thromboplastin and Leukemia--Myeloid--Acute

Cancer cells may promote fibrin formation in the tumor microenvironment through availability of procoagulant activities which are mainly of two types: tissue thromboplastin-like or direct activator of coagulation factor X. The pharmacological modulation of these activities could be potentially important in the control of metastasis growth. However, very limited information is available so far on this issue; it has recently been shown that the direct activator of coagulation factor X is a vitamin K-dependent activity which is depressed by warfarin treatment, not by anticoagulation with heparin or defibrinating enzymes. Whether the inhibition of this peculiar cancer procoagulant is involved in the antimetastatic activity of warfarin is a stimulating hypothesis which needs to be further substantiated.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Blood Coagulation Factors; Cell Membrane; Cysteine Endopeptidases; Endopeptidases; Humans; Leukemia, Myeloid, Acute; Mice; Mucins; Neoplasm Metastasis; Neoplasm Proteins; Thromboplastin; Warfarin

Recent findings of thromboplastin (TRPL) investigations are presented in a brief survey. After enumerating the possibilities of separating this lipoprotein into two shares, the chemical characterization of protein and lipid fraction is represented, the possibilities and conditions of recombining both shares are mentioned and the effectiveness of TRPL in the exogenous coagulation system is illustrated. Furthermore, the liberation of TRPL by leukocytes is referred to and feasible mechanisms of this liberation are discussed. Finally the relations of TRPL to tumour cell materials promoting coagulation and from amnion liquid are discussed.

Topics: Amnion; Animals; Antigens; Blood Coagulation; Blood Vessels; Brain Chemistry; Endotoxins; Enzyme Activation; Factor X; Fibroblasts; Humans; Leukemia, Myeloid, Acute; Leukocytes; Lipids; Lung; Mice; Proteins; Sarcoma, Experimental; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Coagulation Factors; Blood Platelets; Cell Membrane Permeability; Fibrinogen; Fibrinolysis; Hemorrhagic Disorders; Humans; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Thrombocythemia, Essential; Thrombocytopenia; Thromboplastin

Patients with acute myeloid leukemia (AML) are at increased risk of thrombohemorrhagic complications. Overexpressed tissue factor (TF) on AML blasts contributes to systemic coagulation activation. We have recently shown that the heme enzyme myeloperoxidase (MPO) negatively regulates TF procoagulant activity (PCA) on myelomonocytic cells in vitro. We now aimed to further characterize the functional interaction of MPO and TF in AML in vivo.. We prospectively recruited 66 patients with newly diagnosed AML. TF PCA of isolated peripheral blood mononuclear cells (PBMC) was assessed by single-stage clotting assay in the presence or absence of inhibitors against MPO catalytic activity (ABAH) or against MPO-binding integrins (anti-CD18). MPO in plasma and in AML blasts was measured by ELISA, and plasma D-dimers and prothrombin fragment F1+2 were quantified by automated immunoturbidimetric and chemiluminescence assays, respectively.. Patients with AML had significantly higher MPO plasma levels compared to healthy controls and exhibited increased levels of D-dimers and F1+2. In vivo thrombin generation was mediated by TF PCA on circulating PBMC. Ex vivo incubation of isolated PBMC with ABAH or anti-CD18 antibody resulted in either increased or decreased TF PCA. The strong and robust correlation of F1+2 with TF PCA of circulating PBMC was abrogated at MPO plasma levels higher than 150 ng/mL, indicating a modulatory role for MPO on TF-mediated in vivo thrombin generation above this threshold.. Our study indicates that catalytically active MPO released by circulating myeloblasts regulates TF-dependent coagulation in patients with newly diagnosed AML in a CD18-dependent manner.

