thromboplastin and Infections

Venous thromboembolic disease often arises as a complication of another pathological condition and/or triggering event. Infectious diseases result from both the direct action of the pathogens themselves and their effect on the immune system. The resulting inflammatory process and the coagulation and fibrinolysis processes share common pathways, explaining why infection is associated with thrombosis. In this brief overview, besides certain chronic infectious diseases, we also consider some acute infections, as the mechanisms are likely to be similar, particularly in the initial infective stage or the more acute episodes of a chronic infection. The infectious agent can be viral, bacterial, fungal, or parasitic. However, the literature on the link between infections and venous thromboembolism (VTE) is uneven, favoring infections that are found in more developed countries where physicians have access to VTE diagnostic tools. Thus, large epidemiological studies in this field are restricted to a limited number of the common chronic infectious diseases such as tuberculosis, while for other infections, particularly parasitic and fungal infections, the link with VTE is only evoked in a few scattered case reports.

Topics: Cell-Derived Microparticles; Chronic Disease; Developed Countries; Developing Countries; Disease Susceptibility; Endothelium, Vascular; HIV Infections; Humans; Infections; Inflammation; Macrophages; Models, Biological; Risk; Thrombophilia; Thromboplastin; Tuberculosis; Venous Thromboembolism

Venous thromboembolism (VTE) is a known complication of cancer which impacts on patient mortality and quality of life. Despite the known deleterious effects of VTE, the benefits of thromboprophylaxis have not been fully established. Identification of patients at highest risk of VTE could lead to better targeting of thromboprophylaxis. Several risk factors have been identified as contributing to VTE such as site and stage of cancer, age, comorbidities, obesity, and acquired prothrombotic states. Anti-cancer agents as well as the use of growth factor support have also been implicated in VTE. Recent data have identified biomarkers such as blood counts, tissue factor and P-selectin. In this review, we briefly summarize the risk factors for VTE as well as candidate biomarkers for VTE in cancer patients. We also review a validated risk score that can identify cancer patients at high risk for VTE. Risk stratification of cancer patients will allow clinicians to identify those patients at highest risk for VTE, who may derive the most benefit from thromboprophylaxis.

Topics: Aged; Factor V; Female; Humans; Infections; Leukocyte Count; Male; Neoplasms; Obesity; P-Selectin; Platelet Count; Risk Factors; Thromboplastin; Venous Thromboembolism

In the pathogenesis of vascular disease, inflammation and coagulation play a pivotal role. Increasing evidence points to an extensive cross-talk between these two systems, whereby inflammation not only leads to activation of coagulation, but coagulation also considerably affects inflammatory activity. Tissue factor (TF) plays an important role at the crossroad of coagulation and inflammation, as the principal initiator of coagulation and an important modulator of inflammation. Proinflammatory cytokines can induce TF expression on mononuclear cells and endothelial cells and thereby commence pathways that lead to thrombin generation. Simultaneously, TF may bind to cellular receptors, which may affect the production and release of inflammatory mediators. There is increasing experimental evidence that TF inhibition may have beneficial effects in disease states in which the combination of coagulation and inflammation plays a prominent role.

Topics: Blood Coagulation; Cytokines; Humans; Infections; Inflammation; Signal Transduction; Thrombin; Thromboplastin; Vascular Diseases

The incidence of severe complications, such as disseminated intravascular coagulation (DIC) in malignant lymphoma, differs between clinical stages and histological types of the disease, but they occur frequently in stage IV or natural killer (NK) cell lymphoma. Patients with stage IV or NK cell lymphoma exhibit abnormal thrombotic and hemostatic states. One of the mechanisms in DIC might involve elevated cytokine expression by lymphoma cells stimulating the expression of tissue factor (TF) in blood cells or surrounding tissue. During chemotherapy for lymphoma, the white blood cell count was significantly reduced at days 1 and 3, but significantly increased at days 7 and 9. At day 7 of chemotherapy, leukocyte TF mRNA levels were significantly increased. Plasma concentrations of granulocyte elastase derived-XDP (GEXDP) levels correlated with D-dimer levels, suggesting that almost all elevated D-dimer is GE-XDP. C-reactive protein (CRP), GE-XDP and D-dimer were significantly elevated in patients with infection, DIC or acute respiratory distress syndrome (ARDS). Analysis of patients with DIC or ARDS revealed that TF mRNA correlated with D-dimer, and GE-XDP correlated with leukocyte count, CRP and D-dimer, suggesting that inflammatory changes due to thrombosis may cause the activation of leukocytes during chemotherapy.

