Abstract

Metabolism dysfunction including hyperglycemia and hyperlipidemia in diabetes mellitus case are crucial factors in developing vascular diseases, platelet activation and hypercoagutable state. Increasing coagulation factors and hypercoagulability were reported in diabetes mellitus patients which due to increase of coagulation factors that resulted in prothrombotic state and extension of thrombolytic lysis in diabetes patients. Thus, this works amid to exam the association between coagulation index's with hyperglycemia and dyslipidemia in diabetes mellitus patients. FBG, HbA1c, PT, APTT, INR, D-dimer, platelets and MPV values were showed significant increase in diabetic's patients compared with their levels of healthy. Lipids profiles, AIP and TC/HDL ratio were found significantly higher in patients they were suffering from diabetic. Person correlation analysis presented a strong association between prothrombin time and (FBG, PLT, TC and LDL). MPV and AIP were a moderate positive correlate with prothrombin time. Prothrombin time was a weak correlated with HbA1c, TG, HDL and TC/HDL ratio. However, D-dimer and VLDL were negatively associated with prothrombin time. APTT value presented a strong positive association with FBG and LDL, a moderate positive relationship with AIP and TC/HLD. There was a weak positive association between APTT value   HbA1c, D-dimer, PLT, MPV, TC and HDL. However, TG and VLDL were negatively correlated with APTT value.

Highlights:

1. Metabolic Dysfunction: Hyperglycemia and dyslipidemia increase coagulation factors in diabetes.
2. Key Findings: Significant rise in PT, APTT, D-dimer, lipid profiles, and MPV.
3. Correlations: Prothrombin time associates strongly with FBG, PLT, TC, and LDL.

Keywords: diabetes, Prothrombin time, activated partial thromboplastin, atherogenic index of plasma, coagulation factors

Introduction

Diabetes mellitus is a metabolic syndrome described through elevated blood sugar levels (hyperglycemia), resulting from decreased insulin secretion or dysfunction of insulin receptor action [11], [20], [24]. Diabetes is correlated with vascular damage, metabolic disorders, and thrombotic complications [11], [19], [23]. Complications of diabetes can lead to several pathophysiological conditions, including cardiovascular diseases, nephropathy, neuropathy, retinopathy [18], inflammation, dyslipidemia [25], [35], thrombophilia, oxidative stress, endothelial dysfunction, atherogenic, and procoagulant states [11], [55], [67]. Metabolic dysfunction, including hyperglycemia and hyperlipidemia in diabetes mellitus, are crucial factors in developing atherosclerosis, vascular diseases, platelet activation, and hypercoagulable states [11], [14], [58], [71]. Increased coagulation factors and hypercoagulability have been reported in diabetes mellitus patients [11], [44], resulting from elevated coagulation factors like factor VII, proinflammatory cytokines, and fibrinogen, which contribute to a prothrombotic state [11], [16], [23]. Hyperglycemia leads to glycation of hemoglobin, fibrinogen, clotting proteins, and prothrombin, causing dysfunction in the coagulation pathway [11], [60], [75]. Insulin resistance, lipotoxicity, and high glucose levels in diabetes mellitus primarily affect vessel walls, leading to increased inflammation, enhanced platelet aggregation, endothelial dysfunction, and altered coagulation factors [13], [76]. These changes contribute to microvascular complications, which increase the risk of thrombosis and vascular diseases in diabetes [5], [54].

Diabetic patients suffer from lipid disorders, which increase the risk of atherosclerosis and heart problems [36], [37], [70]. Studies have assumed a hypercoagulable state is associated with hypercholesterolemia [77]. Poredos and Jezovnik reported that endothelial damage and prothrombotic states are correlated with blood lipids, which impact coagulation factors, platelet activity, and vascular endothelium, further modulating the function and expression of thrombolytic and fibrinolytic factors [62]. Studies found that increasing blood lipid concentrations is associated with upregulation of coagulation factors [38]. Furthermore, patients suffering from insulin resistance have high visceral lipids [73], which have been shown to be related to increased activity of FVIII, FIX, and FVII [31]. Different studies have observed coagulation abnormalities related to hyperglycemia and dyslipidemia. Therefore, the current work aimed to examine the association between coagulation indexes with hyperglycemia and dyslipidemia in diabetes mellitus patients.

