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Biomedical subjects

H R Baumgartner

Publications and source records attributed to H R Baumgartner.

At least 55 records · Page 3Linked to original sources
PubMed1987

Excessive deposition of fibrin, platelets and platelet thrombi on vascular subendothelium during contraceptive drug treatment.

We investigated the effect of oral contraceptives on thrombogenesis induced by subendothelium of rabbit aorta (SE), exposed to flowing non-anticoagulated blood in an annular flow chamber. Six healthy women on sequential contraceptive drugs (0.05 mg aethinylestradiol/day, 0.125 mg desogestrel/day) were compared with 6 women without hormonal contraception and 6 men. On contraceptive drug treatment, blood values were significantly increased for fibrinogen (2.6 +/- 0.2 vs 1.9 +/- 0.1 g/l) and fibrinopeptide A (3.9 +/- 0.9 vs 0.9 +/- 0.1 ng/ml), whereas antithrombin III was decreased (81 +/- 4 vs 97 +/- 6%). Fibrin deposition on vascular subendothelium was more than four-fold increased when measured morphologically (63.4 +/- 2.5 vs 14.6 +/- 6.8% coverage of SE surface with fibrin) as well as immunologically (29.3 +/- 2.2 vs 4.5 +/- 1.9 micrograms fibrin/cm2 of SE). Thrombus volumes were more than two-fold increased in women with contraceptives (9.0 +/- 1.4 vs 3.7 +/- 1.0 micron 3/micron 2). Our study shows that during contraceptive drug treatment the exposure of flowing blood to vascular subendothelium leads to excessive deposition of fibrin and platelet thrombi. Measurement of blood interactions with subendothelium might be of predictive value in hypercoagulable states such as contraceptive treatment.

Adult↗
PubMed1987

Role of platelet membrane glycoproteins and von Willebrand factor in adhesion of platelets to subendothelium and collagen.

Development of in vitro perfusion systems and quantitative methods to evaluate various aspects of platelet-surface interactions have helped to elucidate some complex interactions in platelet adhesion and platelet-platelet cohesion. The importance of platelet GPs in these interactions was soon evident, and rapid progress in biochemistry and immunology has made it possible to study the roles of these GPs in more detail. From our studies, which made use of platelets with GP deficiencies, MAbs, purified vWF, proteolytic fragments of vWF, a synthetic peptide, and in vitro perfusion systems, it appeared that GPIb and GPIIb/IIIa function as receptors for vWF, which binds platelets to connective tissue at sites of vascular lesions (FIGURE 8). More detailed information about these interactions is expected in the near future when bioengineered products are available for testing in flow models and in other experimental approaches.

Antibodies, Monoclonal↗
PubMed1987

Platelet von Willebrand factor: evidence for its involvement in platelet adhesion to collagen.

Although it is well established that plasma von Willebrand Factor (vWF) is essential to platelet adhesion to subendothelium at high shear rates, the role of platelet vWF is less clear. We studied the respective role of both plasma and platelet vWF in mediating platelet adhesion to fibrillar collagen in a parallel-plate perfusion chamber. Reconstituted blood containing RBCs, various mixtures of labeled washed platelets and plasma from controls or five patients with severe von Willebrand disease (vWD), was perfused through the chamber for five minutes at a shear rate of 1,600 s-1. Platelet-collagen interactions were estimated by counting the radioactivity in deposited platelets and by quantitative morphometry. When the perfusate consisted of normal platelets suspended in normal plasma, platelet deposition on the collagen was 24.7 +/- 3.6 X 10(6)/cm2 (mean +/- SEM, n = 6). Significantly less deposition (16 +/- 2.3) was observed when vWD platelets were substituted for normal platelets. In mixtures containing vWD plasma, significantly greater deposition (9 +/- 2.2) was obtained with normal than with vWD platelets (1 +/- 0.4) demonstrating a role for platelet vWF in mediating the deposition of platelets on collagen. Morphometric analysis confirmed these data. Our findings indicate that platelet, as well as plasma, vWF mediates platelet-collagen interactions at a high shear rate.

Antibodies, Monoclonal↗
PubMed1986

Role of shear rate and platelets in promoting fibrin formation on rabbit subendothelium. Studies utilizing patients with quantitative and qualitative platelet defects.

