G.D.O. Lowe

INCREASED BLOOD VISCOSITY AND FIBRINOLYTIC INHIBITOR IN TYPE II HYPERLIPOPROTEINAEMIA

Blood rheology and several haemostatic factors were studied in patients with type II hyperlipoproteinaemia (HLP) and matched controls. HLP patients had increased blood viscosity (p less than 0.01), the mean level being 18% higher at a low shear-rate (0.94 s-1) and 13% higher at a high shear-rate (94 s-1). The increased viscosity was due partly to a raised haematocrit (p less than 0.05), and partly to increased plasma viscosity (p less than 0.01) associated with increased plasma fibrinogen (p less than 0.02). Red cell deformability was normal, and viscosity was unrelated to either lipid or lipoprotein concentrations. Levels of the major fibrinolytic inhibitor. alpha 2-antiplasmin, measured by both functional and immunological techniques were higher in HLP patients (mean increase 30-32%). Plasminogen activator levels were normal in HLP patients and the ratio of fibrinolytic inhibitor to activator was therefore increased. Plasminogen concentrations were also increased. Levels of factor VIII activity and antigen, antithrombin III and anti-factor Xa activity, alpha 2-macroglobulin, platelet count, and platelet aggregation by adenosine diphosphate and adrenaline did not differ significantly in HLP patients and controls. These results suggest that the premature arterial disease associated with HLP may be related to increased blood viscosity, which reduces arterial blood flow, and increased alpha 2-antiplasmin, the major inhibitor of fibrinolysis.

HTLV-III SEROPOSITIVITY IN EUROPEAN HAEMOPHILIACS EXPOSED TO FACTOR VIII CONCENTRATE IMPORTED FROM THE USA

77 Scottish haemophiliacs and 22 Danish haemophiliacs were serologically tested for antibodies to human T-cell leukaemia virus III (HTLV-III). Since 1979 the Scottish patients had been treated largely with factor VIII concentrate produced in Scotland, whereas all but 2 of the Danish patients had received both locally prepared concentrate and commercial concentrate made from US donor material. 15.6% of Scottish and 59.1% of Danish haemophiliacs were antibody positive (p less than 0.001). None of 11 haemophiliacs not treated in the period 1979-84 was seropositive. 2 (6.7%) of 30 subjects who had been treated with locally produced concentrate only were antibody positive, compared with 23 (39.7%) of 58 subjects who had been treated with commercial concentrate. Among 52 users of both commercially and locally produced factor VIII concentrate, seropositivity was directly correlated with the consumption of commercial concentrate (p less than 0.001) but not locally produced material. These data indicate that European haemophiliacs were exposed to HTLV-III via some factor VIII concentrates obtained from the USA.

Impaired cell mediated immunity in haemophilia in the absence of infection with human immunodeficiency virus

The cell mediated immune response was evaluated in vivo in 29 patients with clinically severe haemophilia by means of the dinitrochlorobenzene skin test. All patients had a response below the median normal value, and in 19 the response was on or below the lower limit of the normal range. There was no difference in skin response between patients positive and negative for the human immunodeficiency virus (HIV; formerly known as human T cell lymphotropic virus III or lymphadenopathy associated virus). In the whole group, and in seronegative patients (n = 17), there was an inverse relation between exposure to clotting factor and skin response. In seropositive patients (n = 12) no such association was apparent. This study shows that clotting factor concentrate impairs the cell mediated immune response to a new antigen in the absence of infection with HIV.

Further studies on the role of red blood cells in spontaneous platelet aggregation.

The influence of red blood cells on platelet aggregation has recently been a subject of considerable interest. We have studied the effect of red cells on spontaneously formed platelet aggregates in rotating vials at 37 degrees C. Platelet aggregation was quantified by measuring the fall in number of single platelets with a whole blood platelet counter. Autologous packed red cells, platelet rich plasma and platelet free plasma were used to reconstitute aliquots of blood with constant platelet count but 0-60% haematocrit (Hct). The fall in platelet count was minimal at zero Hct, increased markedly with the Hct in the anaemic range and less markedly in the normal to polycythaemic ranges of Hct. Scanning electron microscopic observation of whole blood showed the presence of small platelet aggregates after about 3 mins rotation and very large aggregates after about 12 mins. ADP from red cells has been implicated in triggering platelet aggregation in whole blood. Whether aggregates are formed as a result of ADP leaking from the red cells or by their jostling physical action on the platelets is discussed. The marked effect of the red cells on spontaneous platelet aggregation however, justifies the manipulation of the Hct as a useful therapeutic option in the control of thrombotic and bleeding tendencies.

PROGNOSTIC VALUE OF BETA-THROMBOGLOBULIN IN PATIENTS WITH TRANSIENT CEREBRAL ISCHAEMIA

Plasma levels of beta-thromboglobulin (BTG) and fibrinopeptide A (FPA), markers of platelet alpha-granule release and thrombin generation respectively, were measured in 27 subjects with transient cerebral ischaemic attacks (TIA), 43 age-matched controls, and 32 young controls. BTG and FPA were both higher in elderly controls than in young controls. BTG was higher in TIA subjects than in age-matched controls and higher in the 12 TIA subjects who had further vascular events in the next year than in those who had no further events. FPA was not significantly associated with TIA or with further events. These results support a relationship between platelet activation and TIA and suggest that BTG levels indicate a group at higher risk of further vascular events.

