Biomedical subjects

Hugo ten Cate

Publications and source records attributed to Hugo ten Cate.

27 records · Page 2Linked to original sources

PubMed2003

Infections and endothelial cells.

Systemic infection by various pathogens interacts with the endothelium and may result in altered coagulation, vasculitis and atherosclerosis. Endothelium plays a role in the initiation and regulation of both coagulation and fibrinolysis. Exposure of endothelial cells may lead to rapid activation of coagulation via tissue factor (TF) expression and the loss of anticoagulant properties by impairment of antithrombin III, TF pathway inhibitor (TFPI) and the protein C system. Endothelial-derived plasminogen activator inhibitor (PAI) is essential for the regulation of fibrinolysis and impaired endothelial function leads to imbalance in fibrinolysis, resulting in a procoagulant state. The interaction between inflammation and coagulation, soluble adhesion molecules and circulation endothelial cells is important in the pathogenesis of an unbalanced haemostatic system. Rather than being a unidirectional relationship, the interaction between inflammation and coagulation appears to be significant. In the crosstalk, the endothelium is playing a pivotal role.

Acute Disease↗

PubMed2003

Functional thrombomodulin deficiency causes enhanced thrombus growth in a murine model of carotid artery thrombosis.

Thrombomodulin (TM) bound thrombin initiates the protein C anticoagulant pathway and defects in TM result in enhanced coagulation. Recent studies suggest a role for TM in arterial vascular disease. In order to corroborate this association we studied arterial thrombus formation in mice with a functional TM defect. We used mice homozygous for a (404)Glu-to-Pro mutation in the TM gene (TM(pro/pro)) and compared these with wildtype littermates in a model of FeCl(3) induced carotid artery thrombosis. Time-to-occlusion (TTO) was assessed by arterial blood flow measurement, using a Doppler flow probe. Complete occlusion occurred in 8/10 (80%) TM(pro/pro) mice and in 3/11 (27%) littermate controls. Mean time to occlusion (TTO) [+/- SE] was 767 +/- 196 s in the F2-TM(pro/pro) mice, versus 1507 +/- 159 s in controls (p = 0.007, Mann Whitney U test). Histology and immunostaining for tissue factor did not reveal any differences in thrombus morphology or thrombogenicity between the two groups. These data confirm and extend the finding that a functional deficiency in TM results in enhanced thrombus formation in a murine model of carotid artery thrombosis and support a role for TM defects in arterial thrombotic disease.

Animals↗

PubMed2003

The blood coagulation system as a molecular machine.

The human blood coagulation system comprises a series of linked glycoproteins that upon activation induce the generation of downstream enzymes ultimately forming fibrin. This process is primarily important to arrest bleeding (hemostasis). Hemostasis is a typical example of a molecular machine, where the assembly of substrates, enzymes, protein cofactors and calcium ions on a phospholipid surface markedly accelerates the rate of coagulation. Excess, pathological, coagulation activity occurs in "thrombosis", the formation of an intravascular clot, which in the most dramatic form precipitates in the microvasculature as disseminated intravascular coagulation. Thrombosis occurs according to a biochemical machine model in the case of atherothrombosis on a ruptured atherosclerotic plaque, but may develop at a slower rate in venous thrombosis, illustrating that the coagulation machinery can act at different velocities. The separate coagulation enzymes are also important in other biological processes, including inflammation for which the rapid conversion of one coagulation factor by the other is not a prerequisite. The latter role of coagulation enzymes may be related to the old and probably maintained function of the coagulation machine in innate immunity.

Anticoagulants↗

PubMed2003

Chlamydial LPS antibodies, intima-media thickness and ischemic events in patients with established atherosclerosis.

