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

  1. Top of page
  2. Disclosure of conflict of interests
  3. References

The authors state that they have no conflict of interest.


  1. Top of page
  2. Disclosure of conflict of interests
  3. References
  • 1
    Loeffen R, Spronk HMH, ten Cate H. The impact of blood coagulability on atherosclerosis and cardiovascular disease. J Thromb Haemost 2012; 10: 120714.
  • 2
    Girolami A, Randi ML, Ruzzon E, Zanon E, Girolami B. Myocardial infarction, other arterial thrombosis and invasive coronary procedures, in hemophilia B: a critical evaluation of reported cases. J Thromb Thrombolysis 2005; 20: 436.
  • 3
    Girolami A, Ruzzon E, Fabris F, Varvarikis C, Sartori R, Girolami B. Myocardial infarction and other arterial occlusions in hemophilia A patients. A cardiological evaluation of all 42 cases reported in the literature. Acta Haematol 2006; 116: 1205.
  • 4
    Lim M, Pruthi R. Outcomes of management of acute coronary syndrome in patients with congenital bleeding disorders: a single center experience and review of the literature. J Thomb Res 2012; 130: 316–22.
  • 5
    Coppola A, De Simone C, Di Capua M, Tufano A, Cimino E, Conca P, Guida A, Marasco C, Di Minno G. Acute coronary syndrome and severe haemophilia: an unusual association with challenging treatment. Thromb Haemost 2010; 103: 12702.
  • 6
    Petrillo G, Cirillo P, Leosco D, Maresca F, Piscione F, Chiariello M. Percutaneous coronary intervention in a patient with acute non-ST-elevation myocardial infarction and haemophilia A: a ‘genous’ experience. Haemophilia 2011; 17: e2456.
  • 7
    Dalldorf FG, Taylor RE, Blatt PM. Arteriosclerosis in severe hemophilia. A postmortem study. Arch Pathol Lab Med 1981; 105: 6524.
  • 8
    Federici AB, Mannucci PM, Fogato E, Ghidoni P, Matturri L. Autopsy findings in three patients with von Willebrand disease type IIB and type III: presence of atherosclerotic lesions without occlusive arterial thrombi. Thromb Haemost 1993; 70: 75861.
  • 9
    Goodnough LT, Saito H, Ratnoff OD. Thrombosis or myocardial infarction in congenital clotting factor abnormalities and chronic thrombocytopenias: a report of 21 patients and a review of 50 previously reported cases. Medicine (Baltimore) 1983; 62: 24855.
  • 10
    Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM, Davignon J, Erbel R, Fruchart JC, Tardif JC, Schoenhagen P, Crowe T, Cain V, Wolski K, Goormastic M, Tuzcu EM, ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006; 295: 155665.
  • 11
    Shin ES, Garcia-Garcia HM, Okamura T, Serruys PW. Effect of statins on coronary bifurcation atherosclerosis: an intravascular ultrasound virtual histology study. Int J Cardiovasc Imaging 2012; 28: 1643–52.
  • 12
    Tuinenburg A, Rutten A, Kavousi M, Leebeek FW, Ypma PF, Laros-van Gorkom BA, Nijziel MR, Kamphuisen PW, Mauser-Bunschoten EP, Roosendaal G, Biesma DH, van der Lugt A, Hofman A, Witteman JC, Bots ML, Schutgens RE. Coronary artery calcification in hemophilia A: no evidence for a protective effect of factor VIII deficiency on atherosclerosis. Arterioscler Thromb Vasc Biol 2012; 32: 799804.
  • 13
    van Galen KP, Tuinenburg A, Smeets EM, Schutgens RE. von Willebrand factor deficiency and atherosclerosis. Blood Rev 2012; 26: 18996.
  • 14
    Zwiers M, Lefrandt JD, Mulder DJ, Smit AJ, Gans RO, Vliegenthart R, Brands-Nijenhuis AV, Kluin-Nelemans JC, Meijer K. Coronary artery calcification score and carotid intima–media thickness in patients with hemophilia. J Thromb Haemost 2012; 10: 239.
  • 15
    Humphries JE, Yirinec BA, Hess CE. Atherosclerosis and unstable angina in Bernard–Soulier syndrome. Am J Clin Pathol 1992; 97: 6525.
  • 16
    Shpilberg O, Rabi I, Schiller K, Walden R, Harats D, Tyrrell KS, Coller B, Seligsohn U. Patients with Glanzmann thrombasthenia lacking platelet glycoprotein alpha(IIb)beta(3) (GPIIb/IIIa) and alpha(v)beta(3) receptors are not protected from atherosclerosis. Circulation 2002; 105: 10448.
  • 17
    Girolami A, Vettore S, Vianello F, Berti de Marinis G, Fabris F. Myocardial infarction in two cousins heterozygous for ASN41HIS autosomal dominant variant of Bernard–Soulier syndrome. J Thromb Thrombolysis 2012; 34: 513–23.