Clinicopathologic Variables According to Disease Severity in Dogs with Heartworm Disease

Clinicopathologic Variables According to Disease Severity in Dogs with Heartworm Disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinicopathologic Variables According to Disease Severity in Dogs with Heartworm Disease Minsuk Kim, Minwoong Seo DVM, Jaechun Cho, Chul Park This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9420988/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background Canine heartworm disease is associated with various clinicopathologic abnormalities; however, most previous studies have focused on comparisons between infected and non-infected dogs rather than differences according to disease severity. The American Heartworm Society (AHS) clinical classification reflects disease severity in clinical practice, but clinicopathologic changes based on this classification have not been fully characterized. This study aimed to evaluate clinicopathologic variables according to disease severity and to assess their associations with heartworm class in dogs with heartworm disease. Results A total of 35 dogs were retrospectively analyzed and categorized into mild (class 1–2, n = 17) and advanced (class 3–4, n = 18) groups. Compared with the mild group, dogs in the advanced group had significantly higher RDW, BUN, AST, CREA, and thromboelastography reaction time (R), and significantly lower Na⁺, Ca²⁺, and Cl⁻ concentrations. Spearman correlation analysis showed that heartworm class was positively correlated with RDW (ρ = 0.550), BUN (ρ = 0.601), AST (ρ = 0.788), and R (ρ = 0.730), and negatively correlated with Na⁺ (ρ = -0.430), Ca²⁺ (ρ = -0.422), and Cl − (ρ = -0.392) (all P < 0.05). CREA was significantly different between groups but was not significantly correlated with heartworm class. Conclusions Clinicopathologic variables differed according to disease severity in dogs with heartworm disease. These findings suggest that selected variables may reflect increasing clinical severity and provide adjunctive information for clinical assessment. Further studies are needed to validate these associations. Figures Figure 1 Background Canine heartworm disease is a common parasitic infection encountered in clinical practice. Heartworms are transmitted by mosquitoes and are initially located in the subcutaneous tissues and muscles; later, they migrate into the vascular system, where they may cause various complications, including eosinophilic pneumonitis, pulmonary hypertension, and caval syndrome.[ 1 ] Although clinical and cardiac evaluations are typically emphasized in dogs with heartworm disease, this condition may also influence extracardiac organs and clinicopathologic variables, supporting the inclusion of complete blood count, electrolyte, and serum chemistry analyses in the overall assessment. Furthermore, after entering the vascular system, they may compromise perfusion to various tissues and organs and contribute to clinicopathologic abnormalities, as previously reported.[ 2 ] To date, several studies have investigated clinicopathologic changes in dogs with heartworm disease.[ 2 – 6 ] Previous studies have described a range of clinicopathologic abnormalities in dogs with heartworm disease, including changes in red blood cell count, white blood cell count, platelet count, renal variables, liver enzyme activities, and albumin concentration. [ 2 – 4 , 7 , 8 ] However, most previous studies have focused on comparisons between dogs with and without heartworm disease, rather than differences according to disease severity within affected dogs. To date, only one study has investigated such differences, classifying dogs according to microfilarial burden.[ 4 ] Clinical-severity based evaluation may be more relevant to prognosis, monitoring, and clinical decision-making. To the authors’ knowledge, clinicopathologic findings in dogs with heartworm disease have not yet been evaluated according to the American Heartworm Society clinical classification, which reflects clinical severity and disease burden in practice.[ 9 ] Unlike microfilarial burden, the American Heartworm Society clinical classification reflects the overall clinical severity of heartworm disease and is therefore more directly relevant to prognosis and clinical decision-making. Therefore, this study aimed to evaluate clinicopathologic findings according to heartworm class rather than simply comparing dogs based on the presence or absence of heartworm disease. For the clinicopathologic analysis, dogs were categorized according to heartworm class, with classes 1–2 considered the mild heartworm disease group and classes 3–4 considered the advanced heartworm disease group. The aim of the present study was to determine which clinicopathologic variables increase or decrease with increasing clinical severity of heartworm disease and to evaluate their correlations with heartworm class. Methods Study design This retrospective study was based on a review of the medical records of client-owned dogs presented to the Jeonbuk National University Veterinary Teaching Hospital between July 2020 and February 2023. Owner consent for the use of clinical information was obtained at the time of presentation. Inclusion criteria consisted of a positive heartworm antigen test result obtained using a commercial assay kit (SNAP 4Dx; IDEXX Laboratories, Westbrook, ME, USA). Heartworm clinical severity was classified according to the American Heartworm Society guidelines using the information documented in the medical records. The available records variably included history, blood test results, and imaging findings, including thoracic radiography and echocardiography. Dogs were excluded if the available data were insufficient for heartworm class assignment or if concurrent systemic diseases were present. Data collection All clinicopathologic data used in this study were obtained at the time of diagnosis. Because of the retrospective nature of the study, the type and availability of collected data varied among dogs depending on the clinical situation. Therefore, the sample size differed for each variable, and the corresponding number of dogs is reported for each analysis in the results section. Blood samples were collected from either the jugular or cephalic vein, depending on patient condition and venous accessibility. Blood for complete blood count (CBC) was collected into EDTA tubes and analyzed using an automated hematology analyzer (MEK-6450; Nihon Kohden, Tokyo, Japan). Blood for electrolyte analysis was collected into heparin tubes and analyzed using an electrolyte analyzer (i-Smart 300; i-SENS, Seoul, Korea). Blood for serum biochemistry analysis was collected into serum separator tubes and analyzed using a chemistry analyzer (FUJI DRI-CHEM NX700i; FUJIFILM Corporation, Tokyo, Japan). Blood for thromboelastography was collected into citrate tubes and analyzed using a TEG analyzer (TEG 5000; Haemonetics Corporation, Braintree, MA, USA) with kaolin-activated cups. Statistical analysis All statistical analyses were performed using RStudio (version 2024.12.1, PBC, Boston, MA, USA). Normality of continuous variables was assessed using the Shapiro–Wilk test. Depending on the results of the normality test, comparisons between groups were performed using Student’s t -test for parametric data or the Wilcoxon rank-sum test for nonparametric data. Variables in which either group contained fewer than 10 dogs were treated as nonparametric and analyzed using the Wilcoxon rank-sum test. Associations between variables were assessed using Spearman’s rank correlation coefficient. Statistical significance was set at P < 0.05. Results A total of 35 dogs diagnosed with heartworm disease were analyzed, including 15 classified as heartworm class 1, 2 as class 2, 7 as class 3, and 11 as class 4. Mixed-breed dogs were the most common breed across all heartworm classes, accounting for 22/35 dogs overall (class 1, 11/15; class 2, 1/2; class 3, 5/7; and class 4, 5/11). The remaining dogs included Maltese (n = 4), Jindo (n = 3), Poodle (n = 2), and Husky, Spitz, Golden Retriever, Border Collie, and Doberman (n = 1 each). Body weight (BW) differed significantly between the mild and advanced heartworm groups, whereas age did not differ significantly between groups. Sex, age, and BW are summarized in Table 1 . Table 1 Baseline characteristics of dogs according to heartworm class Male (M) Class 1 (n = 15) Class 2 (n = 2) Class 3 (n = 7) Class 4 (n = 11) Total (n = 35) 4 2 3 6 15 Castrated male (CM) 2 0 0 1 3 Female (F) 7 0 4 3 14 Spayed female (SF) 2 0 0 1 3 Age (years) 4.0 [3.0–6.0] 7.5 [6.2–8.8] 6.0 [5.5–7.5] 6.0 [4.0–10.0] 5.0 [3.5–8.5] Body weight (kg) 6.0 [5.0-8.3] 15.4 [11.1–19.7] 21.0 [17.5–31.5] 10.0 [4.9–16.4] 9.1 [5.3–17.6] Data are presented as median [interquartile range]. All