodies in both groups (7 percent of ChAdOx1 recipients and 8 percent of BNT162b2 mRNA vaccine recipients) . Retrospective testing in individuals who had sera available from prior to vaccination showed a mixture of findings (some were positive before vaccination and some were negative). Most positive results were weak (OD of 0.5 to 1), none of the antibodies activated platelets, and none of the patients were symptomatic or thrombocytopenic. These antibodies were not considered clinically significant.
In some institutions, there may be a delay of one or more days while awaiting the results of the PF4 antibody testing. Appropriate treatment (including anticoagulation with a non-heparin agent such as argatroban or a direct oral anticoagulant) and administration of intravenous immune globulin (IVIG) should not be delayed while awaiting the results of confirmatory testing, especially for individuals with thrombocytopenia and thrombosis with the appropriate timing following receipt of one of the implicated vaccines.
Some individuals with isolated thrombosis without thrombocytopenia or isolated thrombocytopenia without thrombosis may delay IVIG until the results of PF4 antibody testing (and subsequent platelet counts) are available, depending on their clinical status. The decision to initiate each treatment (anticoagulation, IVIG) requires clinical judgment regarding the likelihood of VITT versus other diagnoses; input from the consulting hematologist or other hemostasis and thrombosis expert is advised.
PF4 assays — There are different types of platelet factor 4 (PF4) antibody tests, and it is important to verify that the correct test has been done and results are properly interpreted.
●ELISA – Enzyme-linked immunosorbent assay (ELISA) testing is the recommended screening test . Commercial PF4/polyanion ELISA tests are usually positive in VITT, especially the Immucor (PF4/polyvinyl sulfonate [PVS]) ELISA. In preliminary case reports, individuals with VITT have had high optical density (OD) readings, in the range of 2.00 to 3.00 (or even higher) OD units, which would be sufficient to confirm the syndrome (particularly in the absence of proximate heparin exposure) [1,4]. In these individuals with a high OD, a serotonin release assay (SRA) may not be required but may be useful for mechanistic understanding and case reporting.
A study that evaluated multiple ELISA assays found that no single ELISA method detected all cases of VITT . Some false-negative results have been reported with PF4/heparin and PF4/platelet lysate ELISA tests. The observation that high OD readings predict the presence of VITT is similar to HIT. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Immunoassay (eg, ELISA)'.)
●SRA – Functional assays such as the serotonin release assay (SRA) are often positive in VITT, but some are negative . However, if PF4 is supplemented (without heparin), the SRA becomes positive . The functional assay is not required for diagnosis if the ELISA is strongly positive (high OD reading) but may be helpful in cases in which VITT is strongly suspected and the ELISA is negative or equivocal, or in situations of case-identification using specific clinical and laboratory criteria.
●Rapid HIT assays – Rapid HIT assays are generally negative in VITT and should not be used to confirm or exclude the diagnosis due to their poor sensitivity [33,40,47,49]. It is important to notify the laboratory that VITT is under consideration and that an ELISA or functional assay is needed. Examples of rapid HIT assays to avoid include:
•Latex-enhanced immunoassay (HemosIL HIT-Ab(PF4-H) [Instrumentation Laboratory/Werfen]; used in the United States)
•Chemiluminescence immunoassay (HemosIL AcuStar HIT-IgG [Instrumentation Laboratory/Werfen]; used in the United States)
•Particle gel immunoassay (ID-PaGIA Heparin/PF4 Antibody Test [DiaMed]; not used in the United States)
•Lateral flow immunoassay (STic Expert HIT [Diagnostica Stago]; not used in the United States)
The diagnosis is considered confirmed by a positive PF4 ELISA, in the appropriate clinical context of post-COVID-19 vaccine thrombosis and/or thrombocytopenia (including lack of proximate heparin exposure to explain the positive ELISA), typically with an OD >2.00, or by a positive functional assay (SRA, or PF4-enhanced SRA, or other PF4-dependent functional assay).
