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Biomedical subjects

H Halbrook

Publications and source records attributed to H Halbrook.

At least 19 recordsLinked to original sources
PubMed2001

Immunohistochemical model to predict risk for coronary artery disease and failure in heart transplant patients.

Transplant coronary artery disease is the leading cause of long-term morbidity and mortality in cardiac transplantation. We developed a model for early identification of patients who subsequently develop coronary artery disease and graft failure. Serial biopsies obtained from 141 cardiac allografts (5.5 +/- 0.1 biopsies/patient) during the first 3 months post-transplant were evaluated immunohistochemically for deposition of myocardial fibrin, depletion of arteriolar tissue plasminogen activator, presence of arterial/arteriolar endothelial activation markers, and changes in vascular antithrombin. An immunohistochemical risk score was developed with a minimum value of 0 (normal) and a maximum value of 4 (most abnormal). Scores of 0 (low risk), 0.5-3.0 (moderate risk), and 3.5-4.0 (high risk) were analyzed for association with graft failure and development, severity, and progression of coronary artery disease detected using serial coronary angiograms (3.9 +/- 0.2/patient). Allografts with high immunohistochemical risk scores in the first 3months post-transplant developed more coronary artery disease (p<0.001), developed coronary artery disease earlier (p<0.001), developed more severe disease (p<0.001), and showed more disease progression (p<0.001) than allografts with moderate or low scores. Allografts with high immunohistochemical risk scores in the first 3 months post-transplant failed more (p<0.001) and failed earlier (p<0.001) than allografts with moderate or low scores. The present study demonstrates that early changes in the microvasculature are associated with impending coronary artery disease and graft failure in cardiac allograft recipients and suggests that treatment needs to be instituted early after transplantation in order to improve outcome.

Actins↗
PubMed2000

Cardiac-specific troponin I levels and risk of coronary artery disease and graft failure following heart transplantation.

CONTEXT: Previous studies have yielded conflicting data regarding whether a relationship exists between elevated cardiac troponin levels and acute allograft rejection in patients who have received heart transplants. OBJECTIVE: To determine whether cardiac troponin I levels after heart transplantation were associated with a procoagulant microvasculature and long-term allograft outcome. DESIGN: Prospective cohort study with a mean (SE) follow-up of 45.1 (2.5) months. Serum troponin I levels were measured 9.9 (0.2) times per patient during the first 12 months after heart transplantation. SETTING: Heart transplant center in the United States. PATIENTS: A total of 110 consecutive patients who received a heart transplant between 1989 and 1997 and survived at least 1 year after transplantation. MAIN OUTCOME MEASURES: Histological and immunohistochemical biopsy findings, development of coronary artery disease (CAD), and graft failure in patients with vs without elevated serum cardiac troponin I levels. RESULTS: All recipients had elevated troponin I levels during the first month after transplantation. Troponin I levels remained persistently elevated during the first 12 months in 56 patients (51%) and became undetectable in 54 patients (49%). Persistently elevated troponin I levels were associated with increasing fibrin deposits in microvasculature and cardiomyocytes (P<.001). Patients with persistently elevated levels of troponin I had significantly increased risk for subsequent development of CAD (odds ratio [OR], 4. 3; 95% confidence interval [CI], 1.8-10.1; P<.001) and graft failure (OR, 3.4; 95% CI, 1.2-9.7; P =.02), and also developed more severe CAD (OR, 4.2; 95% CI, 1.9-9.3; P<.001) and showed more disease progression (OR, 3.7; 95% CI, 1.3-10.4; P =.009). CONCLUSION: In this study, elevated cardiac troponin I levels, which are considered to be a noninvasive surrogate marker of a procoagulant microvasculature, identified a subgroup of patients with high risk for developing CAD and graft failure after cardiac transplantation. JAMA. 2000;284:457-464

Adult↗
PubMed1996

Utilization of intravenous immunoglobulin to ameliorate alloantibodies in a highly sensitized patient with a cardiac assist device awaiting heart transplantation. Fluorescence-activated cell sorter analysis.

Surgery surrounding the use of mechanical assistance in cardiac transplant candidates often leads to multiple blood/platelet transfusions and subsequent development of alloantibodies. This is a case report of a 50-year-old male patient who had received blood transfusions during coronary bypass grafting 9 years earlier. He presented in acute and chronic heart failure and, despite therapy, became moribund with multisystem organ failure. His ejection fraction was 10%. A Novacor ventricular assist device was implanted on May 19, 1995 (day 0). The patient received 44 U of blood and 20 U of platelets. Although his percent reactive antibodies (PRA) were negative before surgery by fluorescence-activated cell sorter analysis, the PRA 3 days after implantation of the ventricular assist device was 80%; it increased to 100% by day 7. In an attempt to decrease the PRA, intravenous immunoglobulin was given at 3-week intervals. The PRA became negative and the patient received a donor heart that was negative by fluorescence-activated cell sorter cross-match on day 64. On days 69-72, a dramatic increase in alloantibody activity was promptly reversed with additional intravenous immunoglobulin. Currently at posttransplant month 12, the patient shows no humoral, cellular, or vascular evidence of rejection.

