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Biomedical subjects

C S Rinder

Publications and source records attributed to C S Rinder.

At least 19 recordsLinked to original sources
PubMed2001

Platelet PlA2 polymorphism enhances risk of neurocognitive decline after cardiopulmonary bypass. Multicenter Study of Perioperative Ischemia (McSPI) Research Group.

BACKGROUND: Neurocognitive decline, often produced by atherosclerotic plaque embolization, remains a frequent complication of cardiopulmonary bypass. Plaque fragments may initiate local thrombosis, which, in turn, aggravates the embolic insult. Prothrombotic genetic factors may exacerbate this process. We investigated whether the PlA2 polymorphism of platelet GPIIIa, a prothrombotic risk factor in other cardiovascular settings, is associated with early neurocognitive decline after cardiopulmonary bypass. METHODS: Neurocognitive changes were evaluated by the Mini-Mental State Examination administered preoperatively and on postoperative day 4 and the PlA genotype determined in 70 patients undergoing cardiopulmonary bypass. RESULTS: Forty-nine patients were PlA1/A1, and 21 were PlA1/A2 or PlA2/A2. Fifty-two patients (74%) demonstrated post-cardiopulmonary bypass neurocognitive decline, of which 34 were PlA1/A1 and 18 were PlA1/A2 or PlA2/A2 Multivariate analysis revealed that the PlA2 genotype and baseline Mini-Mental State Examination were significantly associated with greater neurocognitive decline (decreased Mini-Mental State Examination scores, p = 0.036 and 0.024, respectively). CONCLUSIONS: This study demonstrates a link between the PlA2 allele of platelet GPIIIa and more severe neurocognitive decline after cardiopulmonary bypass. Although the mechanism is unknown, it could represent exacerbation of platelet-dependent thrombotic processes associated with plaque embolism.

Aged↗
PubMed2001

The effects of heparin, protamine, and heparin/protamine reversal on platelet function under conditions of arterial shear stress.

UNLABELLED: Platelet dysfunction contributes to blood loss after cardiopulmonary bypass. This study examined the antiplatelet effects of heparin, protamine, and varying heparin/protamine ratios in an in vitro physiologic model and further elucidated the mechanism of the antiplatelet and anticoagulant effects of protamine. We used the Clot Signature Analyzer (CSA(TM)), a system that analyzes coagulation in flowing whole blood, to test two aspects of platelet function, with different concentrations of heparin and protamine, under conditions simulating arterial flow: collagen-induced thrombus formation (CITF) under moderate shear and high shear platelet activation, platelet hemostasis time (PHT). In addition, platelet aggregometry, celite activated clotting time (Hepcon(TM) ACT), prothrombin time (PT), and partial thromboplastin time (PTT) were measured. Both PHT and the CITF were prolonged by heparin at 20 microg/mL, protamine at 20 and 40 microg/mL, and heparin/protamine ratios of 1:1 and 1:2, but not at 1:1.5. The Hepcon ACT was prolonged by heparin 20 microg/mL and protamine alone at 20 and 40 microg/mL, was normal at a ratio of 1:1, and was prolonged at 1:1.5 and 1:2. Protamine 80 microg/mL prolonged the PT and PTT. Dependency on thrombin, protein kinase C activation, and nonspecific charge effects were examined. The direct thrombin inhibitor D-phenylalanyl-L-prolyl-L-arginyl-chloromethyl ketone prolonged the PHT and ACT, but not the CITF, whereas the polycationic molecules polyarginine and polylysine prolonged the CITF, but not the PHT. The effect of protamine on the PTT, but not PT, could be shortened by the addition of excess phospholipid. Therefore, heparin inhibits both high shear collagen-independent and moderate shear collagen-dependent platelet activation; however, the latter is not mediated by its antithrombin activity. Protamine's antithrombin effect may explain its inhibition of platelet activation at high shear stress. Protamine's nonspecific charge effects are more important for inhibiting moderate shear collagen-induced platelet activation. IMPLICATIONS: This study suggests that protamine reversal of heparin's antiplatelet effect occurs within a narrow window because of the direct antiplatelet effects of protamine. Antithrombin effects may explain the inhibition of shear activation of platelets by both heparin and protamine. Nonspecific charge effects of protamine may explain the inhibition of collagen platelet activation in the presence of medium shear.

