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Coagulation Abnormalities in Legg-Calvé-Perthes Disease
A. Vosmaer, MD1; R. Rodrigues Pereira, MD2; J.S. Koenderman, MSc3; F.R. Rosendaal, MD, PhD3; S.C. Cannegieter, MD, PhD3
1 Department of Orthopaedics, Ikazia Hospital, P.O. Box 5009, 3008 AA Rotterdam, the Netherlands. E-mail address: a.vosmaer@ikazia.nl
2 Department of Pediatrics, Maasstadziekenhuis, P.O. Box 9100, 3007 AC Rotterdam, the Netherlands
3 Departments of Clinical Epidemiology (J.S.K., F.R.R., and S.C.C.) and Thrombosis and Haemostasis (F.R.R.) and Einthoven Laboratory for Experimental Vascular Medicine (F.R.R. and S.C.C.), Leiden University Medical Center, P.O. Box 9600 2300 RC Leiden, the Netherlands
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Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants of less than $10,000 from MSD (Merck Sharp and Dohme). Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity.

Investigation performed at the Ikazia and St. Clara Hospitals, Rotterdam, the Netherlands

Copyright ©2010 American Society for Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2010 Jan 01;92(1):121-128. doi: 10.2106/JBJS.I.00157
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Legg-Calvé-Perthes disease is a pediatric disorder characterized by osteonecrosis of the proximal femoral epiphysis. The etiology probably involves successive vascular occlusions, in which hypercoagulable disorders may play a role. We evaluated the etiologic role of thrombophilia in Legg-Calvé-Perthes disease in a pediatric population.


One hundred and sixty-nine consecutive patients who had been diagnosed with Legg-Calvé-Perthes disease at two centers in Rotterdam, the Netherlands, when they were between 1.5 and 13.5 years of age were identified between 2000 and 2003. The study also included two control groups: 474 subjects (16.3 to 73.1 years of age) from a population-based case-control study on the etiology of venous thrombosis as well as thirty-eight children (1.8 to 18.8 years of age) who were treated for asthma at one of the centers. We determined levels of protein C, protein S, factor VIII, and fibrinogen and tested for the factor V Leiden and prothrombin G20210A mutations. We calculated age and sex-adjusted odds ratios as measures of the relative risk of the development of Legg-Calvé-Perthes disease.


The incidence of Legg-Calvé-Perthes disease was increased in the presence of the factor V Leiden mutation (odds ratio, 3.3; 95% confidence interval, 1.6 to 6.7), in the presence of the prothrombin G20210A mutation (odds ratio, 2.6; 95% confidence interval, 1.0 to 6.3), in association with elevated levels of factor VIII (>150 IU/dL) (odds ratio, 7.5; 95% confidence interval, 2.2 to 25.2), and in association with protein S deficiency (<67 U/dL) (odds ratio, 2.8; 95% confidence interval, 0.7 to 10.8). Neither high levels of fibrinogen (>4.0 g/L) nor protein C deficiency (=55 U/dL) had an apparent effect on the risk of Legg-Calvé-Perthes disease. (Odds ratios were adjusted for age and sex.) Overall, males had a 2.4 times higher risk of Legg-Calvé-Perthes disease developing than did females. The effect of the factor V Leiden mutation, high levels of fibrinogen, and increasing levels of factor VIII was stronger in males than in females. The risk of Legg-Calvé-Perthes disease increased with an increasing number of coagulation abnormalities in males but not in females.


There appears to be a thrombotic component in the etiology of Legg-Calvé-Perthes disease.

Clinical Relevance: 

The findings of this study contribute to the understanding of the etiology of Legg-Calvé-Perthes disease and may thus have implications for its prevention or treatment.

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    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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    Alexander Vosmaer, MD
    Posted on April 27, 2010
    Dr. Vosmaer and colleagues respond to Dr. Hayek and colleagues
    Ikazia Hospital, Rotterdam, the Netherlands

    We would like to thank Dr. Hayek for his interest in our article and for his valuable remarks. We agree with Dr. Hayek that our study may not yet be the final answer on the role of hypercoagulability in Legg-Calvé-Perthes disease (LCPD). However, our study included the largest group of patients so far which may at least have led to a considerable contribution to the discussion.

