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Biomedical subjects

Graham J Caine

Publications and source records attributed to Graham J Caine.

14 recordsLinked to original sources
PubMed2004

Plasma angiopoietin-1, angiopoietin-2, and angiopoietin receptor tie-2 levels in congestive heart failure.

OBJECTIVES: The goal of this research was to test the hypothesis that plasma angiopoietin (Ang-1), its soluble receptor tie-2, and Ang-2 levels would be abnormal in patients with acute and chronic congestive heart failure (CHF) when compared with healthy controls. BACKGROUND: Increased plasma vascular endothelial growth factor (VEGF) in CHF is suggestive of excess angiogenesis-possibly driven by tissue hypoxia. However, other growth factors also have a major role in angiogenesis, such as those of the angiopoietin family (e.g., Ang-1, which exerts its activity via its receptor, tie-2, and Ang-2). METHODS: We recruited 39 patients with acute CHF (mean age 67 +/- 10 years), 40 patients with chronic CHF (mean age 63 +/- 9 years), and 17 healthy controls (mean age 67 +/- 7 years), all in sinus rhythm. Citrated plasma was analyzed for Ang-1, Ang-2, tie-2, and VEGF by enzyme-linked immunosorbent assay. RESULTS: Angiopoietin-2 (p < 0.001), tie-2 (p < 0.05), and VEGF (p < 0.05) levels were all higher in acute CHF compared with controls. The Ang-2 levels were higher in acute CHF compared with chronic CHF (p < 0.001), but there were no significant differences in Ang-1 levels between the groups. The principal significant correlations were between Ang-2 and tie-2 (Spearman, r = 0.407; p < 0.0001) and between Ang-2 and ejection fraction (r = -0.241, p = 0.043). Although only marginally raised, levels of VEGF correlated with both Ang-2 (r = 0.468, p < 0.001) and tie-2 (r = 0.569, p < 0.001). CONCLUSIONS: We have demonstrated abnormal levels of Ang-2 and tie-2, but normal Ang-1, in both CHF patients. These abnormalities may, alongside VEGF, indicate a role for these angiogenic factors in the pathophysiology of CHF.

Acute Disease↗
PubMed2004

Platelet-derived VEGF, Flt-1, angiopoietin-1 and P-selectin in breast and prostate cancer: further evidence for a role of platelets in tumour angiogenesis.

BACKGROUND: Cancer is a complex multi-factorial disorder that may commonly show abnormal angiogenesis in such patients. Recently, platelets have been postulated to have a major role in both these processes, suggesting that antiplatelet strategies may be useful in cancer treatment. MATERIALS AND METHODS: To further investigate the role of platelets in angiogenesis, we used a novel platelet lysate assay to analyse platelet contents in breast cancer (n = 30) and prostate cancer (n = 30) patients and age- and sex-matched controls (n = 60). Markers of angiogenesis (vascular endothelial growth factor (VEGF), angiopoietin-1 and-2 (Ang-1, -2), and their respective receptors (Flt-1 and Tie-2) plus a marker of platelet activation (P-selectin (P-sel)), were all measured in platelet lysate by enzyme-linked immunsorbent assay. RESULTS: Platelet lysate from breast cancer patients contained higher levels of VEGF (P < 0.0001). Ang-1 (P = 0.0186) and P-sel (P = 0.0002), compared to healthy controls. Platelet lysate from prostate cancer patients had elevated VEGF (P = 0.008) but not Ang-1 or P-sel. There were no significant differences between levels of Fit-1 between patients and controls, and both Ang-2 and Tie-2 were undetectable in both patient groups and control platelet lysate. CONCLUSION: We have shown that our previously developed platelet lysate technique could be used to measure indices of angiogenesis, and their respective receptors, and that this assay can be applied to patients with cancer. Our study also provides further evidence that platelets may influence angiogenic abnormalities in human cancer. The platelet may be a useful target in anti-cancer strategies.

Aged↗
PubMed2004

Platelet adhesion in breast cancer: development and application of a novel assay.

