Pharmacokinetics of low molecular weight heparin in patients with malignant tumors.

Cancer patients have an increased risk for venous thromboembolism (VTE). Low molecular weight heparin (LMWH) is the mainstay of VTE treatment in these patients. Heparanase, which degrades heparin and LMWH, is an enzyme secreted from a variety of malignant tumors. The objective of this study was to elucidate the pharmacokinetics of LMWH in patients with locally advanced or metastatic cancer. A total of 10 cancer patients with VTE treated with the LMWH enoxaparin at a standard dose of 1 mg/kg every 12 h were enrolled. Blood samples were obtained before the injection of LMWH and at 1, 2, 3, 4, 6, and 8 h after LMWH administration, and they were tested for anti-factor Xa activity and heparanase levels. Peak anti-Xa activity was achieved 2-8 h after subcutaneous administration of LMWH. Six patients did not reach a therapeutic anti-Xa activity target (0.6-1.2 IU/ml) at 4 h after LMWH administration. Four patients did not reach anti-factor Xa values of 0.6 IU/ml throughout the trial. The median anti-Xa activity before LMWH injection was 0.24 IU/ml (range 0.07-0.7 IU/ml), as opposed to 0.52 IU/ml in historical controls. The median anti-Xa activity 4 h after LMWH injection was 0.58 IU/ml (range 0.22-1.23 IU/ml), as opposed to 1.2 IU/ml in historical controls. The blood level of heparanase in patients with malignancy and VTE was 6.24 ± 4.3 ng/ml, compared with 2.67 ± 1.09 ng/ml in cancer-free, age-matched, normal controls. In this pilot study, a substantial proportion of cancer patients suffering from VTE and treated with LMWH had subtherapeutic anti-Xa activity.

Failure to predict hemolysis and hyperbilirubinemia by IgG subclass in blood group A or B infants born to group O mothers.

OBJECTIVE: Direct antibody titer-positive, blood group A or B neonates who are born to group O mothers may be at risk for hemolysis and hyperbilirubinemia. Immunoglobulin G1 and immunoglobulin G3 subclasses are associated with increased hemolysis relative to immunoglobulin G2 and immunoglobulin G4. We investigated whether identification of immunoglobulin G subclass 1 or 3 may be predictive of hemolysis and hyperbilirubinemia. METHODS: Direct antibody titer-positive, blood group A and B neonates born to group O mothers were tested for the presence of immunoglobulin G subclasses 1 and 3 in umbilical cord blood by using a commercially available gel testing technology. By inference, neonates in whom neither immunoglobulin G1 nor immunoglobulin G3 were detected were designated immunoglobulin G2 and/or 4. Mandatory plasma total bilirubin was measured at discharge, and additional measurements performed as clinically indicated. Hyperbilirubinemia was defined as any plasma total bilirubin value >95th percentile for hour of life. Blood carboxyhemoglobin and total hemoglobin concentrations were also measured on the predischarge sample. Measured carboxyhemoglobin, expressed as percentage of total hemoglobin, was corrected for ambient carbon monoxide to derive "corrected carboxyhemoglobin," a sensitive index of heme catabolism. The corrected carboxyhemoglobin/total hemoglobin ratio was calculated to correct for any differences in total hemoglobin mass between groups. RESULTS: Eighty-two infants were studied, 18 of whom were designated as immunoglobulin G1, 0 as immunoglobulin G3, and 64 as immunoglobulin G2 and/or 4. The incidence of plasma total bilirubin >95th percentile was similar between the subgroupings. Corrected carboxyhemoglobin values and corrected carboxyhemoglobin/total hemoglobin ratio were also similar between the subgroupings. CONCLUSIONS: Immunoglobulin G1 was found in 22% of direct antibody titer-positive, group A and B neonates who were born to group O mothers, whereas immunoglobulin G3 was rare. Hemolysis and hyperbilirubinemia could not be predicted by this gel technique that enabled identification of these immunoglobulin G subclasses.

Transfusion-related leukocytosis in critically ill patients.

OBJECTIVE: We observed that many critically ill patients developed leukocytosis following blood transfusions. To validate this observation and to explore a possible mechanism, a prospective study was designed. DESIGN: Prospective, non-interventional study. SETTING: Surgical/medical intensive care unit in a university-affiliated community hospital. PATIENTS: Consecutive patients who required packed red blood cells transfusion. INTERVENTIONS: White blood cell count (mean +/- SD) x 10(9)/L before and 2, 4, 6, 12, and 24 hrs following transfusion of non-filtered packed red cells was measured in 96 patients. MEASUREMENTS AND MAIN RESULTS: Twenty patients were septic at the time of transfusion, whereas 76 were not. The incidence of post-transfusion leukocytosis in septic vs. nonseptic patients was 15% vs. 76%, respectively (p <.001). The white blood cell count in nonseptic patients increased from 14.3 +/- 4.8 before transfusion to 19.5 +/- 7.0 2 hrs following transfusion (p <.001) and returned to baseline in 24 hrs. In the septic group, no significant post-transfusion leukocytosis occurred. In 11 nonseptic patients requiring more than one unit of packed red cells, a significant increase in mean white blood cell count occurred 2 hrs after transfusion with non-filtered packed red cells, whereas transfusion with pre-storage-filtered packed red cells did not result in such an increase. Interleukin-8 concentrations (pg/mL) in stored non-filtered packed red cells were significantly higher after 4 wks of storage (745.5 +/- 710, p =.02) than at weeks 1 (61.2 +/- 21.6) and 2 (59.3 +/- 29). In the last 16 nonseptic patients, the units of non-filtered packed red cells were assayed for interleukin-8 immediately before transfusion. Interleukin-8 concentrations were higher in units that caused leukocytosis in the recipients compared with those that did not (408.4 +/- 202 vs. 65.1 +/- 49, p =.02). CONCLUSIONS: Transfusion of non-filtered packed red cells, but not of pre-storage-filtered packed red cells, may frequently cause an acute and transient leukocytosis in critically ill nonseptic patients. Interleukin-8 accumulating in stored non-filtered packed red cells may play a role in this phenomenon. Recognition of post packed red cell transfusion leukocytosis may avoid unnecessary investigations and therapies in false suspicion of sepsis.

Lack of anti-D in women at birth following antepartum immune globulin prophylaxis.

Antepartum prophylaxis using Rh immune globulin suppresses maternal immunization to transplacental transfer of Rh-positive fetal cells, and, theoretically, to be effective, anti-D should be detectable until birth. We used a sensitive gel technique to quantitatively detect the serum concentration of anti-D at birth in 150 women who had received 300 microg of Rh immune globulin at 28 weeks gestation. Our method, which was sensitive enough to detect 20-25 microg, the recommended residual amount at birth, was positive in only 21% total, and in only 13% of women at term. Fifty-seven percent of women with premature births had above the recommended level of anti-D.