Heparin-induced Thrombocytopenia with Thrombosis in COVID-19 versus Vaccine-induced Immune Thrombocytopenia and Thrombosis in the United Kingdom

Heparin-induced thrombocytopenia (HIT) with thrombosis (HITT) is a clinicopathological syndrome caused by IgG antibodies binding to heparin-platelet factor 4 (PF4), creating an immune complex which activates platelets and produces a hypercoagulable state. This results in thrombocytopenia and thrombosis, arising usually 5 to 10 days (range 4–15 days) following heparin exposure.[1] Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare prothrombotic syndrome associated with adenoviral vector-based ChAdOx1 CoV-19 vaccine (AstraZeneca, University of Oxford) or Ad26.COV2.S vaccine (Janssen; Johnson & Johnson).[2] VITT is characterized by thrombocytopenia and thrombosis, often at unusual sites such as cerebral venous sinus thrombosis (CVST), with the development of IgG antibodies which also bind to PF4 but without dependence on heparin or previous heparin exposure.[2] The full extent of the similarity and difference between these two related syndromes has not been fully described. We therefore, compared the incidences, characteristics, and clinical outcomes of HIT in patients with coronavirus disease 2019 (COVID-19), exposed to heparin from a multicenter observational study (coagulopathy associated with COVID-19 [CA-COVID-19]; https://www.clinicaltrials.gov/ct2/show/NCT04405232) with those published for VITT following ChAdOx1 CoV-19 vaccination in the United Kingdom,[3] and also HIT in patients admitted to hospitals without COVID-19.[4]

Of 5,971 patients with COVID-19 admitted to 30 National Health Service (NHS) Trusts across the United Kingdom from the first wave of the COVID-19 pandemic (between April 1, 2020, and July 31, 2020), 26 patients developed HIT at a median 13 (6–27) days following exposure to heparin, making an incidence of 0.43%. Of these 26 patients, 25 (96%) developed HITT (i.e., HIT with associated thrombosis). The median age of the patients who developed HITT was 47 (range 35–73) years. The reported incidence of HIT in the United States is approximately 1 in 1,500 hospital admissions (0.067%).[4] Patients undergoing cardiopulmonary bypass had the highest rates of HIT followed by patients on hemodialysis, while patients who undertook hip and knee arthroplasty had the lowest rates of HIT.[4] In general, it appears that lower frequencies are seen with low-molecular weight heparin (LMWH) versus unfractionated heparin (UFH), prophylactic versus therapeutic doses, medical versus surgical patients, and minor versus major trauma.[5] [6] Although there are no nationwide studies assessing the incidence of HIT in patients admitted to hospitals in the United Kingdom, we anticipate that it is similar to that of the published U.S. study.[4] Although several factors have been reported to affect the incidence of HIT including, as stated in the prior cited studies,[4] [5] [6] such as type of heparin (LMWH vs. UFH), prophylactic versus treatment dose heparin, duration of heparin exposure, type of patients studied (medical vs. surgical) and type of surgery, findings are not necessarily consistent between studies. Furthermore, the number of patients included in published studies vary and most include only small numbers of patients.

Based on the data reported by May 12, 2021, the estimated incidence of VITT was approximately 7 to 10 cases per million persons receiving ChAdOx1 CoV-19 vaccine (309 VITT cases were reported from the 32.9 million doses given in the United Kingdom) and approximately 3.2 cases per million for the Ad26.COV2.S (or 28 cases out of 8.7 million doses administered in the United States).[7] The incidence of VITT varied according to age and was at least 1:100,000 and 1:50,000 among patients ≥50 or <50 years, respectively, in the United Kingdom.[8] In the United Kingdom-wide study of 294 patients who were evaluated for possible VITT, 170 were classified as definite and 50 as probable cases of VITT.[3] Of these patients, median time to diagnosis of VITT following vaccination in the United Kingdom cohort was 14 (range 5–48) days, with a median age of 48 years (range 18–79).[3] Fifty-four percent (119/217) of VITT patients were female compared with only five female patients in our HIT cohort (19.2%, 5/26; p = 0.0007). Pulmonary embolism (PE; 11/26, 42.3%) was the most frequent thrombotic complication in patients with HIT ([Fig. 1]), whereas CVST was the most common thrombotic complication in patients with VITT, accounting for 50% (110/220) of events, followed by PE alone (35%).[3] All patients diagnosed with HIT were treated with argatroban, compared with 68% patients with VITT, the remainder receiving a variety of other nonheparin-based anticoagulants.[3] There was no difference in the overall mortality among patients: 23.0% (6/26) in patients with HIT versus 22.3% (49/220) in VITT, p = 0.99. This is similar to the mortality reported in patients with HIT without COVID-19.[4] Multiorgan failure as a complication of COVID-19 was the cause of death in majority of patients who developed HIT (5/6, 83.3%) and only one patient's death was related to thrombosis, whereas intracerebral hemorrhage (ICH) was the most common cause of death in patients with VITT.[3] [Table 1] summarizes the comparison between HITT and VITT in general.

