The Journal of Bone & Joint Surgery

The Journal of Bone & Joint Surgery, Volume 86, Issue 12

Scientific Articles | December 01, 2004

Legg-Calvé-Perthes Disease and Thrombophilia

Vinod V. Balasa, MD, MBBS¹; Ralph A. Gruppo, MD¹; Charles J. Glueck, MD²; Ping Wang, PHD²; Dennis R. Roy, MD³; Eric J. Wall, MD¹; Charles T. Mehlman, DO, MD¹; Alvin H. Crawford, MD¹

¹ Hemophilia and Thrombosis Center, Hematology/Oncology Division (V.V.B. and R.A.G.) and Department of Orthopedics (E.J.W., C.T.M., and A.H.C.), Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229. E-mail address for V.V. Balasa: vinod.balasa@cchmc.org
² Cholesterol Center, Health Alliance of Greater Cincinnati, ABC Building, 3200 Burnet Avenue, Cincinnati, OH 45229
³ Shriner's Hospital for Children, 3101 S.W. Sam Jackson Park Road, Portland, OR 97239

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The authors did not receive grants or outside funding in support of their research or preparation of this manuscript. They did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

Investigation performed at the Hemophilia and Thrombosis Center, Hematology/Oncology Division, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

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Abstract

Background: Thrombophilia has previously been identified as a potential etiologic factor in Legg-Calvé-Perthes disease. We prospectively studied the association between Legg-Calvé-Perthes disease and coagulation abnormalities by comparing seventy-two children who had the disease with 197 healthy controls.

Methods: A nonselected, consecutive series of seventy-two patients with Legg-Calvé-Perthes disease (mean age [and standard deviation], 6.6 ± 2.6 years) was studied in their order of referral and compared with 197 healthy controls (mean age, 7.6 ± 5.1 years). Assays were done for factor-V Leiden, prothrombin G20210A, methylenetetrahydrofolate reductase C677T, and plasminogen activator inhibitor-1 4G/5G gene mutations. Levels of anticardiolipin antibodies immunoglobulin G and M (IgG and IgM), homocysteine, protein C, protein S, antithrombin III, and plasminogen activator inhibitor-1 were also measured.

Results: The factor-V Leiden mutation was more common in the patients (eight of seventy-two) than in the controls (seven of 197) (chi-square = 5.7, p = 0.017). After we controlled for the false-discovery rate, the case-control difference remained significant (p = 0.017). The odds ratio for the development of Legg-Calvé-Perthes disease in the presence of the factor-V Leiden mutation was 3.39 with a 95% confidence interval of 1.18 to 9.73. A high level of anticardiolipin antibodies (IgG and/or IgM) was found in nineteen of the seventy-two patients compared with twenty-two of the 197 controls (chi-square = 9.5, p = 0.002). After we controlled for the false-discovery rate, the case-control difference remained significant (p = 0.002). The odds ratio of patients with Legg-Calvé-Perthes disease having one or more abnormalities in factor V, anticardiolipin antibody IgG, or anticardiolipin antibody IgM as opposed to normal values for all three variables was 3.29 (95% confidence interval, 1.73 to 6.24; p = 0.0003).

Conclusions: Two thrombophilic risk factors, the factor-V Leiden mutation and anticardiolipin antibodies, are associated with Legg-Calvé-Perthes disease, an association that may reflect causality.

Level of Evidence: Prognostic study, Level II-1 (retrospective study). See Instructions to Authors for a complete description of levels of evidence.

Figures in this Article

Legg-Calvé-Perthes disease involves infarction and necrosis of the capital femoral epiphysis in children. The etiologic factor or factors in Legg-Calvé-Perthes disease remain unknown. Familial and acquired thrombophilia and/or hypofibrinolysis have been implicated as potential causes of osteonecrosis of the proximal part of the femur¹ and of the mandible and maxilla² in adults and proximal femoral osteonecrosis in children (Legg-Calvé-Perthes disease)^3-10. Thrombophilia is defined as a tendency for thrombosis to develop on the basis of inherited or acquired disorders of blood coagulation or fibrinolysis leading to a prothrombotic state¹¹. An association between thrombophilia and Legg-Calvé-Perthes disease has been shown in previous^3-10,12, but not all^13-17, studies. One possible explanation for the lack of consistency in these studies may lie in geographic variability, as seen with certain other orthopaedic conditions¹⁸, and/or small sample size or a lack of a representative control group with comparable age, gender, and ethnicity. Proof of an association of Legg-Calvé-Perthes disease with thrombophilia would substantially enhance our understanding of this disorder.