BACKGROUND: Chlamydia pneumoniae has been associated with cardiovascular disease. However, studies on the presence of chlamydial antibodies and intima-media thickness (IMT) or future ischemic events are inconclusive. We examined the relation between circulating antibodies to chlamydial lipopolysaccharide (cLPS Ab), IMT and the occurrence of ischemic events during follow-up in patients with manifest atherosclerotic disease. METHODS: IgG and IgA antibodies against cLPS were determined in 273 out of 307 consecutive patients with a recent ischemic stroke (IS, n=90), a recent myocardial infarction (MI, n=87) or peripheral arterial disease (PAD, n=96). B-mode ultrasound IMT measurement of carotid and femoral arteries was performed and ischemic events, IS or MI, during follow-up were registered. RESULTS: IgG and IgA were found in 66 and 46% of the patients, respectively. We did not detect any difference in IMT between patients with or without antibodies: IgA-0.97(0.28) mm versus IgA+0.95(0.26) mm, P=0.63, IgG-0.96(0.28) mm versus IgG+0.96(0.26) mm, P=0.98. During follow-up with a mean duration of 3.5 years the combined endpoint, MI or IS, was similar in patients with or without antibodies (IgA-24% vs. IgA+19%, IgG-23% vs. IgG+22%). However, a lower frequency of MI was observed in IgA positive patients (IgA-13% vs. IgA+8%). The number of ischemic events in the 12 patients who used anti-chlamydial antibiotics was similar compared with those who did not use antibiotics. CONCLUSION: In patients with manifest atherosclerotic disease no association between the presence of cLPS Ab and IMT could be detected. In addition, no influence of cLPS Ab on the number of ischemic events was observed, the frequency of MI during follow-up in IgA positive patients was even lower.

Aged↗

PubMed2003

Disseminated intravascular coagulation.

Disseminated Intravascular Coagulation (DIC) is an acquired syndrome representing a hypercoagulable state, haemorrhagic symptoms and multiple organ failure. The clinical relevance of this syndrome is complicated since there is no established way of diagnosing DIC and it is difficult to distinguish whether clinical features are attributable to the underlying disease or DIC. Experimental studies, based on models of gram-negative sepsis and the Generalized Shwartzman Reaction, show that DIC is characterized by strongly enhanced inflammatory activity, activated coagulation and impaired fibrinolysis. In this review we propose that activated neutrophils play a pivotal role in the pathophysiology of DIC, particularly by contributing to inflammation and vascular injury. Additionally, a distinct role for granulocytes in fibrinolysis has also been suggested. Although the underlying procoagulant pathways of DIC and the important role of tissue factor have been unravelled, therapeutic interventions counteracting the mediators of these pathways proved mainly unsuccessful (with the positive exception of activated protein C). Dissecting the molecular interactions at the onset and progression of DIC might therefore help to elucidate the fundamental consequences of DIC, possibly contributing to better diagnostic tools and more effective therapeutic options.

Blood Coagulation↗

PubMed2003

Modified two-step model for studying the inflammatory response during myocardial ischemia and reperfusion in mice.

Studies of myocardial ischemia-reperfusion (MI-R) in the mouse can be accomplished by use of reversible ligation of the left interventricular branch artery (LIB). To study interactions of coagulation, inflammation, and reperfusion injury, the model should not be influenced by effects of the surgery. In existing closed-thorax mouse models, the release of inflammatory factors attributable to surgical intervention could be separated from the release resulting from induction of MI-R. In these models, the final myocardial injury was induced by reversible closure of the LIB several days after preparative surgery that included median thoracotomy. In an attempt to develop a less invasive procedure to approach the LIB, we replaced median thoracotomy with lateral thoracotomy. After this procedure, body weight was regained within four days, and on days 9 to 11 after the preparative surgery, cytokine values were back to baseline. During one hour of ischemia, mean arterial pressure (MAP) remained at 78 +/- 2 mmHg. After induction of reperfusion, MAP was 67 +/- 4 mmHg, indicating better perfusion pressure of myocardial tissue at the microcirculatory level than that in simple open-thorax models. Electrocardiographic recording revealed transient ST elevation indicating reversible transmural ischemia and reperfusion. Evans blue and 2,3,5-triphenyltetrazolium chloride (TTC) staining visualized the extent of area of infarction (AOI) and area at risk (AAR). The procedure-related mortality was 13%, which compared well with published data from median thoracotomy studies. We conclude that our new model provides stable near-physiologic hemodynamics and allows study of the inflammatory response resulting from MI-R, with low procedure-related mortality.

