Osteonecrosis (ON) is commonly differentiated into secondary (eg, due to high-dose corticosteroids or alcohol) and primary idiopathic.1–4 The pathogenesis of ON is multifactorial, but the current authors' estimation is that a pathologic sequence proceeds as follows: venous occlusion causes osseous venous outflow obstruction, leading to increased intraosseous venous pressure, reduced arterial flow, ischemia, bone infarction, and eventual joint collapse.1–4 Experimental models of ON have shown venous occlusion to be the initiating event,5,6 and enoxaparin treatment has been shown to prevent steroid-associated ON in the New Zealand white rabbit ON model.5 Thrombophilia-hypofibrinolysis7 is an underlying etiology of osseous venous occlusion and ON,1,2,4,8 commonly expressed by factor V Leiden heterozygosity,2,7–10 hyperhomocysteinemia,11 anti-cardiolipin (ACLA) immunoglobulin (Ig)M antibodies,12 and high factor VIII.13 Osteonecrosis is also associated with T786C endothelial nitric oxide synthase (eNOS) mutations,14 which reduce nitric oxide production in bone.
Primary ON of weight-bearing joints is conventionally treated in multiple ways: core decompression15 with or without stem cell infusion,16 vascularized fibular graft,17 and/or, ultimately, total joint replacement.18 Newly diagnosed patients with ON19 rarely undergo a workup for thrombophilia-hypofibrinolysis.20 This represents a clinically important missed opportunity because many patients are often treated just for their joint pain21 while an anticoagulant-treatable4,22–25 causative etiology goes unaddressed.20 Because ON is a diagnosis contingent on orthopedic evaluation and imaging,26 the orthopedist is uniquely positioned to recommend that an evaluation for thrombophiliahypofibrinolysis2,4,8 be performed.
Guo et al4 recently reviewed use of anticoagulants for prevention and treatment of femoral head ON22–25 and concluded, in agreement with the current authors' previous studies,22–25 that anticoagulation could be used successfully to halt the progression of primary ON but was not successful in secondary ON.
Chotanaphuti et al27 evaluated 36 patients with bilateral ON, with at least 1 hip pre-collapse, Ficat stage I or II. In 1 study group, 18 patients (26 hips) were anticoagulated with 6000 units of enoxaparin per day for 12 weeks, and a control group (18 patients, 23 hips) received no enoxaparin. All patients were evaluated radiographically every 3 months for 24 or more months. At the last follow-up, 15 (58%) hips from the study group and 5 (22%) hips from the control group remained Ficat I or II (P=.042). Coagulation disorders were observed in 7 (39%) patients of the experimental group and 5 (28%) patients of the control group. Chotanaphuti et al27 concluded that anticoagulation could stop the progression of primary ON if started before joint collapse.
Haydock et al28 recently reported that anticoagulation with enoxaparin (1 mg/kg twice per day) for 6 months and then apixaban (2.5 mg twice per day) for 2 years ameliorated bone pain and entirely stopped progression of ON in a 40-year-old woman with familial hypofibrinolysis and 30% involvement of the distal femur on magnetic resonance imaging (MRI).
Albers et al29 prospectively followed 10 patients with 12 hips with pre-collapse ON who were given aspirin. Osteonecrosis progression occurred in 1 (8%) of 12 patients compared with 30 (67%) of 45 controls at mean follow-up of 3.7 years. Albers et al29 concluded that aspirin might benefit patients with ON if started before joint collapse.
In this study, the authors prospectively assessed long-term anticoagulation outcomes (≥3 years) in 9 patients meeting 4 inclusion criteria: pre-collapse Ficat stage I or II primary ON of hips, factor V Leiden or prothrombin G20210A heterozygosity, no contraindication to anticoagulation, and prior participation in an initial enoxaparin 60 mg/d, Food and Drug Administration–approved protocol for 90 days.25 The primary endpoint was prevention of progression to Ficat stages III and IV (joint collapse). The secondary endpoint was cessation of ON progression. The tertiary endpoint was pain relief. After completion of 90 days of enoxaparin (60 mg/d),25 anticoagulation was continued for 8 patients: 4 receiving warfarin (international normalized ratio targeted to 2 to 2.5), 1 receiving enoxaparin 60 mg twice per day, and 3 receiving novel oral anticoagulants. This study emphasizes the potential clinical benefit4,22–25 in thrombophilic patients with primary ON of the hip when anticoagulation is started before bone collapse (Ficat stages I and II).
