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PLASMA
FIBRINOGEN STUDIES IN DIABETES MELLITUS
ABSTRACT
Plasma
fibrinogen concentration was determined by the clot-weight method of Ingram
(1961) in 27 diabetics comprising 12 males with a mean age of 49.9± 18.3 years
and 15 females with a mean age of 42.9± 11.3 years. 18 normal adults were used
as control comprising 8 males and 10 females with a mean age of 42.9± 14.3
years. The mean fibrinogen concentration was found to be 4.00± 6.70g/1 in
diabetics with a range of 2.7g/1 to 5.3g/1 (P<0.001). There was a sex
variation in the plasma fibrinogen concentration of the diabetics studied with
a higher value in females 4.02±0.60g/1 than in the males
with a mean of 3.92±0.94g/1. The mean
plasma fibrinogen concentration was found to be higher in insulin-dependent
diabetes mellitus (4.80±0.8g/1) than in
non-insulin-dependent diabetes mellitus (3.82±0.71g/1). The
duration of diabetes correlated with an increase in fibrinogen level, 0 – 3
years with a mean of 3.77± 0.8g/1 and 4 – 10
years with a mean of 4.29±0.77g/1, (P<0.1). Diabetics with complication had
a higher plasma fibrinogen level of 4.16±0.78g/1 compared with
those with no complication 3.81±0.72g/1. Diabetics
without hypertension had a higher fibrinogen level (3.81±0.72g/1) than those with
hypertension (3.76±0.88g/1). Diabetics
of the upper class had a higher fibrinogen level (4.12±0.68g/1) than
diabetics of lower class (3.94±0.81g/1). The packed
cell volume of male diabetics was higher (40.4±3.96%) than in
female diabetics (36.47±2.59%). The packed cell volume of
diabetics was found to be 3.82±3.8%1 as compared
to that of the control 3.84±4.09%.
TABLE
OF CONTENTS
Title Page i
Declaration ii
Dedication iii
Acknowledgment iv
Abstract v
Table of
Contents vi
List
of Tables and Graphs vii
CHAPTER ON
Introduction Literature Review
CHAPTER TWO
Materials and Methods
CHAPTER THREE
Results and Analysis
CHAPTER FOUR
Discussion and Conclusion
REFERENCES
LIST
OF GRAPHS AND TABLES
Table
1: Clinical Details of all Subjects in
the Study
Table
2: Mean and S.D of Fibrinogen Values
(g/1) in Diabetes
and control
Table 3: Mean (±S.D.) Fibrinogen Values (g/1) Comparison of Duration of
Diabetes and with or without Complication
Table 4: Mean (±S.D.) Fibrinogen Values (g/1) in Diabetes with or without
Complications
Table 5: Mean (±S.D.) Fibrinogen Values (g/1) in Diabetes with or without
hypertension and Social Class
Table 6: Packed Cell Volume (%) of Diabetes and Control
Table 7: Statistical Analysis of Results
Figure 1: Comparison of Mean Fibrinogen Concentration
between Control and Diabetes
Figure 2: Comparison of Mean Fibrinogen Concentration
between Male and Female Diabetics and Control
Figure 3: Comparison of Mean Fibrinogen Levels between
Males and Females Diabetics
Figure 4: Comparison of Mean Fibrinogen Concentration of
Diabetics of 0 – 3 and 4 – 10 Years Duration
Figure 5: Comparison of Mean Fibrinogen Concentration
between 0 -3 and 4 – 10 Years with Complications
Figure 6: Comparison of Mean Fibrinogen Levels between
Diabetes with Complications and Diabetes without Complications
Figure 7: Comparison of the Packed Cell Volume (%) of
Diabetes and Control and Male and Female Diabetics
Figure 8: Comparison of Mean Fibrinogen Concentration of
NIDDM and IDDM.
CHAPTER ONE
INTRODUCTION AND LITERATURE REVIEW
Fibrinogen
(coagulation factor I) is one of the principal plasma proteins with a molecular
weight of about 340, 000±20,000. Fibrinogen is formed in the liver. The
provision of a fibrin network in hemostasis is the primary physiological
function of Fibrinogen. The essential reaction in coagulation of the blood is
the conversion of the soluble Fibrinogen into the insoluble protein fibrin by
means of an enzyme, thrombin.
Fibrinogen
forms a fibrin barrier in inflammatory tissues for localization of infections,
foreign bodies (Kwaan and Astrup 1964) or possibly even tumor cells (O’Meara
1958). There is a positive correlation between the rise in viscosity and the
plasma Fibrinogen level and it is known that the circulating level of
Fibrinogen is the chief determinant of plasma viscosity. Fibrinogen rises as a
reaction to a number of acute and chronic diseases and has been implicated in
the hemostatic abnormalities associated with diabetes mellitus.
