Heparin-Induced Thrombocytopenia in COVID-19

Infection caused by SARS-CoV-2 virus evokes intense inflammation leading to a prothrombotic state, referred to as COVID-associated coagulopathy (CAC). CAC causes widespread microvascular and macrovascular thrombosis in venous and arterial beds, which can lead to subsequent multisystem organ dysfunction, and sometimes death.¹  The use of anticoagulants has been the cornerstone for the treatment and prevention of CAC-associated thrombotic complications and has been endorsed by evidence-based practice guidelines.²  Due to the frequency of multisystem organ dysfunction, heparin has emerged as the agent of choice in this scenario. While the use of anticoagulants is critical, it can also lead to catastrophic complications such as bleeding and heparin-induced thrombocytopenia (HIT); however, reporting of these complications is only recently emerging.

HIT is a severe, potentially life-threatening immunological complication of exposure to heparinoids.³  HIT is a clinical diagnosis; therefore, clinicians must maintain a high index of suspicion with dynamic monitoring where thrombocytopenia developing after the initiation of heparin should prompt calculation of a 4Ts score⁴  and in the right context, additional evaluation including heparin-PF4 (hep-PF4) antibodies and confirmatory serotonin release assay (SRA). Due to associated high morbidity and mortality, early diagnosis of HIT and prompt switching to another anticoagulant is vital to reduce patient complications and improve outcomes.⁵ 

With widespread use of heparin and heparinoids in patients with COVID-19 infection, it would seem logical to observe a significant increase in the reported incidence of HIT during the pandemic. Yet, the incident reports of HIT are sparse. Given the challenge of clinical distinction between severe COVID-19 infection and HIT, particularly in the setting of HIT and thrombosis (HITT) development, it is postulated that this complication goes unrecognized due to multifactorial origins of thrombocytopenia and is therefore underreported in the literature. Ironically in this scenario, even though both CAC and HIT are hypercoagulable conditions and can occur simultaneously, the management of CAC is dependent on anticoagulants such as heparin and heparinoids, while in patients with HIT, continued heparin exposure can lead to severe adverse outcomes compounding the morbidity and mortality burden of COVID-19 infection.

Current evidence on HIT in COVID-19 is limited but expanding. Much of the evidence to date comes from small, retrospective observational studies including case series, making prevalence estimates difficult in the absence of sample denominators.^6–25  Reporting from retrospective studies is compromised by inconsistent reporting regarding 4Ts score and laboratory testing, and by limited information on the dose and duration of heparin exposure. Data suggest that most adults diagnosed with HIT and severe COVID-19 were admitted to the intensive care unit at HIT diagnosis and were predominantly male.^{6,10,11,13,16,17}  More than half of affected adults were on mechanical ventilation at some time during their hospital course.^{6,10,11,14,17,18}  HIT was also common in adults on extracorporeal membrane oxygenation. Since the timing of interventions such as mechanical ventilation or extracorporeal membrane oxygenation relative to HIT diagnosis were rarely reported, it is difficult to determine if the thrombotic morbidity and mortality were primarily associated with HIT or COVID-19 itself. Lastly, the follow-up duration after HIT diagnosis was rarely reported, creating uncertainty about the impact of HIT on short-term post-hospital and longer-term outcomes.^11,23 

Two recent randomized controlled trials included HIT⁸  or severe thrombocytopenia⁹  as outcomes. The multiplatform randomized controlled trials of adults with COVID-19 included lab-confirmed HIT as a secondary safety end point. The authors reported no cases of HIT among hospitalized adults with noncritical COVID-19 disease on anticoagulation, but they did not report on the presence or absence of HIT in adults who were critically ill with COVID-19 and receiving anticoagulation. Based on the outcomes from retrospective studies, we expected adults deemed critically ill with COVID-19 and on therapeutic-dose anticoagulation to be at a higher risk for HIT in comparison to non-critically ill adults or those on lower-dose anticoagulation. The INSPIRATION trial reported severe thrombocytopenia in 2.2 percent of adults who received intermediate-dose enoxaparin, yet no incidence of severe thrombocytopenia among adults on lower-dose anticoagulation; they did not report a single case of HIT.⁹ 

Two recent systematic reviews summarized mostly observational evidence on HIT in hospitalized adults with COVID-19.^6,7  One meta-analysis⁶  reported the overall pooled incidence of confirmed HIT (19 cases) from seven primary studies (n=5,849 patients) of hospitalized adults with COVID-19 as 0.8 percent (95% CI, 0.2%-3.2%). However, the pooled incidence of HIT was higher among the subset of patients who were critically ill with COVID-19 (2.2%; 95% CI, 0.6%-8.3%) compared with non-critically ill adults (0.1%; 95% CI, 0.0%-0.4%). This is closer to the incidences reported for non-COVID medical patients in up to 5 percent of patients exposed to heparin for more than four days. The authors also noted that the pooled incidence of HIT among low risk of bias (higher quality) studies was significantly lower (0.2%) than among higher risk of bias (lower quality) studies (4.5%), suggesting that lower-quality studies may exaggerate HIT incidence.⁶  The second systematic review was more descriptive (35 HIT cases from 12 retrospective studies or reports), covered diagnostic test utilization, and did not report a pooled incidence of HIT.⁷ 

Our narrative summary of the evidence in its current state identifies a gap in HIT in COVID-19 from one of the most common therapies administered in hospitalized patients to prevent and treat thrombotic events due to COVID-19. The diagnosis and impact of HIT in adults hospitalized with COVID-19 is not well described in the literature. Although higher-quality studies are recently emerging, larger prospective studies reporting on 4Ts score, HIT-specific laboratory data, anticoagulant type, dose, and duration, along with details on patient comorbidity profile and outcomes would help identify and stratify at-risk populations to improve patient outcomes.

The pandemic has been a huge shock to the health care system both in terms of infrastructure as well as approach to patient care. Health care professionals have been forced to constantly evolve their approach in this dynamic environment while having limited resources at times where “business is not as usual.” Unfortunately, this has led to a less organized methodology and reporting in the literature. With such high rates of critical illness and thrombotic morbidity with COVID-19 infections, it is plausible that with limited resources and overflow volumes, many patients who developed thrombosis and subsequently died may have died of complications from HIT, but alas, it will remain a mystery just like so many other aspects of this pandemic.