Investigational assays are under study to address concerns about accuracy of HIT testing for diagnosing VITT. These include a washed platelet functional assay, referred to as PF4-induced platelet activation (PIPA), and a flow cytometry assay, referred to as PF4-induced flow cytometry-based platelet activation (PIFPA) . These assays showed very high sensitivity and specificity when tested on 16 VITT samples and 20 vaccinated controls without VITT.
Imaging to diagnose thrombosis — Diagnostic testing for various sites of thrombosis is summarized in the table (table 2) and discussed in separate topic reviews. If imaging is negative but the suspicion for VITT remains high, presumptive treatment for VITT and repeat imaging may be prudent, especially for suspected CVT. (See 'Thrombosis' above.)
●Portal vein thrombosis – (See "Acute portal vein thrombosis in adults: Clinical manifestations, diagnosis, and management", section on 'Diagnosis'.)
●Mesenteric vein thrombosis – (See "Mesenteric venous thrombosis in adults", section on 'Diagnosis'.)
●Pulmonary embolism – (See "Overview of acute pulmonary embolism in adults", section on 'Diagnostic approach to patients with suspected PE'.)
●Ischemic stroke – (See "Overview of the evaluation of stroke", section on 'Imaging studies'.)
●Limb ischemia – (See "Clinical features and diagnosis of acute lower extremity ischemia" and "Overview of upper extremity ischemia".)
Differential diagnosis — There are other causes of thrombocytopenia and/or thrombosis that should be considered, especially in individuals with negative PF4 antibody testing. None of these diagnoses has been associated with COVID-19 vaccination, with the possible exception of vaccine-associated immune thrombocytopenia (ITP). The table summarizes differences between VITT and other thrombocytopenic disorders (table 4).
In a series of nearly 300 individuals evaluated for possible VITT, alternative diagnoses included metastatic cancer and chronic disseminated intravascular coagulation (DIC) from an aortic aneurysm .
●COVID-19 – COVID-19 carries a high risk of thrombosis and coagulation abnormalities in hospitalized individuals, including severe thrombocytopenia, particularly in individuals in the intensive care unit (ICU). Thrombosis in atypical locations, including cerebral venous thrombosis (CVT) and arterial thrombosis, as well as very high D-dimer levels, have been reported in individuals with COVID-19. Unlike VITT, COVID-19-associated thrombosis is not expected to cause a positive PF4 assay result, and therapeutic anticoagulation for COVID-19-associated thrombosis typically uses low molecular weight (LMW) heparin during hospitalization (or a direct oral anticoagulant during the recuperation phase). (See "COVID-19: Hypercoagulability", section on 'Management'.)
●Other causes of thrombocytopenia – Other causes of thrombocytopenia include infections, immune thrombocytopenia (ITP), medications, hypersplenism, and inherited disorders. Like VITT, there may be symptoms of thrombocytopenia. ITP is a diagnosis of exclusion. Unlike VITT, the risk of thrombosis with these disorders is usually not increased, and anticoagulation can further increase bleeding risk without providing any benefit. Infection with SARS-CoV-2 (virus that causes COVID-19) can itself cause thrombocytopenia. Spontaneous HIT, although extremely rare, is also possible . (See "Diagnostic approach to the adult with unexplained thrombocytopenia" and "COVID-19: Hypercoagulability", section on 'Coagulation abnormalities'.)
●Other causes of thrombosis – Other acquired risk factors for thrombosis include cancer, trauma, surgery, pregnancy, immobility, and estrogen-containing medications. Inherited thrombophilias can also increase thrombosis risk. Like VITT, individuals with thrombosis from other risk factors require anticoagulation. Unlike VITT, thrombosis of other causes (with the exception of HIT) can be treated with heparin and does not require IVIG, which is itself potentially prothrombotic. (See "Overview of the causes of venous thrombosis".)