variables were expressed according to their distribution. Normally distributed data were presented as mean ± standard deviation, whereas non-normally distributed data were presented as median [interquartile range]. Clinicopathologic variables collected from the medical records included complete blood count (CBC), electrolyte, serum chemistry, and thromboelastography (TEG) parameters. The CBC variables included hematocrit (HCT, %), mean corpuscular volume (MCV, fL), platelet count (PLT, K/µL), red blood cell count (RBC, M/µL), red cell distribution width (RDW, %), and white blood cell count (WBC, K/µL). Electrolyte variables included sodium (Na + , mmol/L), potassium (K + , mmol/L), calcium (Ca 2+ , mmol/L), and chloride (Cl − , mmol/L). Serum chemistry variables included albumin (ALB, g/dL), alkaline phosphatase (ALP, U/L), alanine aminotransferase (ALT, U/L), aspartate aminotransferase (AST, U/L), blood urea nitrogen (BUN, mg/dL), creatinine (CREA, mg/dL), gamma-glutamyl transferase (GGT, U/L), globulin (GLB, g/dL), glucose (GLU, mg/dL), phosphate (PHOS, mg/dL), total bilirubin (T-BIL, mg/dL), total cholesterol (T-CHOL, mg/dL), and total protein (TPRO, g/dL). TEG variables included reaction time (R, min), clot formation time (K, min), alpha angle (α-angle, °), clot strength (G, dyn/cm²), and coagulation index (CI). In the CBC analysis, only RDW differed significantly between groups, being higher in the advanced group (13.35 [12.65–13.90]) than in the mild group (12.70 [11.90–12.90], p = 0.002), whereas HCT (44.36 ± 6.00 vs. 39.75 ± 10.40, p = 0.117), MCV (67.28 ± 4.26 vs. 64.22 ± 6.27, p = 0.100), RBC (6.64 ± 1.11 vs. 6.32 ± 2.03, p = 0.564), PLT (316.00 [239.00-360.00] vs. 178.50 [140.00-367.75], p = 0.156), and WBC (13.90 [12.40–18.20] vs. 18.45 [13.45–25.78], p = 0.080) were not significantly different. Among electrolytes, Na+ (146.64 ± 1.91 vs. 142.00 ± 6.81, p = 0.013), Ca2+ (1.36 ± 0.10 vs. 1.26 ± 0.13, p = 0.029), and Cl- (112.09 ± 4.16 vs. 106.39 ± 6.23, p = 0.007) were significantly lower in the advanced group, whereas K + did not differ significantly (4.05 ± 0.27 vs. 4.16 ± 0.43, p = 0.405). CBC and electrolyte measurements are summarized in Table 2 . In the serum chemistry analysis, CREA (0.69 ± 0.15 vs. 1.06 ± 0.58, p = 0.045), AST (24.00 [23.00-26.50] vs. 69.00 [55.00-331.00], p = 0.016), and BUN (19.10 [16.70-26.05] vs. 39.00 [23.60–80.00], p = 0.002) were significantly higher in the advanced group, while ALB (3.08 ± 0.30 vs. 2.97 ± 0.50, p = 0.506), GLB (3.19 ± 0.47 vs. 2.76 ± 0.66, p = 0.083), TPRO (6.28 ± 0.52 vs. 5.87 ± 1.11, p = 0.250), ALP (130.00 [104.50–154.00] vs. 239.50 [186.25–470.50], p = 0.130), GGT (1.00 [1.00-9.50] vs. 16.00 [4.50–36.50], p = 0.270), GLU (102.00 [94.00-112.50] vs. 102.00 [93.00-118.00], p = 0.622), PHOS (3.70 [3.45–3.75] vs. 5.65 [4.78–7.20], p = 0.071), T-BIL (0.30 [0.25–0.40] vs. 0.35 [0.18–1.55], p = 0.942), and T-CHOL (122.00 [114.50–194.00] vs. 134.00 [118.00-163.25], p = 0.943) were not significantly different. In the TEG analysis, only R was significantly prolonged in the advanced group (3.50 [3.10–5.10]) compared with the mild group (1.20 [1.00-2.20], p = 0.013), whereas K (1.00 [0.90–1.30] vs. 1.80 [1.10–3.20], p = 0.180), α-angle (76.10 [70.00-78.50] vs. 53.60 [51.40–74.80], p = 0.062), MA (73.60 [57.70–77.40] vs. 67.30 [66.60–72.70], p = 0.594), G (13900.00 [6800.00-17100.00] vs. 10300.00 [10000.00-13300.00], p = 0.594), and CI (4.25 [3.38–5.70] vs. 0.40 [0.20–4.60], p = 0.142) were not significantly different. Serum chemistry and TEG measurements are summarized in Table 3 . The distributions of selected clinicopathologic variables that differ significantly between groups are shown in Fig. 1 . Table 2 Comparison of CBC and electrolyte measurements between mild and advanced heartworm disease groups HCT Mild (n) Mild Advanced (n) Advanced p-value 17 44.36 ± 6.00 18 39.75 ± 10.40 0.117 MCV 17 67.28 ± 4.26 18 64.22 ± 6.27 0.100 RBC 17 6.64 ± 1.11 18 6.32 ± 2.03 0.564 PLT 17 316.00 [239.00-360.00] 18 178.50 [140.00-367.75] 0.156 RDW 17 12.70 [11.90–12.90] 18 13.35 [12.65–13.90] 0.002 WBC 17 13.90 [12.40–18.20] 18 18.45 [13.45–25.78] 0.080 Na + 11 146.64 ± 1.91 13 142.00 ± 6.81 0.013 K + 11 4.05 ± 0.27 13 4.16 ± 0.43 0.405 Ca 2+ 11 1.36 ± 0.10 13 1.26 ± 0.13 0.029 Cl − 11 112.09 ± 4.16 13 106.39 ± 6.23 0.007 Data are presented as mean ± SD or median [Q1-Q3]. P-values < 0.05 were considered statistically significant. HCT, hematocrit; MCV, mean corpuscular volume; RBC, red blood cell count; PLT, platelet count; RDW, red cell distribution width; WBC, white blood cell count; Na + , sodium; K + , potassium; Ca 2+ , ionized calcium; Cl − , chloride. Table 3 Comparison of serum chemistry and thromboelastography measurements between mild and advanced heartworm disease groups ALB Mild (n) Mild Advanced (n) Advanced p-value 11 3.08 ± 0.3 13 2.97 ± 0.5 0.506 CREA 11 0.69 ± 0.15 13 1.06 ± 0.58 0.045 GLB 11 3.19 ± 0.47 12 2.76 ± 0.66 0.083 TPRO 11 6.28 ± 0.52 13 5.87 ± 1.11 0.250 ALP 3 130 [104.5–154] 12 239.5 [186.25–470.5] 0.130 AST 3 24 [23-26.5] 9 69 [55–331] 0.016 BUN 11 19.1 [16.7-26.05] 13 39 [23.6–80] 0.002 GGT 3 1 [1-9.5] 10 16 [4.5–36.5] 0.270 GLU 11 102 [94-112.5] 13 102 [93–118] 0.622 PHOS 3 3.7 [3.45–3.75] 12 5.65 [4.78–7.2] 0.071 T-BIL 3 0.3 [0.25–0.4] 12 0.35 [0.18–1.55] 0.942 T-CHOL 3 122 [114.5–194] 12 134 [118-163.25] 0.943 R 9 1.2 [1-2.2] 5 3.5 [3.1–5.1] 0.013 K 9 1 [0.9–1.3] 5 1.8 [1.1–3.2] 0.180 α-angle 9 76.1 [70-78.5] 5 53.6 [51.4–74.8] 0.062 MA 9 73.6 [57.7–77.4] 5 67.3 [66.6–72.7] 0.594 G 9 13900 [6800–17100] 5 10300 [10000–13300] 0.594 CI 8 4.25 [3.38–5.7] 5 0.4 [0.2–4.6] 0.142 Data are presented as mean ± SD or median [Q1-Q3]. P-values < 0.05 were considered statistically significant. ALB, albumin; CREA, creatinine; GLB, globulin; TPRO, total protein; ALP, alkaline phosphatase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; GGT, gamma-glutamyl transferase; GLU, glucose; PHOS, phosphorus; T-BIL, total bilirubin; T-CHOL, total cholesterol; R, reaction time; K, clot formation time; α-angle, alpha angle; MA, maximum amplitude; G, clot strength; CI, coagulation index. Spearman correlation analysis was performed only for variables that showed significant differences between the mild and advanced heartworm disease groups. Among these, HW class showed significant positive correlations with RDW (ρ = 0.550, p < 0.001), BUN (ρ = 0.601, p = 0.002), AST (ρ = 0.788, p = 0.002), and R (ρ = 0.730, p = 0.003). In contrast, HW class showed significant negative correlations with Na (ρ = -0.430, p = 0.020), Ca (ρ = -0.422, p = 0.022), and Cl − (ρ = -0.392, p = 0.035). Although CREA was significantly different between groups, it was not significantly correlated with HW class (ρ = 0.286, p = 0.175). Correlation analysis results are summarized in Table 4 . Table 4 Spearman correlation analysis between HW class and selected clinicopathologic variables RDW n Spearman ρ p-value 35 0.550 < 0.001 BUN 24 0.601 0.002 AST 12 0.788 0.002 Na + 29 -0.430 0.020 Ca 2+ 29 -0.422 0.022 Cl − 29 -0.392 0.035 CREA 24 0.286 0.175 R 14 0.730 0.003 P-values < 0.05 were considered statistically significant. RDW, red cell distribution width; BUN, blood urea nitrogen; AST, aspartate aminotransferase; Na, sodium; Ca, ionized calcium; Cl, chloride; CREA, creatinine; R, reaction time. Discussion In the present study, dogs were stratified according to the clinical severity of heartworm disease, following American Heartworm Society Canine Guidelines, and clinicopathologic variables were compared between groups.[ 9 ] In the comparison of baseline characteristics between the mild group (heartworm class 1–2) and the advanced group (heartworm class 3–4), body weight differed between groups, whereas age did not. This finding may reflect regional characteristics. In Korea, small-breed dogs are more commonly kept indoors and tend to receive closer routine care, whereas larger dogs in rural areas are more often kept outdoors and may receive less consistent management, including preventive care.[ 10 ] Furthermore, because Jeonbuk National University Veterinary Teaching Hospital is located in a rural area, some dogs may have been referred only after clinical signs became evident or after prolonged insufficient care, potentially influencing the characteristics and severity distribution of the study population. In the CBC analysis, RDW was the only variable that differed significantly between the mild and advanced groups (p = 0.002). Several possible explanations may account for the higher RDW observed in the advanced group. First, pulmonary hypertension may be a contributing factor. Previous studies in both humans and dogs have shown that RDW is increased in patients with pulmonary hypertension and may also be associated with prognosis.