Correlation of Glycated Hemoglobin and D-dimer in Diabetic Patient

Sry Suryani Widjaja

and Muhammad Syahputra

Biochemistry Department, Medical Faculty Universitas Sumatera Utara, Medan, Indonesia

Keywords: Diabetes, Glycated Hemoglobin, D-dimer, Hypeercoagulable State.

Abstract: Diabetes Mellitus a chronic metabolic disease presented with chronic hyperglycemia, which will cause

abnormalities in the endothelial cells, proinflammatory state, alter platelet function and plasma coagulation

factors that lead to hypercoagulable state and thrombosis. D-dimer an indirect marker of thrombotic activity,

is the final fragment of the plasmin mediated degradation of cross-linked fibrin. The elevated d-dimer level

was detected at the onset of thrombosis, it was used to exclude the venous thromboembolism when it was

negative. D-dimer was increased in diabetic patients under most studies, and when there is a

hypercoagulable state, hyperfibrinolysis will occur, subsequently elevation of D-dimer. This study was

aimed to study the correlation between glycated hemoglobin and d-dimer in diabetic patients. This is a case

control study to evaluate the correlation of glycated hemoglobin (HbA1c) and d-dimer in diabetic patients.

Total 60 patients were recruited, the blood glucose level, HbA1c, d-dimer were measured. There was

statatistical significant correlation between HbA1C and d-dimer (p=0.019, r= 0.27), HbA1c and age

(p=0.002, r=0.36), d-dimer and age (p=0.04), blood glucose and HbA1C (p=0.00, r=0.5), blood glucose and

age (p=0.037, r=0.23).

1 INTRODUCTION

Diabetes mellitus (DM), with an increasing

prevalence worldwide, is a chronic metabolic

disturbance disease with micro and macro vascular

complications such as acute myocardial nfarction,

stroke, and peripheral arterial disease (Fulvio, 2015).

In diabetic patients abnormalities in the endothelial

cells (Kinlay S, 2001), proinflammatory state

(Devaraj, 2010), altered platelet function and plasma

coagulation factors leading to a hypercoagulable

state with the propensity for thrombosis. (Mark AC,

2003) Either acute or chronic hyperglycemia plays

an important role in hemostatic disturbances,

prothrombotic condition (Lemkes, 2010),

hypercoagulable state (Di Minno, 2011) and poor

clinical outcome of thrombotic events. (Lemkes,

2010) From several studies, the risk of

cardioembolic stroke was increased. Per year it was

ranged between 3.6 and 8.6% (Stroke Risk in Atrial

Fibrillation Working Group,

2007). The

prothrombotic state in diabetes was contribute by the

increasing levels of clotting factors, primary

hemostasis changes and impaired of fibrinolysis and

low grade inflammation (Nomura, 2009).

One of the most important pathway that

associated with thromboembolism is platelet

reactivity, (Vinik AI, 2001) this will accelerated

platelet aggregation, hypercoagulable state,

(Winocour PD, 1990) impaired fibrinolysis (Lu tjens

A, 1985) and it was also reported to be correlated

with the concentration of glycated hemoglobin

(HbA1c) (Iwase E, 1998) a standard measure of

chronic glycemia that is used to identifying high

risk persons who will develop diabetes, control of

diabetes and as a predictor of diabetes (William,

2015). Hyperglycemia was an important factor to

induce endothelial dysfunction,

(Jansson, 2007)

increased the prothrombin fragment 1+2 and D-

dimer (Nieuwdorp M, 2006).

An indirect marker of thrombotic activity, d-

dimer (Antovic P, 2013) is the final fragment of

degradation of cross-linked fibrin that was mediated

by fibrin. (Righini M, 2008) The elevated d-dimer

level was detected at the onset of thrombosis,

(Ana

Pilar NR, 2009)and the negative level was used to

exclude the venous thromboembolism. (Nwose EU,

2007) D-dimer was increased in diabetic patients

under most studies, (Nwose EU, 2007, Yamada T,

2000) and when there is a hypercoagulable state,

hyperfibrinolysis will occur, subsequently elevation

648

Widjaja, S. and Syahputra, M.

Correlation of Glycated Hemoglobin and D-dimer in Diabetic Patient.

DOI: 10.5220/0010082206480651

In Proceedings of the International Conference of Science, Technology, Engineering, Environmental and Ramiﬁcation Researches (ICOSTEERR 2018) - Research in Industry 4.0, pages

648-651

ISBN: 978-989-758-449-7

of D-dimer. (Nwose EU, 2007) Due to

hypercoagulable and hypofibrinolytic states,

diabetes was considered important risk factor for

thrombosis. (Yamada T, 2000) One of the marker is

D-dimer, when elevated showed hyperactivation of

hemostatic system (Meigs JB, 2000)

2 METHOD

This is a case control study to evaluate the

correlation of glycated hemoglobin (HbA1c) and D-

dimer in diabetic patients. The study received ethical

approval from Health Research Ethical Committee

Medical Faculty Universitas Sumatera

Utara/H.Adam Malik General Hospital Medan

Indonesia. Total 60 diabetic patients from hospital

and private clinics, who signed the informed consent

were admitted to the study.