●TTP – Thrombotic thrombocytopenic purpura (TTP) is another rare syndrome characterized by thrombocytopenia and thrombosis. In TTP, thrombosis is typically microvascular, affecting various organ systems including the central nervous system and heart. TTP is associated with microangiopathic hemolytic anemia, characterized by findings of hemolysis (anemia, high lactate dehydrogenase [LDH] and bilirubin), high reticulocyte count, and schistocytes (red blood cell fragments) on the blood smear. Absence of schistocytes on the blood smear argues against TTP. Diagnosis of TTP typically correlates with severely reduced ADAMTS13 activity (<10 percent). (See "Diagnosis of immune TTP".)
●Classic HIT – Classic HIT resembles VITT clinically but occurs following heparin exposure. Classic HIT is generally only suspected in an individual with prior hospitalization or heparin exposure, which is not the case for most individuals with suspected VITT. In HIT, PF4 antibodies are heparin dependent, and thrombocytopenia generally resolves rapidly following cessation of heparin exposure. In classic HIT, withdrawal of heparin and anticoagulation with a non-heparin agent are usually sufficient therapy, and IVIG is usually not required. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia".)
Specific testing for PF4 antibodies in individuals with an appropriate clinical history is used to distinguish VITT from these other diagnoses. (See 'Laboratory testing' above.)
MANAGEMENT — VITT is a potentially life-threatening disorder. Management recommendations including those listed below are rapidly evolving.
Input from the consulting hematologist or other hemostasis and thrombosis expert is critical to assist with evaluation (including assessment of the likelihood of VITT versus other conditions) and management (including decisions regarding anticoagulation, intravenous immune globulin [IVIG], therapeutic plasma exchange [TPE] and transfusions), as well as case reporting.
Other consultations may be appropriate, including neurology consult regarding cerebral venous thrombosis (CVT) and individuals with expertise in thrombectomy and other procedures .
Several guideline documents have been produced, as listed below. (See 'Expert groups and guidelines' below.)
Expert groups and guidelines — Our approach is largely consistent with those of expert groups such as the following:
●American Society of Hematology (ASH) – https://www.hematology.org/covid-19/vaccine-induced-immune-thrombotic-thrombocytopenia
●International Society on Thrombosis and Haemostasis (ISTH) – https://www.isth.org/news/561406/
●American College of Cardiology (ACC) – https://www.acc.org/latest-in-cardiology/articles/2021/04/01/01/42/vaccine-induced-thrombotic-thrombocytopenia-vitt-and-covid-19-vaccines
●American Heart Association/American Stroke Association – https://www.ahajournals.org/doi/10.1161/STROKEAHA.121.035564
●National Institute for Health and Care Excellence (NICE) in the United Kingdom – https://www.nice.org.uk/guidance/ng200
Clinicians caring for an individual with suspected VITT should review one of these or other regularly updated online resources describing the most current diagnostic pathways and treatment algorithms. Reporting of confirmed cases to regulators should be undertaken in every case.
Hospitalization — Many individuals are hospitalized due to the severity of their clinical condition, and we would hospitalize anyone with VITT due to the potentially serious nature of thrombotic complications. An exception may be an individual with isolated thrombocytopenia (without thrombosis) who can be treated with a direct oral anticoagulant (DOAC) with very close follow-up. (See 'When is it safe to discharge' below.)
●Indications for anticoagulation – Therapeutic anticoagulation is one of the primary treatments for VITT and is used unless there is a contraindication such as expanding intracerebral hemorrhage. Cerebral venous thrombosis (CVT) associated with central nervous system (CNS) hemorrhage is not a contraindication to anticoagulation; rather, this finding is attributable to increased venous "back pressure" and often resolves rapidly with anticoagulation.
In addition to those with confirmed VITT-associated thrombosis, this includes individuals for whom there is a strong clinical suspicion for VITT who are awaiting confirmatory testing and those with positive laboratory testing for VITT who have not had a thrombosis.