Materials and Methods
Signed informed consent was obtained using a protocol approved by the Jewish Hospital Institutional Review Board.
Radiographs were obtained before anticoagulant treatment; while patients were receiving anticoagulants at 3 to 4, 6 to 8, and 12 to 14 months; and then annually. In the first 12 months after study entry, radiographs were reviewed by an orthopedist and radiologist blinded to the patients' clinical and procoagulant status. In the second and subsequent years, they were reviewed by the orthopedist, similarly blinded. Magnetic resonance imaging quantitation of the initial and follow-up percentage of the femoral head involved with ON was not done. The emphasis was on Ficat stage (Ficat I or II by study design before anticoagulant therapy) and presence or absence of collapse of the femoral head on follow-up (Ficat stages III and IV). The Ficat staging system30 was the earliest classification system used in the diagnosis of ON and remains the most widely used system, with more recent addition of MRI to assess the percentage of ON involvement of the femoral head.31
Measures of Thrombophilia-Hypofibrinolysis and the eNOS T786C Mutation
In all patients and controls, after an overnight fast, blood was drawn in the seated position for assessment of thrombophilia-hypofibrinolysis8 and the eNOS T786C mutation.14 Due to diagnostic laboratory testing limitations, not every control or patient could be evaluated for every form of thrombophilia-hypofibrinolysis (Table 1).
Coagulation Disorders and Endothelial Nitric Oxide Synthase Mutations in 240 Patients With Primary Osteonecrosis Compared With 110 Normal Controls
Healthy normal controls without ON or venous thromboembolism, primarily hospital employees, were studied for thrombophilia-hypofibrinolysis (n=110)8 and for eNOS T786C mutations (n=72)14 (Table 1).
The authors excluded patients with secondary ON characterized by high-dose long-term steroids, alcoholics, and those with postarthroscopy ON.32 In the temporal sequence of their referral, 240 patients with idiopathic (primary) hip ON were serially evaluated.
To be included in the study, and before anticoagulation, patients had to meet 4 criteria: primary ON of hips (Ficat stage I or II), factor V Leiden or prothrombin gene G20210A heterozygosity, participation in the authors' initial 90-day enoxaparin treatment protocol,25 and no contraindication to long-term anticoagulation.
During a period of 24 years, the current authors studied 240 patients with primary ON (Table 1), of whom 190 (79%) were found to have thrombophiliahypofibrinolysis. Fifty-eight of these 190 patients had entry Ficat stage I or II ON of the hip(s). Of these 58 patients, there were 8 heterozygous for the factor V Leiden mutation and 1 with the prothrombin G20210A gene mutation. These 9 patients met study entry criteria and had at least 1 hip Ficat stage I or II by radiography at pre-anticoagulation study entry, and they were monitored with serial radiographs at 3 to 4, 6 to 8, and 12 to 14 months after starting anticoagulation and then on an annual basis (Table 2). There were 49 thrombophilic patients with 71 hips Ficat stages I and II by radiography at study entry who did not meet study criteria and were not entered into the anticoagulation study protocol. They were monitored on an annual basis thereafter.
Outcome of Long-term Anticoagulation in 9 Patients—8 Heterozygous for the Factor V Leiden Mutation and 1 Heterozygous for the Prothrombin G20210A Mutation—With Primary Ficat Stage I or II Osteonecrosis of 1 or More Hips Before Anticoagulant Treatment
The 8 patients in the current study heterozygous for the factor V Leiden mutation came from 21 identified as factor V Leiden heterozygotes (Table 1). Eight of the 9 patients were treated with long-term (12 years on average) anticoagulation (Table 2). One of the 9 patients (patient 9; Table 2), received only enoxaparin for 3 months and no further anticoagulation. Anticoagulation medication therapies were based on third-party insurers' coverage. Patients' activities were not restricted.
Hip ON was staged by radiography as per Ficat30 by readers who were blinded to the patients' clinical statuses and responses to therapy.
Follow-up of anticoagulated ON patients was done by direct clinical evaluation at the authors' research center every 3 to 6 months for those patients who lived in the area. For out-of-town patients, follow-up by email and phone was done every 3 to 6 months. Complete blood count and platelet count was done every 6 months, along with case-by-case review of any clinically significant bleeding.