2.1 Blood Collection

Blood sampling was performed from a clean

venepuncture using the Vacutainer system (Beckton

Dickenson, New Jersey, USA). About 6 mL of blood

was collected into EDTA and heparin tubes. Both

tubes spun for 15 min at 2000g within an hour of

blood collection. Plasma EDTA and heparin samples

were aliquoted and kept at -70 °C until assayed.

2.2 Laboratory Assays

Blood glucose, HbA1C, d-dimer were performed at

the Integrated Laboratory Medical faculty University

Sumatera Utara, Medan Indonesia. Blood glucose

was measured with spectrophotometry, HbA1c with

HPLC method, d-dimer with ELISA method.

Body Mass Index (BMI) was determined by

using the BMI calculator (body weight and height).

2.3 Data Analysis

Non-parametric Mann Whitney U test was used to

evaluate normality distribution of the blood glucose,

HbA1c, D-dimer in diabetes. Spearman's Rho

correlation analysis was used to determine the

correlation between HbA1c against d-dimer seen in

diabetic patients. A P value of less than 0.05 was

considered statistically significant.

3 RESULTS AND DISCUSSIONS

3.1 Results

Total 60 samples were including in this study. The

samples descriptive statistics and Laboratory assays

are shown in table 1.

Table 1: Descriptive Statistics of the samples and

Laboratory Assays.

Paramete

Mean (ran

e 60 (27-80)

Bod

mass index (BMI) 25 (19.5-35.2)

Blood Glucose 240 (28-654)

HbA1c 9.3 (5.4-14.3)

D-dime

1.7(0.15-5)

From the study we got the mean age was 60

years (27-80 years), range of HbA1C was 5.4-14.3%

with the mean 9.3, Blood glucose level ranged from

28-654 mg/dl with the mean 240, the blood glucose

level was not well controlled, there were 78.3%

samples with bad glucose control and 21.7% with

good control. D-dimer ranged from 0,15-5 with the

mean 1,7. The BMI range from 19.5-35.2, with the

mean 25. Most of the samples were normal weight

(55%), over weight (35%) and 10% obesity.

We use the Kolmogorov-Smirnov to test the

normality of the datas and found that the datas were

not distributed normally. The Spearman’s Rho was

used to study the correlation between datas, p < 0.05

is considered statistical significant.

Table 2. Correlation between control of blood glucose and

hypercoagulable state

-dime

BMI HbA1c

Blood

glucose

p=0.085 p=0.27 p=0.00

HbA1c

=0.019

=0.324 1

-dime

=0.117

=0.019

sig (1 tailed)

correlation is significant at the 0.05 level

There is statistical correlation between HbA1c

and d-dimer (p=0.019, r= 0.27).

4 DISCUSSION

This study showed that the blood glucose control is

still an important issue to be warning in this region,

this was showed from the mean level of blood

glucose was 240 mg/dl, the mean of glycated

Correlation of Glycated Hemoglobin and D-dimer in Diabetic Patient

649

hemoglobin was 9.3 and most of the samples were

not well controlled (78.3%). This condition will

caused chronic hyperglycemia that will finally cause

hypercoagulable state, hyperactivation of hemostatic

system as shown in several studies that can be risk

factor of thrombosis in diabetic patients. This study

also showed significant correlation between HbA1c

that reflects the control of blood glucose within three

months with the d-dimer, marker that is use widely

to exclude deep vein thrombosis and also a marker

for hyperactivation of hemostatic system. One of the

most common complications of diabetes that

correlate with the hyperactivation of hemostatic

system are involving macrovascular likes coronary

heart disease, stroke and venous thromboembolism.

Another issue that has to be warning is the body

mass index, in this study there was 35% of samples

with overweight and 10% with obesity, though the

BMI did not showed statistical correlation with the

d-dimer, overweight and obesity were one of the

criterias of metabolic syndrome that was risk factor

of hemostatic disturbance and thrombosis.

5 CONCLUSION

Glycated hemoglobin (HbA1c) has statistical

significant correlation with d-dimer, a marker used

to exlude venous thromboembolism and marker for

hyperactivation of hemostatic system.

ACKNOWLEDGEMENT

There is no conflict of interest. This study is

supported by Ministry of Research and Technology

and Higher Education Republic of Indonesia, under

research grant TALENTA 2018 with contract

number 117/UN5.2.3.1/PPM/KP-TALENTA

USU/2018.