Aged↗
PubMed1999

Role of C3 cleavage in monocyte activation during extracorporeal circulation.

BACKGROUND: We previously demonstrated that inhibiting formation of terminal complement components (C5a and C5b-9) prevents platelet and neutrophil (PMN) but not monocyte activation during simulated extracorporeal circulation (SECC). This study examined whether earlier complement inhibition during SECC, blocking C3a formation, would additionally prevent monocyte activation. METHODS AND RESULTS: SECC was established by recirculating heparinized whole blood from human volunteers on a membrane oxygenator. CAB-2, a chimeric protein constructed from genes encoding the complement regulatory proteins CD46 and CD55, inactivates the C3/C5 convertases and blocks in vitro generation of C3a, C5a, and C5b-9. CAB-2 was used in 4 experiments at a final concentration of 300 micrograms/mL and 4 experiments at 30 micrograms/mL; 4 control runs used vehicle alone. Samples were assayed for C3a and C5b-9, monocyte activation (CD11b upregulation), PMN activation (CD11b upregulation and elastase release), and platelet activation (P-selectin expression and monocyte-platelet conjugate formation). CAB-2 at both doses significantly inhibited formation of C3a and C5b-9 during SECC. High-dose CAB-2 significantly blocked monocyte and PMN CD11b upregulation and PMN elastase release. CAB-2 also inhibited formation of platelet activation-dependent monocyte-platelet conjugates. CONCLUSIONS: Blockade of complement activation early in the common pathway inhibited monocyte CD11b upregulation during SECC, suggesting that early complement components contribute most to monocyte activation during SECC. As expected, PMN and platelet activation were blocked by terminal complement inhibition. This investigation further elucidates the relation between complement and blood cell activation during simulated cardiopulmonary bypass.

Blood Platelets↗
PubMed1999

Selective blockade of membrane attack complex formation during simulated extracorporeal circulation inhibits platelet but not leukocyte activation.

OBJECTIVE: Complement activation is induced by cardiopulmonary bypass, and previous work found that late complement components (C5a, C5b-9) contribute to neutrophil and platelet activation during bypass. In the present study, we blocked C5b-9 formation during extracorporeal recirculation of whole blood to assess whether the membrane attack complex was responsible for both platelet and leukocyte activation. METHODS: In a simulated extracorporeal model that activates complement (C3a and sC5b-9), platelets (CD62P expression, leukocyte-platelet conjugate formation), and leukocytes (increased CD11b expression and neutrophil elastase), we examined an anti-human C8 monoclonal antibody that inhibits C5b-9 generation for its effects on cellular activation. RESULTS: Anti-C8 significantly inhibited sC5b-9 formation but did not block C3a generation. Anti-C8 also significantly inhibited the increase in platelet CD62P and monocyte-platelet conjugate formation seen with control circulation. Moreover, compared with control circulation, in which the number of circulating platelets fell by 45%, addition of anti-C8 completely preserved platelet counts. In contrast to blockade of both C5a and sC5b-9 during simulated extracorporeal circulation, neutrophil activation was not inhibited by anti-C8. However, circulating neutrophil and monocyte counts were preserved by addition of anti-C8 to the extracorporeal circuit. CONCLUSIONS: The membrane attack complex, C5b-9, is the major complement determinant of platelet activation during extracorporeal circulation, whereas C5b-9 blockade has little effect on neutrophil activation. These data also suggest a role for platelet activation or C5b-9 (or both) in the loss of monocytes and neutrophils to the extracorporeal circuit.

