Biomedical subjects
Publications and source records attributed to A Falanga.
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Coagulation abnormalities occurring in patients with acute promyelocytic leukemia (APL) are partially corrected by heparin administration. This study was undertaken to verify if "supra-normal" levels of antithrombin III (AT-III) are similarly able to quench intravascular thrombin generation triggered by APL cells. Eight patients with APL were randomly assigned to receive either 50 U/kg (Group A) or 100 U/kg (Group B) of an AT-III concentrate, starting on the first day of chemotherapy and continuing for 7 days thereafter. Fibrinopeptide A (FPA), prothrombin fragment F1+2 and thrombin-AT III complexes, measured before and 15 minutes after each AT-III infusion, decreased significantly after each infusion, but the effect was minimal and short-lived, despite the achievement of post-infusion levels of AT-III activity well above 150% (Group A) or 200% (Group B). Small amounts of heparin were consistently detected in AT-III concentrates and post-infusion plasma samples. The short-lived quenching of thrombin generation after AT-III concentrate could be partially explained by the infusion of heparin, rather than by supranormal AT-III levels.
This study investigated whether the pre-surgical plasma levels of TAT and F1 + 2 of patients undergoing major surgery for localized tumours could identify patients at higher risk of thrombosis, and how heparin prophylaxis affected in vivo coagulation after cancer surgery. We measured the pre- and post-operative levels of TAT, F1 + 2, total factor VII (FVIIt) and zymogen FVII (FVIIz) in 117 cancer patients, with and without heparin prophylaxis. The end points of this study were DVT, initially detected by 125I-fibrinogen uptake test and confirmed by ascending venography. Pre-operative [TAT] and [F1 + 2] of the cancer patients were significantly higher than those of age-matched control subjects (n = 50) (P < 0.005 and P < 0.05, respectively); pre-operative [FVII] was not significantly different. One of the 83 patients receiving prophylaxis, and 8/34 not receiving prophylaxis developed post-operative DVT. Of the parameters evaluated, only the pre-operative [TAT] > 3.5 ng/ml identified patients at higher risk for post-operative DVT. Heparin reduced plasma TAT levels and FVII consumption following surgery, suggesting that heparin modulates coagulation associated with cancer surgery. The results of this study also suggest that the pre-operative [TAT] may identify patients with higher risk for post-operative DVT.
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We studied several blood coagulation parameters and tumor tissue procoagulant activity (PCA) in nude mice bearing human colorectal carcinomas (HCC). In a control group of 51 tumor-free nude mice, platelet number was 1.2 +/- 0.03 x 10(6)/microliters, thrombotest activity 90% +/- 2.6 and fibrinogen 172 +/- 11 mg/dl. The same parameters were studied in nude mice (n = 71) bearing 7 different HCC lines subcutaneously (s.c.). The results did not significantly differ from those in control mice but there was broad variability among groups of mice injected with different HCC lines, ranging from 0.36 to 2.55 x 10(6)/microliters for platelets, from 100 to 28% for thrombotest activity and from 42 to 460 mg/dl for fibrinogen. The results were significantly (p less than 0.05) different from those in the tumor-free group when each group of HCC-bearing animals was analyzed individually. A malignant HCC line that grew in the liver of nude mice (n = 24) significantly (p less than 0.001) reduced thrombotest activity (58% +/- 5.9). The PCA of tissue extracts from tumors grown s.c. in nude mice was assayed. All the HCC xenografts expressed PCA which differed significantly for the various tumor lines (from 25.5 +/- 1.9 to 2.8 +/- 0.6 unit/mg in tumor tissue). Cancer procoagulant (CP), a cysteine proteinase with a direct factor-X-activating effect, was present in different amounts (84.7 +/- 4.3 to 59.5 +/- 9.0%) in the tumors. Our results indicates that the nude mouse is a suitable model for evaluating the hemostatic changes induced by human tumors and may represent a tool for investigating the underlying biochemical mechanisms.
OBJECTIVE: To assess the efficacy of intravenous immunoglobulin (IVIG), in comparison with plasma exchange (PE), in the treatment of patients with thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS). DESIGN: Prospective, nonrandomized comparative study. SETTING: Hematology department in a general hospital. PATIENTS: 17 consecutive adult patients, six of them pregnant, with diagnosis of TTP/HUS. Three had a severity score at diagnosis less than or equal to 4 and were treated with IVIG and 14 had a severity score of greater than or equal to 5 and/or were pregnant and received PE. The response was evaluated after 5 days of therapy. RESULTS: Complete remission was obtained in 0/3 cases treated with IVIG and 10/14 (71%) with PE (Fisher's exact test P = 0.05). Three patients died for widespread TTP-HUS, and four had persistent disease. In three of the four resistant patients, complete remission was obtained by further PE but not by further IVIG. The overall remission rate was 76% (13/17). CONCLUSIONS: Our study does not confirm the utility of IVIG in the management of TTP-HUS, as suggested by earlier single case reports.