Diabetes mellitus is caused in almost all
instances by diminished rates of secretion of insulin by the beta cells of the
islets of Langerhans. Diabetes is characterized by polydipsia, polyuria, weight
loss in spite of hyper-phagia and hyperynephrities, cataracts, some of the
known cardiovascular complications of diabetes mellitus are atherosclerosis,
myocardial infarot, gangrene, cerebral thrombosis, peripheral nephropathy and
retinopathy. Diabetes mellitus is divided into two types: Insulin Dependent
Diabetes Mellitus (IDDM) or type 1 or juvenile-onset-diabetes mellitus (JOD)
that usually, but not always begins in early life and mainly in obese persons
and non-insulin-dependent diabetes mellitus (NIDDM) or type 2.
Despite recent advances in the understanding of
the natural history of diabetes mellitus with a concurrent improvement in
clinical management, vascular disease and thromboembolic disorders centime to
play a major role in diabetic mortality and morbidity (Sharna, 1981). Two types
of vascular disease occur in diabetes, namely, micro-angiopathy (small-vessel
disease) and large-vessel athercea. The increase in plasma Fibrinogen
concentration in diabetes has important clinical significance in that it
influences such phenomena as increasing red blood cell aggregation or adhesion
and Erythrocyte Sedimentation Rate (ESR) and also increasing whole blood,
plasma and serum viscosity, causing changes in the flow properties of blood and
other hemostatic abnormalities and these could be the link for small and large
vessel disease in diabetes mellitus (Cogan et al, 1961, Skovborg et al, 1960,
Chien et al 1967, Isogal et al 1976, Postlethwaite, 1976, Dods et al 1980 and
Sharma, 1981).
REVIEW OF
LITERATURE
As
early as 1948, Mayer reported an increase in Fibrinogen concentration in
myocardia infection. Losner et al in 1951 using the photoelectric modification
of the one-stage quick prothrombin time determined the Fibrinogen concentration
in a number of clinical conditions such as acute myocardial infection,
rheumatic fever with or without carditis, diabetic and arteriosclerotic
gangrene as well as some form of hepatic disease. In a work reported in 1955
also by Losner et al; the found that in acute rheumatic fever the Fibrinogen
concentration although generally lower than in acute myocardial infection, was
considerably elevated in accordance with the acuity of the rheumatic process.
Also Losner and Volk in 1956 found an increase in plasma Fibrinogen
concentration in the diabetic and arteries clerosis gangrene.
Decean,
Giles and Mcgregor in 1956 reported an increase in erythrocyte sedimentation
rate in Gambian Africans compared to Europeans and also blood protein patterns
of Gambian Africans. In the following year Sucklia reported that the raised
erythrocyte sedimentation rate was attributable mainly to the influence of
plasma Fibrinogen concentration. There are several reports of Fibrinogen
studies in other tropical African countries. For example Shaper and Summerscale
in 1959 working in Kampala found the plasma Fibrinogen concentration in
Ugandans to be 3.0g/1, while Carrington in 1960 used a thrombin-nesslerization
method and found the mean plasma Fibrinogen concentration in 55 Gambian women
to be 3.4g/1.
Cogan
et al in 1961 reported that whole blood plasma and serum viscosity were
elevated in patients with diabetes. This could mean a possible increase in
Fibrinogen concentration since the chief determinant of viscosity is the
circulating level of Fibrinogen. Gelin and Thoren in 1961 suggested that viscosity
may also be related in some way to the rate or frequency of red cell
aggregation. One measure of red cell aggregation is the sedimentation rate and
this has been attributed to increase plasma Fibrinogen concentration (Sucklia,
1957) Wells et al; (1964) showed that the plasma Fibrinogen concentration may
be related to blood viscosity and correlates to low shear rate viscosity. Whole
blood, plasma and serum viscosity was reported in 1966 by Skovborg to be
elevated in patients with diabetic’s mellitus. Wasserman also in the same year
showed that the raised erythrocyte sedimentation rate as observed in various
clinical conditions was attributable mainly to the influence of plasma v
concentration. Blades et al; in 1966 carried out a comprehensive study of
plasma viscosity and failed to observe any sex difference in European
Caucasians.
Chien
et al; in 1967 suggested that it is the plasma Fibrinogen concentration that
influence the rate of red cell aggregation and also to some extent causes the
non-Newtonian behaviour and less thixotropy than normal blood. They also
reported that there is a positive correlation between the rise in viscosity and
the plasma Fibrinogen concentration.
Skovborg
in 1966 and Ditzel in 1968 reported that there is no change in blood viscosity
in uncomplicated diabetes of short duration but there was an increase in blood
viscosity in long-standing diabetes with retinopathy and this was associated
with changes in serum electro-phoretic pattern ans plasma Fibrinogen
concentration.
In a
comprehensive study of the clinical significance of blood viscosity, Dormandy
in 1970 reported changes in blood viscosity with changes in hematocrit, the
blood viscosity of a number range. Also they found that blood viscosity have a
profound influence on the post-operative course of those patients who had
reconstructive vascular surgery and plasma Fibrinogen concentration correlated
with rise in blood viscosity. Labio et al; in 1971 and Isogal et al, also in
1971 reported an increase in whole blood viscosity in patient with diabetes.
