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Biomedical subjects

Henry M Rinder

Publications and source records attributed to Henry M Rinder.

At least 19 recordsLinked to original sources
PubMed2007

Leukocyte effects of C5a-receptor blockade during simulated extracorporeal circulation.

BACKGROUND: Distinct pathways of leukocyte activation during simulated cardiopulmonary bypass are mediated by the complement C5a anaphylatoxin. We hypothesized that a human C5a receptor antagonist would specifically inhibit the inflammatory response of neutrophils to simulated extracorporeal circulation, while preserving the C5b-9 pathway for innate immunity. METHODS: An in vitro extracorporeal circuit recirculated fresh heparinized whole blood through a membrane oxygenator with and without addition of a small molecule human C5a receptor antagonist. Samples were periodically drawn over 90 minutes for complement and leukocyte activation studies. RESULTS: Addition of the C5a receptor antagonist to simulated extracorporeal circulation abrogated both neutrophil CD11b upregulation and interleukin 8 release (p < 0.01 for both), despite full generation of C3a and C5b-9; however, elastase release from neutrophils was unaffected. Although C5a receptor blockade only trended toward inhibiting monocyte CD11b upregulation (p = 0.09), circuit clearance of both monocytes (p = 0.04) and neutrophils (p = 0.01) was significantly decreased. In addition, the C5a receptor antagonist completely blocked both neutrophil-platelet and monocyte-platelet conjugate formation (p < 0.001 for both), without affecting platelet P-selectin expression. CONCLUSIONS: C5a receptor blockade during simulated extracorporeal circulation completely blocked neutrophil beta2 integrin upregulation and induction of plasma interleukin 8, suggesting an acute downregulatory effect on neutrophil chemotaxis-related pathways, while preserving terminal complement generation and neutrophil elastase release. Inhibition of leukocyte-platelet conjugate formation suggests a novel function for leukocyte adhesive receptors, possibly related to preservation of elastase generation.

Blood Platelets↗
PubMed2006

Transcerebral platelet activation after aortic cross-clamp release is linked to neurocognitive decline.

BACKGROUND: Neurocognitive decline after cardiac surgery requiring cardiopulmonary bypass (CPB) may be caused in part by highly prothrombotic atheroemboli to the brain; the source of these emboli is likely the ascending aorta and aortic arch. We examined transcerebral platelet activation gradients using simultaneous measurements in arterial and jugular venous blood and then compared gradients with post-CPB-associated neurocognitive injury. METHODS: Eighty-one patients undergoing elective coronary artery bypass graft surgery requiring CPB were studied. Neurocognitive function was measured preoperatively and again at 6 weeks postoperatively. Paired arterial and jugular venous blood samples were drawn before surgery, immediately before and after aortic cross-clamp removal (an event previously linked to embolic showers), and at the end of the operation. Transcerebral platelet activation gradients (venous minus arterial values) were compared in patients with and without cognitive deficit. RESULTS: Immediately after aortic cross-clamp removal, there was a significant increase in the transcerebral platelet activation gradient (increased % P-selectin-positive platelets during transcerebral passage) in the subset of patients who subsequently developed post-CPB cognitive deficit; this platelet activation gradient did not occur in patients without cognitive injury. In contrast, there was no transcerebral gradient of platelet activation in CPB patients as an entirety, nor was there a gradient at all other time points in the patient subset who went on to have cognitive deficit develop. This fleeting gradient of transcerebral platelet activation after cross-clamp removal was also significantly correlated with the overall change in cognitive injury score. CONCLUSIONS: Transient intracerebral platelet activation after removal of the aortic cross-clamp is associated with post-CPB neurocognitive injury.

Aged↗
PubMed2006

Antithrombin reduces monocyte and neutrophil CD11b up regulation in addition to blocking platelet activation during extracorporeal circulation.