Initial treatment with enoxaparin for patients with thrombophilia-hypofibrinolysis was restricted by a Food and Drug Administration–approved protocol25 to 60 mg/d for 3 or more months (Table 2). Additional enoxaparin treatment courses were administered for 2 patients (patients 3 and 4; Table 1). One patient (patient 9) received only enoxaparin 60 mg/d for 3 months, without subsequent anticoagulation (Table 2). After completion of the 90-day enoxaparin protocol, patients 1, 2, 5, and 6 received warfarin (international normalized ratio targeted to 2 to 2.5) due to restrictions imposed by third-party medical insurers (Table 1). For patients 3, 7, and 8, after initial enoxaparin treatment, novel oral anticoagulants dabigatran, apixaban, or rivaroxaban were given long term when covered by medical insurance (Table 2). The choice of anticoagulant agents was limited by requiring availability of third-party medical insurance to pay for anticoagulation.
Case-control differences in coagulation measures were assessed by Fisher's exact test.
Thrombophilia, Hypofibrinolysis, and the eNOS T786C Mutation in 240 Patients With Primary Osteonecrosis
Table 1 displays only those coagulation abnormalities and eNOS T78C genotypes that differed (P<.05) between cases and controls. Cases were more likely to be heterozygous for the factor V Leiden mutation (9% vs 2%, P=.0180) and to have high homocysteine (15% vs 5%, P=.005), high ACLA IgM antibody (13% vs 2%, P=.0007), high factor VIII (27% vs 7%, P<.0001), and homo-heterozygosity for the eNOS T786C mutation (65% vs 39%, P<.0001) (Table 1).
Of the 21 cases heterozygous for the factor V Leiden mutation (Table 1), 8 were eligible for, and all 8 eligible patients participated in, the current long-term anticoagulation study (Table 2).
Response to Anticoagulation
Of the 13 hips (Ficat stage I or II at entry), 12 remained unchanged (Ficat stage I or II) after 12±5 years (range, 5.5–21 years) of follow-up (Table 1). In 1 (patient 7), the left hip, Ficat stage II pretreatment, was read as normal after 5.5 years of anticoagulation (Table 2).
Of the 3 hips with pretreatment collapse (Ficat stages III and IV), 1 remained unchanged (patient 1) and 2 were replaced (total hip arthroplasty [THA]; patients 6 and 9; Table 2).
Six patients (patients 1, 3, 4, 5, 7, and 9) became symptom free after the first 3 months receiving enoxaparin, 1 (patient 8) was asymptomatic after 6 months of anticoagulation, and 1 (patient 6) was asymptomatic after 10 months of anticoagulation (Table 2). These 6 patients remained asymptomatic throughout subsequent follow-up on anticoagulation (Table 2).
One patient (patient 2) had no change in his Ficat stage I ON during 11.5 years in his right hip but had persistent symptoms requiring oxycodone and acetaminophen (Table 2).
Safety of Long-term Anticoagulation
None of the 9 patients had clinically significant bleeding requiring medical attention or cessation of anticoagulation.
Osteonecrosis Outcome for 49 Patients With Ficat Stage I or II Primary Osteonecrosis and Thrombophilia-Hypofibrinolysis at Study Entry Who Did Not Meet Study Entry Criteria and Did Not Receive Anticoagulation
Annual follow-up was obtained for 32 of those 49 patients with Ficat stage I or II primary ON and thrombophilia-hypofibrinolysis at study entry who were not entered into the anticoagulation study protocol. Of 51 hips (initially Ficat stage I or II) in these 32 patients, 31 (61%) had collapsed after mean follow-up of 3.5 years.
