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Biomedical subjects

A Eldor

Publications and source records attributed to A Eldor.

At least 91 records · Page 5Linked to original sources
PubMed1996

Familial relapsing thrombotic micro-angiopathy in two siblings.

UNLABELLED: Two siblings, a 12-year-old girl and a 7-year-old boy, had recurrent episodes of haemolytic-uraemic syndrome/thrombotic thrombocytopenic purpura, manifested mainly by thrombocytopenia and micro-angiopathic haemolytic anaemia. During 11 years of follow up the girl responded only to steroids, whereas many other therapeutic modalities were ineffective. Following treatment with low dose danazol relapses became fewer and of diminished severity and completely subsided after 6 months. The boy started his illness with signs of haemolytic uraemic syndrome and later developed neurological manifestations. During a 6 year follow up he responded only to plasma exchange. Although chronic thrombocytopenia persisted during the past 3 years, the boy's clinical condition improved. CONCLUSION: A family with two children with recurrent episodes of thrombotic thrombocytopenic purpura is described. In one child danazol could have had a beneficial effect.

Anemia, Hemolytic↗
PubMed1996

Stem cell factor (SCF) synergizes with megakaryocyte colony stimulating activity in post-irradiated aplastic plasma in stimulating human megakaryocytopoiesis.

Plasma obtained from lethally irradiated animals contains a megakaryocyte (MK) growth factor which has recently been identified as the ligand for the c-mpl receptor and has been named thrombopoietin (TPO). We demonstrate that post-irradiation aplastic canine plasma (PICS-J) and plasma from a human subject (ML) who was accidentally exposed to lethal irradiation, contain high levels of this activity, which support both MK proliferation and maturation in a dose-dependent manner. These plasma were far more active in stimulating human MK colony formation than other types of thrombocytopenic plasma or a number of exogenously added human recombinant cytokines and their combinations. The addition of stem cell factor (SCF), which alone has a minimal stimulatory affect, to post lethal-irradiation plasma provided a synergistic stimulation of megakaryocytopoiesis both in colony assays and liquid cultures. In colony assays, the combination of SCF with PICS-J or ML almost doubled the number of burst forming units (BFU-MK) and provided a 1.5-fold increase in colony forming units (CFU-MK). A 1.6-fold increase in the number of CD34+ BM cell-derived MK colonies was also elicited. In liquid cultures, the presence of both SCF and PICS-J or ML induced the appearance of a high proportion of CD34+ (6.56% vs 0.6% control) and CD41+ (3.5% vs 1.2% control) cells after 3 days in culture. By day 10, 66.8 x 10(4) CD41+ cells and 29.8 x 10(4) CD34+ cells were derived from 2 x 10(6) BMMC originally seeded. We propose that these unique plasma, which do not contain elevated level of IL-6, IL-3, GM-CSF, IL-1 beta, erythropoietin or SCF, probably contain high levels of TPO. The addition of SCF to the post-irradiation plasma provides a synergistic stimulation of megakaryocytopoiesis which may become relevant for future clinical application.

Anemia, Aplastic↗
PubMed1996

The role of the leech in medical therapeutics.

Leeching is considered by many to be a discredited medical relic of the past. This view is not justified, since leeches still play an important part in modern medicine, as in microsurgery and in the treatment of patients with post-phlebitic syndrome. Hirudin, the potent thrombin inhibitor of leech saliva, has been cloned and is used in the treatment of cardiological and hematological disorders. In our search for other antihemostatic factors in Hirudo medicinalis saliva, we found inhibitors of platelet aggregation induced by thrombin, collagen, adenosine 5'-diphosphate, epinephrine, platelet-activating factor and arachidonic acid. We purified apyrase (adenosine 5'-triphosphate diphosphohydrolase), which is a non-specific inhibitor of platelet aggregation by virtue of its action on adenosine 5'-diphosphate. We isolated and characterized the platelet-activating factor antagonist and also identified and recovered an inhibitor of coagulation factor Xa from leech saliva. This report summarizes our findings and those of other investigators, as well as the experience of one of us (A.E.) in leech therapy.

