Is it ever appropriate to use heparin in patients with a history of HIT?
Heparin-induced thrombocytopenia (HIT) is an immune-mediated reaction occurring in 0.2-5% of adults treated with heparin causing a ≥50% drop in platelets from baseline.
Patients with HIT have a high risk of thrombosis, which can lead to serious complications including limb loss and death. HIT occurs when heparin binds to platelet factor-4 (PF4), forming heparin:PF4 complexes. HIT antibodies (usually IgG) react with heparin:PF4 complexes to form large macromolecules that activate platelets and monocytes, leading to the release of prothrombotic mediators. This serious reaction typically develops 5-10 days after heparin exposure, but can occur within hours to days after recent re-exposure.1
If heparin-exposed patients have developed this life-threatening reaction in the past, why risk reexposure?
UFH: Anticoagulant of Choice in Cardiac, Vascular surgery, and Hemodialysis2
In cardiac surgery, vascular surgery, and hemodialysis, there are concerns surrounding the efficacy, safety, and reversibility of non-heparin anticoagulants. Specifically, for cardiopulmonary bypass patients, the quality of data are not high enough to consider bivalrudin and argatroban as validated options. UFH is also preferred by surgeons due to familiarity, its short half-life, easy monitoring, and its reversibility with protamine sulfate. Additionally, in hemodialysis patients it is expensive and inconvenient to use alternative non-heparin anticoagulants for intermittent hemodialysis three times per week.
Transiency of Anti-PF4/heparin Antibodies2
n patients that develop HIT, anti-PF4/heparin antibodies typically develop in ~5 days. However, these antibodies are incredibly transient, usually disappearing within 40-100 days. In some patients, antibodies vanish as quickly as 1-2 weeks. In fact, the probability of a positive serotonin-release assay (SRA), a specific test identifying platelet activation, is <5% by 3 months and negligible by 12 months. This allows for heparin re-exposure in emergency settings when there is no time for a repeat SRA.
Regenerating Pathogenic Platelet-activating Antibodies2
The adaptive immune response is a fundamental concern regarding heparin re-exposure in patients with a history of HIT. If patients exposed to heparin develop this life-threatening reaction, the classic, adaptive immune response tells us that upon re-exposure there will be a more rapid and severe secondary response.
Interestingly, HIT does not follow these rules. In fact, any immunizing exposure to heparin, whether first or subsequent re-exposure, leads to a relatively rapid immune response (~5 days). This means that heparin re-challenge despite prior HIT often induces anti-PF4/heparin antibodies, but no faster than seen with typical HIT. It is believed that all cases of HIT likely represent a type of “secondary” immune response. Although the reason for this is unknown, one hypothesis is that “primary” immunization occurs from exposure to PF4-coated bacteria.2,3,4
Since ~5 days of heparin exposure is required to regenerate HIT antibodies, short-term intraoperative or intermittent use should not result in recurrent typical-onset HIT.
Enzyme immunoassay (antibody assay): The enzyme immunoassay (EIA) is a high sensitivity, low specificity assay commonly used to rule out HIT. If negative, there is a low probability that a patient is experiencing HIT. However, 20% of orthopedic surgery and 70% of cardiopulmonary bypass patients may have circulating HIT antibodies even though the majority are not pathogenic and do not activate platelets to cause HIT.
Serotonin-release assay (platelet activation test): The serotonin-release assay (SRA) is a high specificity test for HIT, and is referred to as the gold standard. Unfortunately, it is not widely available and has a longer turnaround time compared to the EIA.
EIA’s and SRA’s can be utilized to carefully select patients who are candidates for re-exposure to heparin.