With ongoing updates to antithrombotic treatment guidelines [10], this study builds on previous research [11]to further assess the risk and prognosis of HIT in patients who underwent TKA between 2010 and 2019, with a specific focus on those who underwent RTKA. According to the ninth edition of the ACCP guidelines [2], the recommendations for HIT treatment and prevention have significantly decreased its incidence among patients with TKA. However, over the past decade, the incidence of HIT in the RTKA group (0.3%) has remained notably higher than that in the TKA group (0.1%), whereas new recommendations have added bivalirudin as a treatment option for HIT and optimized antibody testing protocols. These updates do not fundamentally alter existing strategies for HIT prevention in patients who underwent TKA. These observed differences suggest that HIT risk stratification need to account for the surgical type. This disparity persists despite a broader adoption of newer anticoagulants, as patients who underwent RTKA often require heparin owing to (a) heparin’s reversibility favors its use over DOACs in RTKA with a higher bleeding risk, (b) the need for bridging therapy in patients with prior mechanical complications, and (c) surgeon preferences in complex reconstructions. The identification of RTKA-specific risk factors provides actionable targets for preoperative optimization. Although both procedures can have severe adverse outcomes with concurrent HIT, research on HIT risk factors in RTKAs is limited. Our study seeks to fill that gap.

The observed inverse association between age ≥ 71 years and HIT risk is unlikely to reflect a genuine biological protective effect. Several mechanisms may account for this finding. Older or frailer patients are more often managed with non-heparin alternatives such as aspirin or direct oral anticoagulants, or with lower-dose and shorter-duration heparin regimens, thereby reducing effective exposure. In addition, elderly patients frequently undergo surgery at teaching hospitals or within enhanced recovery pathways, which provide more intensive monitoring and individualized perioperative care [12]. Such practice differences may reduce the likelihood of HIT being triggered or recognized. Furthermore, reliance on ICD coding may bias results: in older patients, postoperative thrombocytopenia is more often attributed to infection, bone marrow suppression, or other comorbidities rather than formally coded as HIT, leading to potential under-ascertainment [13]. Finally, given the very low event rate of HIT, regression estimates are vulnerable to sparse-data bias, which can produce artifactual inverse associations. Taken together, these considerations suggest that the apparent “protective effect” of advanced age is more likely driven by treatment patterns, diagnostic practices, and residual confounding rather than by age itself. Although age does not correlate with outcomes in patients undergoing RTKA, the RTKA group is, on average, younger than the first-time surgery group (65.04 vs. 68.04 years). In contrast to the long-term risks of bone resorption and prosthetic loosening associated with prolonged prosthesis use, younger patients more often undergo surgical treatment for PJI or periprosthetic fractures [14]. These patients differ from those undergoing primary surgery in that, in addition to the bone defects resulting from the initial procedure, the increased complexity of bone and soft tissue structures complicates the repair process [15, 16]. Furthermore, heparin re-exposure can trigger the antibody activation [17], presenting significant challenges related to HIT during the second surgery. From 2011 to 2019, the observed incidence of HIT declined in TKA and RTKA, which may reflect evolving anticoagulation practices, including the broader adoption of alternative agents such as DOACs and aspirin in some centers. Despite this overall decrease, HIT remains a clinically relevant concern, particularly in revision procedures and among younger patients. This finding highlights the need for standardized, personalized anticoagulation monitoring following RTKA, with special attention to younger patients to prevent overlooked HIT diagnoses.

In this study, discharge against medical advice was positively associated with HIT in the TKA group. However, given the small number of events and wide CIs, this association is significantly unstable and should be interpreted with caution. This finding may be confirmed by studies with larger sample sizes. Teaching hospitals serve as a protective factor for TKA group by offering advanced treatment options, including personalized care and platelet count monitoring. This approach facilitates more precise management of anticoagulant therapy and reduces the incidence of HIT [18, 19]. The prevalence of chronic conditions such as obesity, diabetes, and hypertension is higher in the southern United States than in other regions [20], potentially increasing the risk of bleeding in patients with these comorbidities. Although heparin therapy can effectively control postoperative bleeding, it also poses an increased risk of HIT [21]. Therefore, the risks and benefits of heparin use must be carefully assessed in postoperative care.

