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Biomedical subjects

R E Scharf

Publications and source records attributed to R E Scharf.

At least 55 records · Page 3Linked to original sources
PubMed1990

In vitro thromboxane synthesis of depleted blood platelets following renal transplantation.

Renal transplant rejection is associated with platelet activation in vivo which may lead to partially alpha- and delta-granule-depleted platelets that continue to circulate. These "exhausted" platelets are hemostatically defective. To quantitate the extent of platelet granule depletion following kidney transplantation, we determined intraplatelet levels of beta-thromboglobulin (beta TG), platelet factor 4 (PF4), and serotonin (5-hydroxytryptamine, 5-HT) ex vivo in Triton X-100-treated platelet lysates. To explore biochemical alterations of partially depleted platelets, we studied platelet thromboxane A2 (TXA2) synthesis in citrated platelet-rich plasma (PRP) upon stimulation with thrombin or collagen in 45 recipients of renal allografts and 10 healthy volunteers. The patients were divided into subjects with acute and chronic allograft rejection (N = 15), those with compensated renal failure after kidney transplantation but without evidence of allograft rejection (N = 15), and those with functioning renal transplant (N = 15). The mean intraplatelet content of beta TG (38.6 +/- 4.2 micrograms/10(9) platelets), PF4 (11.8 +/- 1.8 micrograms/10(9) platelets), and 5-HT (274 +/- 31 ng/10(9) platelets) in patients with acute or chronic renal allograft rejection was significantly lower than in other recipients of kidney transplants or healthy volunteers (beta TG: 59.9 +/- 4.7 micrograms/10(9) platelets; PF4: 20.4 +/- 2.3 micrograms/10(9) platelets; 5-HT: 461 +/- 48 ng/10(9) platelets; p less than 0.005 in all cases).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Nonsense mutation in the glycoprotein Ib alpha coding sequence associated with Bernard-Soulier syndrome.

Three distinct gene products, the alpha and beta chains of glycoprotein (GP) Ib and GP IX, constitute the platelet membrane GP Ib-IX complex, a receptor for von Willebrand factor and thrombin involved in platelet adhesion and aggregation. Defective function of the GP Ib-IX complex is the hallmark of a rare congenital bleeding disorder of still undefined pathogenesis, the Bernard-Soulier syndrome. We have analyzed the molecular basis of this disease in one patient in whom immunoblotting of solubilized platelets demonstrated absence of normal GP Ib alpha but presence of a smaller immunoreactive species. The truncated polypeptide was also present, along with normal protein, in platelets from the patient's mother and two of his four children. Genetic characterization identified a nucleotide transition changing the Trp-343 codon (TGG) to a nonsense codon (TGA). Such a mutation explains the origin of the smaller GP Ib alpha, which by lacking half of the sequence on the carboxyl-terminal side, including the trans-membrane domain, cannot be properly inserted in the platelet membrane. Both normal and mutant codons were found in the patient, suggesting that he is a compound heterozygote with a still unidentified defect in the other GP Ib alpha allele. Nonsense mutation and truncated GP Ib alpha polypeptide were found to cosegregate in four individuals through three generations and were associated with either Bernard-Soulier syndrome or carrier state phenotype. The molecular abnormality demonstrated in this family provides evidence that defective synthesis of GP Ib alpha alters the membrane expression of the GP Ib-IX complex and may be responsible for Bernard-Soulier syndrome.

Adult↗
PubMed1990

Infection prophylaxis in neutropenic patients with acute leukaemia--a randomized, comparative study with ofloxacin, ciprofloxacin and co-trimoxazole/colistin.

Preliminary results are presented of an ongoing, prospective, randomized, study comparing ofloxacin, ciprofloxacin and co-trimoxazole/colistin for the prevention of infection in patients with acute leukaemia. The results for 59 patients (median age 47 years, range 21-72) included 88 episodes of neutropenia, each associated with a course of cytotoxic therapy. The main factor measured was the time elapsed from the beginning of neutropenia (neutrophils less than 500/microliter) until the first infectious febrile episode. The median time for the period was 12 days (range 1-56) for the cotrimoxazole/colistin group, 15 days (range 1-38) for the ofloxacin group and 20 days (range 1-36) for the ciprofloxacin group (differences not significant). Microbiologically proven major infections occurred in 10/27 treatment courses with co-trimoxazole/colistin 7/31 courses with ofloxacin and 7/30 courses with ciprofloxacin (P not significant). These were mostly due to Gram-positive cocci. There were no Gram-negative infections in the quinolone groups compared with one major Pseudomonas aeruginosa infection in the co-trimoxazole/colistin group. No Pneumocystis carinii infections were encountered. Adverse reactions associated with co-trimoxazole/colistin required discontinuation of medication in 11/27 treatment courses because of compliance problems, skin reactions or gastrointestinal intolerance. There were significantly fewer discontinuations in the ofloxacin (n = 2) and in the ciprofloxacin groups (n = 3). Major side effects of the quinolones included persistent icterus in one patient receiving ofloxacin and psychiatric symptoms in one patient receiving ciprofloxacin. It is concluded from these data that there were no statistically significant differences between the three treatment groups in respect of the prevention of infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Bacterial Infections↗
PubMed1990