Topics: Blood Coagulation; Humans; Leukemia, Myeloid, Acute; Leukocytes, Mononuclear; Peroxidase; Thrombin; Thromboplastin

Idarubicin (IDR), cytarabine (AraC), and tamibarotene (Am80) are effective for treatment of acute myeloid leukemia (AML). In acute leukemia, the incidence of venous thromboembolism or disseminated intravascular coagulation is associated with induction chemotherapy. Procoagulant effects of IDR, AraC, and Am80 were investigated in a vascular endothelial cell line EAhy926 and AML cell lines HL60 (AML M2), NB4 (AML M3, APL), and U937 (AML M5), focusing on tissue factor (TF), phosphatidylserine (PS), and thrombomodulin (TM). IDR induced procoagulant activity on the surface of vascular endothelial and AML cell lines. Expression of TF antigen, TM antigen, and PS were induced by IDR on the surface of each cell line, whereas expression of TF and TM mRNAs were unchanged. Conversely, Am80 decreased TF exposure and procoagulant activity, and increased TM exposure on NB4 cells. In NB4 cells, we observed downregulation of TF mRNA and upregulation of TM mRNA. These data suggest IDR may induce procoagulant activity in vessels by apoptosis through PS exposure and/or TF expression on vascular endothelial and AML cell lines. Am80 may suppress blood coagulation through downregulation of TF expression and induction of TM expression. Our methods could be useful to investigate changes in procoagulant activity induced by antineoplastic drugs.

Topics: Antineoplastic Agents; Benzoates; Cell Line, Tumor; Cytarabine; Gene Expression Regulation, Neoplastic; HL-60 Cells; Humans; Idarubicin; Leukemia, Myeloid, Acute; Phosphatidylserines; Tetrahydronaphthalenes; Thrombomodulin; Thromboplastin

Topics: Adult; Cell-Derived Microparticles; Disseminated Intravascular Coagulation; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Thromboplastin; Thrombosis

Topics: Cell-Derived Microparticles; Disseminated Intravascular Coagulation; Female; Humans; Leukemia, Myeloid, Acute; Male; Thromboplastin

Heparanase is an endo-β-D-glucuronidase dominantly involved in tumor metastasis and angiogenesis. Recently, we demonstrated that heparanase is involved in the regulation of the hemostatic system. Our hypothesis was that heparanase is directly involved in activation of the coagulation cascade.. Activated factor X and thrombin were studied using chromogenic assays, immunoblotting and thromboelastography. Heparanase levels were measured by enzyme-linked immunosorbent assay. A potential direct interaction between tissue factor and heparanase was studied by co-immunoprecipitation and far-western assays.. Interestingly, addition of heparanase to tissue factor and activated factor VII resulted in a 3- to 4-fold increase in activation of the coagulation cascade as shown by increased activated factor X and thrombin production. Culture medium of human embryonic kidney 293 cells over-expressing heparanase and its derivatives increased activated factor X levels in a non-enzymatic manner. When heparanase was added to pooled normal plasma, a 7- to 8-fold increase in activated factor X level was observed. Subsequently, we searched for clinical data supporting this newly identified role of heparanase. Plasma samples from 35 patients with acute leukemia at presentation and 20 healthy donors were studied for heparanase and activated factor X levels. A strong positive correlation was found between plasma heparanase and activated factor X levels (r=0.735, P=0.001). Unfractionated heparin and an inhibitor of activated factor X abolished the effect of heparanase, while tissue factor pathway inhibitor and tissue factor pathway inhibitor-2 only attenuated the procoagulant effect. Using co-immunoprecipitation and far-western analyses it was shown that heparanase interacts directly with tissue factor.. Overall, our results support the notion that heparanase is a potential modulator of blood hemostasis, and suggest a novel mechanism by which heparanase increases the generation of activated factor X in the presence of tissue factor and activated factor VII.

Topics: Adolescent; Adult; Aged; Anticoagulants; Blood Coagulation; Factor VIIa; Factor Xa; Female; Glucuronidase; Glycoproteins; HEK293 Cells; Heparin; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Serine Proteinase Inhibitors; Thromboplastin

