The impact of blood coagulability on atherosclerosis and cardiovascular disease: a rebuttal

Authors


Antonio Girolami, Department of Medicine, Medical School, University of Padua, Via Ospedale 105, Padua 35218, Italy.
Tel.: 39 049 8213026; fax: 39 049 657391.
E-mail: antonio.girolami@unipd.it

We read with interest the remarkable review article entitled ‘Impact of blood coagulability on atherosclerosis and cardiovascular disease’ [1]. We take the liberty of making a few observations on the reported effect of congenital hypocoagulability on atherosclerosis, as the conclusions proposed by the authors appeared, in our opinion, to be a little vague, with a potential discrepancy noted between the general tone of the text and the conclusion reported in Fig. 1.

We think that the lack of protection against atherosclerosis of congenital (i.e. chronic) hypocoagulability has now been fully demonstrated by several clinical and laboratory observations, which could be summarized as follows:

  • 1 The large number of myocardial infarction (MI) and other acute coronary syndromes seen in patients with hemophilia A and B. A few years ago, our group reported on ∼ 70 such patients [2,3]. To date, the number of cases has increased to ∼ 100. Furthermore, the number of coronary invasive procedures carried out in hemophiliacs and in patients with other clotting disorders is increasing rapidly. Indeed, single, double and multiple atherosclerotic occlusions have been described. Stents, coronary bypasses and other invasive procedures have been carried out with standard antiplatelelet therapy after correction of the basic bleeding defect [3–6].
  • The possibility that intensive substitution therapy might neutralize the basic defect is not supported by the observation that ∼ 30% of hemophilic patients who had an MI were patients with mild or moderate forms, and were therefore never, or only rarely, transfused [2,3].

  • 2 Another fundamental argument against the existence of a protective effect is supported by pathology studies. Several studies have unequivocally shown, at autopsy, the presence of variably diffuse atherosclerotic lesions in hemophilia and other related conditions [7–9].
  • The fact that clotting factors and inhibitors have been found incorporated into the plaque cannot be interpreted as pathogenic proof. The association of two biological events is not sufficient to indicate that a causal relationship exist between the two. Endothelial cells are in constant contact with the coagulation-related proteins present in the flowing blood. Some of them are even present in endothelial cells (i.e. von Willebrand factor, plasminogen activators, etc.).

  • 3 Anticoagulant therapies are unable to modify the composition and progression of the plaque. Conversely, statins have been shown to stop the progression of plaque, modify its structure, and even cause, in some instances, its regression [10,11].
  • 4 Finally, today, physicians operating in hemophilia centers are routinely involved with patients who present with cardiovascular atherosclerotic conditions, usually effort angina, coronary and/or aortic calcifications, hypertension, etc. [12–14].

On the basis of the evidence presented above, one has to conclude that the association between congenital hypocoagulability and atherosclerosis is probably non-existent or very weak, much to the frustration of coagulation experts. The well-established cardiovascular risk factors, namely dyslipidemia, diabetes, smoking, and hypertension, appear to neutralize the potential effect that might be exerted by a coagulation defect. A relationship between hypocoagulability and atherothrombosis may still exist, but it must be considered that not all arterial occlusions result from the presence of a thrombus.

There is a tendency to confuse atherosclerosis with atherothrombosis. The two terms are often used interchangeably, but this is wrong. They are two different entities. Atherosclerosis refers to the presence of streaks and plaques on the intima, whereas atherothrombosis refers to the formation of a thrombus on fissured, ruptured or ulcerated plaques.

Even the purported protection afforded by congenital platelet disorders is now under scrutiny, as it has been recently demonstrated that patients with Glanzmann thrombasthenia, a glycoprotein (GP)IIb–IIIa defect, and Bernard–Soulier syndrome, a GPIb–V–IX complex defect, are not protected from atherosclerosis and MI [15–17].

Taken together, these observations and considerations seem to suggest that the impact of hypocoagulability on atherosclerosis and subsequent arterial disease is very limited or non-existent. In this instance, fats (and inflammation) appear to have won over clotting factors.

Disclosure of conflict of interests

The authors state that they have no conflict of interest.

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