[ 11 – 16 ] Because the groups were classified according to the heartworm guidelines, many of the clinical features that distinguish the mild and advanced groups are closely related to pulmonary hypertension.[ 9 ] Therefore, differences in the severity of pulmonary hypertension may have contributed to the observed difference in RDW between groups. Second, mechanical stress on red blood cells may have contributed to the increased RDW. Because higher heartworm class may reflect a greater worm burden, increased intravascular parasite load could impose mechanical injury on circulating erythrocytes. This may produce greater anisocytosis, with some erythrocytes becoming damaged while others remain relatively unchanged, thereby increasing RDW. Another possible explanation is regenerative activity. Although HCT did not differ significantly between groups in the present study, it tended to be lower in the advanced group, and previous studies have reported decreased HCT in dogs with heartworm disease.[ 2 , 4 , 5 ] Marked regenerative activity could also increase RDW; however, because regenerative response was not evaluated in this study, this possibility could not be confirmed.[ 17 ] Other than RDW, no significant differences were identified in CBC variables between groups. This differs from some previous reports, possibly because the present study assessed differences according to disease severity within heartworm-infected dogs rather than comparing infected and non-infected populations.[ 2 – 4 ] Limited sample size may also have contributed to the lack of significance in other CBC variables. In the electrolyte analysis, Na + , Ca 2+ , and Cl − were significantly lower in the advanced group than in the mild group (p = 0.013, p = 0.03, and p = 0.007, respectively). These findings are likely to reflect the clinical condition of the dogs at the time of diagnosis rather than mechanisms specific to heartworm disease itself. Because all data were obtained at presentation, dogs in the advanced group were more likely to be clinically unstable or dehydrated. Under these conditions, activation of the renin–angiotensin system may have occurred, with subsequent antidiuretic hormone activation potentially contributing to lower Na + and Cl − concentrations.[ 18 – 20 ] Ionized calcium was also lower in the advanced group, and several possible explanations can be considered for this finding. First, hypocalcemia associated with critical illness may be one possible explanation. Previous studies have reported that hypocalcemia can occur in critically ill patients.[ 21 – 23 ] Because advanced heartworm disease includes cases with caval syndrome, these dogs may be considered critically ill, and this may have contributed to the development of hypocalcemia. Kidney injury may also be a possible contributor. Kidney injury may also have contributed. Renal-related variables, including phosphorus, were higher in the advanced group. In the setting of kidney injury, increased phosphorus may be associated with reduced calcitriol production and disruption of the PTH axis, which could ultimately contribute to decreased ionized calcium concentrations.[ 24 ] Advanced heartworm cases may benefit from electrolyte evaluation at presentation to assess their clinical status. In the chemistry analysis, BUN, AST, and CREA differed between the mild and advanced groups. The increases in BUN and CREA are consistent with findings from previous studies, and one previous report also showed that renal variables decreased after adulticide treatment.[ 2 , 8 ] Taken together, previous reports and the present findings suggest that renal variables may not be increased in the early stage of heartworm disease in dogs, but may rise as disease severity progresses. [ 25 ] One possible mechanism is immune complex–mediated glomerulonephritis, under which proteinuria may become detectable before overt increases in conventional renal variables. In addition, increased renal variables may reflect prerenal azotemia in dogs with caval syndrome. Renal congestion associated with pulmonary hypertension may also contribute, and heartworm disease itself may predispose affected dogs to thromboembolic or ischemic renal injury, further worsening renal function. AST was also higher in the advanced group than in the mild group. Although this increase could reflect hepatic congestion, consideration of the other hepatic variables suggests that hemolysis associated with advanced heartworm disease may be a more likely explanation. In the TEG analysis, only the R value was increased. Although the number of dogs that underwent TEG analysis was small and the statistical power was therefore limited, one possible explanation is that dogs in the advanced group may have experienced a prolonged hypercoagulable state, leading to consumption of coagulation factors and subsequent prolongation of the R time. In the correlation analysis, AST and R were the only variables with a Spearman’s rho greater than 0.7. Although both variables were evaluated in a limited number of dogs, which reduces statistical power, their stronger correlations may reflect the larger numerical differences observed between the mild and advanced groups compared with other significant variables. In other words, when these variables were abnormal, the magnitude of change appeared to be more pronounced, which may have been captured in the correlation analysis. This study has several limitations. First, its retrospective design inherently limited standardization of data collection. Second, the cases were not controlled, and only data obtained at the time of diagnosis were analyzed, which may have introduced variability related to clinical status at presentation. Third, some variables other than the core dataset were available in only a small number of dogs and should therefore be interpreted cautiously. Finally, heartworm class does not necessarily reflect the actual heartworm burden, which should be considered when interpreting the results. Conclusion This study is the first to evaluate clinicopathologic variables in dogs with heartworm disease by stratifying cases into mild and advanced groups based on heartworm class. This approach provides clinically relevant insight into how laboratory findings may vary with disease severity. This study suggests that several clinicopathologic variables, particularly RDW, renal variables, AST, and selected electrolyte abnormalities, may reflect increasing clinical severity in dogs with heartworm disease. However, further studies are warranted to enable more detailed and comprehensive evaluation of these associations. Declarations Ethics approval and consent to participate nformed owner consent for the use of clinical data was obtained at the time of presentation. Consent for publication Not applicable Funding Not applicable Author Contribution MSK drafted the manuscript and performed the statistical analyses. MWS collected the data and contributed to the study concept and design. JCJ contributed to drafting and revising the manuscript. CP supervised the study, provided overall guidance, and approved the final version of the manuscript. All authors read and approved the final manuscript. Acknowledgements Not applicable. Data Availability The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. References Ames MK, Atkins CE. Treatment of dogs with severe heartworm disease. 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Ionized calcium and ionized magnesium disturbances in dogs and cats with septic peritonitis. Front Vet Sci. 2025;12:1550701. https://doi.org/10.3389/fvets.2025.1550701 . Goggs R, Rosa SD, Fletcher DJ. Electrolyte Disturbances Are Associated with Non-Survival in Dogs—A Multivariable Analysis. Front Vet Sci. 2017;4:135. https://doi.org/10.3389/fvets.2017.00135 . Zambarbieri J, Monari E, Dondi F, Moretti P, Giordano A, Scarpa P. Parathyroid Hormone Concentration in Dogs Affected by Acute Kidney Injury Compared with Healthy and Chronic Kidney Disease. Vet Sci. 2025;12:131. https://doi.org/10.3390/vetsci12020131 . Carretón E, Falcón-Cordón Y, Rodon J, Matos JI, Morchón R, Montoya-Alonso JA. Evaluation of serum biomarkers and proteinuria for the early detection of renal damage in dogs with heartworm (Dirofilaria immitis). Vet Parasitol. 