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Biomedical subjects

F R Rickles

Publications and source records attributed to F R Rickles.

At least 73 records · Page 4Linked to original sources
PubMed1987

Abnormalities of blood coagulation tests in patients with cancer.

Routine blood coagulation tests were performed on 431 consecutive patients enrolled in a study of the role of anticoagulation in cancer treatment (VA Cooperative Study #75). Two hundred sixteen control patients were treated with standard therapy, and 215 patients were treated with standard therapy plus sodium warfarin. At the time of entry into the study, the most common abnormalities were elevated fibrinogen levels, platelet counts, and fibrinopeptide A levels. Serial studies demonstrated a steady increase in platelet count and fibrinogen levels before death. Anticoagulation lowered FPA levels but had no significant effect on fibrinogen levels, platelet counts, or euglobulin clot lysis times. An unexpected finding was a dramatic increase in fibrin split product levels after institution of anticoagulation (means +/- SEM = 42.6 +/- 116.4 vs. 2.9 +/- 7.0 mg/L in control subjects; P less than 0.02). This study supports the presence of subclinical activation of blood coagulation in most patients with cancer. Moreover, the preferential activation of fibrinolysis in anticoagulated patients suggests a role for a vitamin K-dependent factor(s) in the regulation of fibrinolysis in patients with cancer.

Blood Coagulation Tests↗
PubMed1987

Preliminary characterization of the procoagulant material in human ascites.

Disseminated intravascular coagulation invariably accompanies placement of peritoneovenous (LeVeen) shunts, which suggests that ascitic fluid contains procoagulant material capable of activating blood coagulation. In this study, we identified thrombogenic activity in human ascites and the hemostatic pathway by which it acts. Peritoneal fluid was removed percutaneously from patients with ascites due to various causes. Four fractions were prepared by centrifugation: cells, a low-speed, cell-free fluid, a high-speed supernatant, and the precipitate from the high-speed centrifugation. Cellular fractions from all ascitic fluids shortened a one-stage clotting time of normal pooled plasma by 68% in comparison with saline solution and endotoxin controls. Similarly, the cell-free fluids also shortened the clotting time of normal pooled plasma by 41%. The cellular and cell-free fractions shortened the clotting time of factor VIII-deficient plasma but failed to demonstrate procoagulant activity in factor VII-deficient plasma. These fractions had no effect on platelet aggregation or the platelet release reaction. The high-speed precipitate was dissociated by ethylenediaminetetra-acetate (EDTA) into fluid phase and precipitate, both of which demonstrated procoagulant activity. Furthermore, high-speed precipitate contained protein, phospholipid, and sterol in proportions similar to those of plasma membranes and contained membrane-bound vesicles as identified by means of electron microscopy. This material could be rendered inactive by heating to 100 degrees C for 2 minutes or by incubation with phospholipase C for 15 minutes. Finally, the ability of the high-speed precipitate to shorten the clotting time was prevented by preincubation with a monoclonal antibody, which is known to inhibit the procoagulant activity of human tissue factor. We suggest that several entities contribute to the procoagulant properties of human ascites, with procoagulant material deriving at least in part from peritoneal cells. The sedimentable procoagulant factor appears to be associated with cellular membranes or membrane fragments and is thromboplastin-like in its chemical composition, immunoreactivity, and substrate specificity.

Adult↗
PubMed1987

Activation of blood coagulation in Crohn's disease. Increased plasma fibrinopeptide A levels and enhanced generation of monocyte tissue factor activity.

We have examined the relationships among activation of blood coagulation, generation of monocyte procoagulant activity, and clinical activity in patients with Crohn's disease. Subclinical activation of blood coagulation was measured using a radioimmunoassay for fibrinopeptide A. Fibrinopeptide A levels were strongly correlated with the level of disease activity as measured by the Crohn's disease activity index. Patients with active disease who were successfully treated either medically or surgically demonstrated a reduction of fibrinopeptide A levels. Failure of fibrinopeptide A to return to the normal range predicted an early relapse. Monocyte tissue factor generation was assessed in both unstimulated and lipopolysaccharide-stimulated mononuclear cell cultures obtained from the peripheral blood of patients with Crohn's disease. A strong correlation (r = 0.89) was observed between plasma fibrinopeptide A levels and monocyte tissue factor generation. These results suggest that monocyte procoagulant generation may contribute to the activation of blood coagulation in this inflammatory bowel disease. Moreover, fibrinopeptide A levels in Crohn's disease may provide a useful quantitative measure of inflammatory activity.