●Effect of heparin exposure – It is unknown whether heparin (unfractionated or low molecular weight) is safe and effective or deleterious in individuals with VITT. Early reports in which patients were treated with heparins described clinical worsening, including death, and early recommendations were to avoid heparin because of the resemblance of VITT to HIT . However, with the growing understanding of the pathophysiology of VITT, it appears that heparin may be a reasonable choice for anticoagulation.
Accumulating data suggest that heparin does not exacerbate VITT:
•A meta-analysis involving >600 patients did not identify a signal of increased mortality between heparin and non-heparin-based anticoagulation treatment of VITT (risk ratio [RR] 0.84, 95% CI 0.47-1.50; p = 0.80) .
•In a series of 220 individuals with definite or probably VITT, the authors stated that "heparin did not appear to be harmful in patients who received it"; this included approximately one-fourth of individuals who received heparin at some point during their treatment . Mortality was 20 percent in those who received heparin and 16 percent in those who did not; the group that received heparin was heavily biased towards presentations earlier in the pandemic when the syndrome was unrecognized and outcomes may have been adversely affected by delays in diagnosis.
•A series of 99 patients with VITT presenting with CVT did not find a statistically significant difference in survival with use of heparin versus a non-heparin anticoagulant (adjusted odds ratio [OR] for mortality with non-heparin anticoagulants, 0.70, 95% CI 0.24-2.04) .
•In vitro studies also suggest (preliminarily) that heparin is not harmful. (See 'Pathophysiology' above.)
It may be reasonable to avoid heparin in cases of diagnostic uncertainty in which HIT (including delayed or spontaneous HIT) remains possible in the differential diagnosis. (See 'Differential diagnosis' above.)
●Choice of anticoagulant – The choice of anticoagulant depends on the patient's clinical status and anticipated need to stop anticoagulation (based on risk of bleeding or need for an invasive procedure). In an otherwise well individual, anticoagulants in order of preference are:
•A direct oral anticoagulant (DOAC). Options include a factor Xa inhibitor (apixaban, edoxaban, or rivaroxaban); the oral direct thrombin inhibitor dabigatran may also be an option, although it is less studied.
•Fondaparinux or danaparoid (danaparoid is not available in the United States).
The rationale for this order of preference includes the greater experience and safety profile of DOACs; the slight risk of in vivo "cross-reactivity" with fondaparinux (antibody-enhanced platelet activation in the presence of fondaparinux); and the costs, burdens, and bleeding risks of the parenteral direct thrombin inhibitors. The underlying disseminated intravascular coagulation (DIC) in many cases of VITT may also result in failure of parenteral direct thrombin inhibitor therapy due to a phenomenon known as "aPTT confounding" (systematic underdosing due to activated partial thromboplastin time [aPTT] prolongation associated with DIC rather than due to therapeutic levels of anticoagulation).
Additional advantages and disadvantages of non-heparin anticoagulants are summarized in the table (table 5).
●Dose level – Standard full therapeutic dosing is appropriate, provided there is no active bleeding, with appropriate adjustments for body weight and kidney function. Details of dosing for individual agents are discussed separately. (See "Management of heparin-induced thrombocytopenia", section on 'Specific agents'.)
●Duration of anticoagulation – The appropriate duration of anticoagulation is unknown. Analogous with spontaneous HIT following orthopedic surgery, thrombocytopenia can be prolonged (eg, eight weeks). A reasonable approach for VITT with thrombosis would be to continue anticoagulation for three months after normalization of the platelet count, as long as no further thrombosis occurs. For VITT without thrombosis, anticoagulation until platelet count recovery and perhaps longer if tolerated (four to six weeks after platelet count recovery) appears prudent, by analogy with the duration of anticoagulation for classic HIT. It should be noted that the course of the initial patients is as yet unknown, there are no data to guide decision-making, and this advice is likely to be amended as further data accrue.
Individuals who are discharged from the hospital can be switched to a DOAC if they were taking a parenteral anticoagulant in the hospital. Warfarin and other vitamin K antagonists (VKAs) should be avoided while the patient is thrombocytopenic, due to lack of efficacy during ongoing hemostatic activation, but a VKA might be an option following platelet count recovery for an individual who is unable to receive a DOAC, as long as appropriate bridging is used.