Also in 1971 Hickman reported that major surgical operation is associated with
post-operative hypercoagulable state, and a markedly increased both being
influenced by the rise in plasma Fibrinogen concentration after surgery. In
1973 Haore et al; found an increase in whole blood viscosity in diabetes and
this might indicate an indirect rise in plasma Fibrinogen concentration.
McMillian
in 1974 reported that serum viscosity is elevated in early diabetes and it is a
part of the metabolic disturbance of diabetes mellitus and could play a role in
the development of diabetic microangiopathy, studies of serum viscosity changes
in diabetes reported here demonstrated a well-defined increase which is more
pronounced when clinically evident microangiopathy is present. Additional
analysis is this report suggested that the increased viscosity is due to
specific changes in serum composition. The elevation observed in this study is
comparable to the increased serum viscosity observed by Cogan et al; (1961), and the plasma viscosity
increased reported by Isogan et al; (1971). Other studies have not demonstrated
such a larger increase, Bollinger et al; (1969), Langer et al; (1971). Since
serum viscosity elevation in chronic disorders is not unique to diabetes, but
also seen in rheumatic fever, tuberculosis, and carcinoma, three possible
explanations of the relation of increased serum viscosity to diabetic
microangiopathy can be entertained. First, elevated serum viscosity may be due
to an underlying metabolic disturbance which produces both serum protein
changes and diabetic microangiopathy and the plasma Fibrinogen concentration is
known to be elevated. Second, the duration of blood viscosity increase combined
with the degree of elevation might be unique to diabetes so that in other
chronic disorders not enough time elapses to produce a similar microangiopathy
and finally, the elevated blood viscosity may combine with some circulation
change unique to diabetes to generate microangiopathy.
There
is little available information on plasma fibrinogen studies among the Nigerian
population. Essen in 1976 determined the plasma Fibrinogen concentration in 86
(males = 80; 6 females). Using the clot-weight and biuret methods he obtained
mean plasma Fibrinogen concentration of 3.4± 1.2g/1 male and 4.1±1.4g/1
females. He fund a higher degree of fibrinolysis in males residing in the
western regions of Nigeria. Similarly, Dupuy, Fleming and Caen in 1978 also
reported an enhanced fibrinolytic activity in a group of Nigerian males
resident in Zaria.
Schmid-Schonein
and Volgen (19760, Barns et al; mellitus is associated with high prevalence of
micro vascular, atherosclerotic disease, and abnormalities of the physical
properties of the erythrocyte have been reported in diabetic patients. These
abnormalities include whole blood and plasma viscosity and reduced erythrocyte
deformability. Barnes et al; in 1977 reported that viscosity changes are most
marked in patients with retinopathy and it has been postulated that this might
have a pathophysiological significance in the aetiology of diabetic
complications.
Jean-Lne
Wantier et al; in 1981 showed that the addition of a physiology concentration
of fibrinogen resulted in a fivefold enhancement of erythrocyte adhesion in
controls and fourfold enhancement in diabetes. The study showed that washed
erythrocytes from diabetes adhered more strongly to cultured endothelial cells
than did those from control subjects. They found that the extent of red cell
adhesion to endothelial cell was significantly correlated with the extent and
severity of diabetic vascular disease. The study showing the potentiation of
red cell adhesion to endothelial cells by fibrinogen indicates that it may
influence adhesion in vivo.
Sharma
in 1981 reported an increase of plasma Fibrinogen in maturity-onset-diabetes,
while Juvenile-onset-diabetes showed no significant change when compared with
the controls. From this study they showed that factors that contribute to a
hypercoagulable state was reported, as indicated by a significant rise in
platelet adhesiveness and plasma Fibrinogen concentration, which is not
adequately compensated by an increased fibrinolysis activity. Their findings
may have important clinical implications and suggests a definite role for drugs
that reduce hypercoagulation and stimulate the fibrinolysis system in
maturity-onset-diabetes.
Reid
in 1982 found that the plasma Fibrinogen concentration of females to be
3.15±0.50g/1 and the males to be 2.9±0.64g/1 and an increase in plasma
Fibrinogen concentration in pregnant women. Poon et al; also in 1982 reported
that plasma Fibrinogen concentration was higher in those with proliferative
retinopathy than in those with background or n11/minimal
retinopathy. They went further to suggest that fibrinogen may play a role in
blood viscosity. Reid again in 1984 reported that the plasma Fibrinogen
concentration of females were higher than in males in normal subjects, clinical
out-patients, hypertensive and in diabetic patients. He found the mean plus
standard deviation for both male and female diabetics to be higher than for the
normal subjects.
The
aim of this research work is to establish the mean plasma Fibrinogen
concentration in diabetic patients and to assess the relationship between
plasma Fibrinogen concentration and diabetic complications.
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