Effects of low-molecular-weight heparin and unfractionated heparin on patients with exertional heat stroke with thrombocytopenia: A prospective study

Li Cheng; Eric Allen Klomparens; De Lin Liu; Min Na Wang; Xiao Xue Yin; Wei Liu; Yuan Liu; Qi Feng Zhang; Gang Ye

doi:10.4103/ed.ed_2_19

ORIGINAL ARTICLE

Year : 2019 | Volume : 4 | Issue : 2 | Page : 45-49

Effects of low-molecular-weight heparin and unfractionated heparin on patients with exertional heat stroke with thrombocytopenia: A prospective study

Li Cheng¹, Eric Allen Klomparens², De Lin Liu¹, Min Na Wang¹, Xiao Xue Yin¹, Wei Liu¹, Yuan Liu¹, Qi Feng Zhang¹, Gang Ye¹
¹ Department of Emergent Intensive Care Unit, BeiJing LuHe Hospital, Capital Medical University, Beijing, China
² Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA

Date of Submission	14-Jan-2019
Date of Acceptance	15-Apr-2019
Date of Web Publication	17-Jun-2019

Correspondence Address:
Dr Gang Ye
No. 82, Xinhuanan Road, Tongzhou, Beijing 101100
China

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/ed.ed_2_19

Abstract

Background: Thrombocytopenia often occurs in patients with exertional heat stroke (EHS). We aimed to investigate the effect of low-molecular-weight heparin sodium (LMWH) and unfractionated heparin (UFH) on coagulation and prognosis in the treatment of EHS with thrombocytopenia.
Methods: In a prospective cohort study, 64 patients admitted to the emergent intensive care unit (ICU) were studied between July 2015 and October 2018. Patients were randomized to receive LMWH or UFH. Thirty-three patients were given LMWH 4000 IU twice a day for 5 days, by subcutaneous injection. Thirty-one patients were given UFH 5–10 U/kg × h for 5 days, by 24-h continuous intravenous infusion. Demographic and clinical data (platelets [PLTs] counts, activated partial thromboplastin time [aPTT], prothrombin time [PT], fibrinogen [FIB], D-dimer, presence of diffuse intravascular coagulation [DIC]), and mortality in the ICU were recorded along with the 28-day survival rate. The acute physiology and chronic health evaluation (APACHE) II score was calculated within 24 h of admission and used to indicate the severity of disease.
Results: There were no significant differences in sex, age, APACHE II score, and core temperature between the two groups (P > 0.05). PLT and FIB were significantly increased after treatment in both groups (P < 0.05), while aPTT, PT, and D-dimer were significantly decreased after treatment in both groups (P < 0.05). No significant differences between the two groups were found in the incidence of DIC or ICU mortality (P > 0.05), but the incidence of bleeding in the LMWH group was significantly lower than in the UFH group (P < 0.05). There was not a significant difference in the 28-day survival rate between the two groups (P > 0.05).
Conclusions: The results of this study support that the efficacy of LMWH and UFH in the prevention of thrombosis is equivalent. However, the incidence of bleeding was lower in LMWH group. LMWH and UFH had statistically similar rates of ICU mortality, 28-day mortality, and incidence of DIC. Our results suggest that LMWH may be safer than UFH for use in patients with EHS with thrombocytopenia.

Keywords: Acute physiology and chronic health evaluation II, exertional heat stroke, heat stroke, heparin sodium, low-molecular-weight heparin sodium

How to cite this article:
Cheng L, Klomparens EA, Liu DL, Wang MN, Yin XX, Liu W, Liu Y, Zhang QF, Ye G. Effects of low-molecular-weight heparin and unfractionated heparin on patients with exertional heat stroke with thrombocytopenia: A prospective study. Environ Dis 2019;4:45-9

How to cite this URL:
Cheng L, Klomparens EA, Liu DL, Wang MN, Yin XX, Liu W, Liu Y, Zhang QF, Ye G. Effects of low-molecular-weight heparin and unfractionated heparin on patients with exertional heat stroke with thrombocytopenia: A prospective study. Environ Dis [serial online] 2019 [cited 2023 Mar 31];4:45-9. Available from: http://www.environmentmed.org/text.asp?2019/4/2/45/260515