IVIG — High-dose intravenous immune globulin (IVIG) is recommended along with anticoagulation, as a means of interrupting VITT antibody-induced platelet activation. Unless there is a contraindication, we would use IVIG in all individuals with VITT. This includes individuals with a high clinical suspicion for VITT (thrombosis and thrombocytopenia after recent vaccination and high D-dimer) who are awaiting results of the anti-PF4 antibody testing, especially if they are clinically ill or unstable.
A typical dose is 1 gm/kg intravenously once per day for two days, based on actual body weight.
After IVIG is administered, thrombocytopenia can recur (within a few days after IVIG is completed). It is important to continue to monitor the platelet count during hospitalization and following discharge from the hospital. (See 'Monitoring' below.)
Evidence supporting the use of IVIG comes from:
●Use in autoimmune HIT – (See "Management of heparin-induced thrombocytopenia", section on 'Role of IVIG'.)
•In a non-randomized series of 99 individuals with VITT presenting with cerebral venous thrombosis (CVT), use of IVIG was associated with a statistically significant reduction in mortality (29 percent, versus 70 percent in those who did not receive IVIG; adjusted odds ratio [OR] 0.19, 95% CI 0.06-0.58) .
•In a series of three individuals with VITT and arterial thrombosis after receiving the ChAdOx1 nCoV-19 vaccine, treatment with high-dose IVIG was associated with rapid improvements in platelet counts .
•Another series of five individuals with VITT and various thrombotic manifestations had rapid improvements in platelet counts . None of the three individuals in the first series had new or progressive thrombosis following IVIG administration; one individual in the second series had progression of CVT.
These findings suggest that IVIG halts platelet activation in VITT (sometimes, only transiently), and clinicians need to remain vigilant to identify new thrombotic or bleeding complications.
The mechanism of action of IVIG is thought to be similar to its role in other autoantibody-mediated disorders and to involve autoantibody binding to cellular receptors (in this case, platelet FcγIIa receptors). In the series of three patients above, in vitro testing showed that IVIG blocked platelet activation in a functional assay but did not disrupt autoantibody binding to PF4 . (See 'Pathophysiology' above.)
Plasma exchange for refractory disease — Therapeutic plasma exchange (TPE) and immunosuppression have been proposed for refractory disease or disease with concerning features such as cerebral vein thrombosis (CVT) or multiple thromboses with evidence of excessive platelet activation (platelet count <30,000/microL) [34,54].
In a series of three patients with VITT who had persistent thrombocytopenia and ongoing thrombosis despite treatment with anticoagulation and IVIG, TPE using plasma (or plasma plus albumin) as the replacement fluid resulted in cessation of thrombosis and improvement in platelet counts . TPE was performed daily for five to seven days. In one case, IVIG was added after each treatment partway through the course, and in another case, one dose of rituximab was given after the fifth TPE procedure.
In a large series of 220 patients with definite or probable VITT from the United Kingdom, 17 (8 percent) were treated with TPE . The authors noted that TPE in individuals with severe thrombocytopenia plus cerebral venous thrombosis (CVT) or severe thrombocytopenia plus extensive thrombosis was associated with a survival rate of 90 percent, which was higher than would be expected for these individuals (overall mortality for platelet count <30,000/microL, 41 percent), leading them to strongly consider TPE in such individuals.
Minimize platelet transfusions — Platelet transfusions are generally reserved for critical bleeding (bleeding into a critical anatomical site or that causes hemodynamic or respiratory compromise). In such cases, it may be reasonable to transfuse platelets and/or a source of fibrinogen (fibrinogen concentrate, plasma, or cryoprecipitate), depending on the platelet count and fibrinogen level. Hematology and/or transfusion medicine input may be especially helpful in these cases.