    As indicated by Dr. Hayek, the prevalence of genetic coagulation factors are population dependent. Factor V Leiden shows an uneven geographical distribution and is most commonly present in Caucasians. In the Dutch population the prevalence of the Factor V Leiden mutation was previously found to be 3.6% (1) which is similar to the 3.1% we found in our control population and clearly different from the 9.6% in the LCPD patients. It should be noted that we contrasted patients and controls from the same population, so ethnic differences could not have biased our results. The prothrombin G20210A mutation is mainly observed in Western European countries. The prevalence within the Dutch population varies between studies from 1.0-2.3% (2,3), which is again similar to our control group with a prevalence of 2.1%. Nevertheless, these differences in prevalence between populations can not explain the controversy Dr. Hayek refers to. A relative risk (of which an odds ratio is an estimate) compares the risk in unexposed and exposed subjects and, for this comparison, the prevalence of the exposure is not relevant (unless it is completely absent). The discrepancies between reported results are most likely the result of the small size of several previous studies and other methodological deficits.

    We agree that the use of an age-matched control group would have been ideal, but collecting a larger group of children as controls or confirming protein S deficiency in relatives was difficult due to medical ethical constraints. However, the limitations of the use of an adult control group may seem more serious then they really are: the cut-off value of 67U/dL for protein S was well justified because levels in children reach adult ranges early in life and mean levels in children are equal to adult means (4,5). Increased FVIII levels may lead to a hypercoagulable state which is an established risk factor for deep venous thrombosis and may result in an increased risk for developing LCPD. Indeed, testing during the acute phase of LCPD should not be recommended as it is an acute phase protein. However, in our study blood collection was performed on average 3.5 years after the first onset of symptoms of LCPD. There is indeed a possibility that FVIII levels were occasionally increased due to infections or other medical conditions, but even if this occurred sporadically at the time of blood sampling, it is as likely that it occurred in the cases as in the controls. This would at most have resulted in an underestimation of the odds ratio. Of course, none of these issues are relevant for the investigation of factor V Leiden and prothrombin 20210A, which have a prevalence that does not change with age, or concomitant circumstances.

    Dr. Hayek agrees with us that the association with factor V Leiden and LCPD is likely to be true. If we accept that one thrombophilic defect has an effect on LCPD, it makes sense that other thrombophilic abnormalities do so as well, even though these associations may be more difficult to demonstrate due to measurement problems or insufficient power. From our results we concluded that thrombotic abnormalities contribute in the etiology of LCPD. We certainly did not suggest that anticoagulant therapy should be used. Instead, we consider it ineffective, because LCPD is often diagnosed at a late stage and additionally, anticoagulants introduce a bleeding risk. We also would not recommend testing for these abnormalities in the clinical setting, since the presence or absence of them would not affect clinical management.


    1. Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369:64-7.

    2. Doggen CJ, Cats VM, Bertina RM, Rosendaal FR. Interaction of coagulation defects and cardiovascular risk factors: increased risk of myocardial infarction associated with factor V Leiden or prothrombin 20210A. Circulation. 1998;97:1037-41.

    3. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996;88:3698-703.

    4. Andrew M. Developmental hemostasis: relevance to hemostatic problems during childhood. Semin Thromb Hemost. 1995;21:341-56.

    5. Monagle P, Barnes C, Ignjatovic V, Furmedge J, Newall F, Chan A, De Rosa L, Hamilton S, Ragg P, Robinson S, Auldist A, Crock C, Roy N, Rowlands S. Developmental haemostasis. Impact for clinical haemostasis laboratories. Thromb Haemost. 2006;95:362-72.

    Shlomo Hayek, MD
    Posted on March 17, 2010
    Thrombophilia in Legg-Calvé-Perthes Disease
    Department of Paediatric Orthopaedics, Dana ChildrenÂ’s Hospital, Tel Aviv Medical Centre, Israel

    To the Editor:

    We have read with great interest the manuscript "Coagulation Abnormalities in Legg-Calvé-Perthes Disease" (1). After carefully reading it, we would like to comment on the results and methodology of this study.