Patients with haematological malignancies carry increased risk of venous thrombosis (VT). However, the mechanisms that link these malignancies to activated coagulation have not been fully identified. Since anti-haemostatic agents are studied in clinical trials for their potential to prolong survival in cancer patients, a detailed characterisation of haemostatic markers in cancer subtypes is needed. Hence, in this study, we measured the plasma concentrations and mRNA expression in blood mononuclear cells of haemostatic parameters in 93 patients with haematological neoplasias (acute myeloid leukaemia, chronic lymphatic leukaemia, multiple myeloma, and non-Hodgkin's lymphoma) before start and after completion of cancer therapy. At diagnosis we found activation of coagulation and fibrinolysis, especially in patients with acute myeloid leukaemia. This hypercoagulation was not associated with increased levels of tissue factor (TF) or factor VII (fVII) antigen or mRNA, or levels of activated fVII. In conclusion we found a hypercoagulable state in patients with haematological malignancy that did not seem to be initiated by TF.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Blood Coagulation; Case-Control Studies; Factor VII; Female; Fibrin Fibrinogen Degradation Products; Glycoproteins; Hematologic Neoplasms; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid, Acute; Lipoproteins; Longitudinal Studies; Lymphoma, Non-Hodgkin; Male; Middle Aged; Multiple Myeloma; Norway; Peptide Fragments; Prothrombin; RNA, Messenger; Thrombophilia; Thromboplastin; Venous Thrombosis

AML1 mutations were identified in 6.3% of AML patients with chromosomal translocations involving CBF, PML-RARalpha, HOX, or ETS transcription factor (TF) gene families. Rare chromosomal abnormalities, t(16;21) and t(7;11), were also found. This study represents the first series to demonstrate the coexistence of known and novel AML1 mutations with different TF gene mutations. Although the occurrence of two TF gene mutations may appear unnecessary, the possible synergistic mechanism between different TF gene families cannot be excluded and needs to be further explored.

Topics: Core Binding Factor Alpha 2 Subunit; Humans; Leukemia, Myeloid, Acute; Multigene Family; Mutation; Thromboplastin; Transcription Factors; Translocation, Genetic

Over-expression of tissue factor (TF) and activation of the coagulation system are common in cancer patients. Heparanase is an endo-beta-D-glucuronidase that cleaves heparan sulfate chains on cell surfaces and in the extracellular matrix, activity that closely correlates with cell invasion, angiogenesis and tumor metastasis. The study was undertaken to investigate the involvement of heparanase in TF expression.. Tumor-derived cell lines were transfected with heparanase cDNA and TF expression was examined. The effect of exogenous addition of active and inactive heparanase on TF expression and activity was studied in tumor cell lines and primary human umbilical vein endothelial cells. TF expression was also explored in heparanase over-expressing transgenic (Tg) mice. Blast cells were collected from acute leukemia patients and TF and heparanase expression levels were analyzed.. Over-expression of heparanase in tumor-derived cell lines resulted in a 2-fold increase in TF expression levels, and a similar trend was observed in heparanase Tg mice in vivo. Likewise, exogenous addition of heparanase to endothelial or tumor-derived cells resulted in enhanced TF expression and activity. Interestingly, TF expression was also induced in response to enzymatically inactive heparanase, suggesting that this effect was independent of heparanase enzymatic activity. The regulatory effect of heparanase on TF expression involved activation of the p38 signaling pathway. A positive correlation between TF expression levels and heparanase activity was found in blasts collected from 22 acute leukemia patients.. Our results indicate that in addition to its well-known function as an enzyme paving a way for invading cells, heparanase also participates in the regulation of TF gene expression and its related coagulation pathways.

Topics: Blood Coagulation; Cell Line, Tumor; Endothelial Cells; Gene Expression Regulation, Leukemic; Heparin Lyase; Humans; Leukemia, Myeloid, Acute; Neoplasm Invasiveness; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thromboplastin