Introduction

Heat stroke (HS) is a life-threatening illness dating back more than 2000 years. Despite the long history, HS continues to threaten the health and safety of those who undertake physical work in modern times. Athletes, soldiers, fire-fighters, and outdoor laborers are among those who face a higher risk of HS, because of the nature of their lifestyles and occupations.^{[1],[2],[3],[4]} HS is traditionally divided into exertional and classic varieties, where the two forms are distinguished primarily by heat source. Exertional HS (EHS) occurs mainly in young- and middle-aged people and results from strenuous exercise in hot or humid environmental conditions. EHS is a critical illness with rapid progression and high mortality. Patients with severe EHS may develop many complications, including extensive tissue injury, neurological dysfunction, rhabdomyolysis, disseminated intravascular coagulation (DIC), acute liver and kidney damage, acute respiratory distress syndrome, and multiple organ dysfunction syndrome (MODS). During clinical treatment, EHS is more prone to coagulation abnormalities, such as thrombocytopenia, prolonged coagulation times, and elevations of fibrin degradation product and D-dimer.^[5] Mortality can be as high as 50% in EHS, even in the presence of appropriate early body cooling and intensive supportive care.^[6] Anticoagulation is an important aspect of treatment in the case of EHS with dysfunctional coagulation, thrombosis, or DIC. However, there is a sparsity of data related to the superiority of any one anticoagulant agent as compared to another in this specific patient population. The goal of the current study is to compare the anticoagulative efficacy, safety, and effect on outcome of low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH) in patients with EHS with thrombocytopenia.

Methods

Patients

This prospective study was conducted in the emergency intensive care unit (ICU) of the Beijing LuHe Hospital, Capital Medical University in Beijing, China. All patients suffering from EHS with thrombocytopenia between July 2015 and October 2018 who stayed in the ICU were consecutively enrolled, given that they met the following inclusion and exclusion criteria.

Inclusion criteria included – (1) a diagnosis of EHS as defined by a rectal temperature above 40°C, evidence of multiple organ dysfunction,^[7] including acute renal failure, disseminated intravascular coagulation, and extensive hepatic and muscle damage, and central nervous system abnormality caused by vigorous exercise in a hot and humid environment;^[8] (2) decreased platelet (PLT) count (<100 × 10⁹/L).

Exclusion criteria included – (1) current pregnancy or lactation; (2) previous organ transplant; (3) anticoagulant administration within 48 h; (4) history of severe brain injury, cerebral aneurysm, arteriovenous malformation, or gastrointestinal bleeding; (5) cerebral hemorrhage on admission; (6) chronic severe liver disease, immune system disorder, connective tissue disease, malignant tumor, or hematologic disease.

Treatments

All patients were given the following treatments: early cooling treatment, positive fluid resuscitation, water and electrolyte maintenance, acid-base balance, internal environment stability, and organ system supportive treatment. Head computed tomography was performed before admission on all patients to rule out cerebral hemorrhage.

Patients were randomized into two groups by random number tables.

LMWH group – Patients were given 4000 IU LMWH (enoxaparin) immediately on admission to in ICU subcutaneously twice a day for 5 days.

UFH group – Patients were given 5–10 U/kg × h UFH Immediately on admission to in ICU by 24-h continuous intravenous infusion for 5 days.

Observation index

Various patient information, laboratory values, and outcome measures were collected, including demographic characteristics, medical histories, initial and maximum body core temperatures, PLT counts, activated partial thromboplastin time (aPTT), prothrombin time (PT), fibrinogen level (FIB), D-dimer level, the incidence of diffuse intravascular coagulation (DIC), the incidence of bleeding complications (skin ecchymosis organ hemorrhage), ICU length of stay, ICU mortality, and 28-day cumulative survival. Laboratory tests were conducted before treatment and 5 days on the last day of treatment (day 5) for comparison. An index of EHS severity was obtained using the acute physiology and chronic health evaluation (APACHE) II score.^[7] APACHE II scores were calculated within 24 h of admission.