Animals↗
PubMed1996

Platelet aggregation and coagulation inhibitors in leech saliva and their roles in leech therapy.

Prolonged bleeding by the host after the leech ceases to feed and several reports that the use of leeches restores blood flow in the microcirculation after plastic surgery led us to search for inhibitors of platelet aggregation in Hirudo medicinalis saliva. Dilute leech saliva was collected by phagostimulating starved leeches with a solution of arginine in saline. The saliva is shown to inhibit human platelet aggregation induced by thrombin, collagen, adenosine diphosphate (ADP), epinephrine, platelet activating factor (1-O-alkyl-2-acetyl-sn-3-glycerophophoryl choline [PAF]), and arachidonic acid. We have isolated the PAF inhibitor and found it to be an amphipathic phosphoglyceride. We have also purified apyrase adenosine triphosphate ([ATP] diphosphohydrolase), which inhibits ADP-induced platelet aggregation, and have described collagenase. Besides well-known hirudin, Hirudo saliva contains a potent inhibitor of coagulation factor Xa. We also report antiaggregant and anticoagulant activities in the crop content of the closely related Nile leech, Limnatis nilotica. Anticoagulants of hematophagous species are surveyed. We have used medicinal leeches in plastic surgery for decompression of skin flaps and in patients with postphlebitic syndrome and peripheral arterial occlusions. Preliminary results indicate certain beneficial effects of leech therapy.

Animals↗
PubMed1996

Enhancement of recombinant tissue-type plasminogen activator thrombolysis with a selective factor Xa inhibitor derived from the leech Hirudo medicinalis: comparison with heparin and hirudin in a rabbit thrombosis model.

OBJECTIVE: To compare the efficacy of Yagin, a factor Xa inhibitor derived from the leech Hirudo medicinalis, with those of heparin and hirudin as adjuncts to recombinant tissue-type plasminogen activator (rTPA) thrombolysis in a rabbit thrombosis model. METHODS: Thirty-one animals were allocated randomly to three groups, all administered four boluses of 0.25 mg/kg rTPA every 10 min for 30 min, 17 mg/kg aspirin intravenously, and heparin (as a 100 IU/kg bolus followed by infusion of 50 IU/kg heparin per h), hirudin (as a 2 mg/kg bolus followed by infusion of 1 mg/kg hirudin per h), or Yagin (as an 80 micrograms/kg bolus followed by infusion of 43 micrograms/kg Yagin per h). RESULTS: Administration of Yagin was associated with a significant acceleration of the reflow time, this time being 14.5 +/- 1.2 min with Yagin, 25.8 +/- 5.2 min with heparin (P < 0.0001, versus Yagin), and 28.7 +/- 16.0 min with hirudin (P = 0.012, versus Yagin). Overall patency did not differ significantly among the three groups. CONCLUSIONS: At the indicated single doses, inhibition of factor Xa by a relatively low concentration of Yagin was found to be superior than that with either heparin or hirudin for accelerating rTPA thrombolysis.

Animals↗
PubMed1996

Enhanced aggregability of red blood cells of beta-thalassemia major patients.

beta-Thalassemia major (TM), a congenital hemoglobinopathy, is associated with hemodynamic disorders and with structural red blood cell (RBC) anomalies that may indicate impairment of RBC rheological properties. To gain insight into the possible contribution of RBC to the hemodynamic disorders, we studied RBC aggregability, which plays a central role in blood flow, particularly in the microcirculation. RBC aggregate size distribution and morphology of TM RBC were determined using a novel system for image analysis of blood cells in a flow chamber. It was found that the aggregability of RBC of TM patients is markedly enhanced. These cells form large clusters, as opposed to normal rouleaux, and higher shear stress is required to disperse them. The aggregate size of TM RBC is reduced to the normal range after the patients have received a blood transfusion. This study suggests that the hemodynamic disorders observed in TM may be linked to the enhanced RBC aggregability and that improvement of RBC rheological properties may be considered in the treatment of thalassemia.