The frequency of thrombotic complications is increased in patients with acute leukemia. Since coagulation processes take place on cell membranes, we hypothesized that expression of coagulation proteins on blast membrane could determine the hemostatic balance on the surface of leukemic cells and may correlate with thrombotic manifestations.. Fifty-one consecutive patients with newly diagnosed acute leukemia were enrolled over an 11-month period. Twenty-five of the patients had acute myeloid leukemia (AML)-M(0-2), 11 had AML-M3, 6 had AML-M(4-5), and 9 acute lymphocytic leukemia (ALL). Peripheral blood and bone marrow were analyzed by flow-cytometry for tissue factor, protease-activated receptor 1, tissue factor pathway inhibitor, urokinase plasminogen activator receptor, and thrombomodulin.. Regardless of the leukemia subtype, tissue factor was predominantly present on leukemic blast surfaces as compared to protease-activated receptor 1, tissue factor pathway inhibitor, urokinase plasminogen activator receptor and thrombomodulin and it was significantly elevated (mean 63+/-6%) in AML-M3 and AML-M(4-5) as compared to AML-M0(-2) and ALL (mean 37+/-4%, p<0.001). Likewise, urokinase plasminogen activator receptor expression was greater in AML-M(4-5) (49+/-11%) than in in AML- M(0-2), M3 and, ALL (mean 17+/-3%, p<0.001). Thrombotic manifestations were present in 13 out of 51 (26%) patients. The tissue factor to urokinase plasminogen activator receptor ratio was higher in patients with a thrombotic event than in patients without thrombotic events (16+/-4 vs. 6+/-2, p=0.042).. This study demonstrates that tissue factor predominates on leukemic blast surface, particularly in M3 and M4-5 subtypes, while urokinase plasminogen activator receptor is increased on M4-5 blasts. The hemostatic balance on the blast surface may contribute to thrombotic manifestations in leukemic patients.

Topics: Adult; Aged; Cell Membrane; Female; Hemostasis; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Receptors, Cell Surface; Receptors, Urokinase Plasminogen Activator; Thromboplastin; Thrombosis

AML patients may suffer from a disseminated coagulopathy, which can aggravate a pre-existing bleeding tendency due to thrombocytopenia and platelet dysfunction. The cellular and molecular mechanisms underlying this coagulopathy, however, are not completely understood. Indeed, the broad and increasing therapeutic use of cytotoxic drugs and growth factors is likely to contribute to the complexity of hemostatic abnormalities encountered in this hematologic malignancy. The nature of coagulation activation in AML was therefore investigated in vitro using the human leukemic cell line, HL60. Tissue factor (TF) was almost entirely located on the cell surface and bound factor VIIa, but only 15-25% of this TF was primarily functionally active. Treatment with increasing concentrations of daunorubicin or cytosine-beta-D-arabinofuranoside, two cytotoxic drugs commonly used in AML therapy, induced apoptosis and secondary necrosis of HL60 cells and resulted in marked decryption of TF PCA independent of de novo protein synthesis. This PCA-modulating effect was concomitant with and functionally dependent on the exposure of phosphatidylserine on the outer membrane leaflet. Similar observations were made in analogous ex vivo studies on patient-derived myeloblasts. Incubation of HL60 cells with GM-CSF, a cytokine expressed in the bone marrow microenvironment and used as an adjunct to AML treatment, evoked a cellular response, which included both enhanced TF production and release of VEGF-A and uPA into the culture medium. We conclude that both decryption of pre-formed TF PCA by chemotherapeutic drugs and de novo induction of TF by cytokines such as GM-CSF can regulate the pro-coagulant phenotype of HL60 cells in vitro.

Topics: Antineoplastic Agents; Blood Cells; Blood Coagulation; Cell Death; Cells, Cultured; Cytarabine; Daunorubicin; Granulocyte Precursor Cells; Granulocyte-Macrophage Colony-Stimulating Factor; HL-60 Cells; Humans; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Thromboplastin

The aim of study was to evaluate TF activity and TFPI concentration in patients with haematological malignancies and urinary tract tumors. TFPI concentration and activity and TF concentration were measured in 20 patients suffering from acute myeloblastic leukaemia (AML), 21 patients with chronic myelogenous leukaemia (CML), 17 patients with chronic lymphatic leukaemia (CLL), 16 patients with multiple myeloma (MM) and 65 healthy adults. TFPI and TF concentrations were measured also in patients with renal cell carcinoma (n = 12) and bladder cancer (n = 17) and patients with benign prostatic hyperplasia (BPH) (n = 15). Patients with AML, CML, CLL, and cancer revealed elevated TFPI concentrations. Patients with AML, CML, CLL, MM showed decreased TFPI activity. However TFPI concentration correlated inversely with TFPI activity only in the AML group. No significant changes were observed in TF concentrations in all investigated groups.