Antibodies, Monoclonal↗
PubMed1999

Evaluation of hemostasis by the Clot Signature Analyzer: a potentially valuable device for the anesthesiologist.

Rapid detection of hemostatic defects presents a challenge for the anesthesiologist who must balance anesthetic and surgical considerations for maintaining adequate platelet and coagulant factors, while keeping allogenic blood exposure to a minimum. The Clot Signature Analyzer, a point-of-care device capable of rapid response and easy interpretation is described here. Its applicability in two obstetrical patients with platelet dysfunction is discussed.

Adult↗
PubMed1998

Correlation of thrombosis with increased platelet turnover in thrombocytosis.

There are no readily applicable methods to routinely assess thrombosis risk and treatment response in thrombocytosis. Reticulated platelets (RP) define the most recently released platelets in the circulation, and the RP% has been shown to estimate platelet turnover in thrombocytopenic states. We examined whether increased RP values were associated with thrombotic complications in thrombocytosis. Platelet count, RP%, and absolute RP count were measured at presentation in 83 patients with chronic or transient thrombocytosis, 46 patients with deep vein (DVT) or arterial (ART) thrombosis and normal platelet counts, and 83 healthy controls with normal platelet counts. Chronic thrombocytosis patients presenting with thrombosis (n = 14) had significantly higher RP% (14.7% +/- 10. 1%, mean +/- SD) than asymptomatic chronic thrombocytosis patients (n = 23, RP% = 3.4% +/- 1.8%), healthy controls (3.4% +/- 1.3%), DVT patients (n = 21, 3.8% +/- 2.1%), or ART patients (n = 25, 4.5% +/- 4.1%, P < .05 for all comparisons). Chronic thrombocytosis patients with thrombosis also had significantly higher absolute RP counts than asymptomatic chronic thrombocytosis patients (98 +/- 64 x 10(9)/L [range, 54 to 249 x 10(9)/L] v 30 +/- 13 x 10(9)/L [range, 11 to 51 x 10(9)/L]; P = .0004), whereas healthy controls, DVT, and ART patients had similarly low absolute RP counts (6 +/- 6 x 10(9)/L, 9 +/- 7 x 10(9)/L, and 11 +/- 7 x 10(9)/L, respectively; P > .49). The RP% and absolute RP counts remained significantly higher in chronic thrombocytosis patients with thrombosis when patients were further subdivided into primary myeloproliferative disorders versus secondary thrombocytosis. Similarly elevated RP percentages and absolute counts were also noted in transient thrombocytosis patients with thrombosis (n = 6, 11.5% +/- 4.4% and 90 +/- 46 x 10(9)/L, respectively) when compared with asymptomatic transient thrombocytosis patients (n = 40, 4.5% +/- 2.7% and 35 +/- 16 x 10(9)/L, respectively) and to all control groups (P < .05 for all comparisons). In addition, 7 of 8 thrombocytosis patients who were studied before developing symptoms of thrombosis had elevated absolute RP counts compared with only 1 of 63 thrombocytosis patients who remained asymptomatic. Follow-up studies in seven chronic thrombocytosis patients showed that successful aspirin treatment of symptomatic recurrent thrombosis significantly reduced the RP% from 17.1% +/- 10.9% before therapy to 4.8% +/- 2.0% after therapy; absolute RP counts decreased from 102 +/- 67 x 10(9)/L to 26 +/- 10 x 10(9)/L (P < .01 for both). We conclude that thrombosis in the setting of an elevated platelet count is associated with increased platelet turnover, which is reversed by aspirin therapy. Measurement of reticulated platelets to assess platelet turnover may be useful in evaluating both treatment response and thrombotic risk in thrombocytosis.

Adolescent↗
PubMed1998

Differences in platelet alpha-granule release between normals and immune thrombocytopenic patients and between young and old platelets.

