Prevalence and relationship of coagulopathy with glycemic control and complications in type 2 diabetes mellitus patients Cameroon

INTRODUCTION

Diabetes mellitus (DM) is a major global health problem, with type 2 DM (T2DM) accounting for 90% of all cases worldwide.^[1] An increase of as high as 146% is predicted to occur in developing countries by 2050, while the increase would only be 47% in developed countries.^[2] Patients with DM are at a high risk of atherothrombotic events, with 80% of DM patients dying due to a thrombotic cause and 75% being due to cardiovascular complications.^[3] D-dimer, prothrombin time (PT), activated partial thromboplastin time (APTT), and fibrinogen are measured in patients with a suspected abnormal coagulation.^[4] Hypercoagulability in T2DM patients is caused by a combination of lifestyle and other factors, such as diet and poor glycemic control.^[5] Currently in Cameroon, hemostatic profile tests are not part of routine investigations exploited in the management of T2DM patients. Furthermore, diabetic patients who suffer from cardiovascular or cerebrovascular thrombotic events often have a poor prognosis.^[6] The early identification of a prothrombotic state in diabetes is crucial as it allows for proactive interventions which will lower the risk of cardiovascular events, stroke and vascular complications in diabetics.

Studies in other areas have reported abnormalities of hemostatic profiles in diabetic patients. A comparative cross-sectional study in Southwest Ethiopia reported a 58.8% overall hemostatic abnormality in diabetic individuals with noted abnormal low APTT, thrombocytopenia and higher fibrinogen levels.^[7] Furthermore, a similar study in a metabolic clinic in Nigeria reported significantly lower levels of protein C and antithrombin and significantly higher levels of D-dimer and fibrinogen in diabetic patients.^[8] Significantly higher levels of PT correlated with poor glycemic control have been reported in diabetic patients.^[9-11] Similar studies have not been reported in Cameroon diabetic centres.

This study therefore sought to evaluate haemostatic profile (D-dimer, PT, APTT and fibrinogen), associated risk factors and their relationship with diabetic complications.

MATERIAL AND METHODS

This cross-sectional analytical study was conducted in the diabetic clinic of the Laquintinie Hospital, Douala, after approval from the Institutional Review Board of the Faculty of Health Sciences, University of Buea (2024/2304–01/ UB/SG/IRB/FHS). The study was carried out over a period of 4 months (February–May, 2024). The inclusion criteria were T2DM patients at the diabetic clinic of the Laquintinie Hospital, Douala, who consented to be part of the study. It included 23 diabetic patients without complications and 73 patients with at least one microvascular complication such as retinopathy, nephropathy or neuropathy based on visual acuity test, renal function tests and nerve conduction studies, respectively. Diabetic retinopathy was diagnosed if the patient’s visual acuity test was ≤0.02, the estimated glomerular filtration rate <60, or the nerve conduction test value ≤40 m/s. The socio-demographic (age, sex, marital status, level of education, and religion), anthropometric profile (weight, height, waist circumference, waist-to-hip ratio) and clinical data, including duration of diabetes, duration of treatment, family history, alcohol consumption, smoking, hypertension, physical activity and associated complications or comorbidities, were recorded. Body mass index (BMI) was calculated using the formula body weight (kg) divided by the square of the height (m). The waist-to-hip ratio was calculated using the formula waist circumference (cm) divided by the hip circumference (cm). The exclusion criteria considered were patients with a history of known inherited coagulation disorders, cancer, hyperthyroidism, history of venous thromboembolism, pregnancy, recent surgery and patients who were on anticoagulant treatment with either coumarin derivatives or heparins at the time of admission. Venous blood samples (10 mL) were collected in two tubes. Ethylenediamine-tetra-acetic acid test tubes used to measure HbA1c by high-performance liquid chromatography and D-dimer by a turbidimetric immunofluorescence assay with the Finecare analyzer (Naksh Life Sciences, Burari, New Delhi); citrated blood was used for APTT, PT and fibrinogen measurement. Full blood count was performed using an automated hematological analyzer (Horiba, Horiba Abx Sas, France), PT, APTT, and fibrinogen were measured with a HORIBA G400 analyzer (Horiba Abx Sas, France). The international normalized ratio (INR) was calculated as a ratio of the patient’s PT to a control PT standardized for the potency of the thromboplastin reagent developed by the World Health Organization.

RESULTS

Diabetic complications and risk factors

Overall, 73 out of the 96 participants had complications, giving a frequency of diabetic complications of 76% (95% confidence interval [CI]: 66.8–83.5). Retinopathy was the most frequent complication, 49 (67.7%). Furthermore, 6 (8.3%) had nephropathy, 10 (14.6%) had cardiovascular disease, specifically stroke, similarly, 10 (14.6%) had peripheral vascular disease, specifically diabetic foot, and 38 (53.1%) had neuropathy [Figure 1].

