The role of heparin-associated antiplatelet antibodies in the outcome of arterial reconstruction. (17/2217)

PURPOSE: This study was designed to determine the incidence rate of heparin-associated antiplatelet antibodies (HAAb) in patients who require major vascular reconstruction and to determine whether the HAAb were associated with perioperative thrombotic events. METHODS: One hundred six patients who underwent elective arterial reconstruction for cerebrovascular occlusive disease (n = 48), aortoiliac occlusive disease (n = 13), aortoiliac aneurysm (n = 17), mesenteric arterial occlusive disease (n = 1), or infrainguinal arterial occlusive disease (n = 28) prospectively underwent evaluation from July 1, 1996, to June 30, 1997. Heparin-associated antibody tests (with a two-point platelet aggregation assay) and platelet counts (via Coulter counter) were performed before surgery and on or after the 4th day after vascular reconstruction. Arterial reconstruction thromboses were established by means of duplex ultrasound scanning or angiography. Acute myocardial infarction (AMI) and venous thromboses were diagnosed with clinical criteria and duplex ultrasound scanning, respectively. A significant decrease in platelet count was defined as a platelet count of less than 100, 000/mm3 or as a more than 30% drop in the platelet count. RESULTS: Twenty-two patients (21%) had at least one positive HAAb assay: one assay was positive before surgery only (after angiography), six were positive both before and after surgery, and 15 were positive after surgery only. There were three perioperative deaths-one in the HAAb-positive group and two in the HAAb-negative group. Ten thrombotic events occurred in the perioperative period. Four thrombotic events (three operative site thromboses and one AMI) occurred in the HAAb-positive group (18.2%). All of these patients were undergoing heparin therapy. Of the six patients (with three operative site thromboses, two deep venous thromboses, and one AMI) in the HAAb-negative group (7%; P =.21), three were undergoing heparin therapy. No patient who was HAAb positive with a thrombotic event had thrombocytopenia or a significant decrease in platelet count. CONCLUSION: The frequent exposure to heparin by patients with peripheral vascular disease is associated with a high incidence rate (21%) of HAAb formation, which makes it one of the more common hypercoagulable conditions in these patients. The patients who were HAAb positive had a 2.6-fold increase in perioperative thrombotic events. Thrombocytopenia or decreasing platelet counts were not reliable clinical markers for identifying patients who were HAAb positive. It is suggested that all patients who have undergone heparin therapy and who have an unexplained perioperative thrombotic event develop should undergo testing for HAAb.  (+info)

Abrogation of the hematological and biological activities of the interleukin-3/granulocyte-macrophage colony-stimulating factor fusion protein PIXY321 by neutralizing anti-PIXY321 antibodies in cancer patients receiving high-dose carboplatin. (18/2217)

This dose-escalation study was performed to evaluate the hematologic activity, biological effects, immunogenicity, and toxicity of PIXY321 (an interleukin-3/granulocyte-macrophage colony-stimulating factor fusion protein) administered after high-dose carboplatin (CBDCA) treatment. Patients with advanced cancers received CBDCA at 800 mg/m2 intravenously on day 0 of repeated 28-day cycles. In part A of the study, patients were treated with CBDCA alone during cycle 1 and then received PIXY321 on days 1 through 18 of cycle 2 and later cycles. In part B, patients received 18 days of PIXY321 beginning on day 1 of all CBDCA cycles, including cycle 1. PIXY321 was administered subcutaneously in 2 divided doses. Total doses of 135, 250, 500, 750, and 1,000 micrograms/m2/d were administered to successive cohorts of 3 to 6 patients in part A. In part B, patient groups received PIXY321 doses of 750, 1,000, and 1,250 micrograms/m2/d. The hematologic effects of PIXY321 were assessed in the first 2 cycles of therapy. Anti-PIXY321 antibody formation was assessed by enzyme-linked immunosorbent assay (ELISA) and neutralization assay. Of the 49 patients enrolled, 31 were fully evaluable for hematologic efficacy. When comparing the first B cycle (cycle B-1; with PIXY321) with the first A cycle (cycle A-1; without PIXY321), the fusion protein had no significant effect on platelet nadirs or duration of platelets less than 20,000/microL but was able to speed the time of recovery of platelet counts to 100,000/microL (15 v 20 days; P =.01). Significant improvements in neutrophil nadir and duration of ANC less than 500 were observed in cycles A-2 and B-1 (with PIXY321) as compared with cycle A-1 (without PIXY321). Initial PIXY321 prophylaxis (cycle A-2 and cycle B-1), enhanced the recovery of ANC to greater than 1,500/microL by an average of at least 8 days as compared with cycle A-1 (without PIXY321; P +info)

The effect of recombinant human erythropoietin on platelet counts is strongly modulated by the adequacy of iron supply. (19/2217)