Statistical analyses

Continuous data are presented as mean ± standard deviation, and categorical data as numbers and percentages. Comparisons for baseline characteristics between the two groups were performed by independent t-test for continuous data, and Chi-square or Fisher's exact test for categorical data. Paired sample t-tests were conducted to analyze differences before and after treatment within the two groups. For survival-to-discharge, the survival curves were constructed by the Kaplan–Meier method with a log-rank test to detect the difference between the LMWH and UFH group. The 28-day mortality was estimated by the Kaplan–Meier method with a 95% confidence interval. P < 0.05 was considered statistically significant. All statistical analyses were performed with the statistical software SPSS Statistics, version 21 (IBM, Armonk, NY, USA).

Results

Patients demographics, coagulation indices, and disease severity assessment

A total of 64 patients (average age 48.6 ± 7.7 years old) without any underlying illness or chronic medication use were admitted within 24 h of EHS onset. All patients were working when EHS symptoms began. The patient's characteristics are presented in [Table 1]. APACHE II score was analyzed as an indicator of the severity of illness before treatment. There was no significant difference in APACHE II score between the LMWH and UFH groups (15.52 ± 2.14 vs. 16.48 ± 2.39, respectively, P = 0.09).

Table 1: Comparing baseline characteristics and coagulation indices in low-molecular-weight heparin group versus unfractionated heparin group

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Clinical indices before and after treatment in the two groups

Laboratory values, APACHE II scores, and statistical comparisons for both groups before and after treatment are seen in [Table 2]. Posttreatment values of all studied laboratory tests and APACHE II score were significantly improved within each treatment group, as compared to the pretreatment values (P < 0.05). After treatment, PLT and FIB were significantly higher in the LMWH group compared to the UFH group (P < 0.05). PT and D-dimer level were significantly lower in the LMWH group after treatment compared to the UFH group (P < 0.05). There was no significant difference in posttreatment values of APACHE II score or aPTT between the two groups (P > 0.05).

Table 2: Comparing clinical indices in low-molecular-weight heparin group and unfractionated heparin group

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Complications and mortality after treatment

[Table 3] shows rates of complications and mortality in both groups. In the LMWH group, 5 patients (15.2%) developed DIC, 1 patient (3.0%) developed hemorrhagic complications, and incidence of mortality in the ICU was 6 (18.2%). In the UFH group, 4 patients (12.9%) developed DIC, 8 patients (25.8%) developed hemorrhagic complications, and incidence of mortality in the ICU was 8 (25.8%). There was no significant difference between the two groups in the rate of DIC or in the incidence of mortality in the ICU (P > 0.05). Significantly fewer hemorrhagic complications occurred in the LMWH group as compared to the UFH group (P < 0.05). There was no significant difference between the LMWH group and the UFH group in the cumulative 28-day mortality (24.2%, 32.3%, respectively, P > 0.05) [Figure 1].

Table 3: Comparison of incidence of disseminated intravascular coagulation, bleeding complications, intensive care unit mortality and 28-day mortality after treatment

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Figure 1: Cumulative 28-day survival curves for both groups

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Discussion

According to the international classification, heat-related diseases can be divided into heat spasm, heat syncope, heat exhaustion, and HS, with HS considered to be the most serious type of heat-related disease.^[8],[9] If treatment is not timely and effective, the case fatality rate of HS is quite high, with an average of 10%–15%. Once HS progresses to MODS, the case fatality rate can reach higher than 40%. Moreover, more than 30% of the survivors have long-term neurological sequelae and other deficits.^{[10],[11],[12]} Because the diagnostic criteria and treatment options that were used in these studies vary, these results can only be used for general reference. In this study, we report an ICU mortality rate of 18.2% in the LMWH group and 25.8% in the UFH group. At 28 days, 24.2% of patients had died in LMWH group and 32.3% in the UFH group, with no significant difference in mortality between the two groups.

In the process of heat stress, systemic inflammatory reactions and the activation of the coagulation system occur. Coagulation activation can be seen in the results of laboratory studies, including a prolonged PT and aPTT, elevated D-dimer concentration, and a decreased PLT count and protein C level. In vitro studies have shown that heat (43°C–44°C) can directly activate platelet aggregation, leading to irreversible platelet hyperaggregation after cooling.^[13] DIC is a common complication of thermal injury to the vascular endothelium during HS, and is one of the important mechanisms of death from HS with coagulation abnormalities. Therefore, early detection and active prevention of the progression of HS with thrombocytopenia to DIC is extremely important and has been shown to improve prognosis in EHS.^[14],[15] Such improvements have recently led to more research and attention surrounding HS with combined coagulation abnormalities. The current study was designed to further improve our understanding of the efficacy and safety of anticoagulant therapy in the population of patients with EHS with the presence of coagulopathy as indicated by thrombocytopenia.