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Figure 1: Frequency of diabetic complications amongst diabetics at the laquintinie hospital Douala. CVD: Cardiovascular diseases, PVD: Peripheral vascular diseases.

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Age group was a significant risk factor for diabetic complications. Participants aged 30–46 years had significantly lower odds of having complications compared to those aged 64–80 years (Crude odds ratio [cOR]: 0.05; 95% CI: 0.009– 0.26; p < 0.001). Furthermore, BMI was a significant risk factor for diabetic complications. Participants with a BMI of 25–29.9 kg/m² had significantly lower odds of having complications compared to those with a BMI of ≥30 kg/m² (cOR: 0.13; 95% CI: 0.04–0.52; p = 0.004).

Association between coagulopathy and diabetic status

The overall prevalence of coagulopathy among all study participants was 98.96% (95/96). A total of 65.63% (63/96) showed one of the three coagulopathies, 1.04% (01/96) showed two and 32.29% (31/96) showed all three coagulopathies [Figure 2].

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Figure 2: Distribution of coagulopathy among study participants. (1) High prothrombin time; (2) High prothrombin time and activated partial thromboplastin time and (3) High prothrombin time, activated partial thromboplastin time and thrombocytopenia.

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Among all the study participants, 33.3% (32/96) showed shortened APTT and thrombocytopenia was observed in 28.13% (27/96) of them. In addition, the prevalence of prolonged PT was 98.96% (95/96) while the prevalence of the prolonged APTT was 5.2% (05/96) [Table 2].

Table 2: Comparison of coagulopathy between diabetics with complications and those without complications

Coagulopathy	DM with complications n=73 n (%)	DM without complications n=23 n (%)	χ2-value	p-value
Thrombocytopenia	19 (19.8)	08 (08.3)	0.604	0.44
Abnormal high PT (s)	72 (75.0)	23 (23.1)	0.318	0.57
Abnormal high APTT (s)	03 (3.1)	02 (2.1)	0.502	0.48
Shortening of APTT	26 (27.1)	06 (06.3)	0.520	0.47
Increased Platelets	01 (1.0)	0 (0.0)	0.282	0.60
Hyperfibrinogenemia	30 (31.3)	08 (08.3)	0.291	0.59

A p<0.05 was considered statistically significant. Thrombocytopenia: Platelet count <150×109/µL, increased platelets: Platelet count >400×109/µL; abnormal high PT: Prothrombin time >25 s; APTT: 30–40 s; Hyperfibrinogenemia: Fibrinogen levels >400 mg/dL. DM: Diabetes mellitus

There was no significant difference in the mean hemostatic parameters of study participants based on glycemic control status [Table 3].

Table 3: Comparison of hemostatic profile between diabetics with good control and poor glycemic control.

Hemostatic parameter	HbA1c category		p-value
	HbA1c >7% n=65 (mean±SD)	HbA1c ≤7% n=31 (mean±SD)
PT (s)	96.79±22.39		95.10±20.38		0.723
APTT (s)	31.62±6.28		31.74±4.77		0.923
INR	20.75±6.63		20.12±6.08		0.655
Platelets (µL)	196.45±77.64		204.71±68.93		0.615
Fibrinogen (mg/dL)	355.29±86.82		344.90±96.62		0.598

A p<0.05 was considered statistically significant. PT: Prothrombin time (ref: 12–25 s); APTT: Activated partial thromboplastin time (range: 30–40 s), INR: International normalized ratio (range: 0.9–1) and Fibrinogen: 200–400 mg/dL

There was no significant difference in the mean hemostatic parameters of diabetic patients with complications and those without complications [Table 4].

Table 4: Comparison of hemostatic profile between diabetics with complications and those without complications

Hemostatic parameter		Diabetics		p-value
		Complication n=73 (mean±SD)	No complication n=23 (mean±SD)
PT (s)	14.4±3.4		14.4±2.5	0.98
APTT (s)	31.5±6.3		32.1±3.9	0.69
INR	1.2±0.8		1.1±0.2	0.53
D-dimer (mg/dL)	2.6±2.8		2.5±2.7	0.88
Platelets (µL)	205.4±74.3		179.2±73.8	0.17
Fibrinogen (mg/dL)	352.4±92.2		350.6±83.2	1.8

A p<0.05 was considered statistically significant. PT: Prothrombin time (range: 12–25 s); APTT: Activated partial thromboplastin time (range: 30–40 s); INR: International normalized ratio (range: 0-9-1); D-dimer: 0–0.50 mg/L; Platelets: 150–400×109/uL and Fibrinogen: 200–400 mg/dL. SD: Standard deviation

In terms of correlation between hemostatic parameters and glycemic status, there was no significant correlation between hemostatic parameters and HbA1c (p > 0.05). However, there was a significant correlation between some hemostatic parameters, APTT and PT (p < 0.01), and between fibrinogen and PT (p < 0.05).