Relationship of thrombin generation to peripheral blast cell count in patients with acute myeloblastic leukemia (AML).

Disseminated intravascular coagulation (DIC) commonly occurs in patients with acute promyelocytic leukemia (APL, FAB-M3) but may also be seen in other subtypes of AML. DIC in patients with AML has been attributed to procoagulants released from granular fractions of leukemic blast cells. The present study was designed (i) to evaluate thrombin activity in patients with AML by measuring plasma levels of fibrinopeptide A (FPA) prior to chemotherapy, and (ii) to examine whether a relationship between FPA levels and the number of peripheral blast cells exists. Plasma levels of FPA were determined using a commercially available RIA kit. To remove fibrinogen and the majority of elastase-induced fibrinopeptides (A alpha 1-21) known to crossreact with the FPA (A alpha 1-16) antiserum used in this assay, plasma samples were treated with bentonite prior to further processing. The study was conducted on 5 patients with APL and on 22 patients with other subtypes of AML. Peripheral blast cell counts at initial diagnosis ranged from 2100 to 56,000/microliters in patients with APL and from 1900 to 151,000/microliters in patients with other AML subtypes. The mean (+/- 1 SEM) pretreatment plasma level of FPA was significantly higher (p = 0.021) in the 5 patients with APL (38.2 +/- 8.3 ng/ml) than in patients with other AML subtypes (8.1 +/- 0.7 ng/ml). No relationship was found between peripheral blast cell counts and the corresponding FPA levels in the total group of 27 patients. However, when considering the 5 patients with APL separately, a significant correlation was observed between peripheral blast cell number and FPA plasma levels (r = 0.88, p = 0.050). This study confirms that thrombin generation is considerably greater in patients with acute promyelocytic leukemia than in other subtypes of AML. We conclude that type and number of circulating blast cells and their related capacity to express procoagulant activities appear to be major determinants of excessive fibrinogen degradation in AML.

Blood Cells↗
PubMed1990

A prospective study of haemostatic parameters in relation to the clinical course of myeloproliferative disorders.

Platelet function and the clinical course of the disease were prospectively investigated in 29 patients with myeloproliferative disorders. Serial determinations (median: 5 investigations per patient within 17 months) of platelet aggregation, plasma and intraplatelet concentrations of beta-thromboglobulin (beta TG) and platelet factor 4 (PF4), and of fibrinopeptide A (FPA) plasma levels were carried out. In the chronic phase of polycythaemia vera, patients with thrombohaemorrhagic complications during the study period had higher platelet count, more severe platelet aggregation defects, and increased plasma levels of beta TG and FPA compared to patients without complications. However, thrombohaemorrhagic complications were not predicted by changes in these parameters in the individual patient during the chronic disease phase. When patients with chronic myelogenous leukaemia entered blast crisis, bleeding complications were related to thrombocytopenia, impaired platelet function and low intraplatelet concentrations of beta TG and PF4. Cytoreduction by chemotherapy in the chronic phase of CML did not alter beta TG and PF4 plasma levels, whereas treatment of polycythaemia rubra vera by venesection favourably influenced platelet alpha-granule secretion and increased intraplatelet concentrations of beta TG and PF4.

Adult↗
PubMed1989

Failure of preactivated human blood platelets to restore defective thromboxane synthesis despite prolonged incubation in plasma.