Adolescent↗
PubMed1986

Production and characterization of a monoclonal antibody (A1-3) that binds selectively to activated monocytes and inhibits monocyte procoagulant activity.

We describe the generation and characterization of a new monoclonal antibody, A1-3, which possesses two unique properties. First, A1-3 binds selectively to stimulated human monocytes. Secondly, A1-3 inhibits the procoagulant activity expressed by stimulated monocytes and by human brain tissue factor. Unstimulated human peripheral blood cells (granulocytes, lymphocytes, monocytes, red blood cells, and platelets), prepared in the absence of detectable endotoxin, express no procoagulant activity and fail to bind A1-3. Stimulation of peripheral blood monocytes. alveolar macrophages, or the monocyte-like cell line U937, however, results in the expression of procoagulant activity and the binding of A1-3. The surface antigen recognized by A1-3 was recovered from endotoxin-stimulated human monocyte vesicles by immune precipitation and demonstrated an apparent m.w. of approximately 52,000. It is proposed that the monoclonal antibody A1-3 detects a differentiation antigen on human monocytes that is expressed in response to stimuli for monocyte activation.

Animals↗
PubMed1986

Immunohistological studies with A1-3, a monoclonal antibody to activated human monocytes and macrophages.

A wide variety of monoclonal antibodies (mAb) have now been produced which recognize cell surface antigens on human peripheral blood monocytes. However, few of these mAb demonstrate specificity for monocytes, and fewer still recognize antigens exclusively on monocytes activated by one or more stimuli and/or block specific monocyte functions. The mAb A1-3 binds to lipopolysaccharide (LPS)-stimulated monocytes but not to resting blood monocytes, and inhibits the procoagulant activity of these LPS-activated cells. By using this mAb, we examined the reactivity of monocytes/macrophages (MO) in a broad range of normal and inflammatory tissues by means of a sensitive, four-layer immunoperoxidase technique. Cells of the MO system, in addition to lymphocytes and dendritic cells resident in lymphoid tissues, liver, lung, and other organs, were nonreactive with the A1-3 mAb. In contrast, intense staining of inflammatory MO was found in biopsies from patients with renal allograft rejection, acute glomerulonephritis, or granulomatous diseases. This apparent restriction of A1-3 binding to inflammatory, "activated" MO suggests that A1-3 mAb will be useful for the analysis of MO "activation" in many pathologic processes.

Animals↗
PubMed1986

Inhibition of rat skin allograft rejection by cyclosporine. In situ characterization of the impaired local immune response.

Cyclosporine (CsA) is known to induce long-term survival of skin allografts, although the cellular mechanisms responsible for this effect are not well understood. To further define the effects of CsA-induced immunosuppression, we performed a morphological and immunohistological study of acute skin allograft rejection in the rat, comparing untreated and CsA-treated animals. Three significant differences were found between grafts in CsA-treated and untreated rats. First, CsA-allografts contained fewer MRC OX-8+ cytotoxic T cells than untreated allografts. Second, although the presence and numbers of infiltrating macrophages (W3/25+, W3/13- cells) was not influenced by CsA treatment, CsA treatment blocked expression of a macrophage membrane activation antigen, defined by the monoclonal antibody A1-3, which has previously been linked with development of macrophage procoagulant activity (PCA). Third, diminution in MRC OX-8+ lymphocytes and A1-3+ macrophages in CsA allografts was associated with an absence of the widespread thrombotic and necrotizing microvascular injury typical of acute rejection in untreated rats. We conclude that prolongation of skin allograft survival by CsA is related to its ability to prevent cell mediated injury to the endothelium of graft vessels, and possibly also to inhibition of macrophage PCA with consequent reduced thrombus formation.

Animals↗
PubMed1985

Immunohistological analysis of serial biopsies taken during human renal allograft rejection. Changing profile of infiltrating cells and activation of the coagulation system.