Osteonecrosis of the hip is not a common cause of hip arthralgia,33 and the disease process of ON is poorly understood by many clinicians. Although the prevalence of early-stage (pre-joint collapse) primary ON is probably relatively low,34 approximately 20,000 cases per year in the United States, the diagnosis of ON should be considered. The current authors have previously shown,22–25 and now show in a larger treatment group for a longer anticoagulation treatment period, that long-term anticoagulation in patients with familial thrombophilia (factor V Leiden, prothrombin gene heterozygosity) and with primary pretreatment Ficat stage I or II hip ON often prevents joint collapse and often provides complete symptomatic relief. Of the 13 hips in 9 patients that were pre-collapse Ficat stage I or II pretreatment, 12 remained unchanged (still Ficat stage I or II) during 5.5 to 21 years of follow-up on anticoagulant treatment, and 1 reverted to normal by radiograph. Eight of the 9 patients became completely asymptomatic, and none of the 9 restricted their habitual physical or exercise activity during 12 years of follow-up. This long-term joint preservation without collapse should be viewed within the frame of reference of the natural course of ON, with joint collapse and total joint replacement in 60% to 80% of untreated patients within 2 years of original diagnosis.35–38 Hernigou et al39 prospectively studied 40 asymptomatic hips with ON lesions not seen on plain radiographs at study entry and reported that 73% demonstrated collapse after a mean of 7.7 years. In the current study, in 32 of 49 patients with Ficat stage I or II primary ON and thrombophilia-hypofibrinolysis at study entry not entered into the study protocol but who could be followed annually, 61% of hips had collapsed during a mean follow-up of 3.5 years. Mont et al36 reported that “untreated asymptomatic osteonecrosis has a high prevalence of progression to symptomatic disease and femoral head collapse.” Sultan et al40 concluded that “left untreated, the natural history of the disease is progressive collapse of the femoral head and destruction of the joint with substantial pain and disability.”
Multiple studies cited by Chen et al41 have shown that the likelihood of collapse varies with the percentage involvement of the femoral head by MRI, with up to 87% collapse when 50% of the femoral head is necrotic.
Safety was documented by the absence of any clinically significant bleeding events during the 5.5- to 21-year anticoagulant therapy period. Although there were no clinically significant bleeding episodes during long-term anticoagulation4,22–25 in the current 9 patients, this requires careful surveillance because long-term anticoagulation has possible serious complications. The recent availability of novel oral anticoagulants42 and the new availability of the reversal agent andexanet alfa,43 a targeted antidote to stop novel oral anticoagulant–associated clinically significant bleeding,44 should make long-term anticoagulation safer.
As shown in this study and previously,1–3,20 patients with primary ON have more frequent thrombophilia-hypofibrinolysis than healthy normal controls and are also more likely to have eNOS T786 hetero-homozygosity, associated with reduced intraosseous nitric oxide production.2 Documentation that thrombophilia-hypofibrinolysis treated with anticoagulation stops the otherwise inexorable progression of untreated ON35–38 emphasizes the importance of testing for thrombophilia-hypofibrinolysis in patients with primary ON. This represents a unique opportunity because primary ON associated with familial thrombophilia is treatable with anticoagulation4,22–25 started before joint collapse.1,2,4,7,9 The major clinical barrier to reaching this therapeutic benefit is the lack of awareness of the opportunity to anticoagulate4,22–25 patients with thrombophilia-hypofibrinolysis and Ficat stage I or II primary ON.1,2,7,9 An additional potential benefit of diagnosis of thrombophilia-hypofibrinolysis in ON is preoperative recognition of increased risk of postoperative deep venous thrombosis and/or pulmonary embolism in cases with hypercoagulability.45 The current authors do not know whether treatment with L-arginine to increase intraosseous nitric oxide would benefit ON patients heterohomozygous for the eNOS T786C mutation.2
The current study was limited by the small number of patients (N=9) and by the use of differing anticoagulant drugs and doses, primarily dictated by which anticoagulant drugs were approved for long-term use by third-party payers. The study was limited by not having serial measurement of the ON lesion size by MRI as a predictor of progression to collapse.41 However, there was no progression from Ficat stages I and II to joint collapse in 13 hips in the current 9 anticoagulated patients during an average of 12 years of follow-up, whereas there was 61% progression from Ficat stages I and II to collapse during 3.5 years in 32 subjects with primary ON and thrombophilia not entered into the anticoagulation protocol. The current study was further limited by not having a randomized, double-blind structure, but the number of patients required for such a placebo-controlled trial was well beyond the authors' capability, especially because it would be necessary to stratify on the underlying coagulation disorder: anticoagulated case vs placebo case with both having only factor V Leiden heterozygosity, and anticoagulated case vs placebo case with both having prothrombin G20210A gene heterozygosity.