The risk of serious bleeding in patients with immune thrombocytopenic purpura (ITP) appears to be less than in comparably thrombocytopenic patients with megakaryocytic hypoplasia. It has been proposed that this difference is due to enhanced hemostatic activity of young platelets, which are increased in the circulation during ITP. We examined alpha-granule release in reticulated platelets (RP), which are thought to be the youngest circulating platelets, and in older non-reticulated platelets (non-RP) in normal human controls and ITP patients. Normal controls had a mean RP of 7%, compared with 42% in ITP patients. The mean concentration of thrombin receptor agonist peptide (TRAP) causing 50% of control RP to express CD62P (EC50) was 0.82+/-0.08 microM (SEM), significantly higher than the TRAP CD62P EC50 for RP in ITP, 0.57+/-0.06 microM (p = 0.04). Similarly, the TRAP EC50 for non-RP in controls, 0.84+/-0.09 microM, was significantly higher than in ITP, 0.56+/-0.07 microM (p = 0.03), suggesting that all platelets in ITP have an enhanced alpha-granule threshold response to TRAP compared with controls, while RP and older platelets within each patient group have similar threshold sensitivities to TRAP. By contrast, high-dose TRAP caused RP to express twice as much mean and total CD62P as non-RP in both ITP patients and controls (p <0.05 for both comparisons). We conclude that compared with controls, all platelets in ITP are primed to undergo alpha-granule release to TRAP, while in both ITP and controls, the newly circulating, reticulated platelets have the potential to contribute greater amounts of CD62P surface ligand compared with older platelets (non-RP) after stimulation. Both the increased RP% and enhanced platelet response to agonist in ITP may contribute to maintenance of hemostasis despite thrombocytopenia.

Adult↗
PubMed1997

Lymphocyte and monocyte subset changes during cardiopulmonary bypass: effects of aging and gender.

Complications of cardiopulmonary bypass (CPB) may be associated with either immune suppression or immune activation, but the specific effects of CPB on many lymphocyte and monocyte subsets are unclear. In addition, the increasing age of patients undergoing cardiac surgery raises the possibility of even greater effects on the immune system in elderly patients. We measured immunophenotypic alterations of circulating lymphocytes and monocytes after CPB in male and female cardiac surgery patients who were either younger than 60 or older than 75 years of age. The total lymphocyte counts in all patients decreased postoperatively; older patients had significantly lower counts at all time points. The absolute decline was greatest among T cells and particularly CD4+ T cells, which reached an average nadir of 251 cells/microl on postoperative day 1 in the older patients. The percentages of CD8+, CD4+CD45RA+, and CD4+CD45RO+ T cells did not change significantly, whereas the percentages of B cells and natural killer cells increased. Both T and B lymphocytes and monocytes showed evidence of activation, with increased percentages of CD3+HLADr+, CD3+IL2R+, and CD19+CD23+ lymphocytes and increased expression of CD11b on monocytes. By contrast, expression of class II major histocompatibility antigen (HLADr) monocytes decreased significantly. We conclude that CPB produces a profound alteration in the pool of circulating lymphocytes and monocytes, evidenced by decreased numbers of lymphocyte subsets including CD4+ cells and decreased expression of monocyte surface membrane proteins important for antigen presentation; CPB also activates a variety of specific circulating mononuclear cell subsets. Older patients showed patterns of lymphocyte and monocyte activation comparable to those of younger patients; however, they had consistently lower lymphocyte numbers and a trend toward decreased monocyte HLADr expression, potentially placing them at greater risk for infectious complications. Gender had no effect.

Age Factors↗
PubMed1995

Acadesine inhibits neutrophil CD11b up-regulation in vitro and during in vivo cardiopulmonary bypass.