Other than these indications, platelet transfusions are minimized to avoid worsening thrombosis, a theoretical risk based on extrapolation from other conditions in which there is some concern that platelets may cause worsening. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'TTP or HIT'.)
Platelet transfusions should be provided to patients with life-threatening complications including bleeding or need for emergency surgery. (See 'Treatment of bleeding' below.)
In a series of 99 patients with VITT presenting with CVT, receipt of a platelet transfusion did not have a statistically significant impact on survival (adjusted odds ratio [OR] for mortality with platelet transfusion 2.19, 95% CI 0.74-6.54) . The trend towards reduced survival may have reflected the overall greater baseline severity of disease in patients who were transfused.
Treatment of bleeding — Management of bleeding in an individual with VITT is especially challenging due to the competing goals of stopping bleeding and preventing thrombosis. General principles of managing concurrent bleeding and thrombosis should be followed, with input from the consulting hemostasis specialist. Details are presented in separate topic reviews. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Treatment' and "Management of bleeding in patients receiving direct oral anticoagulants".)
Monitoring — Clinical monitoring for signs of thrombosis is critical. Platelet count monitoring is also especially important in VITT because thrombocytopenia can recur after the effects of IVIG wear off.
●Hospitalized patients should have daily platelet count monitoring.
●After discharge, the monitoring interval can be extended according to the patient's clinical status. An example would be twice weekly monitoring for clinical status and platelet count for one to two weeks, as long as the platelet count is increasing or stable.
Other monitoring may include coagulation studies (prothrombin time [PT], aPTT, fibrinogen, D-dimer), especially if abnormal.
When is it safe to discharge — The duration of acute illness in VITT is unknown. Analogous to spontaneous HIT, thrombocytopenia can persist for days to weeks.
We would continue inpatient management until all of the following occur:
●The platelet count is >50,000/microL and improving for at least two to three days.
●The patient is on stable anticoagulation with no new or progressive thrombosis.
●There is no bleeding for at least two to three days.
●Appropriate follow up has been assured.
Prognosis — Prognosis is challenging to establish and may be improving with earlier recognition of the syndrome. In a series of 220 individuals with definite or probable VITT, the mortality rate was 22 percent . Risk factors for death include cerebral venous thrombosis (CVT) and more pronounced hemostatic abnormalities (more severe thrombocytopenia, higher D-dimer, and lower fibrinogen). (See 'Clinical features' above.)
Reporting — Accurate documentation in the medical record and case reporting to the clinician's national agency on vaccine adverse events is advised, as this will assist in characterizing the syndrome and identifying best practices. This may be through a national adverse drug event monitoring system such as the Yellow Card scheme in the United Kingdom or the Vaccine Adverse Event Reporting System (VAERS) in the United States [42,56].
In the unlikely event that an individual with VITT dies and their liver is transplanted to another individual, clinicians caring for the recipient should be informed about the theoretical possibility of transmitting VITT antibody-producing cells in the donor liver .
PREVENTION (COMMON QUESTIONS)
Is there a role for prophylactic aspirin? — There is no role for aspirin in the prevention of VITT. This is based on lack of data that aspirin prevents any of the heparin-induced thrombocytopenia (HIT)-related syndromes, in vitro evidence that aspirin does not prevent platelet activation by platelet factor 4 (PF4) antibodies, and the risk of bleeding with aspirin, which can be significant, especially in individuals with certain comorbidities. (See "Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'Bleeding'.)
Another possible risk with aspirin is blunting of the immune response to the vaccination, although this is a purely theoretical (not documented) risk. (See "COVID-19: Vaccines", section on 'Expected adverse effects and their management'.)
Individuals who are already taking aspirin for another reason can continue taking it, but we suggest not taking aspirin prior to or following vaccination as a strategy to reduce the risk of VITT.
Decisions about vaccines
Thrombotic risk of COVID-19 vaccination versus COVID-19 illness — The importance of vaccination should be emphasized. Vaccination remains the most important measure to prevent COVID-19 and curb the pandemic. There is broad consensus among regulatory agencies and expert panels that the benefits of vaccination greatly outweigh the potential risks of rare vaccine side effects such as VITT .