The risks and benefits of long-term anticoagulation in patients with idiopathic ON, familial thrombophilia, and Ficat stage I or II ON need to be balanced against therapeutic THA, including consideration of the longevity of the hip implant and the need for revision over time. In 63,158 patients who had undergone THA and were followed for a maximum of 20 years; the 10-year implant survival rate was 95.6% (95% confidence interval [CI], 95.3–95.9) and the 20-year rate was 85.0% (95% CI, 83.2–86.6).46 However, “lifetime risk of revision increased for younger patients, up to 35% (95% CI, 30.9–39.1) for men in their early 50s, with large differences seen between male and female patients (15% lower for women in same age group). The median time to revision for patients who had surgery younger than age 60 was 4.4 years.”46 In the current study, 5 patients were younger than 50 years (patients 29, 32, 48, 48, and 49), 2 were 56 and 58 years old, 1 was 62 years old, and 1 was 69 years old. The hypofibrinolytic woman with primary ON successfully anticoagulated by Haydock et al28 was 40 years old. Within this frame of reference, especially for those thrombophilic patients in their 50s and younger46 and in thrombophilic patients at increased risk for post-THA venous thromboembolism,45 long-term anticoagulant therapy with preservation of the native hip may offer a therapeutic alternative to THA.
During 12±5 years (range, 5.5–21 years) of anticoagulation, of 9 patients' 13 primary osteonecrotic hips in the current study (Ficat stage I or II at entry), none collapsed (Ficat stage III or IV) or required surgical intervention. Eight of the 9 patients became asymptomatic. Anticoagulation in primary ON of the hip in patients with entry Ficat stage I or II ON, familial thrombophilia (factor V Leiden, prothrombin G20210A gene heterozygosity), and no contraindication to anticoagulation can change the natural history of ON where most untreated patients have hip collapse and total joint replacement within 2 years of original symptoms.
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- Glueck CJ, Freiberg RA, Boppana S, Wang P. Thrombophilia, hypofibrinolysis, the eNOS T-786C polymorphism, and multifocal osteonecrosis. J Bone Joint Surg Am. 2008;90(10):2220–2229.
- Glueck CJ, Freiberg RA, Wang P. Heritable thrombophilia-hypofibrinolysis and osteonecrosis of the femoral head. Clin Orthop Relat Res. 2008;466(5):1034–1040. doi:10.1007/s11999-008-0148-0 [CrossRef]
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- Beckmann R, Shaheen H, Kweider N, et al. Enoxaparin prevents steroid-related avascular necrosis of the femoral head. Scientific World Journal. 2014;2014:347813. doi:10.1155/2014/347813 [CrossRef] PMID:25110730
- Boss JH, Misselevich I. Osteonecrosis of the femoral head of laboratory animals: the lessons learned from a comparative study of osteonecrosis in man and experimental animals. Vet Pathol. 2003;40(4):345–354. doi:10.1354/vp.40-4-345 [CrossRef]
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- Björkman A, Svensson PJ, Hillarp A, Burtscher IM, Rünow A, Benoni G. Factor V Leiden and prothrombin gene mutation: risk factors for osteonecrosis of the femoral head in adults. Clin Orthop Relat Res. 2004;(425):168–172. doi:10.1097/00003086-200408000-00023 [CrossRef] PMID:15292803
- Glueck CJ, Freiberg R, Glueck HI, Tracy T, Stroop D, Wang Y. Idiopathic osteonecrosis, hypofibrinolysis, high plasminogen activator inhibitor, high lipoprotein(a), and therapy with Stanozolol. Am J Hematol. 1995;48(4):213–220.
- Glueck CJ, Smith D, Gandhi N, Hemachandra K, Shah P, Wang P. Treatable high homocysteine alone or in concert with five other thrombophilias in 1014 patients with thrombotic events. Blood Coagul Fibrinolysis. 2015;26(7):736–742. doi:10.1097/MBC.0000000000000276 [CrossRef]
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- Glueck CJ, Freiberg RA, Oghene J, Fontaine RN, Wang P. Association between the T-786C eNOS polymorphism and idiopathic osteonecrosis of the head of the femur. J Bone Joint Surg Am. 2007;89(11):2460–2468.