Granulocyte adhesion to ischemic tissue, mediated in large part by beta 2 integrin receptors, is important in the pathophysiology of reperfusion injury. Acadesine, a drug that modulates adenosine levels in ischemic tissue, has been shown to reduce reperfusion injury in animal models of ischemia. The purpose of this study was to measure changes in granulocyte CD11b/CD18 in an in vitro assay and in an in vivo trial of acadesine administered during cardiopulmonary bypass to determine whether this agent might modulate up-regulation of this adhesion receptor. In vitro, whole blood was incubated with acadesine or control diluent, stimulated with N-formyl-methionyl-leucyl-phenylalanine, and granulocyte CD11b measured. Acadesine significantly (p < 0.01) inhibited N-formyl-methionyl-leucyl-phenylalanine-induced granulocyte CD11b up-regulation by a mean of 61%. In similar experiments, adenosine also inhibited N-formyl-methionyl-leucyl-phenylalanine-induced granulocyte CD11b up-regulation (p < 0.01). In vivo, 34 patients at our institution participating in a multicenter trial of acadesine during cardiopulmonary bypass were randomized to placebo, low-dose, or high-dose acadesine infusion perioperatively. Combining low- and high-dose treatment groups, there was significant (p = 0.05) inhibition of granulocyte CD11b up-regulation in patients receiving acadesine; granulocyte CD11b expression in the acadesine group peaked at 2.8 times baseline versus 4.3 for placebo. By contrast, monocyte CD11b up-regulation (peaking after cardiopulmonary bypass at 3 times baseline) was not affected by acadesine. Acadesine and adenosine inhibit up-regulation of granulocyte CD11b in vitro, and acadesine is capable of a similar inhibition during in vivo cardiopulmonary bypass. This inhibition may contribute to the ability of these agents to decrease in vivo reperfusion injury.

Adenosine↗
PubMed1995

Nitroprusside inhibition of platelet function is transient and reversible by catecholamine priming.

BACKGROUND: The time course and reversibility of sodium nitroprusside's in vivo inhibition of platelet function are unclear. METHODS: Platelet aggregation and P-selectin expression as measures of platelet dense and alpha-granule release, respectively, were examined before and after administration of sodium nitroprusside (18 mg) to human volunteers and in in vitro studies. Hypotension occurring with sodium nitroprusside administration was treated with intravenous crystalloid and/or phenylephrine. RESULTS: Compared with preinfusion studies, platelet aggregation to epinephrine was significantly inhibited immediately and 4 min after discontinuation of the sodium nitroprusside infusion but returned to baseline at 8 and 12 min after discontinuing sodium nitroprusside. However, both dense and alpha-granule release to adenosine diphosphate after in vivo sodium nitroprusside were never significantly inhibited even at the time when sodium nitroprusside infusion was maximal. In contrast to our in vivo findings, in vitro incubation of platelet-rich plasma with sodium nitroprusside resulted in significant inhibition of dense and alpha-granule release to adenosine diphosphate. These in vitro inhibitory effects of sodium nitroprusside were reversed by pretreatment with epinephrine but not phenylephrine. CONCLUSIONS: In normal volunteers, sodium nitroprusside inhibits platelet aggregation to epinephrine but not adenosine diphosphate; inhibition was reversed within 8-12 min after discontinuing sodium nitroprusside. Sodium nitroprusside in vitro inhibition of platelet function to adenosine diphosphate was reversed by epinephrine pretreatment. Because of the rapid reversibility of its antiplatelet effect, sodium nitroprusside may be clinically useful even when there is the potential for impaired coagulation.

Adenosine Diphosphate↗
PubMed1995

Blockade of C5a and C5b-9 generation inhibits leukocyte and platelet activation during extracorporeal circulation.