Topics: C-Reactive Protein; Cytokines; Disseminated Intravascular Coagulation; Humans; Infections; Leukocyte Elastase; Lymphoma, Non-Hodgkin; RNA, Messenger; Thromboplastin

The role of the haemostatic system in colorectal cancer (CRC) is reviewed. Correlations between the activation of the haemostatic system and overall survival have been suggested. Experimental studies indicate that the haemostatic system plays a key role in growth, invasion and dissemination of tumour cells, and in tumour related angiogenesis. Additional activation by the surgical trauma and postoperative infections are discussed. Finally, anti-cancer modalities directed against regulation of the haemostatic system in CRC are considered.

Topics: Animals; Blood Coagulation; Chemotherapy, Adjuvant; Colorectal Neoplasms; Fibrinolysis; Hemostasis; Humans; Infections; Peptide Hydrolases; Postoperative Complications; Thromboplastin; Venous Thrombosis

Tissue factor is a potent initiator of blood coagulation. In tissue sections, it has been immunologically demonstrated in cells normally not in contact with circulating blood, and elevated activity has been repeatedly demonstrated in peripheral blood monocytes of patients considered to be at risk for thrombosis. Studies with endothelial cells and monocytes in culture have documented the induction of tissue factor synthesis by biochemical mediators of the inflammatory process. Lytic processes, such as those caused by complement activation or viral infections, increase the tissue factor activity several fold over the basal level of the affected cells. Diminished anti-thrombotic properties of endothelium, and induced tissue factor expression in endothelium and monocytes/macrophages, combined with the increased specific procoagulant activity resulting from cell membrane damage, may endow inflammatory foci with dramatically elevated procoagulant activity. Levels of tissue factor activity at which procoagulant mechanisms escape regulation by natural anticoagulant mechanisms and produce thrombosis remain to be determined.

Topics: Blood Coagulation; Complement System Proteins; Endothelium, Vascular; Humans; Infections; Monocytes; Poliovirus; Thromboplastin; Vasculitis

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.

Topics: Animals; Anti-Inflammatory Agents; Antigens; Blood Coagulation; Blood Coagulation Factors; Cell Line; Factor V; Factor VII; Factor X; Factor Xa; Fibrin; Fibrin Fibrinogen Degradation Products; Guinea Pigs; Humans; Hypersensitivity, Delayed; Immunologic Deficiency Syndromes; Infections; Inflammation; Lipopolysaccharides; Macrophages; Mice; Monocytes; Neoplasms; Neutrophils; Rabbits; Rats; T-Lymphocytes; Thromboembolism; Thromboplastin; Warfarin

Mononuclear phagocytes can be activated to develop enhanced expression of a wide range of macromolecules and mediators. Amongst these are several procoagulants, most notably thromboplastin. A variety of stimuli (particles, ligands for cell surface receptors, and some pharmacological agents) enhance procoagulant expression. We indicate that such enhancement may contribute to intra-and extravascular coagulation in several types of infections. We also point to the paucity of knowledge on the biosynthesis and intracellular transport of these procoagulants and speculate on the nature of the mechanisms involved.

Topics: Animals; Blood Coagulation Factors; Blood Coagulation Tests; Cell Membrane; Humans; Infections; Intracellular Fluid; Macrophage Activation; Mice; Monocytes; Rabbits; Thromboplastin

Topics: Adult; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Blood Flow Velocity; Child; Child, Preschool; Clinical Laboratory Techniques; Dextrans; Female; Fibrinolytic Agents; Glomerulonephritis; Hemangioma, Cavernous; Heparin; Humans; Infections; Liver Cirrhosis; Male; Mycoses; Parasitic Diseases; Pregnancy; Pregnancy Complications; Purpura; Shock; Thrombocytopenia; Thromboplastin; Uremia

Microparticles (MP) are shed membrane vesicles released from activation or apoptosis of several cell types and carry a procoagulant activity. Age is associated with a procoagulant state, but the role of MP in this setting is unknown, as the relationship of MP to aging in humans. We tested the hypotheses that elderly persons compared with young persons may have different patterns of expression of MP and procoagulant activity in stable or septic conditions.. Patients from Emergency and Geriatric Departments were divided into four groups according to their age (< 50 or > or = 75 years old) and the presence of systemic infection (yes or no). The diagnosis of infection was reached when it was classified as certain or possible by an expert panel. Circulating MP were isolated from venous citrated blood. Cytofluorometry using specific antibodies was performed to determine the origins of MP (endothelial microparticles [EMP], red blood cell microparticles, or platelet microparticles). Procoagulant activity was determined using annexin V (prothrombinase activity) and tissue factor (TF) assays.. One hundred and eleven patients were included. Elderly patients expressed a decrease in EMP in stable conditions, associated with a decrease in procoagulant annexin V MP in septic conditions (p < .05), and higher EMP levels were found in elderly infected patients who died during hospital stay than in survivors (p = .04). Compared with young patients, response to sepsis was altered in elders concerning EMP, annexin V MP, and TF-bearing MP.. Elderly patients expressed a different pattern of MP in stable conditions, with a different response to sepsis in procoagulant activity modification.