Methods

Study design: 60 blood specimens were taken from diabetes mellitus patients aged 40-65 year. Another 56 samples were collected from healthy people (non-diabetes), they used as a control group aged 40-65 year. These samples were collected from people who frequent the health center specialized in regulating and treating diabetes at Al-Diwaniyah Teaching Hospital/ Iraq. Current work was done during a period from 15 November 2022 to 20 May 2023. Blood was drawn from a vein after overnight ‎fasting, and placed in special test tubes. Each sample was divided into three tubes; the first tube was free of anticoagulant to obtain blood serum. To conduct a blood sugar test, as well as to measure fat concentration. The second tube contained the anticoagulant sodium citrate at a concentration in order to conduct some blood clotting analysis coagulation markers. The third tube also contained the anticoagulant, which is EDTA, to conduct platelets analysis.

Laboratory analysis: Blood glucose analysis was detected through an available kit (Spinreact, Spain). An available kit was used to measure HbA1c level using by Roche Diagnostics Cobas analyzer. Lipids profile; cholesterol (TC), triglycerides (TG), lipoproteins including (HDL-C, LDL-C) estimated using enzymatic colorimetric technique by special reagents with Roche Modular P800 Chemistry Analyzer. VLDL-C was determined by (triglyceride/5). The formula log (TG/HDL-C) ratio was used to calculate atherogenic index of plasma (AIP). TC/HDL ratio was calculated by divided TC value on HDL value. Coagulation indicates (PT), APTT and D-dimer were estimated by standard kits and measurement using automated analyzer ACL TOP 700. International normalized ratio (INR) was estimated by the following formula: PT (patient)/PT (healthy). Hematology parameters (platelet PLT and mean platelet volume MPV) were achieved using automatic cell counter (Thermo Fisher Scientific).

Statistics analysis: Comparisons were drawn between patients and healthy groups using an unpaired t-test by Graph Pad Prism (USA). The data were described statistically (Mean± Standard error). Correlation coefficient test was calculated between coagulation parameters and physiological indicators in diabetes patients group.

Result and Discussion

Result

The diabetes patients showed significantly increasing (p≤0.05) in fasting blood glucose level (227.4±27.11) comparison with control subject (105.8±5.20). A significant greater HbA1c value was showed in patients (8.65±1.50, p≤0.001) compared to the healthy subject (5.32±1.17). Cholesterol level (TC) was increased significantly in diabetic patients (215.2±13.56, p≤0.05) in contrast to control samples (128.7±2.72). Triglyceride concentration (TG) significantly increased in patients (160.3±20.17, p≤0.05) compared with healthy (106.1±9.85). While, HDL level was significantly decreased (23.55±0.27, p≤0.01) in patients compared with level of un-patients samples (27.68±1.69). Level of LDL significantly elevated in diabetic patients (126.0±6.12, p≤0.05) compared with healthy level (99.23±9.56). VLDL level was highly significant increase in patients (31.04±0.75, p≤0.01) comparing with level control (24.38±1.52). A significant differ was obtained (p≤0.05) between diabetic and healthy group in AIP value (0.78±0.05 and 0.59±0.04, respectively). TC/HDL ratio was significantly higher in patient group (9.37±0.67, p≤0.05) compared with control (5.10±0.63), Table (1).

PT was significantly prolonged in diabetes mellitus patients (16.64±0.43, p≤0.05) when paralleled to group of the control (14.28±0.21). APTT value in patients was higher (37.03±3.17, p≤0.05) than those in control group (31.23±4.56). INR values were significantly differ (p≤0.05) between diabetic and non-diabetic groups (1.98±0.07 and 1.04±0.05, respectively), Table (2). D-dimer value significantly increased with diabetic patients (416.6±45.31, p≤0.001) compared with the healthy group (209.4±13.41). Platelets value presented higher level in patients group (265.9±14.14, p≤0.05) than non-patients group (220.9±13.17). MPV exhibited no significant differences (p≥0.05) between patients group (9.40±0.23) and control group (8.79±0.85), Table (2).

A strong positive association was detected between prothrombin time and FBG in patients of diabetes (r=0.6232, p-0.048). HbA1c had a weak positive relationship with prothrombin time in diabetics group (r = 0.2486, p-0.412). However, D-dimer was noted a weak negative association with prothrombin time (r = - 0.2256, p-0.530). A strong positive association was found between prothrombin time and PLT (r = 0.6338, p-0.015). MPV was observed a moderate positive related with PT (r = 0.5061, p-0.033) in patients of diabetes, Table (1) and Figure (1A). APTT value presented a strong positive association with FBG (r = 0.6233, p-0.039). APTT was a weak positive association with HbA1c (r = 0.1404, p-0.324), D-dimer (r = 0.2896, p-0.036), PLT (r = 0.2518, p-0.055) and MPV (r = 0.2102, p-0.049) in diabetic patients, Table (3) and Figure (1B).

Figure 1.Plot scatter showed the correlation coefficient between PT (sec) and physiological parameters (A), APTT (sec) and physiological parameters (B) of diabetic patients.