- Sadile F, Bernasconi A, Russo S, Maffulli N. Core decompression versus other joint preserving treatments for osteonecrosis of the femoral head: a meta-analysis. Br Med Bull. 2016;118(1):33–49. doi:10.1093/bmb/ldw010 [CrossRef]
- Gangji V, Toungouz M, Hauzeur JP. Stem cell therapy for osteonecrosis of the femoral head. Expert Opin Biol Ther. 2005;5(4):437–442. doi:10.1517/147125220.127.116.117 [CrossRef]
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- Lee GW, Park KS, Kim DY, Lee YM, Eshnazarov KE, Yoon TR. Results of total hip arthroplasty after core decompression with tantalum rod for osteonecrosis of the femoral head. Clin Orthop Surg. 2016;8(1):38–44. doi:10.4055/cios.2016.8.1.38 [CrossRef]
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Coagulation Disorders and Endothelial Nitric Oxide Synthase Mutations in 240 Patients With Primary Osteonecrosis Compared With 110 Normal Controlsa
|Subject||Factor V GA, AA||Homocysteine μmol/Lb||ACLA IgM, MPLc||Factor VIII >150%||eNOS GA,AAd|
|Patients with primary ON (N=240), No./total no.||21/235 (9%)||32/212 (15%)||27/209 (13%)||47/175 (27%)||90/138 (65%)e|
|Normal controls (N=110), No./total no.||2/109 (2%)||5/107 (5%)||2/109 (2%)||7/103 (7%)||28/72 (39%)g|
Outcome of Long-term Anticoagulation in 9 Patients—8 Heterozygous for the Factor V Leiden Mutation and 1 Heterozygous for the Prothrombin G20210A Mutation—With Primary Ficat Stage I or II Osteonecrosis of 1 or More Hips Before Anticoagulant Treatment
|Patient No./Race/Sex/Age, y||Thrombophilia||Anticoagulant Treatment||Original Ficat Stage||Follow-up Ficat Stage||Pain Relief||Follow-up, y|
|1/White/M/32||Factor V heterozygous||Enoxaparin 60 mg QD 3 mo, then warfarin, INR target 2 to 2.5||RII
LIII-IV||Asymptomatic in 3 mo, right hip, remained asymptomatic||21|
|2/White/M/48||Factor V heterozygous
PAI-1 gene homozygous||Enoxaparin 60 mg QD 3 mo, then warfarin INR target 2 to 2.5||RII
LII||Symptoms persistent requiring acetaminophen and oxycodone||11.5|
|3/White/M/56||Factor V heterozygous
MTHFR C677T homozygous||Enoxaparin 60 mg QD (4 × 3–mo courses from 2009 to 2010), then dabigatran 150 mg QD in November 2011 for 6 mo, then apixaban 5 mg/d||RII
LI||Asymptomatic in 3 mo, remained asymptomatic||10|
|4/White/F/29||Factor V heterozygous||Enoxaparin 60 mg QD, then 60 mg BID||RI||RI||Asymptomatic in 3 mo, remained asymptomatic||11.5|
|5/White/M/49||Factor V heterozygous
MTHFR C677T homozygous||Enoxaparin 60 mg QD 3 mo, then warfarin INR target 2 to 2.5||RII
LII||Asymptomatic in 3 mo, remained asymptomatic||14.5|
|6/Black/F/69||Factor V heterozygous||Enoxaparin 60 mg QD 3 mo, then warfarin INR target 2 to 2.5||RII
LTHR||Asymptomatic right hip in 10 mo, remained asymptomatic||13|
|7/White/F/48||Prothrombin G20210A mutation heterozygous||Enoxaparin 60 mg QD (2 courses in February 2013, December 2013), then rivaroxaban 10 mg/d since March 2014||RII
L normal||Asymptomatic in 3 mo, remained asymptomatic||5.5|
|8/White/F/58||Factor V heterozygous
MTHFR C677T homozygous Hyperhomocysteinemia||Enoxaparin 60 mg QD 3 mo, then apixaban 5 mg/d||LI||LII||Asymptomatic in 6 mo, remained asymptomatic||6|
|9/White/M/62||Factor V heterozygous||Enoxaparin 60 mg QD 3 mo||RI
LTHR||Asymptomatic in 3 mo||18|
|13 hips Ficat stage I or II pretreatment||12 hips Ficat stage I or II and 1 normal on treatment||Mean follow-up 12±5 y (range, 5.5–21 y); 8 of 9 patients became asymptomatic|