THE JEWISH HOSPITAL RESEARCH COUNCIL

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1 THE JEWISH HOSPITAL RESEARCH COUNCIL 1 1. TITLE: Heritable defects in thrombophilia-hypofibrinolysis and avascularaseptic necrosis of the hip, diagnosis and therapy with low molecular weight heparin or Xarelto (04-14-Revised 1/14/14) 2. DATE OF STUDY SUBMISSION: 1/14/14, Revision of previously approved protocol 04-14, and PRINCIPAL INVESTIGATORS: Cholesterol Center Staff: C.J. Glueck MD, James E. Lang MD, Ping Wang PhD Orthopedic staff: Richard A Freiberg MD, Cincinnati VA Medical Center Jewish Hospital Medical Residents: Caitlin Richardson-Royer, Brittany Forshay MD, Rajiv Sharma MD, Domonique Smith MD, Ahsan Hafeez MD, Atif Hassan MD, 4. PROTOCOL ATTACHED YES X NO 5. INSTITUTIONAL REVIEW COMMITTEE APPROVED: YES X PENDING 6. FINANCIAL STATEMENT ATTACHED: YES X NO 7. LENGTH OF STUDY: 1 YEARS 8. SUM REQUESTED PER ANNUM: $ TOTAL SUM REQUESTED: $ Personnel covered under overall Cholesterol Center Requests 1

2 II. RESEARCH PROTOCOL: 2 2A: Background/Rationale for study: Our studies 1-23,44-51 show that > 85% of adults and children with osteonecrosis of the hip or jaw have inherited thrombophilia (increased risk of thrombus [clot] formation) or hypofibrinolysis (decreased ability to lyse thrombi). Often, "environmental" factors which increase the likelihood of thrombosis (exogenous estrogens, corticosteroids), when superimposed on underlying heritable thrombophilia or hypofibrinolysis, sharply increase the risk of thrombosis. Previously, the only known therapies for osteonecrosis included core decompression (drilling a hole in the head of the femur) and vascularized fibular grafting (drilling a hole in the head of the femur, mobilizing a vascularized fragment of the tibia and inserting it in the head of the femur). Previously, in most cases, however, irrespective of the mode of therapy, the osteonecrosis progresses to segmental collapse of the head of the femur, requiring surgery for insertion of a hip prosthesis. Hip replacement for osteonecrosis is currently being done in 40,000 patients/year (estimated cost $30,000/hip), with another 80,000 having various stages of disease not yet requiring hip replacement. Our studies in adults with osteonecrosis of the hip have shown that, provided that anticoagulant therapy for thrombophilia with low molecular weight heparin is started before irreversible collapse of the head of the femur, osteonecrosis can be arrested or reversed 7,16,18,22,44, Thus, inexpensive anticoagulant therapy with low molecular weight heparin has been shown to arrest the progress of, or reverse osteonecrosis in about 75% of cases, avoiding the necessity for surgical hip replacement, and revolutionizing the therapy of osteonecrosis. 7,16,18,22,44,49-51 Our work has, in aggregate, provided the following entirely new scientific information regarding the diagnosis and therapy of osteonecrosis: Prior to the recent recognition that osteonecrosis is commonly caused by disorders of coagulation, osteonecrosis was characterized as "idiopathic" (cause[s] unknown), and "secondary" Diseases and drugs which were known to cause "secondary" osteonecrosis included corticosteroids, alcoholism, trauma, hemoglobinopathies, "bends" (Caisson disease), systemic lupus erythematosus, Gaucher's disease, sickle cell disease and disseminated intravascular coagulation, etc). About 90% of patients with what had, heretofore, been termed "idiopathic" osteonecrosis in adults or Legg-Perthes disease in children have an underlying pathogenetic coagulation disorder 1,5,7,9,11-16,18,22, Similarly, about 80% of patients with what had previously been termed "secondary" osteonecrosis have a disease or drug thought to cause osteonecrosis superimposed on an underlying coagulation disorder. Based on our studies in the hip and jaw, and those of other investigators 1-23,44-51, we 2