REFERENCES

Fulvio P, Matteo ND Di Minno, Luigi F, Monica G,

Walter A, Francesco D. Is diabetes a hypercoagulable

state? A critical appraisal. Acta Diabetol 2015. DOI

10.1007/s00592-015-0746-8.

Kinlay S, Libby P, Ganz P. Endothelial function and

coronary artery disease. Curr Opin Lipidol.

2001;12:383–389.

Devaraj S, Mohan R , Jialal I. Diabetes is a

proinflammatory state: a translational perspective.

Expert Rev Endocrinol Metab 2010; 5(1): 19–28.

Mark AC, Thomas FL,Francesco C, Joshua AB. Diabetes

and Vascular Disease Pathophysiology, Clinical

Consequences, and Medical Therapy: Part

I.Circulation 2003;108:1527-1532.

Lemkes BA, Hermanides J, Devries H, Holleman F,

Meijers JCM et al. Hyperglycemia a prothrombotic

factor ?. Journal of Thrombosis and Haemostasis

2010; 8: 1663–1669.

Di Minno MN, Tufano A, Ageno W et al. Identifying

highrisk individuals for cardiovascular disease:

similarities between venous and arterial thrombosis in

perspective. A 2011 update. Intern Emerg Med 7:9–

13.

Stroke Risk in Atrial Fibrillation Working Group

Independent predictors of stroke in patients with atrial

fibrillation: a systematic review. Neurology 2007;

69:546–554.

Nomura S.Dynamic role of microparticles in type 2

diabetes mellitus. Curr Diabetes Rev 2009;5:245–251.

Vinik AI, Erbas T, Park TS et al.Platelet dysfunction in

type 2 diabetes. Diabetes Care 2001; 24:1476–1485.

Winocour PD, Bryszewska M, Watala C et al. Reduced

membrane fluidity in platelets from diabetic patients.

Diabetes 1990; 39:241–244.

Lu tjens A, te Velde AA, vdVeen EA et al. Glycosylation

of human fibrinogen in vivo. Diabetologia

1985;28:87–89.

Iwase E, Tawata M, Aida K et al. A cross-sectional

evaluation of spontaneous platelet aggregation in

relation to complications in patients with type II

diabetes mellitus. Metabolism 1998;47:699–705

William C. HbA1c as a Predictor of Diabetes and as an

Outcome in the Diabetes Prevention Program: A

Randomized Clinical Trial. Diabetes Care

2015;38:51–58.

Jansson PA. Endothelial dysfunction in insulin resistance

and type 2 diabetes. Journal of Interna Medicine 2007;

262:173-83.

Nieuwdorp M, van Haeften TW, Gouverneur MC, Mooij

HL, van LieshoutMH, LeviM, Meijers JC, Holleman

F, Hoekstra JB, VinkH, Kastelein JJ, Stroes ES. Loss

of endothelial glycocalyx during acute hyperglycemia

coincides with endothelial dysfunction and

coagulation activation in vivo. Diabetes 2006; 55:

480–6.

Antovic P. D-dimer a laboratory point of view. Srce i

krvni sudovi 2013; 32(3): 195-198.

Righini M, Perrier A, De Moerloose P, Bounameaux H. D-

dimer for venous thromboembolism diagnosis: 20

years later. Journal of Thrombosis and Haemostasis

2008; 6: 1059–1071.

Ana Pilar NR, Susana RR, Marta BG, Juan GA. Utility of

D-dimer level as an analytical marker in pediatric

emergencies. Emergencias 2009; 21: 28-31.

Nwose EU, Richards RS, Jelinek HF, Kerr PG. D-dimer

identifies stages in the progression of diabetes mellitus

from family history of diabetes to cardiovascular

complications. Pathology. 2007; 39(2):252-7.

ICOSTEERR 2018 - International Conference of Science, Technology, Engineering, Environmental and Ramiﬁcation Researches

650

Wakabayashi I, Masuda H. Association of D-dimer with

microalbuminuria in patients with type 2 diabetes

mellitus. J Thromb Thrombolysis.2009;27(1):29-35.

Yamada T, Sato A, Nishimori T, Mitsuhashi T, Terao A,

Sagai H, et al. Importance of hypercoagulability over

hyperglycemia for vascular complication in type 2

diabetes. Diabetes Res Clin Pract. 2000;49(1):23-31.

Meigs JB, Mittleman MA, Nathan DM, Tofler GH, Singer

DE, Murphy-Sheehy PM, et al. Hyperinsulinemia,

hyperglycemia, and impaired hemostasis: the

Framingham Offspring Study. JAMA.

2000;283(2):221-8.

Correlation of Glycated Hemoglobin and D-dimer in Diabetic Patient

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