    So far, a considerable number of case reports, cohort and case control studies have been published on the subject of the prevalence of hypercoagulability in Legg-Calvé-Perthes Disease (LCPD) and it seems that the controversy on this issue has not yet been resolved. In our recent article, "Perthes’ disease and the search for genetic associations: collagen mutations, Gaucher's disease and thrombophilia", we performed a prospective case controlled study as well as a systematic review of 11 case control studies and found that the role of thrombophilia risk factors in LCPD could not be established (2). We do agree that the presence of factor V Leiden seems to be higher in LCPD patients as demonstrated in this study and it also showed a trend towards statistical significance in our literature review. On the other hand, the same systematic review found no evidence of a higher prevalence of prothrombin mutations G20210A in LCPD patients. Since the prevalence of genetic thrombophilia mutations is not equal in different populations, the result of finding this mutation in 5.3% in patients and 2.1% in the controls may be unique to this population (3).

    The use of adult controls as references for tests in pediatric patients may yield some misinterpretation of results. For example: protein S levels are age related and to be considered low should be 2 standard deviations from the age adjusted normal value. In this study (1), levels below 67U/dL were considered low. This cut off value may be true in the adult population, which made up the majority of the control group, yet it may be within normal levels in the LCPD patients whose lowest age when tested was 2.8 years (4-5). In cases where pediatric age- adjusted controls cannot be matched with the patient group, it would have been advisable to repeat testing and confirm the diagnosis of suspected protein S deficiency by testing first degree family members. Factor VIII is an acute phase reactant that may rise in stress related situations, following infections or vaccinations. Thus, levels should be measured repeatedly, preferably following some time interval, in the non-acute phase, to secure a positive result. According to the literature, only levels above 150% may be considered as risk factors for venous thromboembolism (6). Again, among pediatric patients frequently exposed to viral infections or vaccinations, there is a high likelihood of detecting occasionally high factor VIII levels as compared to adult controls, especially if patients were not uniformly tested during the course of their disease with some FVIII tests obtained at acute phase. Considering the above and the results of previous studies, it seems that a clear conclusion that thrombophilia is a risk factor in the pathogenesis of LCPD may not be validated and the suggestion of anticoagulant therapy in these patients is certainly premature. The association of factor V Leiden mutations and LCPD is an important finding that should be further investigated.

    The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity.


    1. Vosmaer A, Pereira RR, Koenderman JS, Rosendaal FR, Cannegieter SC. Coagulation abnormalities in Legg-Calv é-Perthes disease. J Bone Joint Surg Am. 2010;92:121-8.

    2. Kenet G, Ezra E, Wientroub S, Steinberg DM, Rosenberg N, Waldman D, Hayek S. Perthes’ disease and the search for genetic associations: collagen mutations, Gaucher's disease and thrombophilia. J Bone Joint Surg Br. 2008;90:1507-11.

    3. Segal JB, Brotman DJ, Necochea AJ, Emadi A, Samal L, Wilson LM, Crim MT, Bass EB. Predictive value of factor V Leiden and prothrombin G20210A in adults with venous thromboembolism and in family members of those with a mutation: a systematic review. JAMA. 2009;301:2472-85.

    4. Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L. Maturation of the hemostatic system during childhood. Blood. 1992;80:1998-2005.

    5. Monagle P, Barnes C, Ignjatovic V, Furmedge J, Newall F, Chan A, De Rosa L, Hamilton S, Ragg P, Robinson S, Auldist A, Crock C, Roy N, Rowlands S. Developmental haemostasis. Impact for clinical haemostasis laboratories. Thromb Haemost. 2006;95:362-72.

    6. Brouwer JL, Veeger NJ, Kluin-Nelemans HC, van der Meer J. The pathogenesis of venous thromboembolism: evidence for multiple interrelated causes. Ann Intern Med. 2006;145:807-15.

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