DISCUSSION

DM is a metabolic disorder that alters cellular metabolism in several ways, usually leading to alterations in hemostatic parameters. Hyperglycemia in diabetics is associated with hyperfibrinogenemia, which activates the coagulation cascade, leading to increased thrombin formation and fibrin degradation products. Thus, PT, APTT, and fibrinogen tests are widely accepted for the evaluation of the coagulation cascade of diabetics. Furthermore, diabetes is associated with a higher risk of vascular complications, including micro and macro complications. The purpose of this study was to determine the hemostatic profile of diabetic patients and investigate their association with the development of vascular complications in T2DM patients at the Laquintinie Hospital, Douala. The main finding of the study is that although the prevalence of both diabetic complications and hemostatic abnormalities was high among T2DM patients, there was no relationship between hemostatic abnormalities and either complication or glycemic control. This suggests that complications and hemostatic abnormalities affect a diabetic swell independently.

In the present study, significant differences in age and duration of diabetes were observed between diabetic patients with complications and those without complications, and these findings are similar to those of other researchers, such as Agarwal et al.,^[12] Dhawale et al.^[13] and Zhang et al.^[14] The high prevalence of coagulopathy (98.96%) observed in this study emphasizes the importance of regular hemostatic profile monitoring in diabetic patients. The finding of abnormal PT, thrombocytopenia, shortened APTT and elevated fibrinogen levels in this study aligns with earlier reports of altered coagulation profiles in diabetic patients. Getu et al. observed that 12.3% and 8.7% of their diabetic population showed shortened PT and APTT respectively, while the prevalence of prolonged PT and APTT were 5.6% and 3.9%, respectively.^[15] Ephraim et al. also reported that APTT and PT values were significantly shorter among patients with T2DM.^[16]

The current study found no significant differences in the hemostatic parameters in diabetic patients with good (HbA1c ≤7%) and poor (HbA1c >7%) glycemic control [Table 3]. Contrary to this finding, a similar study by Habtu et al. reported significant correlations between glycemic control and hemostatic changes, with mean PT significantly higher in diabetics with good glycemic control (11.04 s vs. 9.68 s) and likewise the mean APTT values (27.10 s vs. 20.23 s).^[17] The difference in findings suggests that other factors, including inflammation, oxidative stress, and endothelial dysfunction, may predispose diabetic patients to hemostatic changes in this study setting than glycemic control. Similar to these findings, Habtu et al. also did not find any difference in the mean platelet counts of diabetics with good glycemic control and those in the poor glycemic control group.^[17]

The overall prevalence of diabetic complications in the current study was high, with retinopathy and neuropathy being the most prevalent [Figure 1]. This is consistent with findings of other studies, which reported microvascular complications to be strongly associated with DM.^[18-20] Participant age group was a significant risk factor of diabetic complications, as participants aged 30–46 years had significantly lower odds of having complications compared to those aged 64–80 years (cOR: 0.05; 95% CI: 0.009–0.26; p < 0.001). These findings are consistent, as advanced age is a major risk factor for diabetes and prediabetes, and therefore, the elderly who have a higher prevalence of diabetes and prediabetes are more likely to develop complications in the cardiovascular, retinal, and renal systems. A study by Yan et al. also reported similar findings.^[21] Furthermore, BMI was found to be a significant risk factor of diabetic complications, where participants with a BMI of 25–29.9 kg/m² had significantly lower odds of having complications compared to those with a BMI ≥309 kg/m². A BMI is a significant risk factor for the development of type 2 diabetes and is associated with a greater risk of complications. Obesity, which is indicated by a high BMI, can lead to poorer glycemic control, thus increasing the chances of microvascular and macrovascular complications in diabetics.

Despite the high prevalence of diabetic vascular complications, the mean values of PT, APTT, INR, and fibrinogen levels observed were not statistically significantly different between those with and without complications (p > 0.05), [Table 4]. This is inconsistent with the findings of Agarwal et al., who reported significant differences in the coagulation parameters between diabetics with and without complications, reporting significantly lower values of APTT and higher fibrinogen levels in diabetic subjects with complications.^[12] The discrepancy may be due to differences in sample sizes, methodologies and population genetics.

This study reported a significant correlation between PT and APTT (p < 0.01), and between fibrinogen and PT (p < 0.05), and this suggests an interrelationship between various hemostatic factors in diabetics. This correlation is indicative of the complex coagulation cascade, where disruptions in one pathway can influence the other.

CONCLUSION

This study revealed a high prevalence of vascular complications and coagulopathy among patients with T2DM at the Laquintine Hospital Douala. Vascular complications such as retinopathy and neuropathy were common. Hemostatic abnormalities, particularly prolonged PT and thrombocytopenia, were observed. The hemostatic profile of diabetic patients in this study was not influenced by glycemic control or the presence of diabetic complications. Routine hemostatic profiling should be incorporated in the management of T2DM patients to enhance early detection and intervention for coagulation abnormalities.