This immunohistological study investigated two aspects of the mechanisms underlying human renal allograft rejection. First, because rejection is a dynamic, complex process, we sought to delineate any changes in the types of cells mediating graft destruction by evaluating the cellular infiltrates in sequential renal biopsies from 14 patients with rejection. Second, because macrophage accumulation and fibrin deposition are major features of kidney rejection, the membrane characteristics of intragraft macrophages were analyzed to determine whether these cells could indeed cause the fibrin deposition frequently observed. Thirty-six biopsies, performed for assessment of renal failure posttransplantation (post-Tx), were studied using a panel of monoclonal antibodies and a 4-layer immunoperoxidase technique. Biopsies were divided into 3 groups depending upon the time post-Tx. Comparison of biopsies taken on days 2-3 post-Tx with those taken either at days 10-12, or later than 30 days, showed similar proportions of T cells, T cell subsets, B cells and macrophages. By contrast, the proportion of natural killer (NK) cells was significantly increased at days 2-3 (P less than .01), and the proportion of activated T cells bearing interleukin-2 receptors was significantly increased at days 10-12 (P less than .01). Granulocytes were restricted to biopsies that displayed areas of infarction, regardless of the time at which this occurred. In addition, various proportions of intragraft macrophages exhibited the membrane phenotype of activated macrophages, as a result of their expression of the procoagulant molecule termed human-tissue-factor--related antigen (HTF:RAg). The proportion of graft macrophages exhibiting HTF:RAg was significantly increased in biopsies on days 10-12 (P less than .05) compared with biopsies on days 3-4, and remained elevated thereafter. Interstitial and perivascular collections of HTF:RAg+ macrophages were closely associated with fibrin deposits and, in two cases, mononuclear cells harvested from rejected grafts were shown to contain significant procoagulant activity in vitro. These studies demonstrate a major temporal variation in the types of cells contributing to human kidney rejection.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies, Monoclonal↗
PubMed1985

Cleavage of blood coagulation factor XIII and fibrinogen by thrombin during in vitro clotting.

Thrombin cleavage of blood coagulation Factor XIII (a2b2) and fibrinogen was studied during in vitro clotting to determine the physiologic sequence of these events. First, the time course of fibrin formation and cleavage of Factor XIII was measured in platelet-rich plasma. Cleavage of fibrinogen was measured by using a radioimmunoassay for fibrinopeptide A. Conversion of trace amounts of radioiodinated a-chains of 125I-Factor XIII to thrombin-modified a-chains was measured in unreduced 10% sodium dodecyl sulfate-polyacrylamide gels. During spontaneous clotting, a similar percentage of 125I-Factor XIII and fibrinogen was cleaved at each time point. Visible gelation of polymerized fibrin monomer occurred when 24 +/- 8% of fibrinogen was cleaved and 21 +/- 6% of Factor XIII was converted to Factor XIII'. Thrombin cleavage of Factor XIII and fibrinogen was also studied in platelet-poor plasma to which thrombin was added. In order to measure Factor XIIIa activity, fibrin polymerization was completely inhibited by the addition of Gly-Pro-Arg-Pro. Factor XIIIa formation was measured by the incorporation of [3H]putrescine into casein. The concentration of added thrombin required to cleave 50% of fibrinogen and Factor XIII was 0.65 U/ml and 0.35 U/ml, respectively. The rate of cleavage of fibrinogen by thrombin was 43-fold greater than cleavage of Factor XIII. Lower Gly-Pro-Arg-Pro concentrations were used to determine the effects of incompletely inhibiting fibrin polymerization on cleavage of Factor XIII and fibrinogen. Thrombin cleavage of Factor XIII but not fibrinogen was dependent on the extent of fibrin polymerization. The more marked the degree of inhibition of fibrin polymerization, the slower the rate of Factor XIIIa formation. Thus, in platelet-rich plasma, thrombin cleavage of Factor XIII and fibrinogen are closely related events during spontaneous clotting. Furthermore, cleavage of Factor XIII during clotting is enhanced by fibrin polymerization in platelet-poor plasma.

Binding Sites↗
PubMed1985

Response of patients with mild and moderate hemophilia A and von Willebrand's disease to treatment with desmopressin.