By comparison to the extremely low rate of VITT following vaccination, the mortality rate for COVID-19 is as high as 1 percent. The rate of thrombosis (including fatal thrombosis) estimated from one meta-analysis was 8 percent in individuals hospitalized for COVID-19 and 23 percent in individuals in the intensive care unit (ICU) . An analysis of cerebral venous thrombosis (CVT) with COVID-19 vaccination versus COVID-19 illness found that the rate of cerebral venous thrombosis (CVT) was much higher in individuals hospitalized with COVID-19 (207 per million) than in those who were vaccinated for COVID-19 (0.9 to 3.6 per million) or hospitalized for other illnesses (2.4 per million) . Other studies have reported similar findings of much higher thrombotic risk from COVID-19 than from vaccination . (See "COVID-19: Hypercoagulability", section on 'VTE' and "COVID-19: Clinical features", section on 'Spectrum of severity and fatality rates'.)
Choice of vaccine — The primary criterion for selection of a vaccine is availability. Efficacy and adverse effects have not been compared in a randomized trial. For individuals who have access to more than one vaccine, the choice is individualized based on values and preferences. Those who place a high value on avoiding VITT may choose an mRNA vaccine, while those who place a high value on receiving a single-dose vaccine may choose Ad26.COV2.S (Janssen; Johnson & Johnson).
In the United States, where vaccines are widely available, the US Food and Drug Administration (FDA) has limited use of the Ad26.COV2.S (due to the risk of VITT) to people ≥18 years for whom other vaccines are not appropriate or accessible and those who opt to take the Ad26.COV2.S vaccine because they otherwise would not get vaccinated . (See "COVID-19: Vaccines", section on 'Indications and vaccine selection'.)
Individuals with thrombotic risk factors, prior thrombosis, or prior HIT — No studies have demonstrated an increased likelihood of VITT (or other thrombotic complications) following vaccination of individuals with prior thrombosis or increased thrombotic risk such as due to factor V Leiden (FVL), other inherited thrombophilia, high body mass index, recent surgery, or others. A prior history of VTE, or predisposition to VTE, is therefore not a contraindication to vaccination with any type of vaccine.
Some organizations have suggested that individuals with a history of heparin-induced thrombocytopenia (HIT) or thrombosis should avoid adenoviral COVID-19 vaccines and receive a different type of COVID-19 vaccine [64,65]. There have not been any reports of VITT in individuals with HIT or thrombosis caused by another risk factor, and the mechanism of VITT differs from HIT (different PF4 epitope) and from other thrombotic disorders (different mechanisms altogether). Early studies indicate that adenoviral vaccines (ChAdOx1 nCoV-19) do not appear to cause exacerbation of HIT or development of VITT in individuals with a history of HIT .
If an individual wishes to receive a non-adenoviral COVID-19 vaccine out of an abundance of caution, we support that choice. However, if the choice is between an adenoviral vaccine and no vaccine, an adenoviral vaccine provides the greatest likelihood of avoiding severe COVID-19, including thrombotic complications. (See "COVID-19: Hypercoagulability", section on 'Clinical features'.)
Second dose (for two-dose vaccines) or booster dose — For individuals who have received one dose of the ChAdOx1 nCoV-19 (AstraZeneca, University of Oxford, and Serum Institute of India) vaccine and have not developed VITT, there are no good data to support omitting the second dose or switching to a different vaccine; completion of the two-dose series is encouraged.
In a review of VITT cases in the AstraZeneca global safety database in Europe and the United Kingdom, 399 cases were identified after the first dose of the vaccine (incidence, 8.1 cases per one million first doses), and 13 after the second dose (incidence, 2.3 cases per million second doses) . Other rare reports of VITT following the second dose of the ChAdOx1 nCoV-19 vaccine have been published [38,68,69]. The incidence of VITT following second doses (2.3 per million) was estimated to be similar to the background rate of autoimmune HIT prior to the pandemic . The authors noted that this supports administration of the second dose, especially given the improved efficacy of receiving both doses. Evidence for vaccine efficacy with one versus two doses of the two-dose series is presented separately. (See "COVID-19: Vaccines", section on 'ChAdOx1 nCoV-19/AZD1222 (University of Oxford, AstraZeneca, and the Serum Institute of India)'.)