Topics: Adult; Aged, 80 and over; Aging; Cell-Derived Microparticles; Female; Flow Cytometry; Humans; Infections; Male; Thromboplastin

Hemostatic parameters were examined before and during 102 courses of chemotherapy in 42 patients with malignant lymphoma with high risk for infection. The white blood cell count was significantly reduced in all patients at days 1 and 3, but significantly increased at days 7 and 9, compared to before chemotherapy. At day 7 of chemotherapy, tissue factor (TF) mRNA levels in leukocytes were significantly increased in all patients, especially those with infection. Plasma concentrations of granulocyte elastase derived-XDP (GE-XDP) levels correlated with D-dimer levels during chemotherapy in patients with malignant lymphoma, suggesting that the elevated D-dimer is fibrin products degraded by granulocyte elastase. GE-XDP, C-reactive protein (CRP), GE-XDP and D-dimer were significantly higher in patients with infection, disseminated intravascular coagulation (DIC) and acute respiratory distress syndrome (ARDS) than those without. In patients with DIC or ARDS, TF mRNA correlated with D-dimer, and GE-XDP correlated with leukocyte count, CRP and D-dimer, suggesting that inflammatory changes due to thrombosis may cause the activation of leukocytes in patients with malignant lymphoma during chemotherapy. Activated leukocytes and granulocyte elastase may elicit a hypercoagulable state and ARDS in patients with malignant lymphoma during chemotherapy.

Topics: Aged; Antineoplastic Agents; C-Reactive Protein; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Hemostasis; Humans; Infections; Leukocyte Count; Leukocyte Elastase; Leukocytes; Lymphoma; Male; Middle Aged; Prospective Studies; Respiratory Distress Syndrome; RNA, Messenger; Thromboplastin; Time Factors

Inflammatory cytokines potently impact hemostatic pathways during infection, but the tissue-specific regulation of coagulation and fibrinolysis complicates studies of the underlying mechanisms.. Here, we describe assays that quantitatively measuring prothrombinase (PTase), protein C-ase (PCase) and plasminogen activator (PA) activities in situ, thereby facilitating studies of tissue-specific hemostasis. Using these assays, we investigate the mechanisms regulating hepatic fibrin deposition during murine toxoplasmosis and the means by which interferon-gamma (IFN-gamma) suppresses infection-stimulated fibrin deposition. We demonstrate that Toxoplasma infection upregulates hepatic PTase, PCase, and PA activity. Wild type and gene-targeted IFN-gamma-deficient mice exhibit similar levels of infection-stimulated PTase activity. By contrast, IFN-gamma-deficiency is associated with increased PCase activity and reduced PA activity during infection. Parallel analyses of hepatic gene expression reveal that IFN-gamma-deficiency is associated with increased expression of thrombomodulin (TM), a key component of the PCase, increased expression of thrombin-activatable fibrinolysis inhibitor (TAFI), a PC substrate, and reduced expression of urokinase PA (u-PA).. These findings suggest that IFN-gamma suppresses infection-stimulated hepatic fibrin deposition by suppressing TM-mediated activation of TAFI, thereby destabilizing fibrin deposits, and concomitantly increasing hepatic u-PA activity, thereby promoting fibrinolysis. We anticipate that further application of these in situ assays will improve our understanding of tissue-specific hemostasis, its regulation by cytokines, and its dysregulation during coagulopathy.