The deposition of platelets on subendothelium of rabbit aortic segments exposed to non-anticoagulated human blood increased progressively with increasing wall shear rates (50-2,600 s-1), whereas fibrin deposition decreased. Studies in normal subjects and patients with platelet disorders suggested that, under the conditions used, platelets were essential for fibrin deposition at intermediate (650 s-1) but not low (50 s-1) shear rates. Fibrin deposition was markedly diminished in a patient with Scott syndrome whose platelets have a diminished capacity to bind Factor Xa and activate Factors IX and II. In glycoprotein IIb-IIIa deficiency, fibrin deposition was normal (or somewhat increased), whereas in glycoprotein Ib deficiency the association of fibrin with platelets, but not subendothelium, was decreased. The findings indicate that platelets, perhaps through surface localization of coagulation proteins, promote fibrin deposition on subendothelium at arterial shear rates and suggest that agents directed against platelet coagulant properties could be antithrombotic.

Blood Platelet Disorders↗
PubMed1986

Platelet adhesion and thrombus formation on subendothelium in platelets deficient in glycoproteins IIb-IIIa, Ib, and storage granules.

Patients whose platelets are deficient in glycoprotein (GP) Ib, IIb-IIIa (thrombasthenia), or granule substances (storage pool deficiency, SPD) were studied to define further the properties of platelets that mediate platelet adhesion and thrombus formation on subendothelium. Both nonanticoagulated and citrated blood were exposed to everted, de-endothelialized rabbit vessel segments under controlled flow conditions and shear rates varying from 650 to 3,300 sec-1. Morphometry was used to measure platelet thrombus dimensions and the percentage of the subendothelial surface covered with contact (C) or spread (S) platelets. Adhesion was defined as C + S. The results in SPD demonstrated (1) reduced thrombus dimensions in delta-SPD (pure dense granule deficiency) in proportion to the magnitude of the dense granule defect; (2) an even greater reduction in thrombus dimensions in patients with combined deficiencies of alpha and dense granules (alpha delta-SPD); and (3) impaired platelet adhesion at several conditions in alpha delta-SPD and, in delta-SPD, a hematocrit-dependent impairment of adhesion in citrated blood at 2,600 sec-1. In thrombasthenia, platelets were present as a monolayer on the subendothelial surface in both nonanticoagulated and citrated blood, indicating an absolute requirement for GPIIb-IIIa in promoting platelet-platelet interaction at all shear rates and perfusion times. Two types of abnormalities in platelet-vessel wall interactions were observed. In nonanticoagulated blood, the percentage of platelets in the C phase was consistently increased at all shear rates, but C + S values were normal. These observations indicate that platelets deficient in GPIIb-IIIa do not spread normally on the subendothelial surface exposed to nonanticoagulated blood. With citrated blood, the C + S value in thrombasthenia was reduced at both 800 and 2,600 sec-1, as in von Willebrand's disease, and a similar degree of reduction (about 50%) was observed in normal blood treated with a monoclonal antibody to GPIIb-IIIa. The findings, together with theoretical considerations, are consistent with an hypothesis that GPIIb-IIIa mediates the spreading of platelets on subendothelium following the initial attachment through GPIb and that GPIIb-IIIa may be considered an adhesion site on the platelet membrane. Abnormalities of GPIIb-IIIa may, depending on the conditions of study, result in either increased values of C platelets or decreased values of C + S. The results of the study further suggest that a complex interaction of platelet granule factors and membrane GP mediate platelet adhesion and thrombus formation.

Adenine Nucleotides↗
PubMed1986

Mediation of platelet adhesion to fibrillar collagen in flowing blood by a proteolytic fragment of human von Willebrand factor.

The effect of purified von Willebrand Factor (vWF) fragments, SpII (dimer of two 110 kd subunits) and SpIII (dimer of two 170 kd subunits) obtained with S aureus V-8 protease was tested upon platelet adhesion to collagen. Purified fibrillar human collagen coated onto cover slips was incubated with SpII, SpIII, or undigested vWF and exposed to reconstituted human blood in a parallel-plate perfusion chamber at a high shear rate. Platelet-collagen interactions were estimated using 51Cr-platelets and quantitative morphometry. When blood was reconstituted with citrated autologous plasma, SpIII and vWF strikingly enhanced platelet adhesion to collagen whereas SpII had no effect. When blood was reconstituted with human albumin and divalent cations, SpIII and vWF again promoted platelet adhesion to collagen. In conclusion, our data suggest that (1) SpIII, the N-terminal portion of vWF which binds to platelet membrane glycoprotein Ib, functionally substitutes for vWF in supporting platelet adhesion to collagen; (2) SpII, the C-terminal portion which binds to glycoprotein IIb/IIIa, has no such effect; (3) in addition to its platelet binding domain, SpIII contains another site for binding to collagen; and (4) the multimeric structure of vWF is not required for platelet adhesion to collagen.

