Discussion
The incidence of HIT is estimated to be about 0.1-5% of patients exposed to heparin. However, despite the low incidence of HIT, it is considered a life-threatening condition with high morbidity and mortality, as demonstrated by our case report (11,12). The pathogenesis of HIT has been researched in depth over the years. It results from autoantibodies IgG directed against PF4 complexes with heparin. Thrombocytopenia (Platelets <150000) with or without thrombosis is the most common feature of HIT, occurring in 90-95% of patients (10,11,13). 5-10% of patients diagnosed with HIT do not present with absolute thrombocytopenia, but have relative thrombocytopenia, which means platelet count drop between 30-50% from baseline (10).
The 4Ts Pretest probability has been widely implemented in patients with suspected HIT since 2006 to identify HIT (14,15). It is a point-based test, with points assigned for thrombocytopenia, the timing of platelet count drip, thrombosis, and other causes of thrombocytopenia. Furthermore, this test has high negative predictive values with low probability scores (9). Our patient’s platelet levels fell from 241 on day one of heparin exposure to 190 on day ten. Despite this drop, levels remained above 150 and were less than a 30% drop from admission. Also, platelets count on day seven, and eight were 271,253 respectively, contradicting the pathophysiology of HIT that includes platelet consumption. With a low pretest probability with the 4Ts score and no initial clinical suspicion for HIT, testing was not indicated nor recommended (9,15,16). Hence, our patient developed multiple life-threatening thromboembolic events, including massive occipital infractions while on heparin, and continued despite its discontinuation. The error, in this case, was to rely on the high negative predictive value and sensitivity of low 4T pretesting that could exceed 98% (9). The reliance on the pretest probability of the 4Ts also deferred the Hematology and Pharmacy teams from further investigation into HIT. The medical team did discuss testing for HIT when the anticoagulation serologies were initially sent. However, they were detracted by the specialists and pharmacists. Therefore, the discontinuation of heparin was delayed leading to more fatal thrombosis. In brief, our patient never had neither absolute nor relative thrombocytopenia, contradicting current guidelines for HIT.
To our knowledge, limited studies have investigated the occurrence of HIT without thrombocytopenia. Busche, Marc Nicolai, et al., published in a case report published in 2009, showed a 26-year-old in a burn ICU who developed thrombotic events after 13 days of heparin infusion without thrombocytopenia (17). Heparin was stopped, and the HFP4 test was positive, later confirmed by ELISA. This finding is consistent with our report that HIT could occur without a fall in platelet count and could be associated with major thromboembolic events. However, in this patient, thrombosis occurred after 13 days of heparin compared to our case, which occurred within 5-10 days of heparin infusion. In another case report titled “Heparin associated thrombosis without thrombocytopenia,” Phelan Brian demonstrated a 64-year-old who developed a series of thromboembolic complications after the initiation of heparin drip (18). He reported that these events were associated with platelets of 187, which did not show absolute thrombocytopenia. However, the platelets baseline, in this case, was 365 before the start of the heparin drip. Hence, there was relative thrombocytopenia due to a more than 50% fall in platelet counts. This finding contradicts the case title and supports the current guidelines’ definition of HIT. Moreover, Greinacher, Andreas, et al., in a retrospective analysis of 408 patients aiming to identify risk factors for developing HIT-associated thrombosis, illustrated that 4.4 % of patients diagnosed with HIT did not have thrombocytopenia. At the time of clinical diagnosis of HIT, a decrease in platelet counts of at least 50% occurred in 271/319 (84.9%) patients. Of the remaining 48 patients, HIT was suspected in 14 patients because new thrombosis without a platelet count fall greater than 30% (4.4%). (19)
Further research into current recommendations of the 4Ts mentions using the pretest probability in conjunction with clinical judgment, as clinical judgment and assessment is required for evaluating the likelihood of HIT. In addition, evidence-based algorithms describe that there may be extremely rare cases of HIT with a low pretest probability. Additionally, the 4 Ts score has yet to be validated on patients receiving prophylactic dose of heparin. However, many institutions use this score to guide testing and at times, strongly discourage testing for HIT unless the 4Ts score is intermediate or high.
Our case touches on not relying blindly on guidelines but using them as therapeutic guides and tools to aid in our clinical diagnosis and treatment of patients. As Physicians, we cannot blindly diagnose or treat diseases. As many of us were taught, diseases do not follow the textbook. Therefore, the physician must remember to trust their clinical judgment and use evidence-based medicine to guide the diagnosis and treatment. Medicine is both a science and an art, and being an artist is human.