Topics: Animals; Carboxypeptidase B2; Fibrin; Fibrinolysis; Hemostasis; Infections; Interferon-gamma; Liver; Mice; Mice, Knockout; Plasminogen Activators; Thrombomodulin; Thromboplastin; Toxoplasmosis, Animal; Urokinase-Type Plasminogen Activator

Patients with diabetes mellitus (DM) are associated with an increased risk of thrombosis, and are susceptible to a series of complications including nephropathy. It has also been known that plasma tissue factor (TF) antigen levels increase significantly in certain disease states. To investigate the clinical significance of an association with the various complications in patients with type 2 non-insulin-dependent DM (NIDDM), we measured the plasma levels of TF antigen in 63 patients (35 males and 28 females, mean age 60.8 yrs) with NIDDM and in 22 normal subjects (14 males and 8 females, mean age 56.0 yrs). The mean concentrations of TF were higher for patients with NIDDM (253.7 +/- 144.9 pg/ml) than in normal subjects (187.3 +/- 108.7 pg/ml with marginal statistical significance (p= 0.0530). The TF levels were higher for patients with a nephropathy than for patients without a nephropathy (p=0.0402). There was a significant positive correlation between levels of TF and BUN (r=0.84, p < 0.0001) or creatinine (r=0.93, p < 0.0001). However, TF levels were found to be similar for both groups with and without thrombosis, neuropathy, retinopathy, or infection. These results suggest that plasma TF antigen levels may be associated with nephropathy and they may reflect a renal dysfunction in NIDDM.

Topics: Biomarkers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; Female; Humans; Infections; Male; Middle Aged; Thromboplastin; Thrombosis

We compared the levels of tissue factor (TF) mRNA in leukocytes with plasma TF antigens of patients in hypercoagulable state caused by various diseases. Flow cytometric analysis showed absence of TF antigen expression on neutrophils and monocytes in healthy subjects but strong expression in both cell types of patients with infections.TF mRNA levels in leukocytes were low in healthy subjects but they were significantly elevated in patients with underlying diseases of disseminated intravascular coagulation (DIC), especially in acute myeloid leukaemia (AML) and infections.TF mRNA levels in leukocytes were significantly high in patients with all diseases except those with thrombosis, and plasma TF antigen levels were significantly high in all diseases. TF mRNA in leukocytes and plasma TF antigen levels were significantly high in patients with overt-DIC, and TF mRNA/antigen ratio was significantly high in patients with overt-DIC. In patients with solid cancers, TF mRNA and TF mRNA/antigen ratio were significantly higher in patients with metastases than those without. TF mRNA levels in leukocytes and plasma levels of TF antigen did not correlate in normal subjects and all patients, but they tended to be correlated in patients with AML, infections or overt-DIC. Our analysis suggests that TF expression in leukocytes plays an important role in various diseases but the expression level does not always correlate with plasma levels of TF antigen.

Topics: Adult; Aged; Base Sequence; Blood Coagulation Disorders; Disseminated Intravascular Coagulation; DNA, Complementary; Female; Humans; Infections; Leukocytes; Male; Middle Aged; Monocytes; Neoplasms; Neutrophils; RNA, Messenger; Thromboplastin

We measured the plasma level of fibrinogen in 560 patients with disseminated intravascular coagulation (DIC) and evaluated its relationship with outcome and with other hemostatic markers. Forty-seven percent of patients had >200 mg/dL of plasma fibrinogen and 24% had <100 mg/dl of plasma fibrinogen, suggesting that plasma fibrinogen level is not a sensitive marker for DIC. In our analysis of outcome and plasma fibrinogen levels, the rate of death was high in leukemia/lymphoma patients with high fibrinogen concentration, but no significant difference in outcome was observed in relation to plasma fibrinogen concentration in non-leukemia/lymphoma patients with DIC. Among patients with leukemia/lymphoma, the frequency of organ failure was markedly high in patients with high plasma levels of fibrinogen. Among patients without leukemia/lymphoma, the frequency of organ failure increased concomitantly with the increase in plasma fibrinogen levels. The international normalized ratio was significantly increased in leukemia/lymphoma patients with low fibrinogen. FDP levels were slightly increased in patients with low fibrinogen. Platelet count was significantly low in patients without leukemia/lymphoma with high fibrinogen. DIC score increased concomitantly with the reduction in plasma fibrinogen levels. Plasma levels of thrombomodulin and tissue factor were significantly high in patients with high fibrinogen levels. Plasma levels of antiplasmin and plasminogen were significantly decreased in patients with low fibrinogen. Plasma levels of plasmin plasmin-inhibitor complex and tissue type plasminogen activator/plasminogen activator inhibitor-1 complex (PAI-I) were significantly higher in patients with low fibrinogen than in those with high fibrinogen. Plasma levels of PAI-I and IL-6 were significantly higher in patients with high fibrinogen than in those with low fibrinogen. Patients with high fibrinogen levels showed less activation of secondary fibrinolysis, which might explain the occurrence of organ failure and poor outcome.