Correlation between coagulation indicators and lipids profiles

Prothrombin time had a strong positive association with cholesterol and LDL levels of diabetic patients (r = 0.6523, p-0.032 and r = 0.6762, p-0.039). A weak positive relationship TG, HDL with prothrombin time in patients (r = 0.1799, p-0.538 and r = 0.2415, p-0.040). However, VLDL had a moderate negative association with prothrombin time (r = -0.4999, p-0.050). Data were appeared a moderate positive correlation prothrombin time value with AIP in diabetics patients (r = 0.5519, p- 0.048). A weak positive association was showed between prothrombin and TC/HDL ratio (r = 0.1467, p-0.616), Table (4) and Figure (2A)

A weak positive correlation was presented in table (4) between cholesterol, HDL and APTT value (r = 0.1235, p-0.661 and r = 3791, p-0.201). Conversely, APTT negatively associated with TG (r = - 0.3469, p-0.020). A strong positive association between APTT value and LDL in diabetic (r = 0.7961, p-0.007). However, VLDL and AIP presented a moderate negative association with APTT value (r = -0.4999, p-0.011 and r = - 0.5519, p-0.313). TC/HDL ratio presented a weak positive association with APTT value in patients group (r = 0.551, p-0.311), Table (4) and Figure (2B).

Figure 2.Plot scatter showed the correlation coefficient between PT (sec) and lipid profiles (A), APTT (sec) and lipids profiles of diabetic patients.

Discussion

Our findings observed a significant increase in lipid profile levels, while HDL levels were reduced in diabetic patients. Current data agree with other research's findings [33], [41]. They reported that lipid levels are related to cardiovascular diseases and diabetes mellitus. People suffering from diabetes often have high levels of TG, LDL, and low levels of HDL [64]. Diabetes plays a role in developing dyslipidemia by evaluating fatty acid release from insulin-resistant fat cells [43]. Insulin resistance has been associated with irregular lipid dysfunction in diabetes because resistance to insulin leads to increased fatty acid release, decreased fatty acid uptake by muscle, and elevated hepatic fatty acid production by the liver [8]. Free fatty acids could enhance triglycerides, which in turn prompt the release of apolipoprotein B and VLDL, increasing the risk of cardiovascular syndromes [43], [69]. High levels of triglycerides in patients with diabetes could stimulate VLDL levels, decrease HDL levels, and contribute to the high prevalence of cardiovascular diseases [43]. Hyperglycemia could negatively affect lipoproteins, including VLDL and LDL, by raising oxidation and glycosylation, reducing vascular compliance, and promoting the development of atherosclerosis [27].

APTT, PT, and INR values of diabetic samples were significantly prolonged compared with healthy samples. These findings agree with results from other studies [57], [72]. Diabetic patients present symptoms of hypofibrinolysis and hypercoagulability. The increased values of PT, APTT, and INR could be due to increased endothelial wall impact, leading to sustained production of vasoactive substances that interfere with coagulation cascades [80]. Some studies found that coagulation indicators do not alter among diabetic patients [26], [50]. However, other studies claimed lower coagulation values in diabetic patients [6], [34]. These alterations in coagulation states are likely due to circulatory disturbances in patients, characterized by changes in coagulopathy, hemorheologic factors, altered endothelial metabolism, platelet activity, and fibrinolytic aberrations [46], [49]. Coagulation factors, including XII, VII, IX, I, and kallikrein, are elevated in diabetes mellitus, likely due to an imbalance of clotting factors with the endothelial surface [7]. Prolonged PT and APTT in diabetic cases imply that the intrinsic and extrinsic pathways are altered, potentially leading to extreme bleeding in case of injuries [12], [53]. Prolonged PT may result from a deficiency of clotting factor VII and cofactors I, II, and X or due to anticoagulant therapy [56]. PT and APTT are used to determine the extrinsic and intrinsic pathways of coagulation and identify bleeding or clotting tendencies. The significant prolongation of PT and APTT could result from hypercoagulable susceptibility due to an alteration of the thrombohemorrhagic balance favoring thrombosis in diabetic patients [18]. Increased PT could refer to FVII deficiency, while increased APTT suggests FXI or FVII decrease. The elongation of APTT and PT proposes deficiencies in FX, FII, fibrinogen, or FV aberrations. Increased APTT may occur due to liver dysfunction, as most coagulation factors are produced in the liver. Elevated PT and APTT values are associated with irregular coagulation mechanisms, suggesting a tendency for cardiovascular dysfunctions [40], [72]. Furthermore, increased values of these factors might be due to fibrin clot formation via inhibitors such as D-dimer and fragments of fibrinogen in diabetic subjects [72]. In diabetics, hyperglycemia is considered a major factor in promoting hypercoagulability, involving molecular mechanisms such as non-enzymatic glycation, increased oxidative stress, and decreased heparin sulfate [3].