Adolescent↗
PubMed1996

Injury models of the vascular endothelium: apoptosis and loss of thromboresistance induced by a viral protein.

Endothelial injury caused by viruses usually involves viral replication or transformation. We report a novel mechanism of endothelial damage by a toxic viral protein. We have isolated a new retrovirus from hemangiosarcomas which appeared among layer hens. The isolated avian hemangiosarcoma virus (AHV) is capable of inducing hemangiomas in hens in-vivo and causes a cytopathic effect (CPE) and loss of thromboresistance in cultured bovine aortic endothelial cells (BAEC). These effects do not require viral replication and can be induced by purified AHV envelop glycoprotein (gp85). AHV causes CPE in BAEC through a typical programmed cell death (apoptosis). Quiescent G0/G1-BAEC are much more sensitive to AHV induced apoptosis than actively dividing cells. These experiments demonstrate the capacity of viral proteins to affect the integrity and functionality of vascular endothelial cells.

Animals↗
PubMed1996

Merkel cell tumor in a woman with chronic lymphocytic leukemia.

We describe a 69-year-old woman with basal cell carcinoma, and chronic lymphocytic leukemia who developed Merkel cell tumor. This latter malignancy first appeared as enlarged lymph nodes in the axilla and elbow regions and responded initially to radiotherapy. Later, the patient developed obstructive jaundice which was due to pancreatic metastases of the Merkel cell tumor, documented by post-mortem examination. To our knowledge, this is the first description of a Merkel cell tumor causing obstructive jaundice, in a patient with chronic lymphocytic leukemia.

Aged↗
PubMed1996

[Pulsed high-dose dexamethasone in resistant immune thrombocytopenic purpura].

Most patients with chronic idiopathic thrombocytopenic purpura (TTP) show a good initial response to treatment with corticosteroids. However the disease relapses in more than 90% when steroid dosage is reduced. Recently 100% success was reported for a new therapeutic protocol in 12 patients (ranging in age from 13-60, half of them women) with chronic ITP refractory to corticosteroids or to splenectomy. They were given pulsed therapy with oral dexamethasone, 40 mg/day on 4 consecutive days each month, for 6 months. This treatment protocol was used in an attempt to avoid splenectomy. 5 patients (42%) had a complete response but 7 did not. The median follow-up in those who responded was 7 months (range 6-8). Of the 7 who did not respond, 5 had not completed treatment: 3 because of urgent splenectomy and 2 because of lack of response after 3 courses of therapy accompanied by side-effects. Most patients suffered typical corticosteroid side-effects, principally restlessness, insomnia, and withdrawal effects. These were milder and better tolerated in those treated with Dexacort solution (20 mg ampules) rather than dexamethasone tablets. Despite complete response in only 5 of the 12 patients (42%), we feel that pulsed high-dose dexamethasone is effective and should be tried in TTP refractory to conventional corticosteroid therapy, before resorting to splenectomy.

Adult↗
PubMed1996

Increased procoagulant activity of red blood cells from patients with homozygous sickle cell disease and beta-thalassemia.

It has recently been proved that, in vitro, red blood cells (RBCs) from patients with homozygous beta-thalassemia behave as procoagulant cells. The procoagulant activity of beta-thalassemia RBCs might be the result of an increased exposure of procoagulant phospholipids (i.e. phosphatidylserine) in the outer leaflet of the membrane. In order to test this hypothesis, we compared the catalytic properties of RBCs of patients with beta-thalassemia and homozygous sickle cell disease (SS-RBCs) with that of controls. The catalytic parameters (Km, kcat) of prothrombin activation by factor Xa were determined both in the absence and in the presence of RBCs. The turn-over number (kcat) of the reaction was not modified by normal, SS- or beta-thalassemia RBCs. The Km was lower in the presence of normal RBCs (mean value: 9.1 microM) than in the absence of cells (26 microM). The Km measured in the presence of either SS-RBCs (mean value: 1.6 microM) or beta-thalassemia RBCs (mean value: 1.5 microM) was significantly lower compared to normal RBCs (p < 0.001). No significant difference was observed between SS-RBCs and beta-thalassemia RBCs. Annexin V, a protein with high affinity and specificity for anionic phospholipids, inhibited the procoagulant activity of both SS-RBCs and beta-thalassemia RBCs, in a dose-dependent manner. More than 95% inhibition was achieved at nanomolar concentrations of annexin V. These results indicate that the procoagulant activity of both beta-thalassemia RBCs and SS-RBCs may be fully ascribed to an abnormal exposure of phosphatidylserine at the outer surface of the red cells.