The increased risk of thromboembolism in cancer may be related to a prothrombotic or hypercoagulable state, with abnormalities of haemostasis and platelet activation. To further investigate the role of platelets in this disease, we developed and applied a new assay to detect and quantify platelet adhesion to the well-defined subendothelial substrate, fibrinogen. Platelet-rich plasma was obtained from 31 females with breast cancer (13 metastatic, 18 benign), and 30 healthy female controls, re-suspended to 2 x 10(8) cells/ml and 100 microl and incubated for 1 h in microtitre plates pre-coated with fibrinogen (5 mg/ml). The supernatant was carefully aspirated, lysed with Triton X-100 and stored at -70 degrees C as supernatant-platelet lysate. The microtitre wells were carefully washed with saline, bound platelets lysed with Triton, and the lysate stored at -70 degrees C as bound-platelet lysate. P-selectin was determined in supernatant-platelet lysate and bound-platelet lysate for each patient by enzyme-linked immunosorbent assay. Interpreting differences in P-selectin in different lysates as reflective of adhesion, patients with cancer had increased platelet adhesion (absolute and percentage, both P < 0.001) compared with healthy controls. There was also more adhesion (P < 0.001) in metastatic disease compared with non-metastatic disease. Patients with breast carcinomas, and, in particular, those with metastatic disease, have a higher degree of platelet adhesion, which may by quantified by a novel method based on cell lysis. This increase in platelet adhesiveness may be related to an increased risk of thromboembolism in these patients.

Blood Platelets↗
PubMed2004

Platelet activation, coagulation and angiogenesis in breast and prostate carcinoma.

In health, haemostasis and angiogenesis are tightly regulated processes, but may become deregulated in cancer. Recent evidence suggests that platelet activation may link these processes as platelets can release angiogenic factors such as vascular endothelial growth factor (VEGF). Furthermore, inflammation has also been implicated in regulating both coagulation and angiogenesis, possibly by activating platelets directly and increasing, for example, plasma fibrinogen. We hypothesized relationships between plasma markers of the processes in two common forms of cancer. Plasma levels of VEGF (reflecting angiogenesis), soluble P-selectin, (marking platelet activation), tissue factor [TF], fibrinogen and fibrin D-dimer (coagulation markers), and serum levels of IL-6 (inflammation) were measured by ELISA in 30 patients with biopsy-proven breast cancer, 30 patients with biopsy-proven prostate cancer, and 30 age- and sex-matched controls for each group. Prostate specific antigen was also measured in the men. Release of VEGF from IL-6 stimulated platelets was assessed by ELISA. Plasma levels of IL-6 (P <0.02), VEGF, soluble P-selectin, fibrinogen, and fibrin D-dimer (all p <0.01) were significantly raised in breast cancer, whereas VEGF, soluble P-selectin, fibrin D-dimer (all p <0.01) and fibrinogen (p <0.05) were significantly raised in prostate cancer. Significant correlations were found between IL-6 and VEGF (p <0.01), and IL-6 and soluble P-selectin (p = 0.038) in breast cancer. Further experiments demonstrated an in vitro IL-6 induced dose-dependent release of VEGF from platelets. In conclusion, strong relationships between IL6 and VEGF, but not with coagulation or platelet markers, and release of VEGF from IL-6 stimulated platelets, suggest a role for inflammation and platelets in angiogenesis.

Aged↗
PubMed2003

Coagulopathic complications in breast cancer.

Patients with cancer are highly susceptible to thromboembolic complications, which account for a significant percentage of the morbidity and mortality of the disease. Up to 15% of patients with clinically overt cancer present with venous thromboembolism during the course of their disease. Moreover, patients with cancer represent 20% of all patients in whom deep venous thrombosis and pulmonary embolism are diagnosed. This prothrombotic state in cancer can occur due to the ability of tumor cells to directly activate the blood-clotting cascade and cause thrombosis or induce procoagulant properties and inhibit anticoagulant properties of vascular endothelial cells, platelets, monocytes, and macrophages. It also is well established that this prothrombotic tendency in patients with cancer can be enhanced greatly by anticancer treatments, such as surgery and chemotherapy. This phenomenon can be seen in patients with breast cancer, particularly after surgery and chemotherapy. Increased clotting risk also is associated with the use of central venous access devices, commonly used to administer chemotherapeutic agents in patients with cancer. Thrombosis prophylaxis, therefore, should be considered for patients with breast cancer who are at risk before and during intervention. In the current review, the authors discuss the problem of thromboembolism in patients with breast cancer who are undergoing therapy, the mechanisms by which thromboembolisms occur, and the potential strategies by which these events may be prevented. Better understanding of these pathogenetic pathways may lead to the development of more targeted strategies to prevent thromboembolism in patients with cancer.

