Biomedical subjects
Publications and source records attributed to B Boneu.
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The family of a 36-year-old man with recurrent deep venous thrombosis and heparin co-factor II (HC II) deficiency was investigated for this deficiency. The deficiency was inherited as an autosomal dominant trait. 4 members of the family had low HC II levels but only the proband had a history of thromboses; however, 2 of 4 affected were only 14 and 23 years old. The deficiency did not affect the anticoagulant action of heparin, with which the patient was treated.
A simultaneous investigation of platelet regeneration time (PRT) based upon malondialdehyde (MDA) recovery after a single oral intake of 500 mg of aspirin and of platelet survival time (PST) after labelling with 51chromium or 111indium oxine was performed in 25 cancerous patients. A pilot study conducted with 9 healthy volunteers demonstrated that the MDA assay was highly reproducible and specific for the platelet cycloxygenase activity. The pattern of MDA recovery after aspirin ingestion was linear in the healthy volunteers and in the patients presenting both a normal and an accelerated platelet turnover. PST were calculated using the four mathematical models recommended by the International Committee for Standardization in Hematology; the best fit was given by the multiple hit model in 22 cases and by the linear regression model in 3 cases. The mean results obtained in the patients investigated with the 51chromium were consistently shorter than those obtained in the patients investigated with the 111indium oxine while the mean PRT were almost identical in the two groups. An excellent correlation between PRT and PST was observed after 111indium oxine labelling and using the weighted mean method for PST determination. These results suggest that the 111indium oxine technique is a better method for platelet labelling and that the results provided by the weighted mean method reflect more closely the in vivo platelet turnover than those provided by the multiple hit model.
Standard heparin, an effective treatment for antepartum thromboembolic disease, is thought to be safe for the fetus since it does not cross the placenta. Recently, a number of low molecular weight heparins have been prepared which have been shown to produce less bleeding than standard heparin for an equivalent antithrombotic effect in experimental animals. These observations suggest that the low molecular weight heparins may also provide superior antithrombotic therapy in antepartum thromboembolic disease. However, it is not known whether the low molecular weight heparins cross the placenta. To determine this, we examined the pharmacokinetics of 125I-labelled standard heparin and a low molecular weight heparin, and their anticoagulant effects in mother and fetus, using a pregnant sheep model. Catheters were inserted into maternal and fetal femoral arteries at 108-119 d gestation (term: 147 d). 1-3 days later the mothers were given a bolus i.v. injection of 5000 anti-Xa units of 125I-labelled standard heparin or low molecular weight heparin, CY 222. Nine serial blood samples were collected over 4 h from both mother and fetus for measurements of radioactivity, anti-Xa activity (chromogenic) and activated partial thromboplastin times. When therapeutic levels of standard and CY 222 heparins were achieved in the mother, there was no detectable radioactivity or anticoagulant effect in the fetus. We conclude that standard heparin and the low molecular weight CY 222 do not cross the placenta in the pregnant sheep.
This study demonstrates that a low haematocrit is the main determining factor of the prolonged bleeding time often encountered in uraemic haemodialysed patients. Thirty-three patients submitted to regular haemodialysis and having a platelet count greater than 100 X 10(9)/l were investigated with the following tests: simplate bleeding time, blood cell count, platelet aggregation induced by ADP, collagen and sodium arachidonate, arachidonate induced MDA synthesis, tests for detection of an acquired storage pool disease, and factor VIII complex level. The results were compared to two other groups; one of uraemic patients not yet subjected to haemodialysis and another of healthy volunteers. The results were basically identical in the two groups of uraemic patients. The only consistent abnormality was a 30-35% reduction in the platelet MDA synthesis in comparison with control subjects. There was a negative correlation between the log bleeding time and the haematocrit (r = 0.78, P less than 0.01). Fourteen uraemic patients having a prolonged bleeding time were submitted to a red cell transfusion programme and were investigated a second time under identical conditions. There was no change in any of the platelet function tests or in the factor VIII complex level, but the bleeding time was normalized when the post-transfusion haematocrit was over 26% (nine patients). This study emphasizes the role of anaemia in the pathogenesis of the prolonged bleeding time in uraemia and suggests that red cell transfusion can be a long-term efficient therapeutic measure to stop bleeding in these patients.
[3H]-yohimbine binding sites were quantified in platelets from Parkinsonians with no clinical signs of dysautonomia. Never-treated Parkinsonians had a lower specific binding than control subjects. This alteration was associated with decreased epinephrine-induced platelet aggregation. Treatment with dopaminergic agents induced a significant increment of [3H]-yohimbine binding sites. These results show that Parkinson's disease is associated with a reduced number of peripheral alpha 2 adrenoceptors and that dopaminergic agents induce partial recovery.