For individuals who have developed VITT with an adenoviral vectored vaccine, another dose of an adenoviral vectored vaccine should not be given . Observational data from small numbers of patients suggest that it is likely to be safe to switch to an mRNA vaccine for the second dose of a two-dose series or a booster dose. (See 'Characteristics of VITT antibodies' above.)
Evaluation of asymptomatic individuals before or after vaccination — As noted in an expert consensus document, the evidence does not support any screening laboratory or imaging evaluations in asymptomatic individuals before or after vaccination .
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: COVID-19 – Anticoagulation" and "Society guideline links: Anticoagulation" and "Society guideline links: COVID-19 – General guidelines for vaccination", section on 'Vaccine-induced immune thrombotic thrombocytopenia (VITT)'.)
SUMMARY AND RECOMMENDATIONS
●Pathophysiology and incidence – Vaccine-induced immune thrombotic thrombocytopenia (VITT) is an extremely rare syndrome that can occur in individuals who received certain adenoviral-vectored coronavirus disease 2019 (COVID-19) vaccines. The available adenoviral vaccines appear to stimulate autoantibodies to platelet factor 4 (PF4), which activate platelets and causes thrombosis in the absence of heparin, similar to spontaneous or autoimmune heparin-induced thrombocytopenia (HIT). Risk factors are unknown. (See 'Pathophysiology' above and 'Epidemiology' above.)
●Presentation – Most individuals present with thrombosis (table 2). Cerebral vein thrombosis (CVT) is common. Isolated thrombocytopenia (without thrombosis) can occur. (See 'Clinical features' above.)
•Laboratory testing includes complete blood count (CBC), platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, D-dimer, imaging for thrombosis, and often testing for SARS-CoV-2 (algorithm 1). Positive PF4 antibody testing (enzyme-linked immunosorbent assay [ELISA] or functional test) is confirmatory. "Rapid HIT assays" are unreliable and should be avoided. (See 'Laboratory testing' above and 'Imaging to diagnose thrombosis' above.)
•Anticoagulation – All individuals with VITT and thrombosis should receive full (therapeutic) dose anticoagulation. We suggest a non-heparin anticoagulant rather than heparin, especially if HIT (including delayed or spontaneous HIT) remains in the differential (Grade 2C). We also suggest anticoagulation for individuals with VITT who do not have thrombosis (Grade 2C). If the suspicion for VITT is high, anticoagulation should not be delayed while awaiting confirmatory testing. (See 'Anticoagulation' above.)
•Plasma exchange – Therapeutic plasma exchange can be used in refractory disease and individuals with especially concerning features (platelet count <30,000/microL with CVT; severe thrombocytopenia with multiple thromboses). (See 'Plasma exchange for refractory disease' above.)
•Bleeding – Platelet transfusions are generally reserved for critical bleeding (bleeding into a critical anatomic site or hemodynamic or respiratory compromise). Administration of fibrinogen (concentrate, plasma, or cryoprecipitate) may be appropriate for individuals with critical bleeding and hypofibrinogenemia but should not be used for asymptomatic hypofibrinogenemia. (See 'Treatment of bleeding' above and 'Minimize platelet transfusions' above.)
●Vaccine questions – Vaccination remains the primary means of preventing COVID-19. The risk of life-threatening thrombosis from COVID-19 greatly exceeds the risk of VITT. We suggest not using aspirin before or after vaccination, unless there is another indication (Grade 2C). People who have recovered from VITT should not receive another adenoviral vectored vaccine, but an mRNA vaccine may be safe. (See 'Prevention (common questions)' above.)