Animals↗

PubMed2002

Arterial wall thickness and the risk of recurrent ischemic events in carriers of the prothrombin G20210A mutation with clinical manifestations of atherosclerosis.

The G20210A mutation in the prothrombin gene is an established risk factor for venous thrombosis. There is controversy about the role of this mutation in arterial thrombotic disease and atherosclerosis. We determined the presence of the prothrombin mutation and examined its influence on carotid and femoral artery intima-media thickness (IMT) and the occurrence of new ischemic events during follow-up in 277 patients with clinically manifest atherosclerotic disease: ischemic stroke, myocardial infarction or peripheral arterial disease. The mean age at entry was 63 years. Mean IMT was significantly higher in carriers of the prothrombin mutation (1.17 (SD 0.29) mm versus 0.97 (SD 0.25) mm: (delta)IMT=0.20, P=0.02). The increase in IMT was not attributable to differences in age, type of arterial disease or cardiovascular risk factors between carriers and non-carriers. During a mean follow-up of 3.5 years, a strong trend for more ischemic events was observed: 4 of the 11 carriers suffered from a recurrent ischemic event, compared with 30 of the 164 male non-carriers (36 versus 18%; P=0.06). These results suggest that the G20210A mutation contributes to the process of arterial wall thickening and is associated with the occurrence of ischemic events in a cohort of elderly persons with established atherosclerosis.

Aged↗

PubMed2002

Endothelium: interface between coagulation and inflammation.

OBJECTIVE: To review the involvement of endothelial cells in the pathogenesis of coagulation abnormalities during severe infection, the differential role of proinflammatory cytokines in these mechanisms, and the cross talk between coagulation and inflammation. DATA SOURCES: Published articles on experimental studies of coagulation activation during inflammation and clinical studies of patients with sepsis and associated hemostatic abnormalities. DATA SYNTHESIS AND CONCLUSION: The endothelium plays a central role in all major pathways involved in the pathogenesis of the hemostatic derangement observed during severe inflammation (i.e., initiation and regulation of thrombin generation and inhibition of fibrinolysis). Rather than being a unidirectional relationship, the interaction between inflammation and coagulation involves significant cross talk in which the endothelium seems to play a pivotal role.

Animals↗

PubMed2002

Recombinant nematode anticoagulant protein c2, a novel inhibitor of tissue factor-factor VIIa activity, abrogates endotoxin-induced coagulation in chimpanzees.

Systemic activation of coagulation leading to disseminated intra-vascular coagulation (DIC) is an important feature in patients with severe sepsis. Tissue factor has been shown to play a primary role in this pathological response, as revealed by the use of specific inhibitors and antagonists of the tissue factor/factor VIIa pathway. This class of agents has been demonstrated to attenuate the coagulation response in human volunteers with induced low-grade endotoxemia and to reduce mortality in primate models of Gram-negative sepsis. The efficacy of these agents in attenuating the activation of coagulation and formation of microvascular thrombosis in sepsis may depend on the mechanism of inhibition. Here we demonstrate the efficacy of recombinant nematode anticoagulant protein c2 (rNAPc2) that specifically inhibits the tissue factor/factor VIIa complex by a novel mechanism, in a model of endotoxin-induced coagulation activation in chimpanzees. Administration of a low dose of Gram-negative endotoxin induced marked increases of thrombin generation as measured by plasma levels of prothrombin activation fragment F(1+2) and thrombin-antithrombin complexes, which were completely blocked by rNAPc2. In chimpanzees receiving rNAPc2 alone, there was a significant reduction in the activation of factor X but not factor IX, compared to animals receiving placebo. In contrast to the effect of rNAPc2 on thrombin generation, there was no effect of this inhibitor on the well known enhanced systemic fibrinolytic response induced by endotoxin. In conclusion, the recombinant peptide rNAPc2 is an effective inhibitor of tissue factor-driven thrombin generation during low grade endotoxemia. These results suggest that rNAPc2 may be a promising therapeutic option to inhibit coagulation activation in patients with sepsis.

Animals↗