Thrombophilia can result from various inherited and acquired disorders of hemostasis¹¹. Deficiencies of naturally occurring inhibitors of the coagulation cascade include those of protein C, protein S, and antithrombin III¹⁹. While deficiencies of these proteins are associated with a high risk of thrombosis, these disorders collectively account for only 6% to 8% of cases of thromboembolic disease^19,20. In individuals with the factor-V Leiden mutation, activated factor V persists in the circulation, leading to continued activation of the coagulation cascade. The presence of the factor-V Leiden mutation was found to be associated with Legg-Calvé-Perthes disease by some investigators^5-7,10,12. Another recent discovery regarding familial thrombophilia has been the prothrombin gene G20210A polymorphism²¹, which is associated with elevated levels of prothrombin and with thrombosis²¹. Similarly, a polymorphism in the plasminogen activator inhibitor-1 gene, referred to as the 4G/5G polymorphism, has been associated with elevated plasminogen activator inhibitor-1 levels^4,22. Plasminogen activator inhibitor-1 inhibits the conversion of plasminogen to active plasmin that mediates fibrinolysis. Thus, elevated plasminogen activator inhibitor-1 levels decrease fibrinolysis and promote coagulation.

While the above-described conditions are important familial risk factors for thrombophilia, antiphospholipid antibodies are the most common acquired risk factors for thrombosis²³. Antiphospholipid antibodies are immunoglobulin-G, M, or A (IgG, IgM, or IgA) antibodies that occur as a result of autoimmune disease or as a reaction to infections or drugs or may be transiently seen in healthy individuals. They can be divided into two broad categories, anticardiolipin antibodies and the lupus anticoagulant, which are distinct and separable groups of antibodies that are distinguished by the tests used to identify them rather than by their function in vivo²³. Both anticardiolipin antibodies and the lupus anticoagulant have been associated with thrombosis, and they are believed to cause the thrombosis by inhibiting the action of activated protein C²³. An association between antiphospholipid antibodies and osteonecrosis has been previously described²⁴.

An additional thrombophilic risk factor is a mild-to-moderate elevation in the plasma homocysteine level, which has been demonstrated to be an independent, significant risk factor for cardiovascular disease (adjusted odds ratio and 95% confidence interval 1.32 [1.19 to 1.45]), for stroke (1.59 [1.29 to 1.96]), and for thrombosis (1.59 [1.29 to 1.96])²⁵. Elevated homocysteine levels can result either from nutritional deficiencies of vitamins involved in homocysteine metabolism (folate and vitamins B12 and B6) or from genetic mutations in enzymes involved in those metabolic pathways^22,25.

Proof of an association of Legg-Calvé-Perthes disease with thrombophilia would enhance our understanding of the etiology of this disorder. Thus, we examined the value of screening for thrombophilia and hypofibrinolysis in patients with Legg-Calvé-Perthes disease by comparing coagulation abnormalities in children who had the disease with those in healthy controls.

Materials and Methods

Materials and Methods | Results | Discussion | Acknowledgements | References

Study Design

A nonselected, consecutive series of seventy-two children with Legg-Calvé-Perthes disease was studied prospectively, in the temporal order of their referral to the Hemophilia and Thrombosis Center. Blood samples were drawn for the evaluation of gene mutations and polymorphisms and for coagulation studies. The study subjects were compared with a previously described control group of 197 healthy children who had been evaluated before same-day outpatient surgery²². The study was carried out according to a protocol approved by our institutional review board and with parental signed informed consent.