Adolescent↗
PubMed1995

Heparin-induced thrombocytopenia and fatal thrombosis in a patient with activated protein C resistance.

We report a 20-year-old woman who developed heparin-induced thrombocytopenia (HIT) associated with devastating and fatal multiorgan thrombosis. The patient, her mother, and her brother were found to have resistance to activated protein C (APC), and the congenital thrombophilia in this family was verified by the finding of the Arg506 Gln mutation in factor V. This is the first case of HIT and APC resistance. The consequences of this association are discussed.

Adult↗
PubMed1995

The response of cord blood megakaryocyte progenitors to IL-3, IL-6 and aplastic canine serum varies with gestational age.

Fetal cord blood (CB) is rich in haemopoietic stem cells and progenitors. We studied the clonogenic, proliferative and maturational responses of megakaryocyte (MK) progenitors in CB, from different gestational ages, to various cytokines: IL-3, IL-6, IL-3 + IL-6, and aplastic canine serum (PICS-J), and compared their responses to those of progenitors in adult peripheral blood (PB) or bone marrow (BM). We found that 34-week gestation CB produced some spontaneous colonies 28 +/- 4.7 CFU-MK in the absence of exogenous cytokines, and produced more CFU-MK and BFU-MK in response to IL-3, IL-6 and IL-3 + IL-6 than the other samples tested. Proliferation of CFU-MK was maximal at 34 weeks and decreased gradually toward term. When compared to adult BM or PB, the CB-derived CFU-MK had increased cellularity and contained significantly more cells undergoing fragmentation into platelet-like particles after stimulation with IL-3 or IL-6. Post-irradiation aplastic canine serum (PICS-J) was a highly potent stimulator of MK progenitors at all developmental stages. Our results indicate that CB MK progenitors are exquisitely sensitive to exogenous cytokines and that the magnitude of their proliferative and maturational responses to cytokines is related to developmental age.

Adult↗
PubMed1995

A controlled trial of tranexamic acid therapy for the reduction of bleeding during treatment of acute myeloid leukemia.

In order to determine the efficacy of the antifibrinolytic agent tranexamic acid (TA) in reducing bleeding and platelet transfusions during the treatment of acute myeloid leukemia (AML), we conducted a randomized placebo-controlled double-blind study. Patients with AML undergoing induction or postremission consolidation chemotherapy were randomized into TA or placebo groups. Patients were not given platelet transfusions prophylactically but only when bleeding occurred. The severity of any bleeding event was scored. Thirty eight patients were randomized during induction. There were no significant differences between the two groups in the number of bleeding events and their severity or in the number of platelet transfusions given. Eighteen patients were studied during consolidation. In contrast, to the induction period, during consolidation there was a significantly less severe bleeding tendency in the TA group resulting in a lower platelet transfusion requirement [3.7 +/- 4.1 vs. 9.3 +/- 3.3 platelet units (p < .05)]. TA was well tolerated and no side effects were seen and no specific thromboembolic events were noticed. We conclude that giving TA during the thrombocytopenic period of AML patients undergoing consolidation chemotherapy is beneficial and safely reduces platelet transfusions.

Acute Disease↗
PubMed1995

Recombinant human interleukin-6 accelerates in-vitro megakaryocytopoiesis and platelet recovery post autologous peripheral blood stem cell transplantation.