Topics: Biomarkers, Tumor; Carcinoma, Renal Cell; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Kidney Neoplasms; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Lipoproteins; Male; Multiple Myeloma; Prostatic Hyperplasia; Thromboplastin; Urinary Bladder Neoplasms; Urologic Neoplasms

To investigate the changes of plasma tissue factor(TF) and tissue factor pathway inhibitor(TFPI) activities in the patients with acute leukemia.. TF and TFPI activities were measured by using chromogenic assays.. Plasma TF activity in the patients with acute leukemia was higher and TFPI activity was lower than those in normal(P < 0.01). In 7 patients who underwent the first chemotherapy, the plasma TF activity was decreased after chemotherapy(P < 0.01), while TFPI activity increased(P < 0.05).. The unbalance between plasma TF and TFPI activities contributes to the coagulant disorders in acute leukemia.

Topics: Adolescent; Adult; Aged; Blood Coagulation; Female; Humans; Leukemia, Myeloid, Acute; Lipoproteins; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thromboplastin

Tissue factor activity of intact cell and cell lysate, and the presence of tissue factor antigen on cell surface, were examined in leukemic cells from patients with acute myelogenous leukemia (AML, M1-M5) or acute lymphoblastic leukemia (ALL-L1), and in mononuclear cells from normal donors. Leukemic cells from AML or ALL had significantly more tissue factor activity not only on intact cells but also in cell lysate than mononuclear cells from normal donors (p < 0.001). Tissue factor activities of the intact leukemic cells and lysate from AML patients with DIC were significantly higher than those without DIC (p < 0.001). The relationship between the percent of positive cells for tissue factor and the presence of DIC at the time of diagnosis of acute leukemia was observed. The patients with DIC showed the higher percentage of tissue factor-positive cells than those without (p < 0.01). The development of DIC following chemotherapy was recognized in 2 out of 7 AML-MI patients and 2 out of 4 ALL-L1 patients who had relatively high tissue factor activities of cell lysate. The release of tissue factor from cytoplasm induced by chemotherapy would be another mechanism for the development of DIC. The report suggests the possibility of the prediction for DIC by the flowcytometric assay of tissue factor antigen.

Topics: Antigens, Surface; Disseminated Intravascular Coagulation; Flow Cytometry; Humans; Leukemia; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thromboplastin

Using clotting assay and radioimmunoassay (RIA), tissue factor activity (TFA) and TF related antigen (TFR:AG) were determined in an extracellular culture medium of HL-60 cells. After 12 h incubation, TFA and TFR:AG in the medium with endotoxin (EDX: 1 microgram/ml) reached maximums which were 1.8 and 2.1 times greater than those in the medium without EDX, respectively. In the leukemic cells of 10 patients with acute nonlymphoid leukemia (ANLL), TFR:AG showed a significant correlation with TFA (p less than 0.01). On day 1 of the induction chemotherapy, TFR:AG in the 7 patients with DIC significantly increased to 288.9 +/- 153.1 ng/ml (p less than 0.01), whereas no increase in TFR:AG was recognized in the 3 patients without DIC. These results suggest that TF may be released from leukemic cells into the culture medium or blood stream, and that this may correlate with the development of DIC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation; Cytarabine; Daunorubicin; Disseminated Intravascular Coagulation; Endotoxins; Humans; Leukemia, Myeloid, Acute; Mercaptopurine; Prednisolone; Thromboplastin; Tumor Cells, Cultured

We investigated the induction of tissue factor by lymphokines in human monoblastic leukemia cell lines (U937) and leukemic cells from AML (acute myelogenous leukemia) patients. After incubation for 24 h, IL-2 enhanced the intracellular tissue factor 15-fold with U937 cells, and GM-CSF enhanced it 6-fold. In contrast, other lymphokines, such as IL-1-alpha, IL-1-beta, IL-3, IL-4 and G-CSF, did not affect the activity of tissue factor. The leukemic blasts, depleted of T-lymphocytes, taken from five out of 16 AML patients showed a 2.5-14-fold increase in the activity of tissue factor per cell following incubation with 200 u/ml of IL-2 for 72 h. The IL-2 induced tissue factor activity more markedly than GM-CSF. Tissue factor stimulation by IL-2 did not correlate with the expression of the IL-2 receptor, Tac, but correlated well with FAB classification of AML cells. IL-2 responders were found in M4 and M5 subtypes only, but not all M4/M5 leukemias responded to IL-2. These findings indicate that IL-2 can mediate the tissue factor induction in the monocytic type of AML and the effect is not mediated by Tac receptors. This may shed a new light on our understanding of hypercoagulability in acute monoblastic leukemia.