Tissue-type plasminogen activator (t-PA) is a promising thrombolytic agent because it can produce thrombolysis without inducing a plasma proteolytic state. It is uncertain if this potentially important feature renders t-PA less hemorrhagic than other plasminogen activators. We have compared the hemorrhagic and thrombolytic effects of t-PA and streptokinase in rabbits. Streptokinase, 4000 U/kg/hr over 4 hr, failed to produce significant thrombolysis and 8000 U/kg/hr streptokinase over 4 hr produced only 28 +/- 6% thrombolysis. Both streptokinase regimens were associated with a plasmin-mediated plasma proteolytic state and both streptokinase regimens produced a significant increase in hemorrhage that was evident within 15 min of beginning the infusion and was progressive over the 4 hr of drug administration. In contrast, t-PA in a dose of 7500 U/kg/hr produced 35 +/- 6% thrombolysis, but it did not produce a plasmin-mediated plasma proteolytic state or a significant increase in hemorrhage over the 4 hr of infusion. t-PA in a dose of 15,000 U/kg/hr produced 85 +/- 4% thrombolysis but was associated with a plasmin-mediated proteolytic state and produced significant bleeding which, in contrast to streptokinase-induced bleeding, was delayed in onset. Therefore, t-PA induced less hemorrhage than streptokinase at doses that produced more effective thrombolysis. Bleeding with both thrombolytic agents was associated with a plasmin-mediated proteolytic state.
Platelet activation may play a part in causing myocardium infarction with angiographically normal coronary arteries. We investigated this possibility by performing ergometric stress testing in a series of 9 patients (Group A) who had suffered myocardial infarction after a violent effort with angiographically documented coronary insufficiency responsible for a stable effort angina (Group B) and 11 healthy subjects (Group C). Blood samples were taken separately before exercise, at the peak of exercise, and during the recovery period. Platelet morphology, a sensitive indication of the degree of platelet activation, was studied by phase contrast microscopy after immediate fixation of the blood. The percentage of non-discoidal platelets presenting with one or several spicules was measured. At the same time, the plasma concentrations of platelet factor 4 (PF4) and beta-thromboglobulin (beta-TG) were measured. At rest, there was no difference in platelet morphology or specific platelet proteins between the 3 groups. At the peak effort, there was a significant increase of the number of morphologically modified platelets in Groups A and B but not in healthy subjects. This platelet activation could not be linked to the presence of myocardial ischaemia because it was found both in patients with a negative maximal exercise stress test (Group A). Finally, no increase of the plasma concentrations of the platelet protein was observed in any of the groups.
The relative importance of antithrombin and anti-factor Xa activities of heparin fractions required to achieve optimal antithrombotic effects is unknown. To study this, we measured the effects of standard heparin, an octasaccharide heparin fraction (anti-factor Xa activity only), and dermatan sulfate (antithrombin activity only) on the prevention of thrombosis and related this to their anticoagulant effects in vivo in rabbits. Thrombosis was measured as the incorporation of 125I-fibrinogen into tissue thromboplastin-induced thrombi using a Wessler-type model. Ex vivo changes in thrombin clotting time (TCT) were used as an index of antithrombin activity, and a chromogenic anti-factor Xa assay was used to measure anti-factor Xa activity. In addition, the ability of the three sulfated polysaccharides to simultaneously inhibit the generation of thrombin activity and to enhance the inactivation of the factor Xa added to initiate thrombin generation in plasma was determined. Standard heparin, in a dose of 10 anti-factor Xa U/kg, inhibited thrombus formation by 90%, prolonged the TCT by two seconds, and resulted in an anti-factor Xa level of 0.32 U/mL. The octasaccharide heparin fraction, in a dose of 10 anti-factor Xa U/kg, inhibited thrombus formation by 41%, had no effect on the TCT, and resulted in an anti-factor Xa level of 0.28 U/mL. Higher doses of the octasaccharide resulted in a further increase in the anti-factor Xa levels but had no further effect on thrombus formation. Dermatan sulfate, in a dose of 500 micrograms/kg, inhibited thrombus formation by 95%, but had no affect on the TCT. These results indicate that the antithrombotic effect achieved by inhibiting factor Xa is limited and that better antithrombotic effects are achieved by heparin or heparin-like substances capable of influencing the inactivation and/or the generation of thrombin.
Platelet activation may participate in the pathophysiology of myocardial infarction occurring in patients with normal coronary arteriogram. We investigated this possibility in a series of 9 such patients (group A) during a standardized bicycle exercise test as myocardial infarction had occurred in all of them during or soon after strong physical exercise. Twelve patients with effort-induced angina and coronary atherosclerosis (group B) and eleven healthy subjects (group C) served as test groups. Peripheral venous blood was collected by separate venipuncture before, at peak exercise and during recovery. As a sensitive index of activation, the shape of the circulating platelets was examined with a phase contrast microscope after instantaneous fixation of the whole blood. The percentage of non strictly disc-shaped platelets with one or more thin pseudopods was determined. Simultaneously, the plasma levels of platelet factor 4 (PF4) and of beta-thromboglobulin (beta-TG) were measured. At rest, there was no significant difference in the platelet morphology nor in the plasma levels of platelet specific proteins between the three groups. During exercise, a significant change in platelet shape occurred in group A and B patients and not in the healthy subjects. This platelet activation was not related to myocardial ischemia since it occurred to a similar extent in group B patients who developed electrocardiographic changes and in group A patients who did not. There was no detectable release of platelet proteins during exercise in any group.