3 postulate that thrombophilia and/or hypofibrinolysis lead to osteonecrosis via the following pathways: 1. Persistent thrombi block venous drainage of bone. The exact cause and timing of the initial thrombus formation remains conjectural. 2. With venous drainage of the bone impaired by thrombi, but with arterial blood influx continuing, venous pressure in the occluded bone compartment rises. This (speculatively) leads to reduced arterial perfusion, anoxia, and subsequent bone death (osteonecrosis). 3. In the early stages of venous occlusion, there is "bone marrow edema" which can be diagnosed by MRI. This progresses to early stages of osteonecrosis (Ficat stages I and II) which appear to be reversible by correction of the underlying coagulation problems. More advanced stages of osteonecrosis (Ficat III,IV) appear to be irreversible by treatment of the coagulation disorders, since they involve segmental collapse of the head of the femur and secondary arthritis. Our studies in 295 adults and children with osteonecrosis of the hip, knee, or jaw have begun to illuminate the pathogenetics of osteonecrosis. 1-23,44-51 The majority (about 80%) of patients with osteonecrosis have thrombophilia (increased likelihood of thrombosis) and/or hypofibrinolysis (reduced ability to lyse thrombi). Thrombophilia and hypofibrinolysis are transmitted as autosomal dominant traits, although their effects can be amplified by diseases and drugs. The major heritable thrombophilic and hypofibrinolytic disorders pathogenetic for osteonecrosis are as follows: 3 3

4 4 Thrombophilic Disorders: Hetero- and [rarely] homozygosity of the mutant Factor V Leiden Gene with Resistance to activated protein C. This is the most common thrombophilia associated with osteonecrosis. A defect in the procoagulant protein, Factor V, does not allow binding by activated protein C, leading to unopposed procoagulant activity and increased risk of venous thrombosis. Activated protein C resistance (APCR) can be amplified by exogenous estrogens (oral contraceptives, post-menopausal estrogen supplementation). Heterozygosity or homozygosity for the mutant Factor V Leiden is now routinely examined in our laboratories by CDNA PCR assays. G20210A Mutation of the prothrombin gene. Heterozygosity for the prothrombin gene mutation is a recognized cause of osteonecrosis. High Factors VIII and XI: Familial high Factors VIII and XI are recognized causes of osteonecrosis. Protein C deficiency: When protein C is deficient, factor V is inadequately suppressed, leading to increased procoagulant activity and increased risk of venous thrombosis. The thrombotic tendency in protein C deficiency can be amplified by exogenous estrogens and by pregnancy. Protein S deficiency: Protein S is a cofactor for protein C. When protein S is deficient, factor V is not adequately suppressed, leading to increased procoagulant activity and increased risk of venous and arterial thrombosis. Anticardiolipin Antibodies and the Lupus Anticoagulant: Anticardiolipin antibodies (ACLA) and the Lupus anticoagulant are antiphospholipid autoantibodies which are directed against negatively charged phospholipid antigens. Anticardiolipin antibodies and the Lupus anticoagulant are prothrombotic by a variety of mechanisms including inhibition of prostacyclin synthesis, impairment of the thrombomodulin-protein C-protein S anticoagulant system, acting as anti-endothelial cell antibodies, or interacting with platelet membrane phospholipids. ACLA and the Lupus anticoagulant are associated with both venous and arterial thrombi. Polymorphism of the MTHFR gene: Homozygosity for this common polymorphism controls serum levels of homocysteine, a major thrombophilic risk factor. Hypofibrinolysis: Low stimulated tissue plasminogen activator activity (tpa-fx) often accompanied by high plasminogen activator inhibitor activity (PAI-Fx): There is an excess of the major inhibitor of fibrinolysis, PAI-Fx, so that the major stimulator of fibrinolysis, tpa-fx, cannot be activated; the process of lysis of thrombi cannot begin, or is slowed. High plasma 4

