Cancer Procoagulant in Acute Non Lymphoid Leukemia: Relationship of Enzyme Detection to Disease Activity

Donati, M. B.; Falanga, Anna; Consonni, R.; Alessio, Maria Grazia; Bassan, Renato; Buelli, M; Borin, Lorenza; Catani, Lucia; Pogliani, Enrico Maria; Gugliotta, Luigi; Masera, Giuseppe; Barbui, Tiziano

doi:10.1055/s-0038-1647145

Cited by 61 publications

(28 citation statements)

References 15 publications

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“…Falanga and colleagues demonstrated CP in circulating leukemia cells, the presence of which they correlated with tumor burden [37,38]. These authors did not comment on any relationship between CP concentration in the leukemic cells of their patients and the presence or absence of DIC.…”

Section: Pathogenesis Of Thromboembolic Compfications Of Cancermentioning

confidence: 91%

Hemostatic alterations in cancer patients

1992

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Nearly all patients with cancer manifest laboratory evidence of hypercoagulability and some develop clinical thromboembolic disease (TED). Routine laboratory studies of blood coagulation have been performed in several large, prospective trials of the use of anticoagulant drugs in cancer treatment. The results of these studies, as well as data from several smaller studies of more sensitive tests of hypercoagulability [e.g. fibrinopeptide A (FPA); thrombin-antithrombin (TAT) complexes; prothrombin fragment F1 + 2)], indicate that the levels of some clotting proteins parallel disease activity. However, no studies of sound methodologic design have yet been performed to indicate that any of these tests of blood coagulation can serve as adequate predictors of TED in patients with cancer. In addition to the important role played by tumor-related procoagulants, several other mechanisms may be involved in the pathogenesis of thromboembolic events in patients with cancer, including stasis and endothelial damage. Considerable variability in the relative importance of these mechanisms in the pathogenesis of TED may exist among patients with different types of cancer. The risk for TED associated with surgical procedures in cancer patients is substantial and prophylactic antithrombotic therapy should be considered for most of these patients. Chemotherapy and hormonal therapy of cancer probably increases the likelihood of TED, particularly in those subjects with indwelling venous catheters. This risk has been particularly well-studied in patients with breast cancer treated with tamoxifen plus cytotoxic drugs. The pathogenic mechanisms may be complex but vascular injury is likely as a proximate cause of venous access catheter thrombosis and can be prevented with low dose coumadin therapy. The utility of low dose coumadin anticoagulation in reducing the risk for TED during breast cancer treatment is unknown but is currently being tested in a large, multiinstitutional study. Since chronic coumadin anticoagulation of cancer patients, and single pulse dose heparin prior to intravenous chemotherapy, both prevent thrombin generation, these agents may be of use in reducing the risk of chemotherapy-associated thrombosis. Prophylactic anticoagulation should be considered for high risk patients.

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Section: Pathogenesis Of Thromboembolic Compfications Of Cancermentioning

confidence: 91%

Hemostatic alterations in cancer patients

1992

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“…20 Our finding of elevated thrombin generation capacity and TF expression in NB4 cells is in agreement with results of a previous study, showing that blast cells isolated from patients with acute promyelocytic leukemia express the highest amount of procoagulant activity compared to blasts from other types of myeloid leukemia. 21 In addition, acute promyelocytic cell-associated procoagulants have been involved in the pathogenesis of life-threatening coagulopathy associated with this disease. 22 The use of the CAT assay may have a significant impact on prophylactic approaches and early intervention in controlling this fatal complication.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the thrombin generation potential of leukemic and solid tumor cells by calibrated automated thrombography