Bleeding is an important complication of heparin therapy. A number of low molecular weight heparin fractions produce less bleeding than standard heparin for an equivalent antithrombotic effect in experimental animals. Low molecular weight heparin fractions and fragments are produced by a number of different procedures but their relative effects on haemostasis and thrombosis have not been evaluated. We have compared the antithrombotic and haemorrhagic effects of two low molecular weight heparin fragments and of a heparinoid with porcine mucosa heparin and related these in vivo findings to the results of ex vivo tests of blood coagulation and in vitro tests of platelet vivo tests of blood coagulation and in vitro tests of platelet function. Haemorrhage was assessed using a rabbit ear bleeding model. The antithrombotic effects were assessed by measuring inhibition of a tissue thromboplastin-induced jugular vein thrombus and by inhibition of fibrin and platelet accumulation in an arterial-venous shunt. The ex vivo anticoagulant effects were assessed with the thrombin clotting time, activated partial thromboplastin time and anti-Xa assay, and the effect of these glycosaminoglycans on platelet function was assessed by measuring collagen-induced platelet aggregation. For a similar antithrombotic effect, standard heparin produced significantly more bleeding than the other 3 glycosaminoglycans. The antithrombotic effects of all 4 glycosaminoglycans occurred at similar levels of anti-Xa activity but there was no relationship between blood loss and the effects of these glycosaminoglycans on any of the other tests of blood coagulation. Standard heparin had a greater inhibitory effect on collagen-induced platelet aggregation than the low molecular weight glycosaminoglycans, supporting the possibility that the increased bleeding observed with heparin is related in part to its inhibitory effect on platelet function.
A simultaneous investigation of the kinetics of serotonin (5 HT) uptake and of binding sites was carried out in the platelets of normal subjects and of 10 patients affected with various types of myeloproliferative disorders (MD). The 5 HT uptake was analysed according to the Lineweaver-Burk and the Eadie-Hofstee methods. With the two methods, the patient's platelets exhibited a dramatic reduction of the Vi max and of the Km; in some patients the Eadie-Hofstee analysis revealed that a passive diffusion phenomenon is superimposed on the active 5 HT uptake at least for the higher concentration used. The binding data were analysed with the Scatchard method. Two classes of binding sites (high affinity - low capacity, low affinity - high capacity) were found in normal subjects and patients. Pharmacological studies with imipramine, a specific inhibitor of 5 HT uptake, suggested that both the sites are involved in 5 HT uptake. The number of both binding sites was significantly decreased in patient's platelets while the affinity constants of these binding sites were not significantly reduced in comparison with those of the control subjects. No correlations were found between Vi max, Km and the number of binding sites. These results suggest that a reduction in the number of platelet membrane acceptors for 5 HT commonly occurs in myeloproliferative disorders but does not provide a full explanation of the uptake defect.
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Twenty-four patients with various types of tumors and without evidence of consumption coagulopathy (normal routine coagulation tests) were investigated for intraplatelet ATP, ADP, serotonin, beta-thromboglobulin and platelet factor 4; the percentage of light circulating platelets was also determined. Evidence for an acquired storage pool defect was found in seven patients (29%) without any correlation with the clinical status, the presence of metastases, platelet count or fibrinogen level. These results show that exhausted platelets are commonly encountered in cancerous patients even in the absence of consumption coagulopathy. The precise mechanism of this abnormality remains to be established.
The authors report the case of an active 32 year old man who developed right leg DVT. Before heparinisation, he was discovered to have a low antithrombin III level (biological activity (B) 60%, immunological level (I) 50) and a further inquiry showed the same abnormality in 4 members of the family, leading to a diagnosis of a congenital deficit: a 35 year old sister with a bilateral post-DVT changes had antithrombin III levels of 70% (B) and 45% (I); two nephews, sons of the affected sister: the one aged 5 years was asymptomatic despite antithrombin III levels of 50% (I) and 70% (B); the other had experience DVT at the age of 2 and, on oral anti-vitamin K drugs, had antithrombin III levels of 55% (I) and 67% (B) at the age of 15 years; the patient's brother died at the age of 29 of cerebral vein thrombosis after pulmonary embolism. The recurrence of local signs of DVT after 12 day's heparin therapy with AT III levels (B) of 40%, led to a change in management with infusion of purified AT III concentrate at a dose of 40 U per kg (2 500 U per hour). This induced a rise in AT III activity to over 100% and enabled early introduction of anti-vitamin K therapy. The patient remains asymptomatic after 6 months follow-up. This case illustrates the value of determining AT III activity in all patients who developed DVT without obvious reason.(ABSTRACT TRUNCATED AT 250 WORDS)
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Plasma fibronectin (pFN) levels were measured in 52 patients throughout their stay in an intensive care unit. At the same time a close watch was kept for signs of sepsis. Low pFN levels regularly accompanied--but did not precede--infectious episodes and were also found in patients without septic complications. These findings indicate that a fall in pFN does not constitute a factor of increased susceptibility to infection.
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