Table 1 Comparison between heparin-induced thrombocytopenia and thrombosis versus vaccine-induced immune thrombocytopenia and thrombosis

Feature	Heparin-induced thrombocytopenia and thrombosis	Vaccine-induced immune thrombocytopenia and thrombosis
Pathogenic antibodies	Directed against heparin-platelet factor 4 and generally undetectable after 100 days	Directed against platelet factor 4, detected longer than 100 days although significance of late detection is not clear
Exposure to triggering event	Heparin, usually within 5–10 days (range 4–15 days)	Within 5–30 days of having had adenoviral vector-based COVID-19 vaccine
Clinical suspicion	Mainly thrombocytopenia	Mainly thrombosis
Investigations	HIT antibodies detected with an immunological assay Functional platelet assays used to confirm diagnosis (e.g., strong response to standard dose heparin with platelet aggregation assays. No spontaneous aggregation of platelets with normal saline [in the absence of heparin].) Detection of platelet activation using Flow cytometry or Serotonin Release Assay	Anti-PF4 antibodies detected with ELISA Functional platelet assays used to confirm diagnosis (note: variable response to heparin with platelet aggregation assay and potentially spontaneous aggregation of platelets with normal saline [in the absence of heparin]) Detection of platelet activation using modified Flow cytometry assays or Serotonin Release Assay
Laboratory findings	Thrombocytopenia Normal or high fibrinogen, D-dimer normal or high depending on the thrombosis and the underlying clinical condition of the patient	Thrombocytopenia, low fibrinogen, and markedly raised D-dimer
Non-ELISA-based commercial assays (e.g., HemosIL AcuStar HIT-IgG, HemosIL HIT-Ab, Diamed PaGIA gel)	Generally sensitive for HIT antibodies	Usually negative for anti-PF4 antibodies in VITT, occasionally weak positives
Site of thrombosis	Thrombosis affects both arterial and venous beds, with venous thrombosis occurring three to four times more commonly than arterial thrombosis. Venous thrombosis, which can extend to unusual sites (e.g., cerebral venous sinus thrombosis, splanchnic vein thrombosis) and arterial thrombosis	Preponderance of unusual sites of venous thrombosis, mainly cerebral venous sinus thrombosis but can be both venous and arterial thrombosis
Bleeding	Major bleeding is unusual	Intracerebral bleeding is common in severe cases and often the cause of death
Treatment	Nonheparin-based anticoagulation is the main treatment. Heparin is contraindicated	IV immunoglobulins, plasma exchange, high dose steroids, rituximab have all have been used, along with anticoagulation, usually with nonheparin-based anticoagulation, represents the main treatment. However, heparin is not necessarily contraindicated

Abbreviations: COVID-19, coronavirus disease 2019; HIT, heparin-induced thrombocytopenia; PF4, platelet factor 4; VITT, vaccine-induced immune thrombocytopenia and thrombosis.

Fig. 1 Site of thrombosis in patients with heparin-induced thrombocytopenia (total 26 patients). DVT, deep vein thrombosis; PE, pulmonary embolism.

The main differences between HITT versus VITT are the sites of thrombosis, ability of non-ELISA-based commercial assays to detect the pathogenic antibodies and the differences in pathogenic antibodies themselves. Furthermore, the management of HITT is achieved mainly by stopping heparin-containing anticoagulant and facilitating anticoagulation with a nonheparin anticoagulant. In contrast, VITT is a predominantly heparin-independent platelet-activating disorder and requires both therapeutic dose anticoagulation and inhibition of FcγRIIa-mediated platelet activation, for example, by high-dose intravenous immunoglobulin. Furthermore, HIT and VITT antibodies bind to different epitopes on PF4[9] [10] and recently developed immunoassays are able to differentiate HIT-like and VITT-like antibodies.[11] [12] CVST is the most frequent site for the thrombosis in VITT, with a consequently higher rate of ICH.[3] It is not clear why patients with VITT have preponderance of CVST, although this may reflect pathophysiologic consequences of differences in the antigen targeted on PF4.[13] Interestingly, in spontaneous HIT, which occurs without exposure to heparin, a high frequency of CVST (40%), with an overall stroke frequency (venous or arterial) of 60% has been reported in a study of 10 patients.[14] Although VITT is rarer than COVID-19-associated HIT, mortality was similar in both groups. With increasing awareness, early detection, and prompt treatment, mortality of VITT fell from approximately 50%, in the first case series reported in April 2021, to 22% by June 2021, in the United Kingdom[3] and more recently to approximately 5% observed in Australia.[15]

In addition to VITT, there are several case reports of individuals with monoclonal gammopathy of clinical significance[16] [17] or recent adenovirus infection, developing anti-PF4 platelet-activating VITT-like antibodies causing a clinical VITT-like syndrome.[18] A high degree of clinical suspicion is important to recognize these cases early and test for the anti-PF4 platelet-activating antibodies using ELISA but not by Latex Immunoassay or Chemiluminescence Immunoassay, as the latter two assays typically provide negative results for VITT-like antibodies.

In conclusion, HIT and VITT are both rare but very serious complications characterized by thrombocytopenia and positive anti-PF4 antibodies. Although mortality is similar, VITT is rarer than COVID-19-associated HIT. Further work to identify the antigen(s) and immune complex(es) involved will shed light on CVST in these conditions and facilitate future vaccine design.

Authors' Contributions

D.J.A. designed the study, interpreted the data, wrote, and reviewed the manuscript. All authors interpreted the data, reviewed, and approved the final version of the manuscript.

Publication History

Article published online:
09 April 2024

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