The effect of intramuscular stanozolol on fibrinolysis and blood lipids

The effects of a single 50 mg intramuscular injection of the anabolic steroid stanozolol (Stromba) on fibrinolysis, blood coagulation and lipids was evaluated in 12 healthy male volunteers. Significantly increased plasminogen activator levels (p less than 0.05) was noted 24 hours following the injection and these remained elevated for one week. Plasminogen levels increased significantly by day two (p less than 0.01) and remained elevated for three weeks. HDL cholesterol fell (p less than 0.01) and both total and LDL cholesterol increased (p less than 0.05) when measured one month post injection. Stanozolol appears to have therapeutic potential as an activator of the fibrinolytic system when given by intramuscular injection.

HTLV-III ANTIBODY IN SEQUENTIAL PLASMA SAMPLES: FROM HAEMOPHILIACS 1974-84

In an earlier report we showed that seropositivity for antibody to human T-lymphotropic virus type III (HTLV-III) among Scottish and Danish hemophiliacs was related to their use of factor concentrate products made from US donor material. We here present the HTLV-III antibody results on sequentially collected plasma (1974-84) from the 12 Scottish patients who were positive in our earlier study in 1983-84. All patients were longterm users of factor concentrate (mean age 26 years range 15-42). As the figure shows patients 9-12 were seropositive on both occasions for which plasma was available and none were tested before 1981. However seroconversion was recorded in the remaining 8 patients and took place after 1981 in at least 6 of them (there were no samples for the period 1978-83 in patients 2 and 3 so we know only that these patients became HTLV-III antibody positive after 1977). These data and others from American hemophiliacs (J.J. Goedert personal communication) support the hypothesis that infection with HTLV-III is new in the hemophiliac environment. More specifically our study suggests that the virus was introduced into Scotland at about the same time as the onset of the AIDS epidemic. (full text)

β-Thromboglobulin and platelet counts - effect of malignancy, infection, age and obesity

Plasma levels of beta-thromboglobulin (BTG) and platelet count were studied in 69 control subjects, 19 patients with operable abdominal malignancy, and 9 patients with acute bacterial infection. In control subjects there was a significant rise in BTG and fall in platelet count with age, and a negative correlation of BTG with obesity. BTG and platelet count were normal in patients with operable malignancy, but significantly increased in patients with acute bacterial infection. These effects must be considered in studies of BTG and thrombosis.

Haematocrit in patients attending a hypertension clinic.

In view of recent interest in the relationship of haematocrit and blood viscosity to hypertension and vascular disease, we have analysed retrospectively the relationship of haematocrit to blood pressure, vascular complications and other variables in 2,381 patients referred to the Glasgow Blood Pressure Clinic. Haematocrit correlated negatively with age and systolic pressure in men, and positively with age and systolic pressure in females. Positive correlations were found in both sexes between haematocrit and serum alanine aminotransferase (possibly due to mutual correlation with alcohol); and between haematocrit and overweight (Quetelet Index) but not obesity (Ponderal Index). Increased haematocrit was also associated with cigarette smoking; and with history of angina, myocardial infarction and intermittent claudication in females. No correlation was observed between haematocrit and history of stroke. These findings suggest that prospective studies of haematocrit in hypertensives may be of interest.

INCREASED PLASMIN ACTIVITY DURING STANOZOLOL ADMINISTRATION

SIR,-Decreased fibrinolysis probably plays a role in a variety of vascular diseases,u2 presumably by allowing inappropriate deposition of fibrin.’ Anabolic steroids such as stanozolol increase the plasma level of plasminogen activators in normal subjects4 and in patients with vascular disease.5,6 However, an increased level of plasminogen activators indicates only a potential for stimulation of plasmin-mediated fibrinolysis. Systemic fibrinolysis with raised fibrin degradation products, as happens with streptokinase or urokinase therapy, does not occur with stanozolol. Kudryk et al7 have described a radioimmunoassay (RIA) for a fragment of the B/3 chain of fibrin (ogen), fragment B 15-42, which is released during the earliest stage of plasmin-induced proteolysis. We have measured plasma levels of B(3 15-42 fragment by RIA (IMCO) in nine healthy men aged 19-35 years before, during, and after a 14-day course of stanozolol (Sterling Research Laboratories) 10 mg daily by mouth. B(3 levels (pmol/ml, mean&plusmn;SEM) increased from 0 84:t0 . 10 to 1 S4:t0 15 (p<0 01) at 7 days, were at 1’18:t0’13(p<0 &middot; 05) on day 14, and returned to baseline values (0’9&plusmn;0’19) 14 days after cessation of therapy. These findings are consistent with an increase in plasmin-mediated lysis of fibrin (ogen). The well-recognised decrease in fibrinogen levels with stanozolol2,4 (which also occurred in this study8), thought to be due to altered synthesis,4 may in part be explained by plasmin activation. In summary, we have shown, for the first time, that stanozolol activates plasmin-induced fibrinolysis.