Antineoplastic Agents↗
PubMed2002

Platelet P-selectin levels in relation to plasma soluble P-selectin and beta-thromboglobulin levels in atrial fibrillation.

BACKGROUND AND PURPOSE: The increased risk of stroke and thromboembolism in atrial fibrillation (AF) may be related to a prothrombotic or hypercoagulable state, with abnormalities of hemostasis and platelet activation. To investigate the role of platelets in AF and the influence of antithrombotic therapy, we developed and then applied a new assay to detect the absolute amount of P-selectin per platelet (pP-selectin) based on cell lysis. Thus, pP-selectin in AF patients was compared with that of healthy controls and also with plasma soluble P-selectin (sP-selectin) and beta-thromboglobulin as established indices of platelet activation. METHODSMDSAH: We studied 122 patients (mean [SD] age, 71 [9] years; 65 men) with chronic AF of >6 weeks' duration: 34 were not on antithrombotic therapy, 30 were taking aspirin (75 to 300 mg/d), and 58 were fully anticoagulated with warfarin. pP-selectin was compared with sP-selectin and plasma beta-thromboglobulin levels (enzyme-linked immunosorbent assay). Results were compared with those of 23 healthy controls (mean [SD] age, 74 [9] years; 7 men) in sinus rhythm. RESULTS: pP-selectin was significantly lower in AF patients on no antithrombotic therapy (P=0.03) than in healthy controls, but sP-selectin and beta-thromboglobulin levels were not significantly different and did not differ in patients taking aspirin or warfarin. However, pP-selectin was lower in patients with AF on aspirin than in those on warfarin (P<0.05). pP-selectin/sP-selectin correlated significantly in healthy controls (r=0.47, P=0.03) but inversely (r=-0.43, P=0.03) in AF patients on no antithrombotic therapy. CONCLUSIONS: Lower levels of pP-selectin may represent a depletion of pP-selectin after platelet activation in AF. Aspirin further decreases pP-selectin levels compared with warfarin. On the basis of the principle of platelet lysis, we demonstrate that it is possible to determine the amount of P-selectin per platelet, which may be regulated in the megakaryocyte through a cyclooxygenase-dependent pathway.

Aged↗
PubMedDate not supplied

The hypercoagulable state of malignancy: pathogenesis and current debate.

A hypercoagulable or prothrombotic state of malignancy occurs due to the ability of tumor cells to activate the coagulation system. It has been estimated that hypercoagulation accounts for a significant percentage of mortality and morbidity in cancer patients. Prothrombotic factors in cancer include the ability of tumor cells to produce and secrete procoagulant/fibrinolytic substances and inflammatory cytokines, and the physical interaction between tumor cell and blood (monocytes, platelets, neutrophils) or vascular cells. Other mechanisms of thrombus promotion in malignancy include nonspecific factors such as the generation of acute phase reactants and necrosis (i.e., inflammation), abnormal protein metabolism (i.e., paraproteinemia), and hemodynamic compromise (i.e., stasis). In addition, anticancer therapy (i.e., surgery/chemotherapy/hormone therapy) may significantly increase the risk of thromboembolic events by similar mechanisms, e.g., procoagulant release, endothelial damage, or stimulation of tissue factor production by host cells. However, not all of the mechanisms for the production of a hypercoagulable state of cancer are entirely understood. In this review, we attempt to describe what is currently accepted about the pathophysiology of the hypercoagulable state of cancer. We also discuss whether or not to screen patients with idiopathic deep venous thrombosis for an underlying malignancy, and whether this would be beneficial to patients. It is hoped that a better understanding of these mechanisms will ultimately lead to the development of more targeted treatment to prevent thromboembolic complications in cancer patients. It is also hoped that antithrombotic strategies may also have a positive effect on the process of tumor growth and dissemination.

Antineoplastic Agents↗