The diagnosis of Legg-Calvé-Perthes disease was based on the children's history, results of physical examinations, and radiographs of the hip that showed typical changes within the capital femoral epiphysis and proximal femoral metaphysis^3-5,8-10. Exclusion criteria included a history of major steroid use, hypothyroidism, epiphyseal dysplasia, sickle cell anemia, metabolic bone disease, and other known causes of osteonecrosis^1,4,13. An additional exclusionary criterion was osteonecrosis occurring after a fracture of the femoral head or after surgical treatment of hip dysplasia. Seventy-two children (fifty-eight boys and fourteen girls) with Legg-Calvé-Perthes disease were included in the study. Sixty-eight were white, and four were black. The mean age (and standard deviation) at the time of the formal diagnosis of Legg-Calvé-Perthes disease was 6.64 ± 2.64 years, the median age was 6.02 years, and the range was 2.16 to 13.4 years. Of the seventy-two children, twenty-three were between two and five years old, forty-one were between five and ten years old, six were between ten and twelve years old, one was between twelve and thirteen years old, and one was between thirteen and fourteen years old.

The control group included 197 healthy children (109 boys and eighty-five girls, with the gender unknown for three children). One hundred and sixty-three were white, twenty-eight were black, one was in another racial category, and the race of five was unknown. The mean age (and standard deviation) was 7.6 ± 5.1 years, the median was 7.2 years, and the range was 0.2 to 16.9 years. The blood samples were obtained from these children before elective same-day outpatient surgery, primarily ear-tube placement as well as other minor surgical procedures unrelated to disorders that might be associated with thrombophilia. No additional information regarding a family history of bleeding or thrombotic conditions or other illnesses was obtained. In order to have an even distribution of children of different ages, at least ten control children per year of age were selected.

Blood Sampling, Plasma Preparation, and Laboratory Methods

Blood samples were drawn from the children with Legg-Calvé-Perthes disease between February 1996 and April 2002 and were obtained from the controls between January 1995 and September 1997. The laboratory methodology for the various coagulation measures did not change during this time-period. Blood was collected in 3.2% buffered sodium citrate (one part citrate:nine parts blood). The samples were immediately transported and were centrifuged at 2600× g for fifteen minutes to obtain platelet-poor plasma. The samples were run in batches. The plasma was frozen in aliquots and was stored at —70°C. Blood for polymerase chain-reaction analysis was drawn in tubes containing the appropriate anticoagulant (EDTA [ethylenediaminetetraacetic acid]), and the DNA was extracted for subsequent analysis.

Commercially available enzyme-linked immunosorbent assay (ELISA)-based assays were utilized to measure antigen levels of protein C and protein S (free and total) and the IgG and IgM anticardiolipin antibody levels^1-4,8-10. We did not study the lupus anticoagulant because of inadequate sample volumes from both the controls and the patients. The anticoagulant activity of protein C was measured with use of commercially available assays, as previously described^3,4,8-10,22. Total plasma homocysteine was measured by high-pressure liquid chromatography, as previously described²².

Genomic DNA for the polymerase chain-reaction assays was obtained by a simple salting-out procedure, and the determinations of methylenetetrahydrofolate reductase C677T, prothrombin G20210A, and plasminogen activator inhibitor-1 4G/5G polymorphisms were performed as previously described^22,26. For determination of the factor-V Leiden mutation, a 224-base-pair fragment of the factor-V gene was amplified and then was digested with the Mn II restriction enzyme, as previously described^10,11.

Protein-C, protein-S, and antithrombin-III levels below the fifth percentile for age-matched controls²² were considered abnormal. Plasma homocysteine and IgG and IgM anticardiolipin antibody levels greater than or equal to the ninety-fifth percentile for age-matched controls²² were considered abnormal. The use of the fifth and ninety-fifth percentiles is standard, not extreme, as exemplified by Eldridge et al.⁷, who identified coagulation values below the 2.5th percentile as low and above the 97.5th percentile as high in their study of the relationships between thrombophilia and Legg-Calvé-Perthes disease.

Statistical Analysis

Comparisons between patients and controls were performed with use of Wilcoxon tests for numerical measures and with chi-square analyses or Fisher tests (when the cell sample size was less than five) for categorical measures²⁷. Power calculations were performed with the method described by Zelterman²⁸.

Since ten coagulation variables were compared between the patients and the controls, the method of Benjamini and Hochberg²⁹ was used to control for the false-discovery rate.