2020;283:109144. https://doi.org/10.1016/j.vetpar.2020.109144 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 27 Apr, 2026 Reviews received at journal 24 Apr, 2026 Reviewers agreed at journal 20 Apr, 2026 Reviews received at journal 18 Apr, 2026 Reviewers agreed at journal 18 Apr, 2026 Reviewers invited by journal 18 Apr, 2026 Editor invited by journal 17 Apr, 2026 Editor assigned by journal 15 Apr, 2026 Submission checks completed at journal 15 Apr, 2026 First submitted to journal 14 Apr, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9420988","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":628984064,"identity":"f97dd276-d25d-4eff-aa29-b82c18e4585b","order_by":0,"name":"Minsuk Kim","email":"","orcid":"","institution":"Jeonbuk National University","correspondingAuthor":false,"prefix":"","firstName":"Minsuk","middleName":"","lastName":"Kim","suffix":""},{"id":628984065,"identity":"d42f7e07-61f2-45b8-866e-95af1764d5c9","order_by":1,"name":"Minwoong Seo DVM","email":"","orcid":"","institution":"Jeonbuk National University","correspondingAuthor":false,"prefix":"","firstName":"Minwoong","middleName":"Seo","lastName":"DVM","suffix":""},{"id":628984066,"identity":"c9cd3863-5087-4b20-a83b-58e63af5ee1f","order_by":2,"name":"Jaechun Cho","email":"","orcid":"","institution":"Jeonbuk National University","correspondingAuthor":false,"prefix":"","firstName":"Jaechun","middleName":"","lastName":"Cho","suffix":""},{"id":628984067,"identity":"e06665ed-6e09-479d-ae0b-4c401945e6b7","order_by":3,"name":"Chul Park","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBUlEQVRIiWNgGAWjYDACCQbGA0DKgI3hYOODDzwHoMIHcGoAaQFLG/AzHj5sOIMkLZLNx9KkeeBK8Wjhn91jcLig5p6xwbEzZtI2MnfyDA4wP/zAcOYebkvunDE4PONYsZnBmTPG1jk8z4oNDrAZSzDcKMapxUAix+AwD1uCjcGNM4a3c3gOJ244wGDGwPAhgYCWf0At998YSFuAtbB/I6yFty3BTLLhWJI0A1gLD9CWG7i1SNxIKzg8sy/BmJ8BGMg9PM8SZx7mKZZIOINbC/+M5I2PC74lGLaBovJnz53EvuPtGz98OIZbCwgww1mMPVAufg3IWhh+EFA6CkbBKBgFIxIAAF45YNrqlUlsAAAAAElFTkSuQmCC","orcid":"","institution":"Jeonbuk National University","correspondingAuthor":true,"prefix":"","firstName":"Chul","middleName":"","lastName":"Park","suffix":""}],"badges":[],"createdAt":"2026-04-15 03:08:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9420988/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9420988/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107867498,"identity":"89731df3-05ae-43a7-8acb-bc65d2189517","added_by":"auto","created_at":"2026-04-27 06:57:03","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":229520,"visible":true,"origin":"","legend":"\u003cp\u003eDistributions of selected clinicopathologic variables in mild and advanced heartworm disease groups.\u003cbr\u003e\nJitter plots showing the distributions of selected variables that differed significantly between the mild (heartworm class 1-2) and advanced (heartworm class 3-4) groups. Variables shown include blood urea nitrogen (BUN), red cell distribution width (RDW), chloride (Cl⁻), sodium (Na⁺), aspartate aminotransferase (AST), ionized calcium (Ca²⁺), creatinine (CREA), and reaction time (R). Each dot represents one dog.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9420988/v1/b769e159490aba6c2d287030.jpg"},{"id":107867674,"identity":"7314467e-1e05-479f-a30e-cc6081cff5d4","added_by":"auto","created_at":"2026-04-27 06:57:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":581818,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9420988/v1/d24b564c-81c4-4909-aa70-c4d23257de09.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinicopathologic Variables According to Disease Severity in Dogs with Heartworm Disease","fulltext":[{"header":"Background","content":"\u003cp\u003eCanine heartworm disease is a common parasitic infection encountered in clinical practice. Heartworms are transmitted by mosquitoes and are initially located in the subcutaneous tissues and muscles; later, they migrate into the vascular system, where they may cause various complications, including eosinophilic pneumonitis, pulmonary hypertension, and caval syndrome.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] Although clinical and cardiac evaluations are typically emphasized in dogs with heartworm disease, this condition may also influence extracardiac organs and clinicopathologic variables, supporting the inclusion of complete blood count, electrolyte, and serum chemistry analyses in the overall assessment. Furthermore, after entering the vascular system, they may compromise perfusion to various tissues and organs and contribute to clinicopathologic abnormalities, as previously reported.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] To date, several studies have investigated clinicopathologic changes in dogs with heartworm disease.[\u003cspan additionalcitationids=\"CR3 CR4 CR5\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/p\u003e \u003cp\u003ePrevious studies have described a range of clinicopathologic abnormalities in dogs with heartworm disease, including changes in red blood cell count, white blood cell count, platelet count, renal variables, liver enzyme activities, and albumin concentration. [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] However, most previous studies have focused on comparisons between dogs with and without heartworm disease, rather than differences according to disease severity within affected dogs. To date, only one study has investigated such differences, classifying dogs according to microfilarial burden.[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] Clinical-severity based evaluation may be more relevant to prognosis, monitoring, and clinical decision-making. To the authors\u0026rsquo; knowledge, clinicopathologic findings in dogs with heartworm disease have not yet been evaluated according to the American Heartworm Society clinical classification, which reflects clinical severity and disease burden in practice.[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] Unlike microfilarial burden, the American Heartworm Society clinical classification reflects the overall clinical severity of heartworm disease and is therefore more directly relevant to prognosis and clinical decision-making.\u003c/p\u003e \u003cp\u003e Therefore, this study aimed to evaluate clinicopathologic findings according to heartworm class rather than simply comparing dogs based on the presence or absence of heartworm disease. For the clinicopathologic analysis, dogs were categorized according to heartworm class, with classes 1\u0026ndash;2 considered the mild heartworm disease group and classes 3\u0026ndash;4 considered the advanced heartworm disease group. The aim of the present study was to determine which clinicopathologic variables increase or decrease with increasing clinical severity of heartworm disease and to evaluate their correlations with heartworm class.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003e This retrospective study was based on a review of the medical records of client-owned dogs presented to the Jeonbuk National University Veterinary Teaching Hospital between July 2020 and February 2023. Owner consent for the use of clinical information was obtained at the time of presentation. Inclusion criteria consisted of a positive heartworm antigen test result obtained using a commercial assay kit (SNAP 4Dx; IDEXX Laboratories, Westbrook, ME, USA). Heartworm clinical severity was classified according to the American Heartworm Society guidelines using the information documented in the medical records. The available records variably included history, blood test results, and imaging findings, including thoracic radiography and echocardiography. Dogs were excluded if the available data were insufficient for heartworm class assignment or if concurrent systemic diseases were present.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003eAll clinicopathologic data used in this study were obtained at the time of diagnosis. Because of the retrospective nature of the study, the type and availability of collected data varied among dogs depending on the clinical situation. Therefore, the sample size differed for each variable, and the corresponding number of dogs is reported for each analysis in the results section. Blood samples were collected from either the jugular or cephalic vein, depending on patient condition and venous accessibility. Blood for complete blood count (CBC) was collected into EDTA tubes and analyzed using an automated hematology analyzer (MEK-6450; Nihon Kohden, Tokyo, Japan). Blood for electrolyte analysis was collected into heparin tubes and analyzed using an electrolyte analyzer (i-Smart 300; i-SENS, Seoul, Korea). Blood for serum biochemistry analysis was collected into serum separator tubes and analyzed using a chemistry analyzer (FUJI DRI-CHEM NX700i; FUJIFILM Corporation, Tokyo, Japan). Blood for thromboelastography was collected into citrate tubes and analyzed using a TEG analyzer (TEG 5000; Haemonetics Corporation, Braintree, MA, USA) with kaolin-activated cups.