The Incidence, Causes, and Prognostic Significance of New-Onset Thrombocytopenia in Intensive Care Units: A Prospective Cohort Study in a Korean Hospital

Thrombocytopenia, which is one of the most commonly observed laboratory abnormalities in the intensive care units (ICU) population, has an incidence ranging from 13.0% to 44.1% (1), depending on the study population, the timing and frequency of platelet monitoring, and the definition of thrombocytopenia (2-5). In critically ill patients, one potential cause is enhanced platelet destruction due to heparin-induced thrombocytopenia (HIT), a prothrombotic disorder that is caused by the development of antibodies against platelet factor 4 (PF4)/heparin complexes (8, 9). Because heparin-based anticoagulation is one of the most commonly prescribed therapies in clinical practice and thrombotic complications related to HIT may be life threatening, the early recognition and treatment of this cause of thrombocytopenia are important.

Thrombocytopenia in ICU patients has been associated with adverse outcomes such as prolonged length of hospital stay and decreased survival (2-5). However, many of these studies were retrospective and performed in European or North American ICUs (2, 10-13). Thus, the incidence and prognostic significance of NOT in Asians, especially Koreans, is not known. Therefore, the objective of this study was to investigate the incidence of NOT, including HIT, in a cohort of Korean medical ICU patients and to examine its impact on outcomes.

This study confirms that NOT is common and an independent risk factor for mortality in Korean critically ill patients. Forty-three percent of patients had pre-existing thrombocytopenia upon admission and 37% of patients who were not thrombocytopenic upon admission developed NOT in the ICU. The most common causes of NOT were sepsis and drugs. HIT developed in 1.6% of the patients receiving heparin therapy, and thrombosis occurred in these two patients. NOT was associated with longer ICU LOS and higher mortality. Patients with NOT had 3.5-fold increased odds ratio of 28-day mortality compared to those without NOT even after adjusting for all relevant confounding variables.

Wide ranges for the incidence (13.0%-44.1%) (3, 5-8) and prevalence (8.3%-67.6%) of thrombocytopenia have been reported in the literature. However, most of these studies were conducted in Europe or North America, and to our knowledge there has never been a study that examined patients specifically for NOT in Asia. A prospective study that was conducted in Singapore looked at the incidence of thrombocytopenia in 53 septic patients (58%), however, did not report the incidence of thrombocytopenia in general medical ICU patients (4). Thus, this is the first prospective study of the incidence of NOT in Asian general medical ICU. The incidence of NOT in this study was similar to those reported for European and North American ICUs.

The causes of thrombocytopenia in critically ill patients are often complicatedly linked and physicians have difficulty to find the exact cause (5). In this study, sepsis with DIC was the main contributing factor for NOT. The mechanisms of sepsis-induced thrombocytopenia, although not fully understood, may include DIC (15), immune mediated platelet destruction, and hemophagocytic histiocytosis (16). Drug-induced thrombocytopenia was the second most common cause for NOT. A study conducted in the USA reported that drug-induced thrombocytopenia, including cases caused by heparin, developed in 25% of acutely ill patients (17); this result was similar to our finding that 22% of thrombocytopenia cases were caused by drugs, including heparin. In a previous study, medications that were commonly associated with drug-induced thrombocytopenia included glycoprotein IIb/IIIa inhibitors, antibiotics, anticonvulsants, and heparin (17).

HIT is a well-described complication of heparin therapy with an incidence of 1%-5% when UFH is used, but < 1% with LMWH (18). Although there have been isolated case reports of HIT in Korea as well as other Asian countries, the magnitude of this potentially life-threatening complication has never been systemically studied in Asia. In this study, HIT occurred in Korean ICU patients at a similar frequency compared to Western ICU patients.

In patients with suspected HIT, the two types of assays are used to detect HIT antibodies: functional and antigen assays (19). Serotonin release assay and heparin-induced platelet activation assay are examples of functional assays (19). The strength of functional assays is their very high specificity (98%), if the appropriate controls are performed (20). However, though functional assays are technically demanded, they may involve dealing with radioactivity, require significant processing time, and can be performed only by a minority of experienced laboratories (19). Antigen assays to detect HIT antibodies are relatively simple and has high sensitivity (up to 100%) (20), however, the specificity of antigen assays for detecting all types of antibodies is low (80%) (20-22). This is because some antibodies to PF4/heparin complex, especially IgM and IgA, can bind to the antigen but is not functionally active. To increase specificity of the assay, IgG-specific assay was used in this study which is known to increase the specificity to nearly 96% (22). Even so, the possibility of antibody assays being false positive still exists. However, retrospective studies or even some prospective epidemiologic studies accept positivity to antigen assays alone as satisfying diagnostic criteria for HIT. Also clinical risk stratification according to the 4T's score for the 2 patients who showed reactivity to antigenic assays was high (6 points) with clinical thrombosis which suggest these patients had clinically significant HIT. The third patient who tested positive on antigen assay to HIT with high OD (3.48) did not meet our criteria because the patients had other explainable cause for NOT, namely sepsis with DIC and had low 4T's score (3 points).

NOT was associated with an unfavorable prognosis. Many previous studies have reported an association between thrombocytopenia and poor outcomes (2, 6, 23). Sprung et al. (23) reported that the presence of thrombocytopenia in patients with sepsis was associated with a relative risk of mortality of 1.7, and Vanderschueren et al. (6) noted that patients with thrombocytopenia had significantly greater ICU mortality (33.8% vs 9.3%) and significantly longer ICU LOS (8 vs 5 days) compared to those without thrombocytopenia. Why is the patient who develops NOT more likely to die? First, thrombocytopenia is a marker of severe organ dysfunction, which is frequently seen in patients with greater disease severity. Second, many instances of thrombocytopenia are associated with the underlying disease processes that necessitated intensive care. For example, in our study, the most frequent cause of NOT was sepsis, which can frequently run a fatal course. Third, thrombocytopenia is associated with hemostatic derangement and the complications associated with this condition, such as bleeding, transfusion, and thrombosis may adversely affect the patient's prognosis.

This study has several limitations. First, this study was based on data from only one tertiary teaching hospital in Korea and the results may not be applicable to other hospitals in other regions and countries. Second, our conclusions were derived from medical ICUs and should be confirmed in other settings. Third, only antigen assays were used to detect antibodies to PF4/heparin complex which can result in false positive assays.

However, this study has several strengths. First, this study is the first prospective study designed to determine the incidence, causes, and outcomes of NOT in critically ill Korean patients. Also for the first time, this study shows the possibility that HIT can be a significant problem in Korean ICU patients and provides a rationale for the implementation of measures that systemically look for and treat HIT, even in Asians.

In conclusion, NOT is common and is an independent risk factor for mortality in Korean medical ICU patients. Therefore, clinicians should make every effort to correct the cause of NOT to improve the outcomes of these patients.