BACKGROUND: Patients undergoing cardiac surgery requiring cardiopulmonary bypass develop a systemic inflammatory reaction. Antithrombin III (AT) has anticoagulant effects but also shows evidence of anti-inflammatory activity. The aim of this study was to examine whether exogenous AT could reduce white blood cell activation (CD11b up regulation or elastase release), in addition to inhibiting platelet (PLT) activation and fibrin generation, during simulated cardiopulmonary bypass (sCPB), undertaken in the absence of endothelium. STUDY DESIGN AND METHODS: sCPB was carried out with minimally heparinized (2 U/mL) human blood for 90 minutes in controls and with supplementation by low-dose (1 U/mL) and high-dose (5 U/mL) AT. RESULTS: High-dose AT blunted thrombin generation during sCPB (prothrombin fragment 1.2); both doses significantly inhibited thrombin activity (fibrinopeptide A). Complement activation (C3a and C5b-9) was unaffected by AT. High-dose AT inhibited PLT activation (P-selectin expression and P-selectin-dependent monocyte-PLT conjugate formation). AT supplementation at the higher dose significantly abrogated monocyte and neutrophil CD11b up regulation and neutrophil elastase release. CONCLUSION: In addition to anticoagulant and anti-PLT effects, pharmacologic AT doses significantly blunted monocyte and neutrophil CD11b up regulation and neutrophil elastase release during sCPB, independent of endothelial effects. These data provide evidence for the direct anti-inflammatory activity of AT that has clinical relevance for CPB complications.

Antithrombin III↗
PubMed2006

Cardiac surgery in a patient with heparin-induced thrombocytopenia--cautions with use of the direct thrombin inhibitor, argatroban.

Heparin-induced thrombocytopenia (HIT) is being recognized in an increasing number of patients referred for cardiac surgery, as a result of previous exposure to heparin. We present a case of a patient with HIT scheduled for aortic valve replacement and coronary bypass graft surgery, who was managed with the direct thrombin inhibitor, argatroban for anticoagulation during cardiopulmonary bypass (CPB). The patient sustained continued bleeding in excess of the acknowledged half-life of the drug and required a substantial number of blood products to restore coagulation following CPB. Pertinent reports using argatroban for cardiac surgery with CPB are reviewed in the context of the present case report. The pharmacologic basis, cost analysis and resource utilization of heparin substitutes are discussed for the patient with HIT requiring CPB.

Aged, 80 and over↗
PubMed2005

Atrial fibrillation after cardiac surgery/cardiopulmonary bypass is associated with monocyte activation.

Atrial fibrillation (AF) contributes significantly to morbidity and mortality in as many as one-third of patients after cardiac surgery that requires cardiopulmonary bypass (CPB). Recent data suggest that inflammatory infiltration of the myocardium may predispose to AF. We conducted an exploratory pilot study to determine if there was an association between the perioperative leukocyte inflammatory response to cardiac surgery/CPB and postoperative AF. We enrolled 72 patients undergoing cardiac surgery with CPB; all patients were in sinus rhythm before surgery. Leukocyte activation (CD11b upregulation) was perioperatively measured in monocytes and neutrophils (PMN). Preoperative C-reactive protein (CRP) and perioperative neutrophil myeloperoxidase (MPO) were also monitored for inflammation, and troponin I was assayed for perioperative cardiac muscle damage. All markers were evaluated for differences between the subset of patients who developed AF versus those who remained in normal sinus rhythm after surgery. All 72 patients completed the study. Postoperative AF developed in 26 (36%) patients. Perioperative monocyte CD11b upregulation was significantly increased in patients who developed AF (P = 0.01), but increases in PMN CD11b were not significantly associated with AF (P = 0.057). The increase in both monocyte and PMN counts after aortic cross-clamp release was significantly associated with postoperative AF (P = 0.007 and P = 0.005, respectively). By contrast, preoperative CRP and perioperative MPO did not differ between AF and normal rhythm patients. Similarly, the peak value of troponin I did not differ between groups. In this pilot study of cardiac surgery/CPB patients, perioperative upregulation of the monocyte adhesion receptor, CD11b, and higher circulating monocyte and PMN numbers were associated with postoperative AF, suggesting that the induction of cellular inflammation during cardiac surgery/CPB may contribute to this pathophysiology.