Complement activation contributes to the systemic inflammatory response induced by cardiopulmonary bypass. At the cellular level, cardiopulmonary bypass activates leukocytes and platelets; however the contribution of early (3a) versus late (C5a, soluble C5b-9) complement components to this activation is unclear. We used a model of simulated extracorporeal circulation that activates complement (C3a, C5a, and C5b-9 formation), platelets (increased percentages of P-selectin-positive platelets and leukocyte-platelet conjugates), and neutrophils (upregulated CD11b expression). to specifically target complement activation in this model, we added a blocking mAb directed at the human C5 complement component and assessed its effect on complement and cellular activation. Compared with a control mAB, the anti-human C5 mAb profoundly inhibited C5a and soluble C5b-9 generation and serum complement hemolytic activity but had no effect on C3a generation. Additionally, the anti-human C5 mAb significantly inhibited neutrophil CD11b upregulation and abolished the increase in P-selectin-positive platelets and leukocyte-platelet conjugate formation compared to experiments performed with the control mAb. This suggests that the terminal components C5a and C5b-9, but not C3a, directly contribute to platelet and neutrophil activation during extracorporeal circulation. Furthermore, these data identify the C5 component as a site for therapeutic intervention in cardiopulmonary bypass.

Antibodies, Monoclonal↗
PubMed1994

Noninvasive measurement of platelet kinetics in normal and hypertensive pregnancies.

OBJECTIVE: Our purpose was to determine platelet kinetics in pregnancy by means of noninvasive reticulated platelet counts and to examine in a pilot study whether increased reticulated platelet values were associated with preeclampsia and pregnancy-induced hypertension. STUDY DESIGN: Nulliparous women had blood samples drawn at enrollment (first prenatal visit) and at 28 and 36 weeks' gestation. The percent of reticulated platelets (an index of marrow platelet release correlating with increased thrombopoiesis), platelet-associated immunoglobulin, and serum antiplatelet antibody were measured and correlated with the clinical course for each patient. RESULTS: In 31 normal pregnancies the percent of reticulated platelets was never significantly higher than the values for normal nonpregnant women (5.8% +/- 2.2%) in spite of a significant decrease in platelet count by 36 weeks. By contrast, the percent of reticulated platelets in four women with preeclampsia rose significantly to 13.9% +/- 11.2% at 28 weeks, before the onset of clinical signs. No women had evidence of immune platelet destruction. CONCLUSION: In normal pregnancy the decline in platelet count is not accompanied by an increase in marrow platelet production, suggesting that the platelet decrease is dilutional without a compensatory thrombopoietic response or alternatively that thrombopoiesis is down-regulated during normal pregnancy. However, platelet production does increase before the onset of symptoms in a small number of women in whom preeclampsia or pregnancy-induced hypertension subsequently develops. These findings may justify a larger prospective study to determine whether noninvasive serial measurement of the percent of reticulated platelets can predict those pregnant women at risk for hypertension and preeclampsia.

Adolescent↗
PubMed1994

Neutrophil but not monocyte activation inhibits P-selectin-mediated platelet adhesion.

Selectins are Ca(2+)-dependent glycoprotein receptors that mediate the adhesion of activated platelets or endothelial cells to unstimulated leukocytes. Using purified cell fractions, we examined activated neutrophil adhesion to P-selectin-expressing platelets and found that phorbol 12-myristate 13-acetate (PMA), platelet activating factor C16 (PAF), and n-formyl-met-leu-phe (fMLP) pretreatment of neutrophils inhibited activated platelet adhesion. Furthermore, PMA and PAF were capable of dissociating established resting neutrophil-activated platelet conjugates. Since L-selectin is downregulated after leukocyte activation and has been postulated as a ligand for P-selectin, we preincubated resting neutrophils with Dreg-2 and Dreg-56, blocking monoclonal antibodies (MoAb) to L-selectin; these MoAb failed to inhibit activated platelet adhesion. To more closely approximate in vivo conditions of leukocyte and platelet activation, we also employed a whole blood (WB) model of leukocyte-platelet adhesion. We found that simultaneous activation of both platelets and leukocytes by PMA caused an immediate rise in the % of P-selectin-positive platelets accompanied by a rapid increase in monocyte-platelet and neutrophil-platelet conjugates; however, the % of neutrophil-platelet conjugates subsequently declined over 30-60 min to baseline levels while monocyte-platelet adhesion remained elevated over 90 min. By contrast, selective platelet activation in WB by thrombin resulted in an increase in platelet P-selectin expression accompanied by a sustained (90 min) elevation in both monocyte- and neutrophil-platelet conjugates. This increase in leukocyte-platelet conjugates after thrombin was not inhibited by preincubation of WB with Dreg-2 or Dreg-56. We conclude that neutrophil activation decreases the expression of the ligand for platelet P-selectin within 30-60 min resulting in inhibition of neutrophil-platelet adhesion and dissociation of existing neutrophil-platelet conjugates.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Adhesion Molecules↗
PubMed1994