Acquired platelet storage pool disease has been shown to be associated with reduced platelet thromboxane synthesis. However, the mechanisms for this dysfunction are incompletely understood. The present experiments were designed to evaluate some of the possible defects which may account for impaired thromboxane formation in human platelets previously exposed to thrombin in vitro. Washed platelets pretreated with 0.5 U/ml thrombin for 20 sec and subsequently recovered as single degranulated platelets were incapable of forming normal amounts of thromboxane upon a second stimulation with thrombin (as compared to Tyrode-pretreated control platelets). In contrast, thrombin-degranulated platelets released additional amounts of thromboxane in response to arachidonate, or collagen, indicating that short-time exposure to thrombin does not irreversibly inactivate platelet cyclooxygenase or thromboxane synthetase. Upon incubation of the thrombin-pretreated platelets in autologous plasma in the presence of 14C-arachidonate, the label became associated with the platelets to the same extent as with control platelets. However, the platelets did not recover their ability to synthesize normal amounts of thromboxane upon restimulation with thrombin, and only about half of the label was lost from the thrombin-pretreated platelets as compared to control platelets in response to thrombin. The ability of collagen to cause loss of 14C-arachidonate and formation of thromboxane was the same regardless of whether or not the platelets had been pretreated with thrombin. Incubation of platelets in plasma in the presence of added arachidonate for 90 min resulted in complete refractoriness to a second stimulation with thrombin but not with collagen.(ABSTRACT TRUNCATED AT 250 WORDS)

Arachidonic Acid↗
PubMed1989

Prevention of amphotericin-B-induced nephrotoxicity by loading with sodium chloride: a report of 1291 days of treatment with amphotericin B without renal failure.

An open, prospective study was performed to evaluate the clinical usefulness of sodium chloride loading for prevention of amphotericin-B-induced nephrotoxicity in 37 patients requiring 44 courses of amphotericin B treatment. The median duration of the treatment course was 22 days (range, 9-136 days), and mean cumulative dose per patient was 1117 mg (range, 231-7831 mg). During amphotericin B treatment, all patients received 50 to 100 ml of 10% sodium chloride (85 to 171 mmol NaCl) via an intravenous line for prevention of amphotericin-B-induced nephrotoxicity evaluated by serum creatinine levels. Using this regimen, none of the patients developed significant nephrotoxicity (increase in serum creatinine of more than twice baseline level, or serum creatinine level greater than or equal to 2.0 mg/dl, respectively) despite the co-administration of other potentially nephrotoxic drugs. It was not necessary to discontinue treatment with amphotericin B in any of the patients. There were no side effects due to sodium chloride loading. Our results demonstrate that sodium chloride loading is useful for the prevention of amphotericin-B-induced nephrotoxicity.

Acute Kidney Injury↗
PubMed1989

[Severe aplastic anemia and pregnancy].

Severe aplastic anaemia was diagnosed in a 24-year-old woman in the 16th week of her pregnancy. She was delivered by cesarean section in the 35th week of a healthy boy, treatment in the intervening period having been exclusively by supportive measures. Allogenic bone marrow transplantation, planned after delivery, had to be cancelled owing to the sudden death of the female donor. Immunosuppressive treatment with antithymocyte globulin, corticosteroids and cyclosporin A failed to improve the haematological picture and the patient died one year after the delivery of intracerebral haemorrhage.

Adrenal Cortex Hormones↗
PubMed1989

Effect of 8 hours of hyperinsulinaemia on haemostatic parameters in healthy man.

The role of variations in plasma insulin concentrations as a factor possibly involved in abnormalities of haemostatic functions, and (or) the development of arterial disease, has been the subject of controversy. This study examines the "in vivo" effect of hyperinsulinaemia on haemostatic parameters in seven healthy men. Two studies were carried out in random order: (a) Hyperinsulinaemia study. Human insulin was infused by a calibrated infusion pump (0.7 mU kg-1 min-1, for 8 h) during a euglycaemic glucose clamp, and (b) Control study 0.15 mmol/l NaCl solution was infused over 8 h. Plasma epinephrine and norepinephrine concentrations remained constant throughout the studies. Mean insulin levels during the hyperinsulinaemia study were 46.2 +/- 1.6 microU/ml, i.e. approximately eightfold higher than those at baseline, whereas plasma glucose levels remained constant at 4.9 +/- 0.1 mmol/l. During the control study, mean insulinaemia was 5.0 +/- 0.9 microU/ml, and plasma glucose 5.2 +/- 0.1 mmol/l. No statistically significant changes were observed during, or after insulin or 0.15 mmol/l NaCl infusions with regard to platelet parameters, blood coagulation, and coagulation inhibitors. These data suggest that abnormalities of the haemostatic function described during insulin-induced hypoglycaemia or in hyperinsulinaemic patients are not due to a direct action of insulin.