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAll statistical analyses were performed using RStudio (version 2024.12.1, PBC, Boston, MA, USA). Normality of continuous variables was assessed using the Shapiro\u0026ndash;Wilk test. Depending on the results of the normality test, comparisons between groups were performed using Student\u0026rsquo;s \u003cem\u003et\u003c/em\u003e-test for parametric data or the Wilcoxon rank-sum test for nonparametric data. Variables in which either group contained fewer than 10 dogs were treated as nonparametric and analyzed using the Wilcoxon rank-sum test. Associations between variables were assessed using Spearman\u0026rsquo;s rank correlation coefficient. Statistical significance was set at \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 35 dogs diagnosed with heartworm disease were analyzed, including 15 classified as heartworm class 1, 2 as class 2, 7 as class 3, and 11 as class 4. Mixed-breed dogs were the most common breed across all heartworm classes, accounting for 22/35 dogs overall (class 1, 11/15; class 2, 1/2; class 3, 5/7; and class 4, 5/11). The remaining dogs included Maltese (n\u0026thinsp;=\u0026thinsp;4), Jindo (n\u0026thinsp;=\u0026thinsp;3), Poodle (n\u0026thinsp;=\u0026thinsp;2), and Husky, Spitz, Golden Retriever, Border Collie, and Doberman (n\u0026thinsp;=\u0026thinsp;1 each). Body weight (BW) differed significantly between the mild and advanced heartworm groups, whereas age did not differ significantly between groups. Sex, age, and BW are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of dogs according to heartworm class\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMale (M)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eClass 1 (n\u0026thinsp;=\u0026thinsp;15)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eClass 2 (n\u0026thinsp;=\u0026thinsp;2)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eClass 3 (n\u0026thinsp;=\u0026thinsp;7)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eClass 4 (n\u0026thinsp;=\u0026thinsp;11)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;35)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCastrated male (CM)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale (F)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpayed female (SF)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.0 [3.0\u0026ndash;6.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.5 [6.2\u0026ndash;8.8]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.0 [5.5\u0026ndash;7.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.0 [4.0\u0026ndash;10.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5.0 [3.5\u0026ndash;8.5]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody weight (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.0 [5.0-8.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.4 [11.1\u0026ndash;19.7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21.0 [17.5\u0026ndash;31.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10.0 [4.9\u0026ndash;16.4]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9.1 [5.3\u0026ndash;17.6]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eData are presented as median [interquartile range].\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAll variables were expressed according to their distribution. Normally distributed data were presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, whereas non-normally distributed data were presented as median [interquartile range]. Clinicopathologic variables collected from the medical records included complete blood count (CBC), electrolyte, serum chemistry, and thromboelastography (TEG) parameters. The CBC variables included hematocrit (HCT, %), mean corpuscular volume (MCV, fL), platelet count (PLT, K/\u0026micro;L), red blood cell count (RBC, M/\u0026micro;L), red cell distribution width (RDW, %), and white blood cell count (WBC, K/\u0026micro;L). Electrolyte variables included sodium (Na\u003csup\u003e+\u003c/sup\u003e, mmol/L), potassium (K\u003csup\u003e+\u003c/sup\u003e, mmol/L), calcium (Ca\u003csup\u003e2+\u003c/sup\u003e, mmol/L), and chloride (Cl\u003csup\u003e\u0026minus;\u003c/sup\u003e, mmol/L). Serum chemistry variables included albumin (ALB, g/dL), alkaline phosphatase (ALP, U/L), alanine aminotransferase (ALT, U/L), aspartate aminotransferase (AST, U/L), blood urea nitrogen (BUN, mg/dL), creatinine (CREA, mg/dL), gamma-glutamyl transferase (GGT, U/L), globulin (GLB, g/dL), glucose (GLU, mg/dL), phosphate (PHOS, mg/dL), total bilirubin (T-BIL, mg/dL), total cholesterol (T-CHOL, mg/dL), and total protein (TPRO, g/dL). TEG variables included reaction time (R, min), clot formation time (K, min), alpha angle (α-angle, \u0026deg;), clot strength (G, dyn/cm\u0026sup2;), and coagulation index (CI).\u003c/p\u003e \u003cp\u003eIn the CBC analysis, only RDW differed significantly between groups, being higher in the advanced group (13.35 [12.65\u0026ndash;13.90]) than in the mild group (12.70 [11.90\u0026ndash;12.90], p\u0026thinsp;=\u0026thinsp;0.002), whereas HCT (44.36\u0026thinsp;\u0026plusmn;\u0026thinsp;6.00 vs. 39.75\u0026thinsp;\u0026plusmn;\u0026thinsp;10.40, p\u0026thinsp;=\u0026thinsp;0.117), MCV (67.28\u0026thinsp;\u0026plusmn;\u0026thinsp;4.26 vs. 64.22\u0026thinsp;\u0026plusmn;\u0026thinsp;6.27, p\u0026thinsp;=\u0026thinsp;0.100), RBC (6.64\u0026thinsp;\u0026plusmn;\u0026thinsp;1.11 vs. 6.32\u0026thinsp;\u0026plusmn;\u0026thinsp;2.03, p\u0026thinsp;=\u0026thinsp;0.564), PLT (316.00 [239.00-360.00] vs. 178.50 [140.00-367.75], p\u0026thinsp;=\u0026thinsp;0.156), and WBC (13.90 [12.40\u0026ndash;18.20] vs. 18.45 [13.45\u0026ndash;25.78], p\u0026thinsp;=\u0026thinsp;0.080) were not significantly different. Among electrolytes, Na+ (146.64\u0026thinsp;\u0026plusmn;\u0026thinsp;1.91 vs. 142.00\u0026thinsp;\u0026plusmn;\u0026thinsp;6.81, p\u0026thinsp;=\u0026thinsp;0.013), Ca2+ (1.36\u0026thinsp;\u0026plusmn;\u0026thinsp;0.10 vs. 1.26\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13, p\u0026thinsp;=\u0026thinsp;0.029), and Cl- (112.09\u0026thinsp;\u0026plusmn;\u0026thinsp;4.16 vs. 106.39\u0026thinsp;\u0026plusmn;\u0026thinsp;6.23, p\u0026thinsp;=\u0026thinsp;0.007) were significantly lower in the advanced group, whereas K\u0026thinsp;+\u0026thinsp;did not differ significantly (4.05\u0026thinsp;\u0026plusmn;\u0026thinsp;0.27 vs. 4.16\u0026thinsp;\u0026plusmn;\u0026thinsp;0.43, p\u0026thinsp;=\u0026thinsp;0.405). CBC and electrolyte measurements are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. In the serum chemistry analysis, CREA (0.69\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15 vs. 1.06\u0026thinsp;\u0026plusmn;\u0026thinsp;0.58, p\u0026thinsp;=\u0026thinsp;0.045), AST (24.00 [23.00-26.50] vs. 69.00 [55.00-331.00], p\u0026thinsp;=\u0026thinsp;0.016), and BUN (19.10 [16.70-26.05] vs. 39.00 [23.60\u0026ndash;80.00], p\u0026thinsp;=\u0026thinsp;0.002) were significantly higher in the advanced group, while ALB (3.08\u0026thinsp;\u0026plusmn;\u0026thinsp;0.30 vs. 2.97\u0026thinsp;\u0026plusmn;\u0026thinsp;0.50, p\u0026thinsp;=\u0026thinsp;0.506), GLB (3.19\u0026thinsp;\u0026plusmn;\u0026thinsp;0.47 vs. 2.76\u0026thinsp;\u0026plusmn;\u0026thinsp;0.66, p\u0026thinsp;=\u0026thinsp;0.083), TPRO (6.28\u0026thinsp;\u0026plusmn;\u0026thinsp;0.52 vs. 5.87\u0026thinsp;\u0026plusmn;\u0026thinsp;1.11, p\u0026thinsp;=\u0026thinsp;0.250), ALP (130.00 [104.50\u0026ndash;154.00] vs. 239.50 [186.25\u0026ndash;470.50], p\u0026thinsp;=\u0026thinsp;0.130), GGT (1.00 [1.00-9.50] vs. 16.00 [4.50\u0026ndash;36.50], p\u0026thinsp;=\u0026thinsp;0.270), GLU (102.00 [94.00-112.50] vs. 102.00 [93.00-118.00], p\u0026thinsp;=\u0026thinsp;0.622), PHOS (3.70 [3.45\u0026ndash;3.75] vs. 5.65 [4.78\u0026ndash;7.20], p\u0026thinsp;=\u0026thinsp;0.071), T-BIL (0.30 [0.25\u0026ndash;0.40] vs. 0.35 [0.18\u0026ndash;1.55], p\u0026thinsp;=\u0026thinsp;0.942), and T-CHOL (122.00 [114.50\u0026ndash;194.00] vs. 134.00 [118.00-163.25], p\u0026thinsp;=\u0026thinsp;0.943) were not significantly different. In the TEG analysis, only R was significantly prolonged in the advanced group (3.50 [3.10\u0026ndash;5.10]) compared with the mild group (1.20 [1.00-2.20], p\u0026thinsp;=\u0026thinsp;0.013), whereas K (1.00 [0.90\u0026ndash;1.30] vs. 1.80 [1.10\u0026ndash;3.20], p\u0026thinsp;=\u0026thinsp;0.180), α-angle (76.10 [70.00-78.50] vs. 53.60 [51.40\u0026ndash;74.80], p\u0026thinsp;=\u0026thinsp;0.062), MA (73.60 [57.70\u0026ndash;77.40] vs. 67.30 [66.60\u0026ndash;72.70], p\u0026thinsp;=\u0026thinsp;0.594), G (13900.00 [6800.00-17100.00] vs. 10300.00 [10000.00-13300.00], p\u0026thinsp;=\u0026thinsp;0.594), and CI (4.25 [3.38\u0026ndash;5.70] vs. 0.40 [0.20\u0026ndash;4.60], p\u0026thinsp;=\u0026thinsp;0.142) were not significantly different. Serum chemistry and TEG measurements are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. The distributions of selected clinicopathologic variables that differ significantly between groups are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of CBC and electrolyte measurements between mild and advanced heartworm disease groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eHCT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMild (n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMild\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdvanced (n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAdvanced\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44.36\u0026thinsp;\u0026plusmn;\u0026thinsp;6.00\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e39.75\u0026thinsp;\u0026plusmn;\u0026thinsp;10.40\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.117\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMCV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67.28\u0026thinsp;\u0026plusmn;\u0026thinsp;4.