Congenital afibrinogenemia: mutations leading to premature termination codons in fibrinogen AO-chain gene are not associated with the decay of the mutant mRNAs

Congenital afibrinogenemia is a rare coagulation disorder with autosomal recessive inheritance, characterized by the complete absence or extremely reduced levels of fibrinogen in patients, plasma and platlets. Eight afibrinogemic probands, with very low plasma levels of immunoreactive fibriogen were studied. Sequencing of the fibrinogen gene cluster of each proband disclosed 4 novel point mutations (1914C>G, 1193G> T, 1215delT, and 3075C> T) and 1 already reported (3192C>T). All mutations, localized within the first 4 exons of the AO-chain gene, were null mutations predicted to produce severely truncated AO-chains because of the presence of premature termination codons. Since premature termination codons are frequently known to affect the metabolism of the corresponding messenger RNAs (mRNAs), the degree of stability of each mutant mRNA was investigated. Contransfection experiments with plasmids expressing the wild type and each of the mutant AO-chains, followed by RNA extraction and semiquantative reversetranscriptase-polymerase chain reaction analysis, demonstrated that all the identified null mutations escaped nonsense-mediated mRNA decay. Moreover, ex vivo analysis at the protein level demonstrated that the presence of each mutation was sufficient to abolish fibrinogen sectretion. (AU)

The influence of persistent hyperglycaemia of hyperfibrinogenaemia and hyperviscosity in diabetes mellitus

The effect of hyperglycaemia on hyperfibrinogenaemia and its consequence on plasma viscosity was investigated in 69 diabetic patients during the course of hypoglycaemic treatment. Glycaemic control was assessed by measurement of glycosylated haemoglobin (HbA). Plasma fibrinogen concentration (PFC) was determined by a clot-weight method. The relative plasma viscosity (RPV) was measured by capillary viscometry. The mean PFC and RPV were significantly (p<0.001) elevated in the diabetic patients as compared with a non-diabetic control group. Both PFC and RPV showed a distinct, step-wise increase with progressively poorer glycaemic control. The data strongly indicate that persistent hyperglycaemia is associated with a frank hyperfibrinogenaemia and hyperviscous plasma in most of the diabetic patients studied. These abnormal haemorrheological changes could impact adversely on both the haemostatic process and circulation in diabetic patients(Au)

Acute-phase protein response to infection in severe malnutrition

It is not known whether malnourished infant can mount a comprehensive acute-phase protein (APP) response and, if so, whether this is achieved by increasing APP synthesis rates. To address these issues, we measured 1) the plasma concentrations of five APPs (C-reactive protein, O1-acid glycoprotein, O1-antitrypsin, haptoglobin, and fibrinogen) and 2) the synthesis rates of three APPs (O1-antitrypsin, haptoglobin, and fibrinogen) using a constant intragastric infusion of [2H3] leucine in nine infected marasmic children at 2 days postadmission (study 1), 9 days postadmission when infections had cleared (study 2), and 59 days postadmission at recovery (study 3). Except for fibrinogen, the plasma concentrations of all APPs were higher in study 1 than in studies 2 and 3. Although the rate of synthesis of haptoglobin was significantly greater in study 1 than in study 2, the rates of fibrinogen and O1-antitrypsin synthesis were similar in all three studies. These results show that 1) severely malnourished children can mount an APP response to infection which does not include fibrinogen and 2) the APP response is accomplished through different mechanisms. (AU)

Haemorrheological disturbance in diabetes mellitus - abstract

Diabetes mellitus is one of several metabolic diseases in which haemorrheological disturbances have been observed. In diabetes, particularly of long duration, there are marked alterations of the microcirculation. These changes are associated, at least in part, with rheological disturbances. Diabetic microangiopathy affects the retina, the enal glomeruli, the nerves and probably the entire network of capillaries. Rheological studies in both insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetics have shown a decrease in red cell deformability, an increase in red cell aggregation and plasma fibrinogen concentration. These alterations are aggravated by concurrent hypertension and the severity of the disease. The combined effect of these changes is the development of a hyperviscosity syndrome in the diabetic patient. The clinical significance of diabetic hyperviscosity is a marked impairment in blood-flow, in particular, across the microcirculation; hence diminished tissue perfusion (AU)

Hyperfibrinogenemia and hyperviscous plasma in hypertensive Africans

Changes in plasma fibrinogen concentrations (PFC) and relative plasma viscosity (RPV) were investigated in 61 Nigerian Africans while they were being treated for essential hypertension. The association of these hemorhelogic variables with blood pressure was examined. An analogous study was done on 30 normotensive controls for comparison. The hypertensive patients had, overall, a significant increase in both PFC and RPV (p<0.001) as compared with control values. However, 44.3 percent of the hypertensive patients had PFC and RPV values within the defined normal limits. This indicates that in a proportion of the hypertensive, treatment notwithstanding, PFC and RPV are altered only within the physiologic limits.(AU)

Comparison of plasma viscosity and fibrinogen concentration in African insulin-dependent diabetes with and without hypertension

Alterations in Relative Plasma Viscosity (RPV) and Plasma Fibrinogen Concentration (PFC) were compared in 24 insulin-dependent (IDDM) and33 non-insulin-dependent (NIDDM) black Nigerian diabetics, during the course of treatment. Both PFC and RPV were significantly (p<0.001) increased in the diabetics, as a group, compared to a non-diabetic control group. PFC and RPV showed consistently marginal, though insignificant, increases in the IDDM vs NIDDM. Hypertensive diabetics, as a group, had significantly greater PFC (p<0.025), and RPV (p<0.025) than normotensive diabetics. Although PFC was significantly (p<0.05) raised in hypertensive IDDM, there was no marked change between hypertensive and normotensive NIDDM. The implication of the present findings is that insulin-dependent diabetics may be more prone than non-insulin-dependent diabetics to develop haemorheological and hence circulatory disorders (AU)

Thrombocytopenia in leptospirosis: the absence of evidence for disseminated intravascular coagulation

In a prospective study of human leptospirosis, thrombocytopenia was demonstrated in 54 percent of 24 cases. The only additional laboratory evidence suggestive of disseminated intravascular coagulation lay in a mild elevation of fibrinogen degradation products, but this occurred with equal frequency in nonthrombocytopenic patients. There is therefore no causal relationship between disseminated intravascular coagulation and the thrombocytopenia of human leptospirosis. (AU)

Plasma fibrinogen changes in cerebral catastrophies

Plasma fibrinogen levels were determined on 25 unselected, consecutive cases of "stroke" admitted to Kingston Public Hospital, Jamaica. Of these 84 percent were found to have levels above 270 mgms percent. Of those that died, 32 percent had an average level of 417 mgm percent (males) and 367 mgm percent (females). The possibility of a semi quantitative relationship to hypertension is discussed (AU)