Incidence, Outcomes and Risk Factors of Heparin-Induced Thrombocytopenia after Total Joint Arthroplasty: An Analysis of the National Inpatient Sample Database

Background Heparin-induced thrombocytopenia (HIT) is a severe immune-mediated complication of heparin exposure, leading to negative consequences after total hip (THA) and knee arthroplasty (TKA). However, the incidence and risk factors of HIT remain to be elucidated. This study aimed to identify the incidence, outcomes, and risk factors of HIT after THA and TKA. Methods A retrospective study was conducted using the National Inpatient Sample (NIS) database from 2005 to 2014. The incidence and outcomes of HIT after THA or TKA were documented. Logistic regression analysis was performed to identify the postoperative HIT risk factors. Results A total of 593,045 patients who underwent THA and 1,228,707 patients who underwent TKA were identied. The cumulative incidences were 0.02% and 0.01%, respectively. The HIT group presented signicantly higher Charlson Comorbidity Index (CCI) and Elixhauser Comorbidity Index (ECI) scores, longer hospital stays (LOS), and higher medical costs. HIT led to a signicantly higher mortality rate after THA (2.17% vs. 0.16%, p =0.0091). Although not statistically signicant, the HIT mortality rate after TKA was also increased (0.58% vs. 0.07%; p =0.1178). In THA, the risk factors of HIT were racial minority, AIDS, pulmonary circulation disorders (PCD), psychoses, and hypertension; the protective factors were large-scale and teaching hospitals. In TKA, the HIT risk factors were racial minority, PCD, and weight loss. Teaching hospitals served as protective factors. Conclusions The incidence of HIT after THA and TKA is relatively low; however, HIT signicantly increases inpatient mortality, LOS, and medical cost. Therefore, HIT warrants considerable attention and further investigation.


Introduction
Heparin-induced thrombocytopenia (HIT) is a severe immune-mediated complication caused by heparin drugs during anticoagulant therapy. It is characterized by the formation of antibodies against the complex of heparin and platelet factor 4 (PF4). 1,2 Such immune complexes further initiate coagulation.
The clinical signs and symptoms include a signi cant decline in the platelet count (thrombocytopenia), thrombosis, and ulcerating skin lesions. These all lead to nancial and health burdens. 1,3 Anti-PF4/heparin antibodies have been uncommonly detected in healthy individuals with an incidence of only 0.3-0.5%. 4,5 In cases of infection and surgical in ammation, HIT might occur without heparin exposure. This is known as spontaneous HIT and is an infrequent clinical disorder. [6][7][8] However, most HIT cases usually occur after heparin exposure-especially unfractionated heparin (UFH)-either prophylactically or therapeutically. 9 Patients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA) are recommended to receive routine chemical thromboprophylaxis 10,11 to prevent severe complications. These include deep vein thrombosis (DVT) and pulmonary embolism (PE). Although the incidence of thrombotic complications after THA or TKA have decreased substantially, the use of heparin carries a risk of potentially resulting to HIT. Therefore, HIT after THA or TKA has become increasingly common and has lead to a higher risk of hemorrhage and thrombosis. 12 Currently, there is no large-scale study on HIT in post-THA and post-TKA patients. Hence, the aim of this study was to investigate the incidence and risk factors of HIT in patients after TKA or THA using the National Inpatient Sample (NIS) database. To the best of our knowledge, this is the rst study based on a large sample size that focuses on HIT after THA or TKA.

Methods
This retrospective cohort study was conducted using the NIS database. This database has been recognized as the largest national database in the United States since 1998. 9,13 We investigated patients who underwent either THA or TKA in the United States from 2005 to 2014. The patients were identi ed according to the International Classi cation of Diseases, Ninth Revision, Clinical Modi cation (ICD-9 CM) procedure codes 81.51 and 81.54. For each procedure, the identi ed patients were divided into two groups, according to the presence of postoperative HIT (ICD-9 code 289.84). Those who were diagnosed with thrombocytopenia unrelated to heparin exposure were excluded. Studies on the baseline characteristics, hospital conditions, and risk factors of HIT were performed.
A chi-square test was used to evaluate the categorical variables which included grouped age and gender.
A rank-sum test was used to assess the continuous variables including age, Charlson Comorbidity Index (CCI), Elixhauser Comorbidity Index (ECI), length of hospital stay (LOS), and total medical cost. CCI aggregated the prognostic burden of comorbid diseases. This index was used as an indicator to predict 1year mortality. The ECI was applied to identify elevated mortality or hospital readmission risks. In addition, a logistic regression analysis was conducted to analyze the potential predictors of HIT. The odds ratios (OR) and 95% con dence intervals (CI) were calculated. The level of statistical signi cance was de ned as p < 0.05. 9,14 All analyses were performed using the SPSS version 23 software (IBM; Armonk, New York).