On the basis of binomial distribution, the 95% confidence limits were calculated^13,30 for the proportion of the patients with Legg-Calvé-Perthes disease who had each coagulation abnormality. The proportion of the patients with each coagulation abnormality was compared with the estimated population frequency^28,31,32.

Three stepwise logistic regression²⁷ models were run with patients and controls as a binary dependent variable. In the first model, the explanatory variables included four polymerase chain-reaction determinations: G1691A factor-V Leiden, G20210A prothrombin gene, C677T methylenetetrahydrofolate reductase gene, and the 4G/5G polymorphism of the plasminogen activator inhibitor-1 gene promoter. In the second model, the explanatory variables included levels of anticardiolipin antibodies IgG and IgM (normal or high as compared with the age-specific ninety-fifth percentile in normal children). In the third model, the explanatory variables included the G1691A factor-V Leiden, IgG and IgM, and a combined variable (one or more abnormal values for factor V, IgG, and IgM compared with normal values for all three parameters).

With the incidence of Legg-Calvé-Perthes disease in the general pediatric population¹⁶ assumed to be 11.7 per 100,000, and on the basis of the proportions of patients with factor-V Leiden mutation, a high IgG level, and/or a high IgM level in the current study, the likelihood of Legg-Calvé-Perthes disease in children with the factor-V Leiden mutation, a high IgG level, and/or a high IgM level was estimated with use of the Bayesian formula³³.

Results

Materials and Methods | Results | Discussion | Acknowledgements | References

The G1691A Leiden mutation in the factor-V gene was more common in the patients with Legg-Calvé-Perthes disease (eight of seventy-two, 11%) than it was in the controls (seven of 197, 4%) (chi-square = 5.7, p = 0.017). After we controlled for the false-discovery rate (=0.05), which would require p < 0.025²⁹, the case-control difference remained significant (p = 0.017). The odds ratio for the development of Legg-Calvé-Perthes disease in the presence of the factor-V Leiden mutation compared with no mutation was 3.39, with a 95% confidence interval of 1.18 to 9.73. With the incidence of Legg-Calvé-Perthes disease assumed to be 11.7 per 100,000 (i.e., one [0.0117%] of 8547 children) in the general pediatric population, as reported by Kealey et al.¹⁶, and with use of the above results, it was estimated that Legg-Calvé-Perthes disease develops in one (0.036%) of 2777 children in whom the G1691A Leiden mutation is present.

The factor-V Leiden mutation was more common in white patients (seven of sixty-eight, 10%) than in white control subjects (six of 163, 4%) (chi-square = 4.0, p = 0.047). After we controlled for the false-discovery rate (=0.05), which would require p < 0.032, the p value for the case-control comparison of the factor-V Leiden mutation in whites was 0.047. The factor-V Leiden mutation was present in one of four black patients compared with one of twenty-eight black control subjects (Fisher exact test, p = 0.23). The sample of black patients and control subjects was small. On the basis of the observed data, our sample size had 35% power and a 65% chance that it would fail to show a significant difference when a true significant difference existed (Type-II error). For an alpha of 0.05 and a power of 80%, at least forty-two black patients and black control subjects would be needed.

With use of the 95% confidence interval for the observed proportion of the patients with Legg-Calvé-Perthes disease who had the factor-V Leiden mutation (5% to 21%), the factor-V Leiden mutation was found to be marginally more common than the estimated population frequency of 5%.

The patients differed from the controls with regard to the levels of anticardiolipin antibodies IgG and/or IgM, with nineteen (26%) of the seventy-two patients having high anticardiolipin antibody levels compared with twenty-two (11%) of the 197 controls (chi-square = 9.5, p = 0.002). After we controlled for the false-discovery rate (=0.05), which would require p < 0.01²⁹, the case-control difference remained significant (p = 0.002). With the incidence of Legg-Calvé-Perthes disease assumed to be 11.7 per 100,000¹⁶, and with use of the above results, Legg-Calvé-Perthes disease was estimated to develop in one (0.028%) of 3571 children with high levels of the anticardiolipin antibodies IgG and/or IgM.