Blood Transfusion↗
PubMed1995

The use of tranexamic acid to reduce postoperative bleeding following cardiac surgery: a double-blind randomized trial.

Bleeding during the first 24 hours following cardiac surgery using cardio-pulmonary bypass (CPB) is a serious complication. Attempts to modify the degree of postoperative bleeding with pharmacologic therapy have met with limited success. Tranexamic acid, a potent inhibitor of plasminogen, may decrease the amount of mediastinal bleeding following surgery utilizing CPB. We assigned 30 patients who were about to undergo cardiac surgery to a double-blind randomized trial. The treatment group received tranexamic acid, given intravenously as 10 mg/kg over 30 minutes, at the time of skin incision, followed by a 1 mg/kg/hr infusion for 12 hours. The control group received a placebo (saline) of equal volume. Measurements of shed mediastinal blood and transfused homologous blood were made at 6, 12, and 24 hours postoperatively. Mediastinal blood loss in the treatment and control groups was 382 mL versus 594 mL at 6 hours (P = 0.08), 502 mL versus 848 mL at 12 hours (P = 0.04), and 711 mL versus 1160 mL at 24 hours (P = 0.02). The mean transfusion volumes after 24 hours were 356 mL in the treatment group and 528 mL in the placebo group (P = NS). Prophylactic tranexamic acid infusion decreases mediastinal blood loss following cardiopulmonary assisted cardiac surgery.

Blood Transfusion↗
PubMed1994

Tissue plasminogen activator, plasminogen activator inhibitor-1, and fibrin as indexes of clinical course in cardiac allograft recipients. An immunocytochemical study.

BACKGROUND: Tissue-type plasminogen activator (TPA) is the principal activator of plasminogen. Since hemostasis in the microcirculation of allografts is a well-recognized complication of transplantation, we asked (1) whether the distribution and amount of cellular TPA in biopsies of transplanted human hearts are associated with fibrin deposits in and around the microcirculation, (2) whether such changes involve the physiological inhibitors of TPA and plasmin, and (3) whether the presence of these activators and inhibitors of fibrinolysis in tissue is correlated with clinical outcome. METHODS AND RESULTS: We immunocytochemically quantified the presence of fibrin, plasmin, TPA, and the TPA inhibitor PAI-1 in 938 biopsies from 68 consecutive cardiac allografts over a 54-month period. The localization, distribution, and quantification of TPA in arteriolar smooth muscle cells revealed that 35 of the 68 allografts maintained vascular TPA reactivity consistent with time-zero biopsies of autologous donor hearts: this was designated as the normal TPA group. In contrast, 33 of the 68 allografts significantly lost vascular TPA reactivity compared with time-zero biopsies of autologous donor hearts: this was designated as the depleted TPA group. Analysis of sequential biopsies from both groups during 54 months revealed that the mean cumulative quantitative TPA value for the normal TPA group was 1.0 +/- 0.01, whereas the depleted TPA group value was 1.9 +/- 0.02 (P = .0001), and the mean cumulative quantitative fibrin value for the normal TPA group was 1.0 +/- 0.01, whereas the depleted TPA group value was 1.5 +/- 0.05 (P = .0001). Biopsies of allografts in the depleted TPA group contained endothelial reactivity for TPA-PAI-1 complexes, whereas biopsies from the normal TPA group did not. Plasmin-associated molecules were rarely identified in biopsies of the normal TPA group but were present in the depleted TPA group, and the fibrin-to-plasmin ratio in the normal TPA group always was less than the fibrin-to-plasmin ratio in biopsies from the depleted TPA group. Analysis of demographic and risk factors revealed no significant differences between patients in the normal and depleted TPA groups, but none of the 35 patients in the normal TPA group died or were retransplanted, and 13 of the 33 patients in the depleted TPA group died or required retransplantation (P = .0001). CONCLUSIONS: Time-zero hearts (n = 68) and 34 of 38 stable allografts contained immunocytochemically detectable TPA only in vascular smooth muscle cells. Twenty-nine of 30 patients with normal TPA in their time-zero biopsies who subsequently developed a poor clinical outcome were found to have depleted TPA in biopsies evaluated during their first postoperative month and remained depleted throughout the study. Of 33 patients with depleted TPA, 39% died or required retransplantation. Depleted arteriolar TPA associated significantly with vascular and interstitial deposits of fibrin, plasmin, and endothelial TPA-PAI-1 complexes. These findings indicate that hemostatic and fibrinolytic pathways are activated in falling allografts, and they reveal evidence of depleted TPA before clinical or histopathological signs of failure. Patients with such allografts were found to be at high risk of death independently of other widely used clinical/laboratory parameters of prediction.