Platelet-leukocyte activation and modulation of adhesion receptors in pediatric patients with congenital heart disease undergoing cardiopulmonary bypass.

Cardiopulmonary bypass has been shown in adults to activate platelets and leukocytes, lead to the formation of circulating platelet-leukocyte conjugates, and alter adhesive receptors on both cell types. Pediatric patients with congenital heart disease undergoing cardiopulmonary bypass, however, have not been extensively studied and may represent a group at particular clinical risk for bleeding and pulmonary dysfunction. We studied 13 patients with congenital heart disease undergoing operations necessitating bypass, 7 with cyanotic and 6 with noncyanotic congenital heart disease. We determined that (1) the surface density of platelet glycoprotein Ib was significantly lower at baseline and throughout bypass in patients with cyanotic heart disease than in noncyanotic patients; (2) platelet glycoprotein Ib in both cyanotic and noncyanotic congenital heart disease decreased significantly during bypass, with a nadir of 75% of baseline values; (3) platelets were activated to a high degree, comparable with that seen in adults; (4) mean circulating monocyte-platelet conjugates rose significantly during bypass, increasing from 36% to 66% by the end of bypass, whereas neutrophil-platelet conjugates and lymphocyte-platelet conjugates declined; and (5) both monocytes and neutrophils were activated by cardiopulmonary bypass, as assessed by increased surface expression of CD11b and, in the case of monocytes, CD11b expression continued to increase even after termination of bypass. Patients with cyanotic and noncyanotic heart disease did not differ with respect to platelet or leukocyte activation or the formation of platelet-leukocyte conjugates. We conclude that in children with congenital heart disease cardiopulmonary bypass causes loss of platelet adhesion receptors, activation of platelets, formation of platelet-leukocyte conjugates, and leukocyte activation. Cyanotic and noncyanotic patients are qualitatively similarly affected; however, cyanotic patients demonstrate a baseline deficit in the platelet adhesion receptor glycoprotein Ib. These cellular changes may contribute to both the hemostatic and inflammatory complications associated with cardiopulmonary bypass.

Blood Platelets↗
PubMed1993

Aspirin does not inhibit adenosine diphosphate-induced platelet alpha-granule release.

The involvement of metabolites of arachidonic acid in platelet-dense granule secretion and secondary platelet-platelet interactions is well characterized. However, their role in heterotypic interactions dependent on alpha-granule secretion is less well understood. Using platelet-surface expression of P-selectin as a marker of alpha-granule secretion, we have shown that: (1) aspirin treatment of platelets at doses that block dense granule secretion does not inhibit alpha-granule secretion to adenosine diphosphate (ADP); (2) synergism between epinephrine and ADP in the induction of P-selectin expression is similarly unaffected by aspirin; and (3) the ability of P-selectin to mediate adhesion of activated platelets to monocytes and polymorphonuclear lymphocytes in whole blood is also unchanged by aspirin treatment. To further explore the mechanisms responsible for platelet alpha-granule secretion, we have shown that inhibition of Na+/H+ exchange by either acidification of the extracellular medium or amiloride treatment blocked ADP-induced P-selectin expression. In contrast, incubation with the platelet lipoxygenase inhibitor 5,8,11-eicosatrynoic acid, by itself and with aspirin, did not decrease ADP-induced P-selectin expression. We conclude that platelet alpha-granule secretion in response to ADP is dependent on intact Na+/H+ exchange but is independent of the lipoxygenase- and cyclooxygenase-dependent metabolites of arachidonic acid.