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e64.22\u0026thinsp;\u0026plusmn;\u0026thinsp;6.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRBC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.64\u0026thinsp;\u0026plusmn;\u0026thinsp;1.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.32\u0026thinsp;\u0026plusmn;\u0026thinsp;2.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.564\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePLT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e316.00 [239.00-360.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e178.50 [140.00-367.75]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.156\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRDW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.70 [11.90\u0026ndash;12.90]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13.35 [12.65\u0026ndash;13.90]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWBC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.90 [12.40\u0026ndash;18.20]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18.45 [13.45\u0026ndash;25.78]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.080\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNa\u003csup\u003e+\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e146.64\u0026thinsp;\u0026plusmn;\u0026thinsp;1.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e142.00\u0026thinsp;\u0026plusmn;\u0026thinsp;6.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.013\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eK\u003csup\u003e+\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.05\u0026thinsp;\u0026plusmn;\u0026thinsp;0.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.16\u0026thinsp;\u0026plusmn;\u0026thinsp;0.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.405\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCa\u003csup\u003e2+\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.36\u0026thinsp;\u0026plusmn;\u0026thinsp;0.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.26\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.029\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCl\u003csup\u003e\u0026minus;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e112.09\u0026thinsp;\u0026plusmn;\u0026thinsp;4.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e106.39\u0026thinsp;\u0026plusmn;\u0026thinsp;6.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.007\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eData are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or median [Q1-Q3]. P-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eHCT, hematocrit; MCV, mean corpuscular volume; RBC, red blood cell count; PLT, platelet count; RDW, red cell distribution width; WBC, white blood cell count; Na\u003csup\u003e+\u003c/sup\u003e, sodium; K\u003csup\u003e+\u003c/sup\u003e, potassium; Ca\u003csup\u003e2+\u003c/sup\u003e, ionized calcium; Cl\u003csup\u003e\u0026minus;\u003c/sup\u003e, chloride.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of serum chemistry and thromboelastography measurements between mild and advanced heartworm disease groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eALB\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMild (n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMild\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdvanced (n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAdvanced\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.08\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.97\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.506\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCREA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.69\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.06\u0026thinsp;\u0026plusmn;\u0026thinsp;0.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.045\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGLB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.19\u0026thinsp;\u0026plusmn;\u0026thinsp;0.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.76\u0026thinsp;\u0026plusmn;\u0026thinsp;0.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.083\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTPRO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.28\u0026thinsp;\u0026plusmn;\u0026thinsp;0.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.87\u0026thinsp;\u0026plusmn;\u0026thinsp;1.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.250\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e130 [104.5\u0026ndash;154]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e239.5 [186.25\u0026ndash;470.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.130\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 [23-26.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e69 [55\u0026ndash;331]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.016\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBUN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19.1 [16.7-26.05]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e39 [23.6\u0026ndash;80]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGGT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 [1-9.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16 [4.5\u0026ndash;36.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.270\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGLU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e102 [94-112.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e102 [93\u0026ndash;118]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.622\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePHOS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.7 [3.45\u0026ndash;3.75]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.65 [4.78\u0026ndash;7.2]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.071\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT-BIL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.3 [0.25\u0026ndash;0.4]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.35 [0.18\u0026ndash;1.55]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.942\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT-CHOL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e122 [114.5\u0026ndash;194]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e134 [118-163.25]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.943\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.2 [1-2.2]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.5 [3.1\u0026ndash;5.1]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.013\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eK\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 [0.9\u0026ndash;1.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.8 [1.1\u0026ndash;3.2]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.180\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eα-angle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76.1 [70-78.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e53.6 [51.4\u0026ndash;74.8]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.062\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e73.6 [57.7\u0026ndash;77.4]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e67.3 [66.6\u0026ndash;72.7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.594\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13900 [6800\u0026ndash;17100]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10300 [10000\u0026ndash;13300]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.594\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.25 [3.38\u0026ndash;5.7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.4 [0.2\u0026ndash;4.6]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.142\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eData are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or median [Q1-Q3].\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eP-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eALB, albumin; CREA, creatinine; GLB, globulin; TPRO, total protein; ALP, alkaline phosphatase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; GGT, gamma-glutamyl transferase; GLU, glucose; PHOS, phosphorus; T-BIL, total bilirubin; T-CHOL, total cholesterol; R, reaction time; K, clot formation time; α-angle, alpha angle; MA, maximum amplitude; G, clot strength; CI, coagulation index.