Marchetti¹,

Diani²,

Cate³

et al. 2012

Haematologica

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BackgroundThrombin, the final enzyme of blood coagulation, is a multifunctional serine protease also involved in the progression of cancer. Tumor cells may activate blood coagulation proteases through the expression of procoagulant activities. However, specific information about the thrombin generation potential of malignant tissues is lacking. In this study we applied a single global coagulation test, the calibrated automated thrombogram assay, to characterize the specific procoagulant phenotypes of different tumor cells. Design and MethodsMalignant hematologic cells (i.e. NB4, HEL, and K562) or solid tumor cells (i.e. MCF-7 breast cancer and H69 small cell lung cells) were selected for the study. The calibrated automated thrombogram assay was performed in normal plasma and in plasma samples selectively deficient in factor VII, XII, IX or X, in the absence or presence of a specific anti-tissue factor antibody. Furthermore, cell tissue factor levels were characterized by measuring antigen, activity and mRNA expression. ResultsIn normal plasma, NB4 induced the highest thrombin generation, followed by MCF-7, H69, HEL, and K562 cells. The anti-tissue factor antibody, as well as deficiencies of factors VII, IX and XII affected the thrombin generation potential of malignant cells to different degrees, allowing differentiation of the two different pathways of blood clotting activation -by tissue factor or contact activation. The thrombin generation capacity of NB4 and MCF-7 cells was tissue factor-dependent, as it was highly sensitive to inhibition by anti-tissue factor antibody and factor VII deficiency, while the thrombin generation capacity of H69, HEL and K562 was contact activation-dependent, as no thrombin was generated by these cells in factor XII-deficient plasma. ConclusionsThis study demonstrates that the calibrated automated thrombogram assay is capable of quantifying, characterizing, and comparing the thrombin generation capacity of different tumor cells. This provides a useful tool for understanding the key factors determining the global procoagulant profile of tumors, which is important for addressing specific targeted therapy for the prevention of thrombosis and for cancer.Key words: leukemic cells, thrombin generation, tissue factor, tumor, thrombosis. 2012;97(8):1173-1180. doi:10.3324/haematol.2011 This is an open-access paper. Citation: Marchetti M, Diani E, ten Cate H, and Falanga A. Characterization of the thrombin generation potential of leukemic and solid tumor cells by calibrated automated thrombography. Haematologica Characterization of the thrombin generation potential of leukemic and solid tumor cells by calibrated automated thrombography ABSTRACT© F e r r a t a S t o r t i F o u n d a t i o n

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“…Experiments with warfarin and vitamin K deficient diet suggest CP is a novel vitamin K dependent activity [12]: this is also true for human malignant cells (such as melanoma or colon carcinoma cells) as indicated by experiments in nude mice [15]. CP represents also the main procoagulant activity of cells from human acute promyelocytic leukemia, consi dered since many years the prototype of cells activating blood clotting [16], CP levels, both in peripheral and bone marrow blasts, corre late closely with the disease activity follo wing chemotherapy and represent an early sign of relapse [17], Interestingly enough, CP levels may be modulated also by alltransretinoic acid treatment [18], Studies with CP and other tumor cell acti vities have also contributed greatly to the concept that clotting activation could play a direct pathogenetic role in the progression of malignancy and particularly in metastasis growth. This evidence has been mainly obtained with the modulation of metastasis growth in pharmacological studies on anti coagulant and antiplatelet treatment of tumor bearing animals and on few clinical studies [19,20].…”

mentioning

confidence: 99%

Cancer and Thrombosis

Donati¹

1994

Pathophysiol Haemos Thromb

102

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Thrombosis is the most frequent complication and the second cause of death in patients with overt malignant disease. Increasing evidence suggests that thrombotic episodes may also precede the diagnosis of cancer by months or years thus representing a potential marker for occult malignancy. Recently, emphasis has been given to the potential risk of cancer therapy (both surgery and chemotherapy) in enhancing the risk for thromboembolic disease. Post-operative deep vein thrombosis is indeed more frequent in patients operated for malignant diseases than for other disorders. On the other hand, both chemotherapy and hormone therapy are associated with an increased thrombotic risk, which can be prevented by low-dose oral anticoagulation. Possible contributory causes for thromboembolic disease in cancer include the capacity of tumor cells and their products to interact with platelets, clotting and fibrinolytic systems, as well as their interactions with endothelial cells and tumor-associated macrophages. Cytokine release, acute phase reaction and neovascularization may contribute, in cancer patient, to in vivo clotting activation, which is well documented by several plasmatic markers of an hypercoagulable state. Last but not least, a direct pathogenetic role of clotting activation in the progression of malignancy has been repeatedly proposed on the basis of pharmacological studies with anticoagulant/fibrinolytic drugs in experimental animals and selected clinical malignancies, as well as, lately, in genetically modified animal models (e.g. mice transgenic for PAI-1).

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Cancer Procoagulant in Acute Non Lymphoid Leukemia: Relationship of Enzyme Detection to Disease Activity

Cited by 61 publications

References 15 publications

Hemostatic alterations in cancer patients

Hemostatic alterations in cancer patients

Characterization of the thrombin generation potential of leukemic and solid tumor cells by calibrated automated thrombography

Cancer and Thrombosis

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