Aged↗
PubMed2004

Comparison of coronary artery specific leukocyte-platelet conjugate formation in unstable versus stable angina pectoris.

This study evaluates transcoronary changes in neutrophil and platelet activation and conjugate formation in patients with angina pectoris secondary to coronary artery disease. We examined parameters of neutrophil and platelet activation as well as the neutrophil-platelet conjugate formation in patients who underwent diagnostic coronary angiography. Thirty-nine patients with chest pain referred for cardiac catheterization were studied (23 patients with unstable angina pectoris [UAP] and 16 with stable angina pectoris [SAP]). Before coronary angiography, blood samples were obtained simultaneously from the aortic root and coronary sinus to assess leukocyte (CD11b) and platelet (CD62P) activation and leukocyte-platelet conjugates. There was a 94% increase in CD62-expressing platelets from the aorta to the coronary sinus in patients with UAP compared with a 49% increase in patients with SAP. The percentage of neutrophil-platelet conjugates increased by 22% in patients with UAP compared with a 16% decrease in those with SAP (p <0.01). In contrast, monocyte-platelet binding across the coronary bed increased to a similar degree in both groups. This study demonstrates an increase in neutrophil-platelet conjugates across the coronary circulation in UAP, compatible with a higher activation state in both cell types.

Angina Pectoris↗
PubMed2004

Platelet abnormalities associated with cerebral perfusion defects in cocaine dependence.

BACKGROUND: This study assessed whether reduced regional cerebral blood flow (rCBF; hypoperfusion) in cocaine-dependent (CD) patients is associated with platelet abnormalities and whether these platelet abnormalities predict improvement in hypoperfusion after 1 month of abstinence. METHODS: We correlated platelet number and aggregation with rCBF hypoperfusion in 54 CD patients at baseline and after a month of abstinence while taking either 325 mg aspirin or placebo. We measured rCBF by (SPECT) with (Tc-HMPAO). Platelet aggregation to adenosine diphosphate was compared at baseline and after treatment. RESULTS: At baseline the number of hypoperfused voxels positively correlated with higher platelet aggregation, and five brain regions (bilateral frontal, right insula, right cingulate, left temporal lobes) showed significantly more hypoperfusion in the high than low platelet aggregation group. After abstinence, hypoperfusion significantly improved regardless of treatment assignment, and greater platelet aggregation at baseline predicted greater improvement in hypoperfusion. After abstinence, only the cingulate continued to show more hypoperfusion in the high- than low-aggregation group. CONCLUSIONS: Because platelet function was related to hypoperfusion primarily in the distribution of the middle cerebral artery, where CD patients most commonly have strokes, more potent antiplatelet agents than aspirin might be effective.

Adult↗
PubMed2004

Effects of epsilon-aminocaproic acid and aprotinin on leukocyte-platelet adhesion in patients undergoing cardiac surgery.

BACKGROUND: The administration of aprotinin during cardiopulmonary bypass (CPB) is hypothesized to decrease activation of leukocytes and platelets and possibly reduce their adhesion. Although epsilon-aminocaproic acid (EACA) shares the ability of aprotinin to inhibit excessive plasmin activity after CPB, its effect on leukocyte and platelet activation and leukocyte-platelet (heterotypic) adhesion is largely unknown. This study was performed to determine the relative effectiveness of the antifibrinolytics, aprotinin and EACA, at reducing leukocyte and platelet activation and leukocyte-platelet conjugate formation in patients undergoing CPB. METHODS: Thirty-six patients scheduled to undergo cardiac surgery with CPB were randomized in a double-blind fashion to receive EACA, aprotinin, or saline (placebo). Markers of plasmin activity (D-dimer concentrations), platelet activation (CD62P), leukocyte activation (CD11b), and leukocyte-platelet adhesion (monocyte- and neutrophil-platelet conjugates) were measured before, during, and after CPB. RESULTS: Platelet CD62P (P-selectin), monocyte CD11b, and monocyte-platelet conjugates were all significantly increased (compared with baseline) in the saline group during and after CPB. Despite equivalent reductions in D-dimer formation in patients receiving EACA (P < 0.0001) and aprotinin (P < 0.0001), decreases in platelet CD62P and monocyte CD11b expression were incomplete (not significantly different from saline control). In contrast, peak monocyte-platelet conjugate formation was significantly reduced by both EACA (P = 0.026) and aprotinin (P = 0.039) immediately after CPB. CONCLUSIONS: EACA seems to be as effective as aprotinin at reducing peak monocyte-platelet adhesion after CPB. Furthermore, inhibition of excessive plasmin activity seems to influence monocyte-platelet adhesion. The findings suggest that monocyte-platelet conjugate formation may be a useful marker of monocyte and platelet activation in this clinical setting.