D-dimer increased in the diabetes group compared with healthy controls. These data are consistent with previous investigations [10], [59]. The high D-dimer value could be due to oxidative stress and hyperglycemia over the period of diabetes mellitus [52]. The higher D-dimer value is a consequence of fibrin clot formation and its breakdown. Platelet count was elevated in patient specimens compared to the healthy group, in agreement with previous studies [81]. In diabetes, platelet hyperactivity occurs via endothelial vascular dysfunction due to inflammation, promoting vasoconstriction and increased production of cytokines and adhesion molecules that mediate platelet activation and adhesion to the endothelium [48]. Soares et al. found significant platelet values due to endothelial and platelet hypersensitivity, which could implicate endothelial dysfunction and vascular disorders [66]. This study observed an increase in MPV values in diabetic patients, consistent with Ragab et al., who documented an increase in MPV in diabetic patients [63]. MPV represents an indicator of thrombosis triggering and function. Larger platelets have increased thrombotic potential [21], [28].

Current work found that PT positively correlated with hyperglycemia index (FBG, HbA1c), PLT, and MPV, while PT negatively correlated with D-dimer. In addition, APTT has a positive relationship with all the criteria mentioned above. This data aligns with previous studies [18], [16], which noted a positive association between APTT, PT, and FBG in diabetics. Gopalakrishnan et al. reported a positive linear association between HbA1c and clotting markers (PT, APTT) [22]. Other studies found a negative correlation between coagulation indices and FBG among diabetic patients [16], [78]. Alao et al. showed no correlation between PT, APTT, and HbA1c [2]. This could result from hyperglycemia affecting hemostasis through chronic glucose exposure, leading to hemoglobin glycation and reduced production of coagulation factors [15], [65]. Increased glucose levels lead to insufficient activation of the intrinsic and extrinsic coagulation pathways [45]. Grant and Lemkes et al. indicated that hyperglycemia due to insulin resistance contributes to a thrombotic state by inducing fibrinolysis deficiency and activating coagulation [23], [42].

PT showed a positive correlation with lipid profiles, including TC, TG, HDL, LDL, AIP, and TC/HDL, while negatively associating with VLDL. Additionally, a positive correlation was observed between APTT and lipid profiles (TC, HDL, LDL, and TC/HDL), while APTT negatively correlated with TG, VLDL, and AIP. Morishita et al. demonstrated a strong association between coagulation factor levels and lipids, particularly triglyceride-rich lipoproteins [51]. Hiraga et al. found coagulation factors such as factor VII correlated with triglycerides [30]. Yang et al. reported that elevated TG increases blood viscosity, enhancing coagulation factor VII production, which is a risk factor for venous thrombosis [79]. TG levels have been shown to correlate with PAI-1 and factor VII levels [79]. High TG levels, reduced HDL, glucose intolerance, obesity, increased factor VII, decreased fibrinolytic capacity, and hyperinsulinemia are interconnected [74]. Alzghoul et al. highlighted the impact of hyperlipidemia on coagulation states [4]. Hyperlipidemia can contribute to coagulation abnormalities [17]. Lipid metabolism dysfunction is a primary cause of abnormal glucose levels, endothelial damage, and activation of blood coagulation pathways, leading to increased fibrinogen levels and a hypercoagulable state [1]. Endothelial damage, phospholipids from damaged tissue, and hemolysis can lead to intravascular coagulation [9], [32], [47].

Conclusion

In conclusion, this study underscores the significant alterations in lipid profiles, coagulation parameters, and platelet activity in diabetic patients, highlighting their elevated risk for cardiovascular diseases and thrombotic events. The findings reveal a pronounced increase in triglycerides, LDL, and platelet count, alongside a decrease in HDL, which are in line with previous research. Furthermore, prolonged PT, APTT, and INR values suggest an altered coagulation cascade, likely due to endothelial dysfunction and insulin resistance. These changes are associated with hyperglycemia and dyslipidemia, reinforcing the need for early monitoring and intervention to manage coagulation and lipid abnormalities in diabetic individuals. The positive correlations between coagulation markers and lipid profiles indicate the intertwined relationship between metabolic disturbances and thrombotic risk, suggesting that targeting lipid metabolism may help reduce complications. Further research is needed to explore the underlying molecular mechanisms of these associations and evaluate potential therapeutic interventions, including those that address both coagulation and lipid imbalances in diabetes management.

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