Topics: Adult; Aged; alpha-2-Antiplasmin; Antifibrinolytic Agents; Antithrombin III; Biomarkers; Disseminated Intravascular Coagulation; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolysin; Fibrinolysis; Hematologic Neoplasms; Hemorrhage; Humans; Infections; Interleukin-1; Interleukin-6; International Normalized Ratio; Male; Middle Aged; Multiple Organ Failure; Neoplasms; Peptide Hydrolases; Plasminogen; Plasminogen Activator Inhibitor 1; Platelet Count; Prognosis; Thrombomodulin; Thromboplastin; Thrombosis; Tissue Plasminogen Activator

High cholesterol is a well-established risk factor of myocardial infarction (MI). Since monocytes play a pivotal role in the development of atherosclerosis, one might anticipate that their functional properties are very important in relation to MI. In the present study, we have explored how the lipopolysaccharide (LPS)-induced reactivity of monocytes in whole blood in vitro relates to the serum lipid profile of healthy subjects with a history of MI or cancer in their close family. Twenty of the 54 subjects (of the total 266 test subjects) in the MI families had moderately high cholesterol (7.1-10.2 mmol/l), whereas 34 had normal cholesterol. Nineteen of the normocholesterol individuals had hyperactive monocytes (high responders), whereas 15 had monocytes responding normally. Two of the 20 subjects in the high cholesterol group had hyperactive monocytes. LPS-induced tissue factor, tumour necrosis factor-alpha and interleukin-6 were on the average three to four times higher in the normocholesterol group compared with the moderately hypercholesterol group, and hence no positive correlation was found between hyperactive monocytes and cholesterol. The 42 subjects in the families with cancer had normal cholesterol, and two of these subjects had very high LPS-induced tissue factor, tumour necrosis factor-alpha and interleukin-6, whereas eight of the 170 subjects without MI or cancer in their family were high responders. This further substantiates the notion that moderately high cholesterol is not associated with enhanced monocyte activation in whole blood. Hyperactive peripheral blood monocytes are suggested to be associated with a significant risk factor in developing coronary heart disease.

Topics: Adolescent; Adult; Aged; Cholesterol; Coronary Disease; Family Health; Female; Fibrinolysis; Genetic Predisposition to Disease; Humans; Hypercholesterolemia; Infections; Interleukin-6; Lipopolysaccharides; Male; Middle Aged; Monocytes; Myocardial Infarction; Neoplasms; Plasminogen Activator Inhibitor 1; Risk Factors; Thromboplastin; Tissue Plasminogen Activator; Triglycerides; Tumor Necrosis Factor-alpha

Microparticles (MPs) resulting from vesiculation of platelets and other blood cells have been extensively documented in vitro and have been found in increased numbers in several vascular diseases, but little is known about MPs of endothelial origin. The aim of this study was to analyze morphological, immunological, and functional characteristics of MPs derived from human umbilical vein endothelial cells (HUVECs) stimulated by TNF, and to investigate whether these MPs are detectable in healthy individuals and in patients with a prothrombotic coagulation abnormality. Electron microscopy evidenced bleb formation on the membrane of TNF-stimulated HUVECs, leading to increased numbers of MPs released in the supernatant. These endothelial microparticles (EMPs) expressed the same antigenic determinants as the corresponding cell surface, both in resting and activated conditions. MPs derived from TNF-stimulated cells induced coagulation in vitro, via a tissue factor/factor VII-dependent pathway. The expression of E-selectin, ICAM-1, alphavbeta3, and PECAM-1 suggests that MPs have an adhesion potential in addition to their procoagulant activity. In patients, labeling with alphavbeta3 was selected to discriminate EMPs from those of other origins. We provide evidence that endothelial-derived MPs are detectable in normal human blood and are increased in patients with a coagulation abnormality characterized by the presence of lupus anticoagulant. Thus, MPs can be induced by TNF in vitro, and may participate in vivo in the dissemination of proadhesive and procoagulant activities in thrombotic disorders.

Topics: Antiphospholipid Syndrome; Autoimmune Diseases; Cell Adhesion Molecules; Cells, Cultured; Endothelium, Vascular; Factor VII; Flow Cytometry; Humans; Infections; Lupus Coagulation Inhibitor; Lupus Erythematosus, Systemic; Microscopy, Confocal; Neoplasms; Receptors, Vitronectin; Thrombophilia; Thromboplastin; Tumor Necrosis Factor-alpha; Umbilical Veins

Topics: Adult; Female; Humans; Infections; Male; Middle Aged; Monocytes; Reference Values; Thromboplastin