Heparin-induced thrombocytopenia-II in hospitalized patients with surgery or deep vein thrombosis.

Am J Blood Res 2024;14(3):14-21 www.AJBlood.us /ISSN:2160-1992/AJBR0159408 Original Article Heparin-induced thrombocytopenia-II in hospitalized patients with surgery or deep vein thrombosis Narges Gomar1, Tahereh Abbasi Garavand2, Fatemeh Amiri3, Alireza Goodarzi3, Sayed Payam Hashemi4 School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran; 2Urology and Nephrology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran; 3Department of Medical Laboratory Sciences, School of Paramedicine, Hamadan University of Medical Sciences, Hamadan, Iran; 4Nerophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran 1 Received July 23, 2024; Accepted October 11, 2024; Epub October 15, 2024; Published October 30, 2024 Abstract: Objectives: Heparin-induced thrombocytopenia (HIT) is clinically the most relevant non-hemorrhagic complication of heparin, which is associated with the increased risk of thrombosis and mortality. This study was conducted to determine platelet activation in HIT-II in hospitalized patients with surgery or deep vein thrombosis (DVT). The clinical outcomes of the patients was also assayed. Methods: In this descriptive/cross-sectional study, 754 heparin-receiving-hospitalized patients with surgery or DVT were evaluated for the incidence of thrombocytopenia 7 days after heparin therapy. Clinical assessment 4Ts and ELISA for heparin-platelet factor 4 (HPF4) antibodies were performed to diagnose HIT-II. Production of platelet microparticles (PMPs), soluble P-selectin (sP-selectin), IL-1, IL-6, and tumor necrosing factor-α (TNF-α) were evaluated in the HIT suspected patients. Results: The frequency of HIT-II was 4.50%. More HIT-II was diagnosed in the elder patients (P = 0.008) and female (P = 0.005). Thrombosis rate was higher in the HIT-II (P = 0.0001). More PMPs, sP-selectin, IL-1, IL-6, and TNF-α was detected in the HIT-II patients. The length of hospital stay was significantly different in HIT-II (P = 0.015). Mortality rate of the HIT-II patients was higher than non-HIT ones (P = 0.0007). Conclusion: Platelet activation in the HIT-II patients mediated more thrombosis formation. It was associated with the increased length of hospital stay and mortality. Keywords: Thrombocytopenia, P-selectin, platelet microparticles, thrombosis, interleukin-6 Introduction Heparin-induced thrombocytopenia (HIT) is one of the dangerous side effects of heparin treatment. It could lead to the activation of platelets, thrombosis, and finally to the death. HIT needs to the special attention as an important complication of drug therapy [1, 2]. Two types, I and II, have been defined for HIT based on underlying mechanism, immune or non-immune depended. The first type, known as nonimmune heparin associated thrombocytopenia and is not mediated by antibody. HIT-I often occurs 24 hours after heparin admission and has mild symptoms and severity [3]. The platelet count normalizes without any complication or heparin discontinuation in the HIT-I [3, 4]. HIT-II is the immune-mediated one with antibody production against the heparin-platelet factor 4 (HPF4) complex. Platelet factor 4 (PF4), a cationic protein, is stored in the alpha gran- ules of platelets and is released by the platelet activation. Due to its positive charge, PF4 has strong tendency to bind to negatively charged molecules such as glycosaminoglycan and heparin. Formation of HPF4 complex leads to the production of antibodies. Large HPF4 immune complexes are formed both inside the bloodstream and on the surface of platelets [5, 6]. HIT-II is the most significant non-bleeding clinical complication of heparin therapy. Thrombocytopenia might be absolute, platelet count < 150,000/µL, or relative, a platelet count drop about 50% or more from baseline pre-heparin platelet count [4, 7]. Thrombocytopenia occurs at least 4 days after heparin exposure, usually 5 to 14 days [1, 3]. Its prevalence is 0.1 to 5% of heparin-treated-patients [1, 3, 7]. HIT-II diagnosis is based on 4Ts clinical assessment scoring and the HPF4 antibody assay. Enzyme-linked immune sorbent assay (ELISA) is usually used to detect antibodies in patients with 4 or https://doi.org/10.62347/JMFO7582 HIT in DVT and surgery more scores of 4Ts scoring system. Serotonin Release Assay (SRA) and heparin induced platelet activation assays (HIPA) should be used to confirm the presence of antibodies. But in case of confirmatory test non-availability, OD > 2 in ELISA method could be used to confirm HIT-II [1, 3]. IgM, IgG, and IgA are produced against HPF4 complexes. It has been determined that the binding of IgG antibody to platelet FcγRIIa activates them leading to alteration of membrane, releasing of different components, and production of platelet microparticles (PMPs) [8]. The antibodies active neutrophils and monocytes through their FcγRIIa receptors too. On the other hand, PF4 binds to platelet, neutrophil, monocyte, and endothelial cell glycosaminoglycan, leading to the production of more antibodies. This damages endothelial cells and lead to the production of tissue factor. Furthermore, these antibodies can attach to the surface receptors of monocytes and induce the release of tissue factor. These events along with PMPs production lead to the creation of procoagulant conditions that can persist for days even after discontinuing the heparin admission [1, 9]. Then, thrombosis can occur in 20 to 64% of the patients because of cross-talking of different blood and/or endothelial cells [10]. Receiving heparin is identified as a factor contributing to the further worsening of thrombocytopenia. In addition, spontaneous thrombocytopenia also occurred in a significant number of patients, which caused their thrombocytopenia to intensify when they were treated with heparin [1, 10, 11]. Therefore, thrombocytopenia requires accurate and timely diagnosis. This issue can also affect the clinical outcomes of the patients. Considering the widespread use of heparin, especially in hospitalized patients, the researchers of this study decided to investigate platelet activation in HIT-II in hospitalized patients with surgery or deep vein thrombosis (DVT) at Shahid Beheshti and Beasat Hospitals in Hamadan province, the west zone of Iran. HIT-II relationship with the clinical outcomes of the patients was also analyzed. Material and methods Study design and outline DVT and surgery candidate patients admitted to Shahid Beheshti and Beasat hospital in Hamadan from May 2021 to August 2023 who 15 had been administered heparin were included in the study. To normalize the data of two different types of patients, DVT and surgery candidate, and to remove confounding variables, relatively equal numbers were selected from the two groups. The sampling method was performed as a census method and 754 people were selected from the files of eligible patients. The study conducted after officially approval by ethic committee in Hamadan university of medi (...truncated)