Hemostatic Abnormalities and Arterial Thrombosis

Hereditary and acquired hemostatic risk factors are associated with the occurrence of venous thrombosis. Hemostasis also plays an important role in arterial thrombosis because a prothrombotic state, through enhanced platelet activation, thrombin generation, or decreased fibrinolysis, increases the risk of arterial events. Interestingly, several observational studies have suggested that patients with an arterial cardiovascular event also have an increased risk of developing venous thrombosis,[1] [2] which may challenge the concept that arterial and venous thrombosis are separate entities. In addition, common cardiovascular risk factors, such as dyslipidemia and diabetes, also seem associated with the occurrence of venous thrombosis.[3] This implies that treatment usually given to reduce the risk of arterial cardiovascular events may also be effective in primary or secondary prevention of venous thrombosis. Indeed, several case-control and cohort studies have suggested that statin treatment reduces the occurrence of venous thrombosis.[4] [5] [6] In addition, in the recent randomized placebo-controlled Jupiter trial, rosuvastatin lowered the risk of both cardiovascular and venous thrombotic disease in healthy subjects.[7]

Although the link between arterial and venous thrombosis may be of clinical relevance, much knowledge has to be gained about the pathophysiological mechanisms underlying this association. In this issue of Seminars in Thrombosis and Hemostasis, various topics regarding mutual risk factors for venous and arterial thrombosis are discussed.

The metabolic syndrome, which consists of abdominal obesity, hypertension, insulin resistance, and dyslipidemia with high triglycerides levels and low high-density lipoprotein cholesterol, is associated with atherosclerosis. Patients with the metabolic syndrome generally have systemic inflammation and a hypercoagulable state, which predisposes them to myocardial infarction and ischemic stroke. The metabolic syndrome may also increase the risk of venous thrombosis. The classification of the metabolic syndrome, its prevalence, and the influence on platelet function, thrombin generation, and fibrinolysis is discussed in the article by Dentali et al. The authors critically evaluate current evidence whether the metabolic syndrome is indeed causally related to venous thrombosis.

Clot formation is the key element in the occurrence of both venous and arterial thrombosis, which is influenced by multiple environmental and genetic risk factors. Standeven and colleagues discuss the determinants of clot structure and how fibrin formation and fibrinolysis can influence both the function and structure of the clot. Interestingly, there seems to be a genetic variation in clot structure, as shown in twin and family studies. Interactions between genetic and environmental factors regulate fibrin formation and are very likely relevant for thrombotic disease.

The occurrence of both venous thrombosis and myocardial infarction is enhanced by hypercoagulability but also by hypofibrinolysis. Meltzer et al discuss the effect of overall hypofibrinolysis on venous and arterial thrombosis. Levels of individual fibrinolytic components seem to play a more prominent role in arterial than in venous disease, which may be explained by the properties of fibrinolytic components in processes other than the dissolution of a blood clot such as inflammation, vascular remodeling, atherosclerosis, and the metabolic syndrome Several hormones are associated with cardiovascular disease, partly by inducing secondary hypertension, insulin resistance, or dyslipidemia. Van Zaane and colleagues discuss whether thyroid hormones, cortisol, somatotropic hormones, and prolactin increase the risk of cardiovascular events. They show that not only hormone excess or hormone deficiency, but even subtle hormonal disturbances, may affect cardiovascular disease outcome. The potential pathophysiological mechanisms that can induce atherogenesis as well as potential targets for treatment are discussed.

In recent years, the role of microparticles in several disorders, such as cancer and arterial thrombosis, has attracted considerable attention. Microparticles are cell-membrane-derived particles, size 200 to 1500 nm, shed by cells in different circumstances. Blood cells such as platelets, monocytes, leukocytes, and red cells can shed microparticles but also endothelial cells. Microparticles activate the coagulation cascade. Phosphatidylserine induces fibrin formation because it is thought to assemble complexes of coagulation factors. In addition, some microparticles express tissue factor on their surface. Patients with atherosclerosis risk factors such as hypertension and diabetes or with an acute coronary syndrome have elevated levels of circulating microparticles. These subjects are discussed by Blann et al. Elevated levels of microparticles may be a prognostic marker for cardiovascular complications.

Heart failure is a highly prevalent disorder and associated with a high mortality, mostly as a result of sudden death. Many patients with heart failure also suffer from atrial fibrillation. These patients are generally treated with oral anticoagulant treatment to prevent ischemic stroke. The incidence of thrombotic complications in patients with heart failure in sinus rhythm, however, is virtually unknown. In patients with systolic heart failure, a prothrombotic state is induced by platelet hyperactivity, increased thrombin generation, and an impaired fibrinolysis. Anticoagulant treatment could therefore be of additional value, but its beneficial effect in patients with heart failure has not been established, as de Peuter and colleagues discuss.

One of the most obvious links between venous and arterial thrombosis is the occurrence of stroke due to right-left shunting in patients with patent foramen ovale (PFO). Especially in cryptogenic stroke in patients <55 years of age, PFO is prevalent, supporting the concept that paradoxical embolism could be a relevant cause of stroke. Recent studies have shown that also in older patients with stroke the presence of a PFO may be important, notably in the presence of atrial septum aneurysm. Handke et al discuss the epidemiology of stroke and a PFO, and what diagnostic methods should be used for the detection and imaging of PFO and atrial septal aneurysm. The authors discuss therapeutic options, such as aspirin and vitamin K antagonists, and the usefulness of percutaneous closure.

Finally, Sobieraj-Teague and colleagues discuss the anticoagulant treatment of patients with atrial fibrillation, focusing both on currently available therapy and the development of new compounds. Atrial fibrillation is the most common indication for anticoagulant treatment worldwide. Because the majority of patients are of advanced age, there is a delicate balance between the risk of ischemic stroke due to atrial fibrillation and the occurrence of major bleeding. New anticoagulant agents have to prove both efficacy and safety in this fragile population. The authors conclude that, given the chronic nature of atrial fibrillation and the often indefinite duration of treatment, long-term safety evaluation of the new anticoagulants will be essential. Another safety aspect is the ability to directly reverse the anticoagulant effect in case of major bleeding.

In summary, we think that the various articles in this issue of Seminars of Thrombosis and Hemostasis provide an interesting and useful overview of the state of the art regarding hemostatic abnormalities in arterial thrombosis. We are grateful to all the authors for their valuable contributions.

REFERENCES

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