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSpearman correlation analysis was performed only for variables that showed significant differences between the mild and advanced heartworm disease groups. Among these, HW class showed significant positive correlations with RDW (ρ\u0026thinsp;=\u0026thinsp;0.550, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), BUN (ρ\u0026thinsp;=\u0026thinsp;0.601, p\u0026thinsp;=\u0026thinsp;0.002), AST (ρ\u0026thinsp;=\u0026thinsp;0.788, p\u0026thinsp;=\u0026thinsp;0.002), and R (ρ\u0026thinsp;=\u0026thinsp;0.730, p\u0026thinsp;=\u0026thinsp;0.003). In contrast, HW class showed significant negative correlations with Na (ρ = -0.430, p\u0026thinsp;=\u0026thinsp;0.020), Ca (ρ = -0.422, p\u0026thinsp;=\u0026thinsp;0.022), and Cl\u003csup\u003e\u0026minus;\u003c/sup\u003e (ρ = -0.392, p\u0026thinsp;=\u0026thinsp;0.035). Although CREA was significantly different between groups, it was not significantly correlated with HW class (ρ\u0026thinsp;=\u0026thinsp;0.286, p\u0026thinsp;=\u0026thinsp;0.175). Correlation analysis results are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSpearman correlation analysis between HW class and selected clinicopathologic variables\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRDW\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSpearman ρ\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.550\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBUN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.601\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.788\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNa\u003csup\u003e+\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.430\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.020\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCa\u003csup\u003e2+\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.422\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.022\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCl\u003csup\u003e\u0026minus;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.392\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.035\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCREA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.286\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.175\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.730\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.003\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eP-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eRDW, red cell distribution width; BUN, blood urea nitrogen; AST, aspartate aminotransferase; Na, sodium; Ca, ionized calcium; Cl, chloride; CREA, creatinine; R, reaction time.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e In the present study, dogs were stratified according to the clinical severity of heartworm disease, following American Heartworm Society Canine Guidelines, and clinicopathologic variables were compared between groups.[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] In the comparison of baseline characteristics between the mild group (heartworm class 1\u0026ndash;2) and the advanced group (heartworm class 3\u0026ndash;4), body weight differed between groups, whereas age did not. This finding may reflect regional characteristics. In Korea, small-breed dogs are more commonly kept indoors and tend to receive closer routine care, whereas larger dogs in rural areas are more often kept outdoors and may receive less consistent management, including preventive care.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] Furthermore, because Jeonbuk National University Veterinary Teaching Hospital is located in a rural area, some dogs may have been referred only after clinical signs became evident or after prolonged insufficient care, potentially influencing the characteristics and severity distribution of the study population.\u003c/p\u003e \u003cp\u003eIn the CBC analysis, RDW was the only variable that differed significantly between the mild and advanced groups (p\u0026thinsp;=\u0026thinsp;0.002). Several possible explanations may account for the higher RDW observed in the advanced group. First, pulmonary hypertension may be a contributing factor. Previous studies in both humans and dogs have shown that RDW is increased in patients with pulmonary hypertension and may also be associated with prognosis.[\u003cspan additionalcitationids=\"CR12 CR13 CR14 CR15\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] Because the groups were classified according to the heartworm guidelines, many of the clinical features that distinguish the mild and advanced groups are closely related to pulmonary hypertension.[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] Therefore, differences in the severity of pulmonary hypertension may have contributed to the observed difference in RDW between groups. Second, mechanical stress on red blood cells may have contributed to the increased RDW. Because higher heartworm class may reflect a greater worm burden, increased intravascular parasite load could impose mechanical injury on circulating erythrocytes. This may produce greater anisocytosis, with some erythrocytes becoming damaged while others remain relatively unchanged, thereby increasing RDW. Another possible explanation is regenerative activity. Although HCT did not differ significantly between groups in the present study, it tended to be lower in the advanced group, and previous studies have reported decreased HCT in dogs with heartworm disease.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] Marked regenerative activity could also increase RDW; however, because regenerative response was not evaluated in this study, this possibility could not be confirmed.[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] Other than RDW, no significant differences were identified in CBC variables between groups. This differs from some previous reports, possibly because the present study assessed differences according to disease severity within heartworm-infected dogs rather than comparing infected and non-infected populations.[\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] Limited sample size may also have contributed to the lack of significance in other CBC variables.\u003c/p\u003e \u003cp\u003eIn the electrolyte analysis, Na\u003csup\u003e+\u003c/sup\u003e, Ca\u003csup\u003e2+\u003c/sup\u003e, and Cl\u003csup\u003e\u0026minus;\u003c/sup\u003e were significantly lower in the advanced group than in the mild group (p\u0026thinsp;=\u0026thinsp;0.013, p\u0026thinsp;=\u0026thinsp;0.03, and p\u0026thinsp;=\u0026thinsp;0.007, respectively). These findings are likely to reflect the clinical condition of the dogs at the time of diagnosis rather than mechanisms specific to heartworm disease itself. Because all data were obtained at presentation, dogs in the advanced group were more likely to be clinically unstable or dehydrated. Under these conditions, activation of the renin\u0026ndash;angiotensin system may have occurred, with subsequent antidiuretic hormone activation potentially contributing to lower Na\u003csup\u003e+\u003c/sup\u003e and Cl\u003csup\u003e\u0026minus;\u003c/sup\u003e concentrations.[\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] Ionized calcium was also lower in the advanced group, and several possible explanations can be considered for this finding. First, hypocalcemia associated with critical illness may be one possible explanation. Previous studies have reported that hypocalcemia can occur in critically ill patients.[\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] Because advanced heartworm disease includes cases with caval syndrome, these dogs may be considered critically ill, and this may have contributed to the development of hypocalcemia. Kidney injury may also be a possible contributor. Kidney injury may also have contributed. Renal-related variables, including phosphorus, were higher in the advanced group. In the setting of kidney injury, increased phosphorus may be associated with reduced calcitriol production and disruption of the PTH axis, which could ultimately contribute to decreased ionized calcium concentrations.[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] Advanced heartworm cases may benefit from electrolyte evaluation at presentation to assess their clinical status.\u003c/p\u003e \u003cp\u003eIn the chemistry analysis, BUN, AST, and CREA differed between the mild and advanced groups. The increases in BUN and CREA are consistent with findings from previous studies, and one previous report also showed that renal variables decreased after adulticide treatment.