Adenosine Diphosphate↗
PubMed1992

Cardiopulmonary bypass induces leukocyte-platelet adhesion.

Cardiopulmonary bypass (CPB) has been demonstrated to activate platelets, producing an increased number of circulating platelets that have undergone alpha-granule release and express granule membrane protein-140 (GMP-140) on their surface. In vitro, GMP-140 mediates activated platelet adhesion to neutrophils (PMN) and monocytes, causing the formation of leukocyte-platelet conjugates. Using a newly developed assay that measures the percentage of circulating leukocyte-platelet conjugates in whole blood, we studied 17 patients undergoing CPB and have determined that (1) monocyte-platelet conjugates increased significantly during CPB, from 18% +/- 1.5% to 44% +/- 4.5% (mean +/- SEM) by the end of CPB, while PMN-platelet conjugates increased only slightly and lymphocyte-platelet conjugates decreased; (2) the time course of the increase in monocyte- and PMN-platelet conjugates paralleled that of the increase in circulating activated platelets, as determined by the presence of surface GMP-140; and (3) monocyte activation, as assessed by increased surface expression of CD11b, showed a gradual increase similar to the increase in monocyte-platelet conjugates, while PMN surface CD11b peaked immediately after the start of CPB. We conclude that CPB, through increased platelet GMP-140 expression, causes formation of monocyte-platelet, and to a lesser extent, PMN-platelet conjugates. The activation of monocytes and PMN on CPB, as evidenced by CD11b expression, occurs with differing time courses.

Blood Platelets↗
PubMed1991

Dynamics of leukocyte-platelet adhesion in whole blood.

The dynamics of leukocyte-platelet adhesion and platelet-platelet interaction in whole blood are not well understood. Using different platelet agonists, we have studied the whole blood kinetics of these heterotypic and homotypic interactions, the relative abilities of different leukocyte subsets to participate in platelet adhesion, and the ligands responsible for adhesion. When platelet aggregation was inhibited by the Arg-Gly-Asp-Ser (RGDS) peptide, thrombin stimulation of whole blood resulted in platelet expression of granule membrane protein 140 (GMP-140) and, simultaneously, a marked increase in the percentage of monocytes and neutrophils (PMN) binding platelets, as well as an increase in the number of platelets bound per monocyte and PMN. Lymphocytes were unaffected. Monocytes bound more platelets and at an initially faster rate than PMN. This increase in monocyte and PMN adhesion to platelets was completely inhibited by the blocking monoclonal antibody (MoAb), G1, to GMP-140. When the combination of epinephrine and adenosine diphosphate (epi/ADP) was used as a less potent agonist in the presence of RGDS, GMP-140 expression per platelet was less, and while monocyte-platelet conjugates formed, PMN-platelet conjugates did not. With epi/ADP in the absence of RGDS, there was an immediate, marked decrease in the percentage of all leukocytes with bound platelets, simultaneous with an increase in the percentage of unbound platelet aggregates. As these platelet aggregates dissociated, the percentage of monocytes and PMN with adherent platelets increased, with monocytes again binding at a faster initial rate than PMN. This recovery of monocyte and PMN adhesion to platelets was also inhibited by the G1 MoAb. We conclude that: (1) monocytes and PMN bind activated platelets in whole blood through GMP-140; (2) monocytes have a competitive advantage over PMN in binding activated platelets, particularly when less potent platelet agonists are used; and (3) platelet aggregate formation initially competes unactivated platelets off leukocytes; subsequent aggregate dissociation allows the now activated platelets to readhere to monocytes and PMN through GMP-140. These studies further elucidate the dynamic interaction of blood cells and possible links between coagulative and inflammatory processes.

Adenosine Diphosphate↗