Biopsy↗
PubMed1993

Tissue plasminogen activator in human cardiac allografts.

The activation of hemostasis and fibrinolysis frequently is observed in allografted organs. Plasminogen is activated by urokinase and tissue plasminogen activator (tPA). We have studied human hearts before and after transplantation to determine if fibrin deposition within the microcirculation is associated with a depletion of myocardial tPA, and if such depletion of tPA is associated with decreased fibrinolysis. We found that tPA in pretransplanted hearts and in biopsies from hearts of most patients with a stable clinical course is confined to arterial and arteriolar smooth muscle cells. The depletion of smooth muscle cell reactivity was associated with microvascular fibrin deposition in unstable allografts, and the appearance of endothelial cell tPA reactivity heralded a bad prognosis. Successful medical management was signaled by a loss of endothelial tPA reactivity and a return of tPA reactivity in arterial and arteriolar smooth muscle cells. These findings indicate a central role for tPA in maintaining the integrity of the microcirculation in transplanted human hearts.

Biopsy↗
PubMed1988

Immunologic monitoring of the cardiac transplant patient.

Peripheral blood lymphocyte morphology and cell surface markers were repeatedly evaluated in 49 orthotopic cardiac transplant patients over a period of three years to determine the utility of these parameters in predicting an episode of acute cardiac rejection. Lymphocytes were measured with a calibrated microscope and termed "activated" if greater than 10 mu in diameter. If a patient demonstrated greater than 30 activated lymphocytes/cu mm, the same lymphocytes were stained with monoclonal antibodies directed to T-cell subsets and B cells. These findings were retrospectively correlated with endomyocardial biopsy results. Absolute numbers of T-cell subsets and B cells were analyzed via Student's t test to identify significant differences during acute cardiac rejection. Of 347 biopsy specimens, 47 demonstrated histologic features of acute cardiac rejection. Simultaneous immune activation of lymphocytes occurred with 33 of 47 samples, while another 51 episodes of lymphocyte activation were detected without acute rejection. No statistically significant differences in absolute numbers of T-lymphocyte subsets were noted at the time of acute rejection.

Acute Disease↗
PubMed1985

Heart transplantation at a private institution: a two year experience.

Since October 1982, 45 patients were referred and 15 underwent orthotopic heart transplantations. Eleven patients are presently alive. The donor heart ischemic time averaged 104 minutes for locally procured hearts and 183 minutes for hearts harvested in distant cities. Ninety-three percent of the patients survived the perioperative period. Survival rate at six months was 84%, at one and two years 72% and 52%, respectively. The one year survivors spent 80% of their time out of the hospital. The average cost for the transplant admission was $58,023. Four patients died 11 days, 57 days, 8 and 12 months after the operation. During the first three months there were 0.75 rejection episodes, 1.13 infections and 1.40 other complications per patient. We conclude that heart transplantation can be successfully carried out at a private institution, with excellent survival rates and at reasonable costs. In spite of progress, infection and rejection still account for most of the mortality and morbidity.

Adolescent↗
PubMed1975

A comparison of membrane and bubble oxygenation as used in cardiopulmonary bypass in patients. The importance of pericardial blood as a source of hemolysis.

A prospective clinical study involving more than 500 patients was designed to compare the Landé-Edwards membrane oxygenator and the Bentley bubble oxygenator. First, the importance of exposure of blood to the pericardium as the major source of hemolysis during open-heart surgery was confirmed. Because of this finding, we included in this study only those patients in whom the blood spilled into the pericardium was not returned to the pump. Under these circumstances, we found that hemolysis was relatively low in patients oxygenated with the membrane oxygenator.

Blood Platelets↗
PubMedDate not supplied

Natural anticoagulant pathways in normal and transplanted human hearts.