The case is presented of a patient who showed visual naming disturbances caused by a left occipital infarction. His performance on tests of visual naming, of recognition not requiring a verbal response, and of verbal-visual matching demonstrated a wide range of qualitatively different errors, including complete inability to recognize the object, access to partial semantic knowledge, and mere name finding difficulty. On the basis of the present case and of a review of the recent literature, the clinical distinction between visual associative agnosia and optic aphasia and the relation of these disorders with the anatomical site of lesion are discussed.
The platelet aggregating activity (PAA) of serum and plasma from thrombotic thrombocytopenic purpura (TTP, eight patients) and haemolytic uraemic syndrome (HUS, three patients) was investigated. Sample-induced aggregation of washed platelets and the parallel 3H-serotonin release were studied both in the presence and the absence of purified von Willebrand factor (vWF) or defibrinated cryoprecipitate, according to Kelton et al (1987). All the samples but two were positive in the test, vWF being indispensable for aggregation in all but two of the active cases. Samples from five patients during remission were ineffective under the same conditions, as were 14 controls from healthy donors. An inhibition study using four cysteine proteinase inhibitors (1 mM iodoacetamide, 0.5 mM E-64, 0.1 mM antipain and 0.1 mM leupeptin) and two serine proteinase inhibitors (200 U/ml aprotinin and 0.2 U/ml hirudin) confirmed that TTP/HUS's PAA behaved enzymatically as a cysteine proteinase, as described (Murphy et al, 1987a). These results were confirmed on a protein preparation obtained from pooled plasmas after Al(OH)3 adsorption, ammonium sulphate precipitation, binding to and elution from a p-(chloromercuri)benzoate (PCMB) affinity resin. To further characterize this activity we investigated whether it was a calcium-dependent neutral protease or a lysosomal cathepsin by testing the sensitivity to a series of peptidyl diazomethyl ketones, synthetic inhibitors specifically designed for cysteine proteinases. We confirm here the presence of a circulating platelet aggregating cysteine proteinase in TTP/HUS and provide evidence for the first time that this activity behaves like a lysosomal cathepsin.
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Blast cell extracts from patients with acute non lymphoid leukemia (ANLL) express cancer procoagulant (CP). This factor X (FX) activator is distinct from tissue factor (TF) in that it does not require factor VII (FVII) to trigger blood coagulation, it acts as a cysteine proteinase and is not present in normal mononuclear cells. To assess whether there is any relationship between the presence of CP and the status of the disease, ANLL patients have been studied at diagnosis, during remission, at relapse. The procoagulant activity in either the presence or absence of F VII and sensitivity to cysteine proteinase inhibitors were tested on cell extracts. Immunoreactivity was explored with an anti-CP polyclonal antibody. Data obtained in 91 newly-diagnosed ANLL patients (subtypes M1 to M5, FAB classification) confirmed the presence of CP in M1 to M4 groups (mean +/- SE FVII-independent activity: M1 = 2.1 +/- 0.7 unit/mg; M2 = 5.7 +/- 1.7 unit/mg; M3 = 31.5 +/- 8 unit/mg; M4 = 1.6 +/- 1.2 unit/mg); CP was absent in the M5 type. In eight patients analyzed in a subsequent phase of partial remission, specific activity had dropped from 26.9 +/- 7.8 to 10.5 +/- 4.0 unit/mg. Activity was virtually absent (0-0.05 unit/mg) in the bone marrow of 37 patients studied at complete remission. Bone marrow samples from six subjects tested at different intervals after complete remission were repeatedly negative for CP but became positive 2 to 5 months before relapse. Upon relapse, the FVII independent activity rose to 24.2 +/- 8.2 unit/mg.(ABSTRACT TRUNCATED AT 250 WORDS)
In a previous study we characterized cancer procoagulant (CP), a 68 kd cysteine proteinase which directly activates coagulation factor X in various subtypes (from M1 to M5) of acute non-lymphoblastic leukemia (ANLL). The aim of this study was to determine whether CP is also expressed by acute lymphoblastic leukemia (ALL) cells. Blasts from 25 ALL patients were extracted and tested for their procoagulant properties. 16 samples (64%) shortened the recalcification time of normal human plasma, and 9 (36%) did not. 8 of the 16 active samples showed properties compatible with CP, i.e. independence from factor VII in triggering blood coagulation and sensitivity to cysteine proteinase inhibitors. Selected samples also cross-reacted with a polyclonal antibody raised against purified CP. The specific activity of CP in ALL extracts was significantly lower than in most ANLL types previously studied (all but M4). These finding indicate that CP can be a property of the lymphoid phenotype although its expression may be lower than in the myeloid phenotype.