The precise pathogenesis of severe HS with thrombocytopenia is still unclear, and there are currently four contending theories. The endothelial cell injury theory proposes that a series of factors such as high metabolism and hypoxia caused by the high temperature lead to damage of vascular endothelial cells, which activates the endogenous coagulation system,^[16] promotes leukocyte adhesion, and causes platelet aggregation in the blood vessels, resulting in the formation of microthrombi and causing thrombocytopenia.^[17] The myelosuppression theory suggests that HS leads to the production of endotoxin,^[18] which inhibits the formation of platelets in the bone marrow.^[19] The blood concentration theory states that the high-temperature state of the body leads to dehydration resulting in hemoconcentration, leading to a pro-coagulation state which promotes platelet aggregation and leads to the formation of thrombi.^[20] The final theory, the inflammatory factor response theory, proposes that the heat stress caused by high temperature can directly activate the body's inflammatory response system, inducing the activation of a large number of inflammatory cells such as neutrophils, macrophages, and monocytes, which release various inflammatory factors including interleukin 1 (IL-1), IL-2, IL-6, tumor necrosis factor, and oxygen-derived free radicals, thereby further inducing the body's cascading inflammatory response, which in turn promotes the coagulation pathway which itself further aggravates the inflammatory response, thereby forming a vicious circle.^{[21],[22],[23]}

Some scholars have found that heat stress caused by high temperature causes extensive microthrombi in the lungs, brain, heart, kidney, liver, and intestines of animals at autopsy.^[24] This result suggests that dysfunctional thrombosis is a precursor to multiple organ failure during heat-induced disease, and studies have confirmed that dysfunctional coagulation may aggravate existing multiple organ failure. Therefore, in the case of HS combined with abnormal coagulation function, early correction of abnormal coagulation and prevention of multiple organ failure is a positive means to reduce the mortality of severe HS. As an anticoagulant, heparin is a multimer composed of two polysaccharides. It has an anticoagulant effect in vivo and in vitro, and exerts this effect by multiple mechanisms. Heparin enhances the affinity of antithrombin III for thrombin, prevents the activation of thrombin, inhibits the adhesion and aggregation of platelets, enhances the activity of protein C, and stimulates the release of anticoagulant substances and fibrinolytic substances from vascular endothelial cells. However, UFH has a short half-life and results in highly increased risk of bleeding, which limits its clinical use.^[17] LMWH has the advantages of a longer half-life, high bioavailability, and a clear dose-effect relationship. Unlike UFH, the dose of LMWH can be conveniently adjusted without laboratory monitoring.^[25] The ratio of its active/anticoagulant activity is 1.5–4.0, while that of UFH is 1.^[26] LMWH maintains the antithrombotic effect of heparin and reduces the risk of bleeding^.[27] Therefore, it is widely used in the prevention and treatment of thrombotic diseases.

The present study revealed that PLT count and indicators of coagulation were improved after 5 days of treatment with LMWH and UFH in patients with EHS with thrombocytopenia, and there were no significant differences in the incidence of DIC, ICU mortality, or 28-day mortality between the two treatments. Many laboratory values were significantly different between the two groups after treatment, including PLT, PT, FIB, and D-dimer levels, but the clinical significance of these laboratory value differences is questionable. However, LMWH did lead to significantly fewer bleeding complications than UFH. The results of this study suggest that early LMWH anticoagulation therapy has equivalent efficacy and superior safety as compared to UFH in EHS with thrombocytopenia.

This trial is a single-center prospective study with a relatively small number of cases. A large, multicenter, randomized controlled trial is still needed to validate the efficacy of LMWH and UFH in the treatment of patients with EHS with thrombocytopenia.

Conclusions

The efficacy of LMWH and UFH in the prevention of thrombosis is equivalent. However, the incidence of bleeding was lower in LMWH group. LMWH and UFH had statistically similar rates of ICU mortality, 28-day mortality, and incidence of DIC. Our results suggest that LMWH may be safer than UFH for use in patients with EHS with thrombocytopenia.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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