We have studied two natural anticoagulant pathways in normal and in transplanted human hearts. The first is the thrombomodulin pathway. Our immunocytochemical results show thrombomodulin localized to endothelium in heart biopsy specimens before transplantation. This reactivity persists in the absence of cellular rejection, but the infiltration of immune cells is associated with a lack of endothelial thrombomodulin. The second pathway is composed of antithrombin III (ATIII) bound to heparan sulfate proteoglycan (HSPG) molecules on endothelial cells. These ATIII-HSPG complexes bind and inactivate thrombin at the endothelial surface. Our immunocytochemical results show ATIII localized to endothelium in heart biopsy specimens before transplantation. This reactivity is present in the absence of vascular rejection as defined by either angiography or microscopy. The absence of thrombomodulin and ATIII is always associated with fibrin deposition within the microcirculation. Thrombomodulin and ATIII pathways appear to be independent, for cellular rejection often is associated with thrombomodulin-negative ATIII-positive endothelium, and vascular rejection often is associated with thrombomodulin-positive ATIII-negative endothelium. Cytokines from activated macrophages down-regulate endothelial thrombomodulin without generally affecting the ATIII-HSPG pathway. Immunosuppressive therapy depletes cytokine-producing cells that affect thrombomodulin, but there presently is no therapy to protect endothelium in vascular rejection. It is possible that heparin could interact with endothelium and bind ATIII to maintain a state of thromboresistance.

Antithrombin III↗
PubMedDate not supplied

Major histocompatibility antigens in transplanted human hearts before perfusion.

The expression of major histocompatibility class I and II antigens is described in human normal donor hearts before perfusion with recipients' blood. Class I and II major histocompatibility antigens were found on interstitial but not on myocardial cells. Endothelial cells accounted for most of the generic class I reactions (that is, W6/32 and beta 2 microglobulin), and endothelial cells accounted for most of the HLA-DR and -DP reactivity. HLA-DQ antigens were not found in this series of normal donor hearts. The earliest time we were able to identify HLA-DQ antigens during the follow-up biopsies from these patients was 1 week after the allograft had been in place. Macrophages accounted for little of the class II reactivity. Variations in the HLA-DQ antigen expression on endothelial cells may be useful in the follow-up of transplanted hearts, considering that these antigens have been found to be more susceptible to the effects of interferon-gamma than either HLA-DR or -DP.

Adult↗
PubMedDate not supplied

Conversion of IgG-mediated complement-dependent cytotoxicity by reducing reagents.

Reducing reagents used in complement-dependent crossmatches reduce IgM but not IgG. A positive IgM crossmatch is not an absolute contraindication to allografting. We have studied an alloantiserum from a patient with 100% panel reactive antibody awaiting heart transplantation whose serum was reduced. Absorption of this serum with the patient's erythrocytes or leukocytes had no effect on the third-party cytotoxicity. Absorption with third-party plasma or serum was without effect. Crossmatch of this serum with an HLA-A,B,C-identical nonrelated target was positive, whereas crossmatches with the patient's HLA-identical siblings were negative. Crossmatches with the patient's five children showed one strong, three intermediate, and one weak cytotoxic reactions. No antibody-dependent cellular cytotoxicity activity was observed. Fluorescence-activated cell sorter analyses showed no IgM but strong IgG1 antibody present before and after reduction of the serum. Our data indicate some IgG antibodies are reducible. The transplantation outcome in the presence of reducible IgG alloantibodies is not known, but it is possible these antibodies are associated with graft failures in patients observed to have positive standard crossmatches that become negative in the presence of reducing reagents.

Complement System Proteins↗
PubMedDate not supplied

Conversion from cyclosporine to azathioprine in heart transplant recipients.

Cyclosporine has proved to be of benefit for heart transplantation. Complications of therapy, however, occasionally require discontinuation of the cyclosporine and replacement with azathioprine. We report two cases in which changing from cyclosporine to azathioprine was followed by fatal rejection episodes.

Adult↗
PubMedDate not supplied

Immunoglobulin M antibodies in transplanted human hearts.

We have studied 56 human hearts before and after transplantation for the presence of immunoglobulin M. None of the 56 time-zero biopsy specimens studied contained immunocytochemically detectable immunoglobulin M, but they all had immunoglobulin M deposits on vascular endothelial cells after transplantation. The vascular location of immunoglobulin M was confirmed in double-antibody experiments with antibodies to von Willebrand factor and immunoglobulin M. None of the immunoglobulin M antibody reactivity was shown to colocalize with complement. Biopsy specimens from 29 of the 56 patients contained abundant deposits of immunoglobulin M. These patients were clinically stable, and only one of them has died. Biopsy specimens from 27 of the 56 patients had scant deposits of immunoglobulin M. These patients were clinically unstable; eight of them have died, and one has undergone retransplantation. In addition, biopsy specimens from stable allografts contained fewer fibrin deposits than biopsy specimens from unstable grafts, suggesting a protective role for non-complement fixing immunoglobulin M. The observation that immunoglobulin deposits were found soon after transplantation prompts us to consider them to be natural antibodies. Efforts to identify the antigen for immunoglobulin M natural antibodies in heart transplant recipients are currently under study.

Coronary Vessels↗