Results
A total of 593,045 patients undergoing THA and 1,228,707 patients undergoing TKA were identi ed ( Fig. 1). The annual incidence of HIT from 2005 to 2014 is shown in Fig. 2. The baseline characteristics and hospital conditions are presented in Table 1. The predictors for postoperative HIT are summarized in Table 2 below.   19 However, HIT -one of the most dangerous pro-thrombotic disorders -may occur during anti-thrombotic prophylaxis. 1,12,21 HIT patients have a higher risk of developing paradoxical thrombotic syndrome. [22][23][24] Hence, it is critical to understand the incidence and risk factors of HIT.
Despite the performance of TJA soaring from 2005 to 2014, the incidence of HIT after TJA has remained at 0.01-0.03%. This is consistent with the results reported by Craik. 10 In 2008, the American Academy of Orthopedic Surgeons (AAOS) released a guideline recommending thromboprophylaxis after TJA. 17 Thereafter, chemoprophylaxis has been done more routinely. 10,12,25 Although it has not been commonly diagnosed, HIT has been recognized as one of the thromboembolic complications of patients after TJA.
HIT has resulted to negative effects on surgical outcomes. Interestingly, compared with the incidence of postoperative HIT to other procedures, Dhakal et al. 26 reported that the risk of HIT after TJA was lower. A possible explanation might be the application of low molecular weight heparin (LMWH) rather than UFH.
Thus, routine laboratory monitoring was not recommended for HIT after TJA. 10,25,27 However, according to our study, the cases of inpatient mortalities in post-THA patients were 13.75 times higher (2.2% vs. 0.16%) and 8.3 times higher than in post-TKA patients (0.58% vs. 0.07%), respectively. It is critical to identify the HIT risk factors and keep in mind that HIT may take place during LMWH exposure.
There have been controversial conclusions about the risk factors of HIT. In contrast to our results, Warkentin et al. 28 and Chaudhry et al. 29 found the female gender as a risk factor to HIT. This may be due to the different immune responses after various surgeries 29 , or the different thromboprophylactic therapies employed. 28 The racial differences 30 and polymorphism variabilities 31 have also been reported by other researchers. For example, non-Caucasians had higher thrombotic risks of HIT development after undergoing any procedure on their current admission. 30 Furthermore, large-scale and teaching hospitals served as protective factors after THA.
The study of preoperative comorbidities may be valuable in preventing HIT. For THA, AIDS, hypertension, psychoses, and pulmonary circulation disorders increased the risk of postoperative HIT. In TKA patients, pulmonary circulation disorders and weight loss were identi ed as risk factors. To date, there is no established mechanism able to explain the above ndings. One possible explanation is the formation of nonspeci c and dysregulated antibodies triggered by pathological processes. 32 Specially, in the case of psychoses, the combined use of heparin and psychotropic medications may result in adverse hematologic effects. 33 The application of novel anticoagulants may provide a good opportunity of decreasing HIT. Argatroban and lepirudin, both direct thrombin inhibitors, have been estimated to have comparative e cacy and safety in the management of HIT. 34 Danaparoid has been found to have less in uence on platelets compared with other anticoagulants because it inhibits factor Xa selectively. 35 However, given the low incidence of HIT after TJA, LMWH is still the preferred chemoprophylaxis after TJA in patients without a history of HIT. 17,19,20 This study had several limitations. First, as a retrospective study utilizing the NIS database, coding and data-entry errors may have existed and led to an erroneous estimation of the HIT. Second, the limited elements and absence of follow-up in the NIS database made it impossible to analyze the long-term HIT outcomes. For instance, we were unable to accurately select patients with heparin therapy through the ICD-9 code. This made it inevitable to rule out patients without heparin admission. Finally, the different risk factors of HIT after THA and TKA were identi ed without established mechanisms. Bias in the medical records, utilization of tourniquet in the TKA, and the different seroconversion rates of anti-PF4/heparin antibodies between the two procedures 36 might have contribute to the difference in the results. Further prospective, evidence-based studies are needed to determine the exact causalities between comorbidities and HIT.

Conclusion
According to our study based on a large sample size, the incidence of HIT in patients undergoing THA and TKA is relatively low. However, HIT signi cantly increases inpatient mortality. Thus, considerable attention and further investigations regarding HIT are warranted. Orthopedic surgeons should remain vigilant to the occurrence of HIT during postoperative anticoagulant therapy. They should also be aware of the risk factors of HIT to further improve patient outcomes. Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.