Cancer procoagulant (CP) is a cysteine proteinase from cancer cells that initiates blood coagulation. Members of two classes of unique and highly specific cysteine proteinase inhibitors, peptidyl diazomethyl ketones (PDK) and peptidyl sulfonium salts (PSS), were studied to determine whether or not they inhibited CP. The inhibitors did not impair the activity of the coagulation system. There was a differential inhibitory effect of the 6 PDK and 2 PSS inhibitors, influenced by the amino acid composition or sequence of the peptide moiety, that suggests differences in structural features of the active site of CP and papain. CP was inhibited by both classes of inhibitors.
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We have investigated concomitantly the pro-aggregating and pro-coagulant activities of 11 breast and 2 colon human carcinomas. Tumor tissues, obtained at surgery, were immediately processed to prepare tumor-cell suspensions for the study of aggregating activity and tissue extracts for the study of procoagulant capacity. Nine carcinomas (8 breast and 1 colon) possessed a high, dose-dependent platelet-aggregating activity, which was present in the cell-free supernatant and was inhibited by HgCl2 and iodoacetic acid, specific cysteine proteinase inhibitors, while apyrase and hirudin had no significant effect; in contrast, the other tumors did not aggregate platelets. All the tumor extracts tested from 12 carcinomas (11 breast and 1 colon) were able to activate blood coagulation in both the presence and the absence of F VII. The activity was inhibited by HgCl2 and iodoacetamide, while Con A was less effective. Therefore, these tumors do not aggregate platelets through the production of ADP or thrombin, nor promote blood coagulation through the production and release of tissue factor; a tumor-associated cysteine proteinase plays a major role in both pro-aggregating and pro-coagulant activities.
This study was originally designed to investigate whether there is any correlation between the type of procoagulant activity (PCA) and the tumorigenicity of transformed cells. The data obtained are relevant to this question and to defining the differences in the expression of cellular activities depending on the in vitro system used. PCA was measured and characterized in normal, immortalized, and tumorigenic mouse fibroblasts. In all the cell lines studied the activity was of tissue factor type, as established with functional, enzymatic, and immunochemical criteria. However, the PCA of cells freshly isolated from the tumors induced by tumorigenic cell lines was of cancer procoagulant type, i.e. a cysteine protease with direct factor X activator activity. The same cells, when cultured in vitro, expressed again PCA of tissue-factor type. These results suggest that either a tumor-host interaction is required for the expression of cancer procoagulant or the latter activity, produced by tumor cells under in vitro conditions, is destroyed or inactivated during the culture period. Our findings caution against defining the procoagulant activity of tumors based on experiments on cultured cells.
To verify whether cancer procoagulant (CP), a cysteine proteinase procoagulant distinct from tissue factor (TF), is associated with leukemic cells, we assayed the procoagulant activity of blast cell extracts from 26 patients with different cytological subtypes of acute nonlymphoid leukemia (ANLL) according to the French-American-British classification. All the samples except two shortened the recalcification time of normal human plasma, the effect being significantly greater in the M3 subgroup. The two criteria used to distinguish between CP and TF, independence from factor VII in initiating blood coagulation and sensitivity to cysteine-proteinase inhibitors, were positive in 19 samples from M1, M2, M3, and M4 cytological subtypes. None of the M5 samples fulfilled these criteria. In addition, M1, M2, M3, and M4 samples immunoreacted with an anti-CP goat polyclonal antibody on an Ouchterlony immunodiffusion plate. This study provides the first evidence for a procoagulant other than TF that is associated with leukemic cells.
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Cancer Procoagulant (CP), a cysteine proteinase which triggers blood coagulation by directly activating Factor X (FX) in the absence of Factor VII (F VII), has recently been isolated from rabbit V2 carcinoma and biochemically characterized. We have studied the procoagulant activity of tissue extracts from 4 murine experimental tumors in order to define whether or not a F VII-independent activity with cysteine proteinase characteristics was present. The tumors studied were: Lewis lung carcinoma (3LL), B16 melanoma (B16), JW sarcoma (JWS) and the M4 variant of the mFS6 fibrosarcoma (M4). Extracts from 3LL, B16 and JWS tumor initiated coagulation in both the presence and absence of F VII, their procoagulant activity was sensitive to iodoacetamide (1 mM) and mercury chloride (0.1 mM). The procoagulant of M4 extract was dependent on the presence of F VII and was not significantly affected by the cysteine proteinase inhibitors. An Ouchterlony double immunodiffusion study showed immunological cross-reactivity of all but M4 extracts to a polyclonal antibody to purified CP. The present study suggests that the procoagulant(s) present in the murine tumors 3LL, B16 and JWS are enzymatically and immunologically indistinguishable from cancer procoagulant of the rabbit V2 carcinoma.