Aged↗
PubMed2003

Aspirin or amiloride for cerebral perfusion defects in cocaine dependence.

Cocaine dependent (CD) patients have regional cerebral blood flow (rCBF) deficits that may be related to occlusion of blood vessels by vasoconstriction and abnormal platelet aggregation. This study determined whether aspirin, which reverses platelet aggregation, or amiloride, a vasodilator, significantly reversed this rCBF hypoperfusion. This 1-month randomized trial compared clusters of voxels with significant hypoperfusion in recently abstinent CD patients after aspirin (325 mg daily), amiloride (10 mg daily) or placebo treatment. Forty-nine primary CD patients and 18 non-drug abusing controls were compared using single photon emission computed tomography (SPECT) neuroimaging with 99mTc-hexamethyl-propyleneamine-oxime and statistical parametric mapping (SPM). Platelet aggregation to adenosine diphosphate (ADP) was examined after treatment to determine whether rCBF improvement was related to decreased platelet aggregation. Following treatment, areas of hypoperfusion were improved with amiloride, unchanged with aspirin, and worsened with placebo in comparison to baseline levels. Platelet aggregation after ADP showed no significant change during the month, but reduced rCBF significantly improved after 1-month treatment with amiloride compared with placebo and cocaine abstinence alone.

Adult↗
PubMed2003

Neutrophil CD11b upregulation during cardiopulmonary bypass is associated with postoperative renal injury.

BACKGROUND: Renal injury remains a persistent complication of cardiopulmonary bypass (CPB) that, when sufficient to require dialysis, increases mortality eight-fold. The high prevalence of renal failure in sepsis and adult respiratory distress syndrome has been linked to the systemic inflammatory response associated with those disorders. We hypothesized that components of the inflammatory response to CPB may similarly contribute to post-CPB acute renal injury. METHODS: Markers of leukocyte and platelet activation peri-CPB were measured in 75 patients undergoing cardiac operation with CPB and were correlated with acute renal injury, defined as an increase (> or = 50%) in peak serum creatinine post-CPB. RESULTS: Eleven patients sustained post-CPB acute renal injury. This subset of patients demonstrated significantly greater increases in neutrophil CD11b density (p = 0.01), as well as higher total neutrophil counts (p = 0.045), compared with patients with preserved renal function. Hemodynamic instability sufficient to require postoperative hemodynamic support also predicted an increased risk of acute renal injury. However, neutrophil CD11b upregulation did not correlate with this or any other clinical variables associated with renal risk, suggesting that this marker of the neutrophil inflammatory response may independently predict renal injury. By contrast other inflammatory markers, neutrophil myeloperoxidase levels, monocyte CD11b, base line C-reactive protein, and platelet CD62P expression did not differ between the two patient groups. CONCLUSIONS: Upregulation of the neutrophil adhesion receptor CD11b and high circulating neutrophil numbers are associated with acute renal injury after CPB, suggesting a contribution by activated neutrophils to the pathophysiology of this complication.

Acute Kidney Injury↗
PubMed2003

Cotransplantation of human mesenchymal stem cells enhances human myelopoiesis and megakaryocytopoiesis in NOD/SCID mice.