In the revision cohort, comorbidities were significantly associated with increased HIT risk. Multivariate analysis revealed that increased number of comorbidities was a risk factor, suggesting that certain conditions, which do not significantly increase the risk during the initial TKA, are associated with HIT following revision surgery. Although some risk factors exhibited particularly high effect sizes, the consistent increase in thrombotic comorbidities across TKA and RTKA groups supports the fundamental pathophysiology of HIT. These conditions include tumors, nonhemorrhagic ulcers, and valvular heart disease. Pulmonary circulation disorders may be risk factors for HIT after two surgical procedures, such as chronic obstructive pulmonary disease (COPD) [22]. COPD has been identified as a risk factor for HIT following cardiac surgery [23]. Conversely, in pulmonary arterial hypertension, heparin therapy can improve hemodynamics, lower pulmonary artery pressure, and alleviate patient symptoms [24]. Even if heparin is discontinued preoperatively, prior exposure may still lead to antibody formation, increasing the likelihood of postoperative HIT [25]. A retrospective study revealed that adult patients receiving continuous IV heparin before cardiac surgery had a tenfold higher risk of postoperative HIT [26]. Therefore, patients with pulmonary circulation disorders should undertake additional measures to reduce the risk of postoperative HIT. The complexity of RTKA is usually greater than that of TKA, particularly when dealing addressing bone defects and joint instability. RTKA may require the use of bone grafts or specific repair components to address joint failure caused by infection or other complications. In addition, RTKA typically results in higher rates of re-repair and longer recovery periods, making postoperative management more complex and increasing complication risks. This study indicates that valvular heart disease is a potential risk factor in RTKA. Such patients are more likely to have had heparin exposure during valve replacement surgery, cardiopulmonary bypass, and postoperative unfractionated heparin therapy. In patients with cancer, platelet counts may not accurately reflect HIT because of factors such as chemotherapy effects, bone marrow infiltration, myeloproliferative neoplasms, disseminated intravascular coagulation, and thrombotic microvascular disease. Moreover, LMWH is a primary anticoagulant in patients with cancer, and warfarin is a poor choice in this situation, making HIT management more challenging. At a comprehensive cancer center, the annual incidence of HIT was 0.24%, with approximately 0.57 HIT cases occurring per 1000 patients with cancer using heparin [27]. The link between cancer and HIT needs further investigation. This study also revealed an association between nonbleeding ulcers and HIT in the RTKA group; however, the number of events was extremely small and the confidence interval was wide. Thus, this finding is significantly unstable and should be interpreted with caution. Such ulcers are often related to diabetic foot complications or prior warfarin therapy. Chronic ulcers can create a hypercoagulable state, and bacterial biofilms can hinder healing, highlighting the importance of infection control [28,29,30]. The inverse association between depression and HIT is unlikely to reflect a true biological protective effect. More plausible explanations involve differences in clinical management. Patients with depression frequently use selective serotonin reuptake inhibitors (SSRIs) or serotonin–norepinephrine reuptake inhibitors (SNRIs), which are associated with increased bleeding risk. This may lead clinicians to adopt more cautious anticoagulation strategies, including avoidance of heparin or closer monitoring when heparin is administered [31]. In addition, depressed patients often receive multidisciplinary care and more frequent medical follow-up, which may indirectly alter perioperative anticoagulation practices [32]. Finally, because HIT is a rare event, regression estimates for small subgroups are vulnerable to instability and sparse-data bias. Taken together, these factors suggest that the apparent protective association is more likely due to clinical practice patterns and residual confounding rather than a causal effect of depression.

Regardless of surgery type, thrombosis-related diseases after HIT are expected to increase, resulting in higher hospitalization costs, prolonged hospital stays, and increased mortality [8, 33]. TKA and RTKA have notably similar postoperative complications. Following TKA surgery, HIT can develop, prompting clinicians to restrict patient activity and initiate anticoagulation therapy, which may increase the risk of pneumonia. A study investigating the effect of postoperative physical activity on the incidence of pneumonia in patients with esophageal cancer revealed that the average number of steps taken between postoperative days 8–10 serves as a critical predictor for postoperative pneumonia development. Particularly, patients who recorded < 1,494 steps per day were more likely to develop postoperative pneumonia, underscoring the significant influence of early postoperative physical activity levels on pneumonia occurrence [34]. Although RTKA does not increase the risk of PE, it may increase the likelihood of respiratory conditions such as dyspnea. TKA increases the risk of infection and postoperative pain; thus, clinicians should be prepared to ensure adequate monitoring and timely detection of HIT.

The analysis highlights several considerations for clinical practice. Patients who ultimately require revision procedures, particularly those with pulmonary circulatory disorders or valvular heart disease, appear to be more vulnerable to HIT. In these high-risk settings, closer postoperative surveillance—including routine platelet monitoring and timely adjustment of anticoagulation regimens—may help reduce the likelihood of delayed recognition and related complications. Equally important, efforts to optimize primary TKA and minimize the need for revision surgery may represent a critical strategy to lower the overall incidence of HIT and associated adverse outcomes.

This study has several limitations, including potential errors and biases inherent in the NIS database that could affect the accuracy of the results. This study uses ICD coding to identify the following potential biases in HIT: (1) Heterogeneity of diagnostic criteria: different institutions may use different diagnostic criteria (e.g., 4 T score, PF4 antibody detection, or functional testing), which may lead to diagnostic error classification bias. However, institutionally validated ICD-10 codes can be integrated with other data sources to improve accuracy in identifying postoperative complications [35]. (2) There may be false positives all together: non-immune HIT (HIT type I). (3) False negative inclusion: some cases with serological confirmation but without ICD documentation may be missed owing to time window limitations, such as some HIT occurring 5–10 days after exposure to heparin [36]. Given that NIS does not contain outpatient data, we cannot track the two surgeries. Moreover, this study represents an initial exploratory analysis of retrospectively collected data, which primarily reveals associations rather than causal relationships. Thus, further prospective studies with more granular clinical data are warranted to confirm the present findings and clarify potential causal mechanisms. Despite these limitations, NIS data can still effectively reflect the epidemiological characteristics of HIT confirmed during hospitalization, providing important insights for hospital quality assessment and acute management.