Topics: Cytokines; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-2; Kinetics; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Receptors, Interleukin-2; Thromboplastin; Tumor Cells, Cultured

Tissue factor activity (TFA) of leukemic cells (1 x 10(8) cells/mL) was measured in 44 patients with acute nonlymphoid leukemia (ANLL) by the one-stage assay using factor-IX deficient plasma (OSA-dIX) and two-stage assay (TSA). According to the preventative heparin dose schedule based on the TFA measured by the TSA, all disseminated intravascular coagulation (DIC) was controlled successfully. The procedure of the TSA was too complicated for clinical use, and its minimal measurable value was 125 units (U)/L of TFA. The OSA-dIX was simpler in its procedure and sensitive enough to measure accurately a TFA quantity as small as 30 U/L with high reproducibility. In 20 ANLL patients with 125 U/L or more of TFA measured by both assays, there was a significant relationship between their logarithms of TFA (r = 0.93, P less than 0.01). These results suggested that DIC complication in ANLL patients would be controlled successfully by the administration of heparin dosage based on the TFA measured by the OSA-dIX.

Topics: Adult; Blood Coagulation; Blood Coagulation Tests; Bone Marrow; Disseminated Intravascular Coagulation; Factor IX; Female; Humans; Leukemia, Myeloid, Acute; Leukocytes; Male; Middle Aged; Reproducibility of Results; Thromboplastin; Tumor Cells, Cultured

We have studied tissue factor gene expression in the leukocytes of 22 patients with acute myeloblastic leukemia (AML). Total RNA from peripheral blood or bone marrow cells depleted of monocytes was analyzed by Northern blot analysis using a 32P-labeled tissue factor cDNA probe. Cells from 10 cases expressed tissue factor mRNA and positive cases were distributed among the myeloblastic, myelomonocytic, and monocytic subtypes of AML. Tissue factor transcripts were not detected in cells derived from normal bone marrow. The expression of this gene product on the surface of leukemic cells could contribute to the excessive thrombin generation that has been observed in some individuals with this disorder.

Topics: Blood Coagulation Factors; Bone Marrow; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Leukocytes, Mononuclear; Neoplasm Proteins; RNA, Messenger; RNA, Neoplasm; Thromboplastin

Inhibition of Factor VIIa-tissue factor activity by a plasma component(s) that requires factor Xa has been described recently. In this communication, we have developed a specific radiometric assay (which utilizes 3H-Factor IX and is sensitive to less than 1% of plasma level) for this inhibitor and have measured its activity in various disease states. Strikingly, the levels of this inhibitor were found to be normal in patients with advanced chronic hepatocellular disease but low in patients with disseminated intravascular coagulation (DIC). When endotoxin was used to induce DIC in rabbits, the levels of this inhibitor fell by 25-90%. Human umbilical vein endothelial cells (HUVE), bovine pulmonary artery endothelial cells, and a human hepatoma cell line (HepG2) all synthesized and secreted this inhibitor, whereas a promyelocytic cell line (HL-60) did not and a monocytic cell line (U937) appears to synthesize only small amounts. When ammonium sulfate-fractionated human plasma and serum-free conditioned media from both HUVE and HepG2 cells were electrophoresed on sodium dodecyl sulfate acrylamide gels, two activity peaks corresponding to Mr approximately 45,000 and Mr approximately 33,000 were eluted in each case. These observations suggest that (a) the inhibitor is consumed in DIC and that (b) endothelial cells (or other cells) synthesize sufficient amounts of this inhibitor in vivo to compensate for any decreased production by liver cells.