Prolonged thrombocytopenia complicated by bleeding episodes represent a major problem following autologous bone marrow transplantation (ABMT). Recombinant human interleukin-6 (rhIL-6) has been shown to be a maturation factor for both mouse and human megakaryocytes. We administered rhIL-6 to a 43 year old woman who developed marked resistant and prolonged thrombocytopenia with bleeding episodes following autologous peripheral blood stem cell transplantation (APBSCT). Twenty days after the initiation of rhIL-6 therapy, the number of megakaryocyte (MK) progenitors (CFU-MK and BFU-MK) cultured from the peripheral blood increased followed by a moderate increase in the number of bone marrow megakaryocytes. The platelet count increased and the bleeding episodes disappeared. Although spontaneous platelet recovery cannot be ruled out in this case it seems that rhIL-6 may be an important thrombopoietic factor for severe thrombocytopenia following APBSCT.

Adult↗
PubMed1995

[Resistance to activated protein C--a novel cause of thrombophilia].

A point mutation in coagulation factor V which causes resistance to cleavage of factor Va by activated protein C (APC), was recently found to underlie thrombotic events. We examined 20 consecutive patients, under the age of 40, who suffered from idiopathic venous or arterial thrombosis. In 8 (40%) there was resistance to APC manifested by absence of the expected prolongation of activated partial thromboplastin time (aPTT). In 3, the addition of normal plasma corrected the anomaly in the patient's plasma, although the addition of factor V- deficient plasma caused no change. In a family of a 17-year-old boy with idiopathic deep venous thrombosis we found a mutation in factor V which was responsible for APC resistance. The patient and 4 family members showed a single G to A transition in position 1691 in their cDNA, resulting in substitution of arginine (506) for glutamine. The mutation in this area, which is the cleavage site for APC, is associated with thrombotic episodes and is frequently observed in patients with familial thrombophilia.

Adolescent↗
PubMed1995

Ex vivo expansion of megakaryocyte precursors by preincubation of marrow allografts with interleukin-3 and granulocyte-macrophage colony-stimulating factor in vitro.

Protracted thrombocytopenia and bleeding remain serious complications in bone marrow transplantation (BMT). Major progress has been made in facilitating myeloid and erythroid engraftment, but little has been made in accelerating thrombopoiesis post-BMT. We report that in vitro preincubation of T cell-depleted BM allografts with a combination of interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) (0.1 microgram/mL each) (n = 8), for 3 days prior to infusion, expands megakaryocyte (MK) precursors. MK-progenitor proliferation was assessed in plasma clot colony assays and liquid cultures following pre-exposure to IL-3/GM-CSF. We observed a 2.8-fold increase in the number of colony-forming units-megakaryocyte (CFU-MK) (17.3 +/- 5.2 vs. 6.1 +/- 3.4) (p = 0.001) and a two-fold increase in burst-forming units-megakaryocyte (BFU-MK) (0.2 vs. 0.1) (p = 0.01) per 2 x 10(5) cells/mL compared to control BM samples cultured for 3 days in medium alone. In secondary cultures, the continued presence of IL-3 and GM-CSF increased the number of CFU-MK by 200-fold (p < 0.0001) over controls and by 9.7-fold over fresh BM. A 33-fold increase (p < 0.0001) in the number of BFU-MK was elicited compared to controls. In addition, IL-3 plus GM-CSF supported increased cellularity within the colonies. The presence of IL-3 or GM-CSF alone resulted in fewer MK colonies and fewer cells per colony than both cytokines combined. In liquid cultures, the percentage of cells expressing platelet glycoprotein (GP) IIb/IIIa in the continued presence of IL-3 and GM-CSF increased following preincubation, yielding a total of 16.0 +/- 2.3 x 10(4) MK/2 x 10(6) cells at day 10 of culture. We propose that ex vivo preincubation with IL-3 and GM-CSF can expand the number of MK precursors and may facilitate platelet recovery post-BMT.

Bone Marrow Transplantation↗