In the first and second stepwise logistic regression models, the G1691A factor-V Leiden mutation and a high level of IgM were found to be significantly associated with Legg-Calvé-Perthes disease (odds ratio [95% confidence interval], 3.39 [1.18 to 9.73], p = 0.023, for G1691A factor-V Leiden mutation and 3.16 [1.42 to 7.00], p = 0.005, for IgM). In the third logistic regression model, the odds ratio of Legg-Calvé-Perthes disease being present in subjects with one or more abnormalities in factor V, IgG, and IgM compared with normal values for all three variables was 3.29 (95% confidence interval, 1.73 to 6.24, p = 0.0003).

With the numbers tested, there were no case-control differences for other gene mutations, including the prothrombin gene G20210A polymorphism (4% compared with 4%), the plasminogen activator inhibitor-1 4G/5G polymorphism (22% compared with 20%), or homozygosity for the methylenetetrahydrofolate reductase C677T mutation (11% compared with 11%) (all p > 0.10). For alpha = 0.05, beta was >0.93 for the case-control comparisons of the prothrombin, plasminogen activator inhibitor-1, and methylenetetrahydrofolate reductase gene mutations. This indicated that the patients were very similar to the controls in these three comparisons. The prevalences of protein-C, protein-S, and antithrombin-III deficiencies, hyperhomocysteinemia, and elevated plasminogen activator inhibitor-1 activity were also similar between the patients and controls (data not shown).

Discussion

Materials and Methods | Results | Discussion | Acknowledgements | References

Osteonecrosis develops, at least in part, as the end result of reduced blood flow to the femoral head^{1,4,5,7,9,10,24,34-42}. A postulated sequence of venous thrombosis, increased intraosseous venous pressure, reduced arterial flow, and hypoxia appears to be important in the development of ischemic osteonecrosis^{1,4,5,7,9,10,24,34-42}. The thrombophilia-based hypothesis of Legg-Calvé-Perthes disease is predicated on the idea that venous thrombi selectively block outflow from the femoral head, leading to increased intraosseous pressure and subsequent osteonecrosis. Thrombophilia (an increased tendency to form thrombi) and hypofibrinolysis (a reduced ability to lyse thrombi) both appear to play an important role in the pathogenesis of osteonecrosis^{1,3,5,8-10,24,34-42}.

Having initially reported relationships between thrombophilia and hypofibrinolysis and osteonecrosis of the hip and mandible in adults^1,2, Glueck et al. found associations between the G1691A Leiden mutation of the factor-V gene and Legg-Calvé-Perthes disease^3,4,8-10, and they postulated¹⁰ that screening for thrombotic disorders was indicated for patients with Legg-Calvé-Perthes disease and their families. Subsequently, Gruppo et al.⁵ reported finding the G1691A factor-V Leiden mutation in a kindred in which three siblings had Legg-Calvé-Perthes disease. In 2001, Eldridge et al. found "a statistically significant increased risk of Legg Perthes disease with decreasing levels of protein C and a nearly significant increased risk with decreasing levels of protein S."⁷ They also concluded that "abnormalities of the coagulation system leading to a thrombophilic state play a role in Legg-Perthes disease." In 1999, Arruda et al.⁶ reported that the G1691A factor-V Leiden mutation was more common in children with Legg-Calvé-Perthes disease than it was in the general population (5% compared with 1%, p = 0.03)⁶. Finally, in a retrospective study of forty-seven patients with Legg-Calvé-Perthes disease reported in 2004, Szepesi et al.¹² found that five (11%) had the factor-V Leiden mutation; four of the five were homozygous for the mutation and had the most severe form of the disease.

In contrast to these positive associations of the factor-V Leiden mutation with Legg-Calvé-Perthes disease^5-7,10,12, Hresko et al.¹³ found, in a cohort of fifty consecutive patients with Legg-Calvé-Perthes disease, that the proportion of children with the factor-V Leiden mutation (4%) did not differ from the "expected population frequency of 5%."¹³ In a study of forty-four children, Gallistl et al.¹⁴ reported that 7% had resistance to activated protein C and that 2% were protein-C deficient; however, no controls were included in that study. In a comparison between twenty-two children with Legg-Calvé-Perthes disease and twenty-two healthy children matched for age and sex, Sirvent et al.¹⁵ found that one child with Legg-Calvé-Perthes disease (5%) and none of the controls had the factor-V Leiden mutation. Schmitz et al.¹⁷ found the factor-V Leiden mutation in two (10%) of twenty children with Legg-Calvé-Perthes disease as compared with the population estimate of 5% in Germany. It is possible that the studies by Sirvent et al. and Schmitz et al. lacked the power to detect a difference between patients and controls. In a large study in Northern Ireland of 139 children with Legg-Calvé-Perthes disease and 220 age and gender-matched primary-school children, Kealey et al.¹⁶ found no case-control difference in the resistance to activated protein C. However, they did not perform the polymerase chain-reaction cDNA assay for factor-V Leiden mutation. The population in that study¹⁶ had a high incidence of Legg-Calvé-Perthes disease (11.7 per 100,000 children). We speculate that additional factors, as yet unidentified, may be contributing to that high incidence, perhaps masking the contributory effects of the thrombophilic factors that Kealey et al. analyzed.