Desmopressin was administered intravenously to 68 patients with hemophilia and von Willebrand's disease of mild or moderate severity to assess the safety, reproducibility, and range of response to this new therapeutic alternative. A rise in factor VIII-von Willebrand factor levels was seen in 64 patients, and the magnitude was sufficient to provide normal hemostasis in 55 to 68 spontaneous or traumatic bleeding episodes, dental procedures, or operations. Thus, our experience shows that most patients with mild or moderate hemophilia and von Willebrand's disease can be treated effectively without plasma derivatives. Patients who had two or more infusions of desmopressin at different times had similar responses each time, and members of the same family also had similar responses after desmopressin infusions. Because this drug can be administered without significant side effects, it should have an important role in the management of patients with mild or moderate hemophilia and von Willebrand's disease.

Adolescent↗
PubMed1984

Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck, and prostate. Final report of VA Cooperative Study #75.

VA Cooperative Study #75 was established to test in a controlled, randomized trial the hypothesis that warfarin anticoagulation would favorably affect the course of certain types of malignancy. No differences in survival were observed between warfarin-treated and control groups for advanced non-small cell lung, colorectal, head and neck and prostate cancers. However, warfarin therapy was associated with a significant prolongation in the time to first evidence of disease progression (P = 0.016) and a significant improvement in survival (P = 0.018) for patients with small cell carcinoma of the lung, including the subgroup of patients with disseminated disease at the time of randomization (P = 0.013). A trend toward improved survival with warfarin treatment was observed for the few patients admitted to this study with non-small cell lung cancer who had minimal disease at randomization. These results suggest that warfarin, as a single anticoagulant agent, may favorably modify the course of some, but not all, types of human malignancy, among which is small cell carcinoma of the lung. Further trials of warfarin may be indicated in patients with limited disease who have cell types that failed to respond when advanced disease was present.

Adenocarcinoma↗
PubMed1984

Accrual of patients into a multihospital cancer clinical trial and its implications on planning future studies.

Little information exists on the population of cancer patients from which individual patients are selected for admission to a clinical trial. In fact, most reports of clinical trials of cancer chemotherapeutic agents begin by describing samples of treated patients but neglect to collect data and describe the population from which the samples were taken. In a multi-institutional VA Cooperative Study in which two different cancer treatments were compared, an attempt was made to screen all lung, colorectal, prostate, and head and neck patients seen at participating hospitals prior to randomization to a therapeutic regimen. Of a total of 2687 patients screened, 437 (16.3%) were randomized and 2250 (83.7%) were excluded for 2981 reasons. Protocol reasons were the basis for 68.6% of all exclusions, 21.3% were physician refusals, and 10.1% were patient refusals. The number of patients randomized did not correlate well with number of patients screened across participating centers. Patients admitted to the study tended to be younger and in better health than excluded patients. Overestimates of randomization rates projected initially from published information point to the need for improved screening data in the planning of future studies. Factors such as screening methods, physician acceptance of the experimental approach, number of competing protocols within each center, and cooperation among medical center departments and personnel all are important ingredients in any screening effort.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

Comparison of local versus central tumor measurements in a multicenter cancer trial.

Four hundred nineteen solid tumors from 92 patients were measured by a local team consisting of a physician and nurse oncologist or physician's assistant, and centrally by one radiologist. The central radiologist also remeasured 137 tumors on 30 patients to assess intraexaminer agreement. Tumor measurements at specific points in time as well as changes in tumor measurements over time were evaluated. When signed differences were calculated, there was little overall difference between local and central examiners, although three of the eight centers did show a significant difference. However, when absolute differences were calculated, the relative errors of the width times length products ranged from 35 to 55%. Although local and central examiners agreed 75% of the time on change in disease, there was only 42% agreement on the subset of patients who had a remission. In general, the intraexaminer agreement was slightly better than the interexaminer agreement. This study suggests that solid tumor measurements are not particularly reliable, and that survival time remains the most satisfactory endpoint in a cancer clinical trial.

Clinical Trials as Topic↗
PubMed1984

Macrophage procoagulants.