OBJECTIVE: For approximately 5% of autologous transplant recipients and a higher proportion of allogeneic transplant recipients, low level and delayed platelet engraftment is an ongoing problem. Mesenchymal stem cells (MSC), which can be derived from bone marrow as well as other organs, are capable of differentiation into multiple cell types and also support hematopoiesis in vitro. Because cotransplantation of marrow-derived stromal cells has been shown to enhance engraftment of human hematopoietic stem cells, we hypothesized that cotransplantation of MSC could enhance platelet and myeloid cell development. MATERIALS AND METHODS: We tested this hypothesis by transplantation of CD34-selected mobilized human peripheral blood stem cells (PBSC) into sublethally irradiated NOD/SCID mice with or without culture-expanded human MSC and evaluated human myeloid, lymphoid, and megakaryocytic engraftment with flow cytometry and in vitro cultures. RESULTS: We find that MSC cotransplantation enhances human cell engraftment when a limiting dose (<1 x 10(6)) of CD34 cells is administered. This enhancement is characterized by a shift in the differentiation of human cells from predominantly B lymphocytes to predominantly CD13(+), CD14(+), and CD33(+) myeloid cells with a corresponding increase in myeloid CFU in the marrow. Megakaryocytopoiesis is enhanced by MSC cotransplantation as assessed by an increase in both marrow CFU-MK and circulating human platelets. In contrast, MSC do not affect the percentage of human bone marrow cells that expresses CD34(+). CONCLUSIONS: Cotransplantation of human mesenchymal stem cells with CD34(+)-selected hematopoietic stem cells enhances myelopoiesis and megakaryocytopoiesis.

Animals↗
PubMed2003

Reversibility of severe metabolic stress in stored platelets after in vitro plasma rescue or in vivo transfusion: restoration of secretory function and maintenance of platelet survival.

BACKGROUND: Determining reversible aspects of the platelet storage lesion may result in improved function and survival of transfused platelets. STUDY DESIGN AND METHODS: Using a model of high-dose (apheresis-derived) platelet concentrates (PC), functional changes imposed by transient adverse metabolic conditions (pH < 6.0 for 1-2 hr) that could be reversed by autologous plasma rescue followed by standard platelet storage were investigated. Whole-blood-derived PCs were transfused into a small number of normal volunteers to determine platelet recovery and survival. RESULTS: Without rescue, high-dose PCs developed severe in vitro functional derangements at the time of the pH nadir including 1) loss of resting morphology; 2) complete abrogation of osmotic recovery and platelet aggregation and glycoprotein IIb/IIIa up-regulation to agonist; and 3) decreased alpha-granule release. By contrast, spontaneous and agonist-induced binding of annexin V were unaffected by adverse metabolic conditions. Plasma rescue to an optimal pH improved morphology scores, stabilized osmotic recovery, and completely restored platelet secretory responses, as measured by aggregation, glycoprotein IIb/IIIa up-regulation, and alpha-granule release. In a limited number of studies, plasma rescue was accompanied by preserved in vivo platelet recovery and survival after autologous transfusion after 5 days of storage. CONCLUSION: Transient derangement of platelet metabolism, which does not increase membrane phosphatidylserine exposure, causes in vitro functional abnormalities that are fully reversed or stabilized by metabolic rescue. Preliminary data suggest that such rescued platelets may have normal posttransfusion recovery and survival.

Acidosis↗
PubMed2003

Increased leukocyte-platelet adhesion in patients with graft occlusion after peripheral vascular surgery.

Graft occlusion following peripheral vascular surgery is attributable to some combination of acute thrombosis, and progression of atherosclerosis: interactions between leukocytes and activated platelets may play a role in both of these processes. This investigation measured perioperative leukocyte-platelet conjugate formation, and leukocyte and platelet activation in 46 patients undergoing surgery for lower extremity peripheral vascular disease (PVD). All patients were followed for graft patency over the next 6 months; 27 patients had grafts that remained patent while 19 had graft occlusion. On postoperative day #1 (POD#1), the graft occlusion group demonstrated a significantly greater increase in circulating levels of both monocyteplatelet and neutrophil (PMN)-platelet conjugates compared to the patent graft patients (p=0.015 and 0.018, respectively). PMN activation, assessed by increases in surface CD11b expression, was also significantly increased on POD#1 in the graft occlusion group compared to the patent group (p=0.026). The percentage of circulating activated (CD62P+) platelets did not differ between groups, but patients with graft occlusion demonstrated a higher percentage of younger, reticulated plate-lets throughout the study period (p=0.008), indicating increased platelet turnover. We conclude that in the early postoperative period, leukocyte-platelet adhesion, PMN activation, and platelet turnover are significantly greater in PVD patients who go on to develop later graft occlusion. Cellular activation and heterotypic cell interactions in peripheral vascular surgery patients may be important in the etiologies of thrombosis and/or accelerated atherosclerosis leading to graft loss.