Binding Sites↗
PubMed1985

7-Bromo-1,5-dihydro-3,6-dimethylimidazo[2,1-b]quinazolin-2(3H)- one (Ro 15-2041), a potent antithrombotic agent that selectively inhibits platelet cyclic AMP-phosphodiesterase.

This study with the new analog Ro 15-2041 (7-bromo-1,5-dihydro-3,6-dimethylimidazo[2,1-b]quinazolin-2(3H)-on e) confirms and substantially extends the activity spectrum of imidazoquinazolinones as potent platelet function inhibitors. Ro 15-2041 inhibited platelet aggregation induced by all common platelet agonists in platelet-rich plasma obtained from various species including man (IC50 = 1-3 microM). The compound potentiated platelet inhibition by prostacyclin, the prostacyclin-induced increase of intraplatelet cyclic (c) AMP levels and inhibited the collagen-induced release of serotonin and beta-thromboglobulin. Ro 15-2041 reduced the increase and accelerated the normalization of cytosolic free Ca++ in thrombin-stimulated human platelets. Ro 15-2041 is a potent (IC50 = 70 nM) and selective inhibitor of platelet cAMP-phosphodiesterase activity. Whereas Ro 15-2041 caused complete inhibition of cAMP-phosphodiesterase activity in human platelet supernatants, breakdown of cAMP in cardiac homogenates was depressed to maximally 50%. In human brain and rabbit uterus Ro 15-2041 was at least 1000 times less potent. By comparison, papaverine fully inhibited phosphodiesterase activity in all four tissues with similar IC50 values of about 5 microM. Furthermore, Ro 15-2041 selectively inhibited cAMP-phosphodiesterase activity of a bovine calmodulin-independent but not of a calmodulin-dependent enzyme preparation. The compound exhibited significant p.o. activity in various ex vivo and in vivo platelet function tests.(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1984

Hybridoma antibodies to human von Willebrand factor. II. Relative role of intramolecular loci in mediation of platelet adhesion to the subendothelium.

Hybridoma antibodies specific for seven independent topographical sites were used to characterize von Willebrand factor (vWF) and to relate the epitopes to functional loci required for vWF-mediated adhesion of platelets to subendothelium and ristocetin-induced platelet aggregation. The capacity of antibodies to influence the adhesion of human platelets to rabbit aortic subendothelium was analysed in annular perfusion chambers. At a high shear rate similar to that of the microcirculation, four monoclonal antibodies inhibited adhesion. In contrast, no inhibition was observed at low shear. Only one of the four antibodies that inhibited platelet adhesion also attenuated ristocetin-cofactor activity (VIIIR:RCo). Conversely, one antibody that inhibited VIIIR:RCo had no effect upon platelet adhesion. These data support the hypothesis that the molecular loci involved in the two biological functions of vWF are not identical. When these conclusions are considered within the context of a spatial map of the vWF protein surface developed by competitive displacement analysis, the epitopes related to platelet adhesion appear to be spaced and differ from those involved in ristocetin-induced platelet-platelet interaction.

Animals↗
PubMed1984

Platelet interaction with rabbit subendothelium in von Willebrand's disease: altered thrombus formation distinct from defective platelet adhesion.

Blood interaction with the subendothelium of rabbit aorta was investigated in an annular perfusion chamber using patients with von Willebrand's disease, hemophilia, and afibrinogenemia. The vessels were exposed to nonanticoagulated blood for a range of flow conditions (wall shear rates of 650-3,300 s-1) and exposure times (1.5-10 min). The resultant platelet and fibrin interaction was quantified by the use of several morphometric techniques, one of which was developed to measure more precisely the dimensions (height and volume) of platelet thrombi attached to the subendothelium. A major finding was that under flow conditions in which little or no defect in platelet adhesion was observed in von Willebrand's disease, platelet thrombus height and volume in this disorder were significantly reduced as compared with normal controls or patients with hemophilia. Thus, Factor VIII/von Willebrand factor (VIII/VWF) may mediate not only the adhesion of platelets to subendothelium but also platelet-platelet attachments necessary for normal thrombus development. The level of Factor VIII:coagulant activity (VIII: C) was also observed to influence the resultant thrombus height and volume deposited on subendothelium, presumably through the generation of thrombin or some other procoagulant factor preceding fibrin formation, since normal values of thrombus dimensions were always observed in a patient with a fibrinogen deficiency. The influence of VIII:C became greater as shear rate was reduced, whereas as shear rate was increased, VIII/VWF was more dominant in determining the resultant platelet deposition on subendothelium. Thus, the deficiencies of VIII:C and VIII/VWF in hemophilia and von Willebrand's disease can lead to various abnormalities in platelet and fibrin association with subendothelium. The importance of a particular deficiency will depend strongly on the local blood flow conditions.