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] Taken together, previous reports and the present findings suggest that renal variables may not be increased in the early stage of heartworm disease in dogs, but may rise as disease severity progresses. [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] One possible mechanism is immune complex\u0026ndash;mediated glomerulonephritis, under which proteinuria may become detectable before overt increases in conventional renal variables. In addition, increased renal variables may reflect prerenal azotemia in dogs with caval syndrome. Renal congestion associated with pulmonary hypertension may also contribute, and heartworm disease itself may predispose affected dogs to thromboembolic or ischemic renal injury, further worsening renal function. AST was also higher in the advanced group than in the mild group. Although this increase could reflect hepatic congestion, consideration of the other hepatic variables suggests that hemolysis associated with advanced heartworm disease may be a more likely explanation. In the TEG analysis, only the R value was increased. Although the number of dogs that underwent TEG analysis was small and the statistical power was therefore limited, one possible explanation is that dogs in the advanced group may have experienced a prolonged hypercoagulable state, leading to consumption of coagulation factors and subsequent prolongation of the R time.\u003c/p\u003e \u003cp\u003eIn the correlation analysis, AST and R were the only variables with a Spearman\u0026rsquo;s rho greater than 0.7. Although both variables were evaluated in a limited number of dogs, which reduces statistical power, their stronger correlations may reflect the larger numerical differences observed between the mild and advanced groups compared with other significant variables. In other words, when these variables were abnormal, the magnitude of change appeared to be more pronounced, which may have been captured in the correlation analysis.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, its retrospective design inherently limited standardization of data collection. Second, the cases were not controlled, and only data obtained at the time of diagnosis were analyzed, which may have introduced variability related to clinical status at presentation. Third, some variables other than the core dataset were available in only a small number of dogs and should therefore be interpreted cautiously. Finally, heartworm class does not necessarily reflect the actual heartworm burden, which should be considered when interpreting the results.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study is the first to evaluate clinicopathologic variables in dogs with heartworm disease by stratifying cases into mild and advanced groups based on heartworm class. This approach provides clinically relevant insight into how laboratory findings may vary with disease severity. This study suggests that several clinicopathologic variables, particularly RDW, renal variables, AST, and selected electrolyte abnormalities, may reflect increasing clinical severity in dogs with heartworm disease. However, further studies are warranted to enable more detailed and comprehensive evaluation of these associations.\u003c/p\u003e"},{"header":"Declarations","content":" \u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003enformed owner consent for the use of clinical data was obtained at the time of presentation.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003eNot applicable\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eNot applicable\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eMSK drafted the manuscript and performed the statistical analyses. MWS collected the data and contributed to the study concept and design. JCJ contributed to drafting and revising the manuscript. CP supervised the study, provided overall guidance, and approved the final version of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAmes MK, Atkins CE. Treatment of dogs with severe heartworm disease. Vet Parasitol. 2020;283:109131. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.vetpar.2020.109131\u003c/span\u003e\u003cspan address=\"10.1016/j.vetpar.2020.109131\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNiwetpathomwat A, Kaewthamasorn M, Tiawsirisup S, Techangamsuwan S, Suvarnvibhaja S. 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Vet Parasitol. 2020;283:109144. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.vetpar.2020.109144\u003c/span\u003e\u003cspan address=\"10.1016/j.vetpar.2020.109144\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-veterinary-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [BMC Veterinary Research](http://bmcvetres.biomedcentral.com/)","snPcode":"12917","submissionUrl":"https://submission.nature.com/new-submission/12917/3?","title":"BMC Veterinary Research","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-9420988/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9420988/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eCanine heartworm disease is associated with various clinicopathologic abnormalities; however, most previous studies have focused on comparisons between infected and non-infected dogs rather than differences according to disease severity. The American Heartworm Society (AHS) clinical classification reflects disease severity in clinical practice, but clinicopathologic changes based on this classification have not been fully characterized. This study aimed to evaluate clinicopathologic variables according to disease severity and to assess their associations with heartworm class in dogs with heartworm disease.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 35 dogs were retrospectively analyzed and categorized into mild (class 1\u0026ndash;2, n\u0026thinsp;=\u0026thinsp;17) and advanced (class 3\u0026ndash;4, n\u0026thinsp;=\u0026thinsp;18) groups. Compared with the mild group, dogs in the advanced group had significantly higher RDW, BUN, AST, CREA, and thromboelastography reaction time (R), and significantly lower Na⁺, Ca\u0026sup2;⁺, and Cl⁻ concentrations. Spearman correlation analysis showed that heartworm class was positively correlated with RDW (ρ\u0026thinsp;=\u0026thinsp;0.550), BUN (ρ\u0026thinsp;=\u0026thinsp;0.601), AST (ρ\u0026thinsp;=\u0026thinsp;0.788), and R (ρ\u0026thinsp;=\u0026thinsp;0.730), and negatively correlated with Na⁺ (ρ = -0.430), Ca\u0026sup2;⁺ (ρ = -0.422), and Cl\u003csup\u003e\u0026minus;\u003c/sup\u003e (ρ = -0.392) (all P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). CREA was significantly different between groups but was not significantly correlated with heartworm class.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003e Clinicopathologic variables differed according to disease severity in dogs with heartworm disease. These findings suggest that selected variables may reflect increasing clinical severity and provide adjunctive information for clinical assessment. Further studies are needed to validate these associations.\u003c/p\u003e","manuscriptTitle":"Clinicopathologic Variables According to Disease Severity in Dogs with Heartworm Disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-27 06:54:44","doi":"10.21203/rs.3.rs-9420988/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-27T04:55:11+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-24T11:53:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"270500917775523485690080934123845024639","date":"2026-04-20T11:40:42+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-18T14:59:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"152669294636297859386955537870956260784","date":"2026-04-18T13:32:47+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-18T13:06:42+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-04-17T07:55:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-16T03:33:45+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-16T03:33:02+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Veterinary Research","date":"2026-04-15T02:50:51+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-veterinary-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [BMC Veterinary Research](http://bmcvetres.biomedcentral.com/)","snPcode":"12917","submissionUrl":"https://submission.nature.com/new-submission/12917/3?","title":"BMC Veterinary Research","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5767e55a-167b-4e48-adbd-16e69de3eb4d","owner":[],"postedDate":"April 27th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-04T09:25:03+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-27 06:54:44","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9420988","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9420988","identity":"rs-9420988","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}