The effect of recombinant human erythropoietin (rHuEpo) on megakaryopoiesis remains controversial. Treatment with rHuEpo in renal failure patients has been associated with a slight elevation of platelet counts. In animal studies, high doses of rHuEpo produced an increase of platelet counts followed by a gradual return to normal after 7 to 15 days or even a substantial degree of thrombocytopenia. However, because iron deficiency is also known to be associated with thrombocytosis, (functional) iron deficiency during rHuEpo could be contributing to these observations. We investigated the impact of iron supply on changes in platelet counts induced by rHuEpo. Rats were either fed normal food (normal rats) or received 1% carbonyl iron for 2 weeks or 3 months, as well as during the experiment, to achieve iron supplementation or overload, respectively. Rats of all three categories then received daily intravenous injections of rHuEpo (10, 50, or 150 U) or normal saline (0 U) for 20 days. With 0 to 10 U rHuEpo, platelets remained stable. In normal rats receiving 50 to 150 U rHuEpo, platelets increased to 120% to 140% of baseline at 4 to 12 days to level off at 120% at 16 to 20 days. This response was less sustained in splenectomized animals. Iron-supplemented rats receiving 50 to 150 U rHuEpo also increased platelets initially, but the peak was at day 4, followed by a gradual return to baseline and even a moderate thrombocytopenia later on. Iron-overloaded rats receiving 50 to 150 U rHuEpo also had increased platelets at day 4, but the duration of platelet increase was shorter, and they experienced a more pronounced degree of thrombocytopenia in proportion to the dose of rHuEpo. Because the early elevation of platelets was of larger magnitude than hematocrit changes, it is unlikely that it could be accounted for by shrinkage of plasma volume. Because it was observed in all three iron conditions, there appears to be some direct positive effect of rHuEpo on platelet production. However, after this transient effect, expanded erythropoiesis appears to exert a negative impact upon platelet production. Secondary thrombocytopenia was not related to splenic pooling, and its very slow correction after cessation of rHuEpo therapy is not compatible with changes in platelet survival. Rather, it is consistent with stem cell competition between erythroid and megakaryocytic development. However, this secondary thrombocytopenia is masked by (functional) iron deficiency in rats not receiving an adequate iron supply from food or stores.  (+info)

Complement activation and increased systemic and pulmonary vascular resistance indices during infusion of postoperatively drained untreated blood. (20/2217)

In nine healthy young patients, operated on for thoracic scoliosis, a pulmonary artery catheter was inserted for the study of haemodynamic variables and blood sampling during autologous transfusion of postoperatively drained blood. At 1-3 h after wound closure, 10 ml kg/body weight of drained untreated blood from the wound was collected and recirculated over a l-h period. The concentration of the complement activation product, C3bc, increased from a mean of 5.4 (SD 1.5) AU ml-1 before infusion to 11.1 (3.9) AU ml-1 during infusion and then returned to 7.8 (2.8) AU ml-1 after infusion. The concentration of the terminal complement complex (TCC) increased from 0.5 (0.2) to 1.3 (0.5) AU ml-1 and was reduced to 0.7 (0.3) AU ml-1 after infusion. Only TCC exceeded the reference values which are 14 AU ml-1 for C3bc and 1.0 AU ml-1 for TCC. Pulmonary vascular resistance index concomitantly increased from a mean of 130 (SD 52) to 195 (88) dyn s cm-5 m-2 and was reduced to 170 (86) dyn s cm-5 m-2 after infusion. Systemic vascular resistance index increased from a mean of 1238 (SD 403) to 1349 (473) dyn s cm-5 m-2 and returned to 1196 (401) dyn s cm-5 m-2 after infusion. White blood cell count (WCC) increased from 14.4 (4.3) x 10(9) litre-1 before infusion to 17.8 (7.2) x 10(9) litre-1 during and after infusion. No change in platelet count during infusion was observed. There were no differences in WCC or platelet count between mixed venous or peripheral arterial blood. Pulmonary and systemic vascular resistance indices may be influenced by activated complement in drained untreated blood when it is recirculated.  (+info)

Effects of asymptomatic abdominal aortic aneurysm on the soluble coagulation system, platelet count and platelet activation. (21/2217)

OBJECTIVES: the aim of the study was to determine the effects of infrarenal asymptomatic abdominal aortic aneurysm (AAA) on platelet count and activation. DESIGN: prospective clinical study in a University Department of Vascular Surgery. PATIENTS: one hundred and five patients with AAA. Thirty-two control patients with symptomatic carotid artery stenoses. METHODS: platelet count (PC), plasma glycocalicin levels, prothrombin ratio (PTR), activated partial thromboplastin time (APPT), fibrinogen and D-dimer were measured in 23 patients with AAA and 16 control patients with symptomatic carotid artery stenoses. PC alone was measured in a further 84 patients with AAA and 16 with carotid artery stenoses. RESULTS: PC was below the normal range in 8/105 patients and mean PC (215x10(9)/l, S.D. 47.5) was significantly lower than that of a control population (242x10(9)/l, S.D. 16.8) and patients with carotid disease (269x10(9)/l, S.D. 57). Glycocalicin level was above the normal range in 7/23 patients and the median level (28 fg/plt) was significantly higher than that of a normal population (21.6 fg/plt) and patients with carotid disease (12.3 fg/plt). Fibrinogen levels, PTR and APPT were all within the normal range. One patient had a minimally elevated level of D-dimer. CONCLUSIONS: the combination of low PC and high glycocalicin levels suggests that there is increased platelet destruction, most likely due to activation within the aneurysm sac.  (+info)