From the preceding exposition it is now clear that the regulation of monocyte/macrophage PCA is dependent upon a complex network of interacting pathways, some of which amplify the response of the monocyte/macrophage, while others inhibit. In all probability many more will emerge. The construct illustrated in Figure 3, therefore, is a simplified view of the two major stimulatory pathways: the T cell-dependent pathway, activated by immune recognition and mediated by lymphokine(s); and the T cell-independent pathway, activated by direct perturbation of monocytes by such stimuli as LPS. At least 2 or 3 different PCAs can be expressed by monocyte/macrophages from different species, depending upon the anatomic site of the origin of the cell and the types of stimuli imposed. Inhibition of PCA expression is accomplished by at least one set of regulatory lipoproteins, and other inhibitory loops may be found. The result of these multiple interactions is the deposition of fibrin on the cell surface or in the surrounding milieu. It is our belief that this close relationship between coagulation reactions and inflammatory reactions, resulting in fibrin deposition, represents a fundamental host defense designed to delimit the inflammatory response. Nevertheless, the precise role of monocyte procoagulants in vivo remains unclear. A number of potential mechanisms exist for activation of coagulation in both inflammatory and neoplastic disorders, and the finding of enhanced monocyte procoagulant activity by no means establishes its importance in physiologic or, pathosphysiologic responses in vivo. Further studies, possibly with agents capable of specific inhibition of monocyte procoagulants in vivo, will be necessary to define the precise importance of these procoagulants in clinical disorders.

Animals↗
PubMed1983

Abnormalities of blood coagulation in patients with cancer. Fibrinopeptide A generation and tumor growth.

Fibrinopeptide A (FPA) levels have been followed sequentially in a three-year study of 50 patients with advanced carcinoma. Evidence for activation of blood coagulation was found in 26 of 43 subjects (60%) at the time of entry into the study. Serial FPA determinations revealed an upward trend which paralleled the progression of clinical disease. Persistent elevation of the FPA level suggested treatment failure and a poor prognosis. Anticoagulation with sodium warfarin significantly reduced the FPA level in subjects with cancer. Short-term anticoagulation with heparin decreased FPA levels in two patients with thromboembolic disease but failed to reduce FPA to the normal range in any of the three patients with cancer so tested. These data suggest that most patients with advanced cancer have evidence for activation of blood coagulation and suggest that serial FPA determinations may be useful in following tumor progression or response to therapy in patients with cancer.

Aged↗
PubMed1983

Expression of procoagulant activity in a human monocyte-like cell line.

Peripheral blood monocytes generate the potent membrane-bound procoagulant TF in response to a number of immune-related stimuli. Although the contribution of the monocyte/macrophage and its soluble mediators to the immune response has been recognized, the role of macrophage procoagulant in the pathogenesis of this response is less certain. Previous studies have suggested that MTF generation is important in the pathogenesis of fibrin deposition in the inflammatory response. In order to pursue this relationship, we have studied the activation of a procoagulant in a human monocyte-like cell line, the U937. The U937 procoagulant has been characterized as TF by the following criteria: the PCA requires factors VII and X for expression; the PCA is not due to serine protease activity; PCA is neutralized by a monospecific antibody to purified bovine TF. The expression of TF in these cells was amplified after stimulation with LPS, a potent activator of peripheral blood MTF expression, and was inhibited by actinomycin D and cycloheximide. Cytosine arabinoside, an inhibitor of cell division, failed to affect U937 TF generation. The U937 cell line appears to be a useful in vitro model for the study of the activation of MTF.

Cell Line↗
PubMed1982

Platelets and malignancy. Rationale and experimental design for the VA Cooperative Study of RA-233 in the treatment of cancer.

Considerable evidence has accumulated in recent years which implicates blood coagulation reactions in the growth and spread of malignancy. In particular, platelets may accumulate on embolic tumor cells and facilitate their adhesion to the endothelium at distant sites perhaps by enhancing blood coagulation reactions. Alternatively, platelets may promote tumor cell proliferation by contributing a growth-promoting factor or through interactions mediated by prostaglandins. Inhibition of tumor growth and spread by platelet-inhibitory drugs has been demonstrated in several experimental tumor systems. Preliminary data suggest that similar effects may be seen in human malignancy. The purpose of this paper is to review relevant literature which provides the rationale for therapeutic trials of platelet-inhibitory drugs in human malignancy and to describe the experimental design for a trial involving one such drug, RA-233, in a recently established VA Cooperative Study.

Adenocarcinoma↗