Aged↗
PubMed2002

Reticulated platelets predict platelet count recovery following chemotherapy.

BACKGROUND: A laboratory measure that predicted the timing of platelet recovery after chemotherapy could guide prophylactic platelet transfusion. Reticulated platelets (RPs) are the youngest circulating platelets; an increased percentage of RPs is diagnostic of increased marrow platelet production, such as seen with idiopathic thrombocytopenic purpura, whereas a low percentage of RPs with thrombocytopenia indicates marrow suppression. This study examined whether the percentage of RPs, in combination with a newly devised measurement of "stress thrombopoiesis," the RP maturation index (RP-MI), could predict platelet count recovery following chemotherapy-induced thrombocytopenia. STUDY DESIGN AND METHODS: Platelet count nadirs were retrospectively determined in 35 chemotherapy-induced thrombocytopenia patients; percentage of RPs and RP-MI values were assayed at the early nadir (no imminent platelet recovery) and the late nadir (imminent platelet recovery). The latter was defined by a platelet count increase of 20 x 10(9) per L or more in the subsequent 48 hours without platelet transfusion. RESULTS: Early in the nadir (when platelet recovery did not occur in the subsequent 48 h after sampling), a low RP-MI and a low percentage of RPs were found in 29 of 35 patients. Late in the nadir, when recovery was imminent, 27 of 30 evaluable patients had elevated percentages of RPs or RP-MI values; the mean time from sampling to an increase of 20 x 10(9) per L or more was 42 hours. The positive and negative predictive values of this assay were 82 and 91 percent, respectively. Furthermore, when thrombocytopenia was severe (platelet count < or = 20 x 10(9)/L), an elevated RP-MI and/or percentage of RPs correctly predicted imminent platelet count recovery in five of five patients. CONCLUSION: This noninvasive, rapid, whole-blood assay of stress thrombopoiesis provides reproducible indices for timing platelet recovery following chemotherapy and the potential to optimize the use of prophylactic platelet transfusions in chemotherapy patients.

Adult↗
PubMed2002

Platelet PlA2 polymorphism and platelet activation are associated with increased troponin I release after cardiopulmonary bypass.

BACKGROUND: The PlA2 polymorphism of platelet glycoprotein IIIa has been identified as a prothrombotic risk factor in a number of cardiovascular settings. The aim of this study was to determine whether the PlA2 polymorphism of platelet glycoprotein IIIa and degree of platelet activation were associated with more severe myocardial injury as indicated by troponin I release following cardiopulmonary bypass. METHODS: The PlA2 genotype was determined in 66 patients undergoing elective coronary artery bypass grafting requiring cardiopulmonary bypass. Troponin I concentrations and the percentage of circulating, activated (CD62P+) platelets were measured at predetermined intervals perioperatively. RESULTS: Forty-six patients were Pl(A1,A1), and 20 were Pl(A1,A2) or Pl(A2,A2). Patients with at least one PlA2 allele had significantly greater postoperative troponin I concentrations than PlA1 homozygotes (P = 0.006, analysis of variance). Peak troponin I concentrations also correlated significantly with the increase in circulating, activated platelets (P = 0.02, Spearman rank correlation). CONCLUSIONS: The PlA2 allele of platelet glycoprotein IIIa is associated with higher troponin I concentrations following cardiopulmonary bypass surgery, suggesting that this platelet polymorphism contributes to perioperative myocardial injury.

Adult↗