Platelet number and interleukin-6 correlate with VEGF but not with bFGF serum levels of advanced cancer patients. (22/2217)

We have compared the platelet number and the serum concentration of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and interleukin-6 (IL-6) in 80 blood samples of 50 patients with advanced cancer. We have also measured the mitogenic effect of patient sera on endothelial cells in vitro in order to estimate the biological activity of serum VEGF. Serum VEGF concentration correlated with platelet number (r = 0.61; P < 10(-4)). Serum IL-6 levels correlated with platelet count (r = 0.36; P < 10(-3)), with serum VEGF levels (r = 0.55; P < 10(-4)) and with the calculated load of VEGF per platelet (r = 0.4; P = 3 x 10(-4)). Patients with thrombocytosis had a median VEGF serum concentration which was 3.2 times higher (P < 10(-4)) and a median IL-6 serum level which was 5.8 times higher (P = 0.03) than in other patients. Serum bFGF did not show an association with any of the other parameters. Patient sera with high VEGF and bFGF content stimulated endothelial cell proliferation significantly more than other sera (P = 4 x 10(-3)). These results support the role of platelets in the storage of biologically active VEGF. Platelets seem to prevent circulating VEGF from inducing the development of new blood vessels except at sites where coagulation takes place. IL-6, besides its thrombopoietic effect, also seems to affect the amount of VEGF stored in the platelets. This is in accordance with the indirect angiogenic action of IL-6 reported previously. The interaction of IL-6 with the angiogenic pathways in cancer might explain the stimulation of tumour growth occasionally observed during IL-6 administration. It also conforms to the worse outcome associated with high IL-6 levels and with thrombocytosis in several tumour types and benign angiogenic diseases.  (+info)

Sequential homoharringtonine and interferon-alpha in the treatment of early chronic phase chronic myelogenous leukemia. (23/2217)

Homoharringtonine (HHT) is a novel plant alkaloid that produced a complete hematologic remission (CHR) in 72% of patients with late chronic phase chronic myelogenous leukemia (CML). Cytogenetic (CG) remissions were noted in 31%. In this study, six courses of HHT were administered to 90 patients with early chronic phase CML (< 1 year from diagnosis). Patients then received interferon-alpha (IFN-alpha) with a target dose of 5 MU/m2 daily. Results were compared with those in a prior group of patients treated with IFN-alpha-based therapy between 1982 and 1990. Ninety-two percent of patients achieved CHR with HHT; CG responses were observed in 60% and were major in 27%. Both CHR and CG response rates were significantly higher than those seen in historical control patients after 6 months of IFN-alpha therapy. After receiving HHT, patients required lower doses of IFN-alpha to maintain a CHR. The median dose delivered was 2.4 MU/m2. This reduction in IFN-alpha dose was associated with a lower incidence of myalgia and gastrointestinal (GI) disturbances than that seen in patients treated at the 5 MU/m2 dose. Overall, CG responses were seen in 66% of the patients who received HHT and IFN-alpha compared with 61% of the historical control patients. HHT is a very effective treatment of early chronic phase CML, and ongoing trials are investigating the simultaneous administration of HHT and IFN-alpha, as well as that of HHT and low-dose cytosine arabinoside in patients failing IFN-alpha therapy.  (+info)

Examination of synovial fluid and serum hyaluronidase activity as a joint marker in rheumatoid arthritis and osteoarthritis patients (by zymography). (24/2217)

OBJECTIVE: Hyaluronic acid (HA) is an important joint marker and the substrate for hyaluronidase (HAase). Synovial fluid (SF) and serum HAase were measured to investigate the potential use of HAase as a joint marker in rheumatoid arthritis (RA) and osteoarthritis (OA) patients. METHODS: The subjects were 39 patients with RA and 42 patients with OA. HAase activity was measured by zymography and its relation with various parameters examined statistically. RESULTS: In RA SF a positive correlation (r = 0.458, p = 0.0186) was found between SF HAase activity and the concentration of serum C reactive protein. A positive correlation (r = 0.45, p = 0.024) was also found between SF HAase activity and platelet count in the RA group. Serum HAase activity in the RA group was significantly higher than in the OA group (p < 0.0001) and normal controls (p < 0.0001). CONCLUSION: The results suggest that SF HAase activity could be used as a marker of synovial inflammation.  (+info)