Adult↗
PubMed1989

Bleeding and thrombosis in chronic myeloproliferative disorders: relation of platelet disorders to clinical aspects of the disease.

Bleeding and thrombosis are a major cause of morbidity and mortality in myeloproliferative disorders (MPD). This study evaluates the relation between thrombohemorrhagic complications and platelet abnormalities in different subgroups of MPD. In 57 MPD patients thrombohemorrhagic complications occurred in 71% of patients with polycythemia rubra vera and 50% of patients with osteomyelofibrosis and primary thrombocythemia but in only 29% of patients with chronic myelogenous leukemia. Increased beta-thromboglobulin and platelet factor 4 plasma levels, platelet aggregation defects, and increased dispersion of the platelet volume distribution curve were most frequent in those subgroups where most serious thrombohemorrhagic complications were observed, and multiple platelet-related abnormalities were often found simultaneously. Fibrinopeptide A plasma levels were rarely elevated, however. Our results indicate that platelet abnormalities associated with bleeding and thrombosis are primarily determined by the clinical subgroup of myeloproliferative disease.

Adult↗
PubMed1988

[Alcohol-induced disorders of the hematopoietic system].

Alcohol has a variety of pathologic effects on hematopoiesis. It directly damages erythroid precursors, thereby contributing to macrocytosis and the anemic state of chronic alcoholics. Megaloblastic anemia in chronic alcoholism results from a combination of nutritional deficiency and the effect of ethanol as a folate antagonist. Experimental studies suggest that alcohol may disturb hepatic folate metabolism. Ethanol induces sideroblastic anemia, perhaps by direct interference with heme synthesis. Further, chronic ingestion of alcohol can lead to various types of hemolytic anemia caused by alterations in the erythrocyte membrane lipids which occur in association with alcoholic liver disease. Alcohol directly suppresses platelet formation and decreases the platelet life span. These two mechanisms contribute to thrombocytopenia which is a common complication to chronic alcoholism. Since ethanol also interferes with platelet function, prolongation of bleeding the time is common at all stages of alcoholism. Chronic ingestion of alcohol is associated with a diminished marrow granulocyte reserve and may lead to neutrocytopenia. Ethanol-induced dysfunction of granulocytes, monocyte-macrophages and T-lymphocytes undoubtedly contributes to the predisposition to infection observed in alcoholics. In contrast to alcohol-induced changes in liver, heart and central nervous system, hematopoietic disorders are reversible after alcohol withdrawal.

Alcoholism↗
PubMed1987

Acute myelofibrosis in megakaryoblastic leukemia with translocation between chromosomes 8 and 14.

In a 45-year-old woman with severe normochromic anemia (Hb 2.8 g%) an extensive myelofibrosis and infiltration of the bone marrow with small blasts was observed histologically. Cytochemical examination of the blasts showed a negative peroxidase and a strongly positive alpha-NE reaction. PAS reaction was slightly granular positive in the cytoplasmic protuberances of the blasts and in the platelets. Marker analysis yielded no evidence of lymphatic origin of the blasts. In flow-cytometric studies of 230,000 cells a homogeneous 2c blast population could be identified. Cytogenetic analysis revealed an abnormal pseudo-diploid karyotype characterized by 2 acrocentric marker chromosomes caused by a translocation of chromosomes 8 and 14, as usually seen in Burkitt type lymphoma. Finally the reaction product of platelet-specific peroxidase could be demonstrated in the perinuclear cisternae of the endoplasmic reticulum by electron microscopy. Highly elevated beta-thromboglobulin and platelet factor 4 plasma levels were also measured. Following an ineffective treatment with daunoblastine and ARA-C, the patient died of pseudomonas aeruginosa septicemia after having received high-dose ARA-C treatment.

Biopsy, Needle↗
PubMed1987

Thrombosis and atherosclerosis: regulatory role of interactions among blood components and endothelium.

Complex interactions among constituents of blood and components of the vessel wall are involved in the pathogenesis of atherosclerosis and its subsequent thrombotic complications. Alterations in the endothelium are central both to the slowly progressive process of atherogenesis and to the acute events leading to thrombotic occlusion. Recent data, obtained by systematic evaluation of chronologic events that occur in diet-induced atherosclerosis, have extended our understanding of interactive processes among endothelium, monocytes, platelets, vascular smooth muscle cells, and humoral hemostatic elements in atherogenesis.

Animals↗