Topics: Animals; Carcinoma, Hepatocellular; Cattle; Cells, Cultured; Chronic Disease; Disseminated Intravascular Coagulation; Factor VII; Factor VIIa; Humans; Infant, Newborn; Leukemia, Myeloid, Acute; Liver Diseases; Liver Neoplasms; Lymphoma, Large B-Cell, Diffuse; Pulmonary Artery; Rabbits; Thromboplastin; Umbilical Veins

Disseminated intravascular coagulation (DIC) is a frequent occurrence in acute promyelocytic leukemia (APL), especially after onset of chemotherapy. We have used a human promyelocytic leukemic established cell line (HL-60) and various other human leukemic cells to investigate the effect of cytotoxic drugs on generation of procoagulant activity (PCA). The results indicate that, unlike normal human peripheral blood monocytes and certain other cell types where PCA induction requires active mRNA and protein synthesis, in HL-60 cells, compounds such as actinomycin D, puromycin, and cytosine arabinoside and a variety of other cytotoxic agents, induced generation of a potent PCA. Although different in its mechanism of induction, this HL-60 cell PCA was similar, and may be identical, to mononuclear cell tissue factor. The PCA induction was rapid and preceded the lytic effect of the drugs. It was first detected on the outer cell surface but, following prolonged exposure to the drugs, upon lysis of the cells, it was also found in the extracellular medium. This in vitro effect mimics the development of DIC in patients with APL. The system may, therefore, serve as a model for the study of the cellular and molecular events associated with PCA generation by malignant promyelocytes and DIC occurrence in patients with APL and other malignancies.

Topics: Antimetabolites; Antimetabolites, Antineoplastic; Cell Line; Dactinomycin; Disseminated Intravascular Coagulation; Granulocytes; Humans; Leukemia, Myeloid, Acute; Lymphoma, Large B-Cell, Diffuse; Puromycin; Thromboplastin

Topics: Acute Disease; Animals; Aprotinin; Blood Coagulation; Chromatography, Gel; Disseminated Intravascular Coagulation; Fibrinolysis; Heparin; Humans; Leukemia, Lymphoid; Leukemia, Monocytic, Acute; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukocytes; Rabbits; Thrombin; Thromboplastin; Tranexamic Acid; Trypsin Inhibitors

Topics: Animals; Blood Coagulation Tests; Disseminated Intravascular Coagulation; Female; Fibrinolysis; Humans; Leukemia, Myeloid, Acute; Leukocytes; Methods; Pregnancy; Prothrombin; Rabbits; Snake Venoms; Thrombin; Thromboplastin

Topics: Blood Coagulation; Humans; Leukemia, Myeloid, Acute; Male; Thromboplastin

Topics: Bone Marrow; Bone Marrow Cells; Child; Humans; Leukemia, Myeloid, Acute; Male; Thromboplastin

Topics: Blood Coagulation Tests; Bone Marrow; Bone Marrow Cells; Bone Marrow Examination; Daunorubicin; Disseminated Intravascular Coagulation; Fibrinogen; Hemorrhage; Hemorrhagic Disorders; Hemostasis; Heparin; History, 20th Century; Humans; Leukemia, Myeloid, Acute; Thromboplastin

Topics: Acute Disease; Adolescent; Child; Child, Preschool; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Lymphatic Diseases; Thromboplastin

Topics: Blood Coagulation; Disseminated Intravascular Coagulation; Fibrinolysis; Humans; In Vitro Techniques; Leukemia; Leukemia, Myeloid, Acute; Leukocytes; Phosphatidylethanolamines; Thromboplastin

Topics: Adult; Afibrinogenemia; Blood Cell Count; Blood Coagulation Tests; Fibrinolysis; Hemorrhage; Humans; Leukemia, Myeloid, Acute; Male; Prothrombin Time; Thromboplastin

Topics: Blood Coagulation; Blood Coagulation Tests; Heparin Antagonists; Humans; Leukemia; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukocytes; Prothrombin; Thromboplastin; Tissue Extracts

Topics: Blood Coagulation Factors; Blood Coagulation Tests; Factor VIII; Fibrin; Heparin; Humans; In Vitro Techniques; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Thrombin; Thromboplastin

Topics: Adolescent; Adult; Animals; Blood Coagulation; Child; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Rabbits; Rheology; Thrombin; Thromboplastin; Time Factors