Adult↗
PubMed1984

Fibrin formation, fibrinopeptide A release, and platelet thrombus dimensions on subendothelium exposed to flowing native blood: greater in factor XII and XI than in factor VIII and IX deficiency.

Fibrin deposition and platelet thrombus dimensions on subendothelium were studied in four groups of patients with coagulation factor deficiencies. Five patients with factor VIII deficiency (APTT 120 +/- 8 sec) and three patients with factor IX deficiency (APTT 125 +/- 11 sec) were severe bleeders, whereas four patients with factor XII deficiency and seven with factor XI deficiency were either asymptomatic or only mild bleeders despite APTT values of 439 +/- 49 and 153 +/- 13 sec, respectively. Everted segments of deendothelialized rabbit aorta were exposed at a shear rate of 650 sec(-1) for 5 and 10 min to directly sampled venous blood in an annular chamber. Blood coagulation was evaluated by measuring fibrin deposition (percent surface coverage) on the subendothelium and post-chamber fibrinopeptide A levels; platelet thrombus dimensions on the subendothelium were evaluated by determining the total thrombus volume per surface area (using an optical scanning technique) and the average height of the three tallest thrombi. Consistent differences were observed among the patient groups for both the 5-min and 10-min exposure times. The larger of the 5- and 10-min exposure-time values was used to calculate group averages. Fibrin deposition in normal subjects was 81% +/- 5% surface coverage, and post-chamber fibrinopeptide A values were 712 +/- 64 ng/ml. Markedly decreased fibrin deposition and fibrinopeptide A levels were observed in factor VIII deficiency (2% +/- 1% and 102 +/- 19 ng/ml) and factor IX deficiency (11% +/- 7% and 69 +/- 11 ng/ml). In contrast, significantly higher values were obtained in patients deficient in factor XI (33% +/- 5% and 201 +/- 57 ng/ml) and factor XII (66% +/- 12% and 306 +/- 72 ng/ml). Differences in thrombus dimensions were also observed. In normal subjects, the value for thrombus volume and average height of the tallest thrombi were 8.3 +/- 1.3 cu micron/sq micron and 145 +/- 11 micron, respectively, and in patients were as follows: FVIII, 2.7 +/- 0.6 and 71 +/- 7; FIX, 4.5 +/- 1.8 and 88 +/- 14; FXI, 11.8 +/- 1.9 and 125 +/- 10; and FXII, 7.9 +/- 3.1 and 130 +/- 25. Platelet thrombus dimensions were normal in a patient with fibrinogen deficiency, indicating that the smaller thrombi in factor VIII and factor IX deficiencies were probably due to impaired evolution of thrombin rather than diminished fibrin formation.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1983

Activation of human and rabbit blood platelets by synthetic structural analogs of platelet activating factor.

The proaggregatory potencies of synthetic analogs of platelet activating factor (PAF-acether: 1-0-alkyl 2-0-acetyl sn-glycero-3-phosphorylcholine) were tested in rabbit and human platelet rich plasma (PRP). For activation of human compared to rabbit platelets about 30 to 100 times higher concentrations of the compounds were needed, but the relative potencies of the analogs tested were quite similar in both species. The absolute stereospecificity required for platelet activation could be confirmed and extended also to the pair of enantiomers with a cis-9 double bond in the 0-alkyl chain and to the enantiomers with the 0-alkyl chain at C-2 of glycerol. The propionyl ester at C-2 of glycerol proved to be as potent as the acetyl ester but replacement by the formyl as well as by the butyryl ester reduced the activity to less than three per cent. Variations at the 3-phosphorylcholine substituent all abolished the activity. It appears that the correct stereochemistry and a phosphorylcholine group in a strictly defined position towards the asymmetric C-2 of the glycerol backbone are absolute requirements for activity whereas variations in the alkyl and the short chain acyl groups have not as dramatic consequences.

Animals↗