To our knowledge, the current study is the largest prospective assessment of children with Legg-Calvé-Perthes disease in which the G1691A factor-V Leiden mutation, other thrombophilic genetic polymorphisms, and coagulation measures associated with thrombophilia and hypofibrinolysis were compared with the same parameters in a healthy pediatric control group. The 11% prevalence of the factor-V Leiden mutation in the children with Legg-Calvé-Perthes disease in our study was comparable with the 13% prevalence (eight of sixty-four) in the study by Glueck et al.¹⁰, the 11% prevalence (five of forty-seven) in the study by Szepesi et al.¹², and the 9% prevalence (five of fifty-five) in the study by Eldridge et al.⁷.

Assuming that the prevalence of Legg-Calvé-Perthes disease is as high as that estimated by Kealey et al.¹⁶ (0.0117%) and on the basis of our data on the presence of the G1691A factor-V Leiden mutation and anticardiolipin IgG and IgM antibodies, it can be estimated that the prevalence of Legg-Calvé-Perthes disease is 0.036% when factor-V Leiden mutation is present and 0.028% when the anticardiolipin antibody IgG and/or IgM level is high.

Our finding that the prevalence of IgG and/or IgM levels above or in the ninety-fifth percentile for age-matched controls²² was higher in children with Legg-Calvé-Perthes disease (26%) than it was in our control group (11%) (p = 0.002) is consistent with the findings of previous studies of osteonecrosis of the mandible² and of the hip in adults^24,40. In our study, the odds ratio of Legg-Calvé-Perthes disease being present in individuals with one or more abnormalities in factor V, anticardiolipin antibody IgG, and anticardiolipin antibody IgM as opposed to normal values for all three variables was 3.29 (95% confidence interval, 1.73 to 6.24). The association of thrombophilic conditions with Legg-Calvé-Perthes disease lends support to the hypothesis that venous thrombosis of the capital femoral epiphysis leads to Legg-Calvé-Perthes disease.

In conclusion, the current study confirms^5-7,10,12 that Legg-Calvé-Perthes disease is associated with both familial thrombophilia (factor-V Leiden mutation) and acquired thrombophilia^2,24,40,42 (anticardiolipin antibodies). We believe that discovery of the factor-V Leiden mutation in a patient with Legg-Calvé-Perthes disease should stimulate discussion regarding the value of extended screening of all first-degree family members. Furthermore, better understanding of the associations between thrombophilia and Legg-Calvé-Perthes disease might lead to better treatments, both to shorten the acute phase of the disease in childhood and to possibly reduce adult osteoarthritic sequelae. ?

Acknowledgements

Materials and Methods | Results | Discussion | Acknowledgements | References

Note: The authors thank Ann Becker, BS, Ann Pillow, RN, Marcia Shepherd, RN, and Davis Stroop, MS, for their technical assistance in conducting this study.

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Topics

mutation ; thrombophilia ; antibodies, anticardiolipin ; factor v leiden ; factor v ; legg-perthes disease ; immunoglobulin g ; immunoglobulin m ; protein c

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Vinod V. Balasa, Ralph A. Gruppo, Charles J. Glueck, Ping Wang, Dennis R. Roy, Eric J. Wall, Charles T. Mehlman, Alvin H. Crawford; Legg-Calvé-Perthes Disease and Thrombophilia. The Journal of Bone & Joint Surgery. 2004 Dec;86(12):2642-2647.

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