5 triglycerides and/or hyperinsulinemia can increase PAI-Fx, causing a decrease in tpa-fx. The 4G4G and 4G5G polymorphisms of the PAI gene are now routinely examined in our laboratories by CDNA PCR assays. High lipoprotein (a) [Lp(a)]: In the closed space of bone, we believe that high Lp(a) may reduce fibrinolysis. The apparent hypofibrinolytic action of Lp(a) in bone appears to be augmented by corticosteroid therapy. Preclinical and prior clinical studies: 1: Glueck CJ, Richardson-Royer C, Schultz R, Burger T, Labitue F, Riaz MK, Padda J, Bowe D, Goldenberg N, Wang P. Testosterone, thrombophilia, and thrombosis. Clin Appl Thromb Hemost Jan;20(1): doi: / Epub 2013 Apr 23. PubMed PMID: : Glueck CJ, Freiberg RA, Boriel G, Khan Z, Brar A, Padda J, Wang P. The role of the factor V leiden mutation in osteonecrosis of the hip. Clin Appl Thromb Hemost Sep;19(5): doi: / Epub 2012 Jun 12. PubMed PMID: : Glueck CJ, Bowe D, Valdez A, Wang P. Thrombosis in three postmenopausal women receiving testosterone therapy for low libido. Womens Health (Lond Engl) Jul;9(4): doi: /whe PubMed PMID: : Glueck CJ, Goldenberg N, Budhani S, Lotner D, Abuchaibe C, Gowda M, Nayar T, Khan N, Wang P. Thrombotic events after starting exogenous testosterone in men with previously undiagnosed familial thrombophilia. Transl Res Oct;158(4): doi: /j.trsl Epub 2011 Jun 23. PubMed PMID: : Glueck CJ, McMahon RE, Bouquot JE, Khan NA, Wang P. T-786C polymorphism of the endothelial nitric oxide synthase gene and neuralgia-inducing cavitational osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endod Apr;109(4): doi: /j.tripleo Epub 2010 Feb 24. PubMed PMID:

6 6: Glueck CJ, Freiberg RA, Boppana S, Wang P. Thrombophilia, hypofibrinolysis, the enos T-786C polymorphism, and multifocal osteonecrosis. J Bone Joint Surg Am Oct;90(10): doi: /JBJS.G PubMed PMID: : Glueck CJ, Freiberg RA, Wang P. Heritable thrombophilia-hypofibrinolysis and osteonecrosis of the femoral head. Clin Orthop Relat Res May;466(5): doi: /s Epub 2008 Mar 19. PubMed PMID: ; PubMed Central PMCID: PMC : Bouquot JE, McMahon RE, Glueck CJ. Bone marrow edema: mild or nascent variant of ischemic bone disease. J Oral Maxillofac Surg Jan;66(1): PubMed PMID: : 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 Nov;89(11): PubMed PMID: : Glueck CJ, Tracy T, Wang P. Legg-Calve-Perthes disease, venous and arterial thrombi, and the factor V Leiden mutation in a four-generation kindred. J Pediatr Orthop Oct-Nov;27(7): PubMed PMID: : McMahon RE, Bouquot JE, Glueck CJ, Griep JA, Adams WR, Spolnik KJ, Deardorf KA. Staging bisphosphonate-related osteonecrosis of the jaw should include early stages of disease. J Oral Maxillofac Surg Sep;65(9): PubMed PMID: : McMahon RE, Bouquot JE, Glueck CJ, Griep J. Beyond bisphosphonates: thrombophilia, hypofibrinolysis, and jaw osteonecrosis. J Oral Maxillofac Surg Nov;64(11): PubMed PMID: : Glueck CJ, Freiberg RA, Sieve L, Wang P. Enoxaparin prevents progression of stages I and II osteonecrosis of the hip. Clin Orthop Relat Res Jun;(435): PubMed PMID: : Balasa VV, Gruppo RA, Glueck CJ, Wang P, Roy DR, Wall EJ, Mehlman CT, Crawford AH. Legg-Calve-Perthes disease and thrombophilia. J Bone Joint Surg Am. 6

7 2004 Dec;86-A(12): PubMed PMID: : McMahon RE, Bouquot JE, Glueck CJ, Spolnik KJ, Adams WR. Osteonecrosis: a multifactorial etiology. J Oral Maxillofac Surg Jul;62(7): PubMed PMID: : Jones LC, Mont MA, Le TB, Petri M, Hungerford DS, Wang P, Glueck CJ. Procoagulants and osteonecrosis. J Rheumatol Apr;30(4): PubMed PMID: Overall summary of data to date: Overall, the data show that 85% of patients with osteonecrosis of the hip have heritable thrombophilia and/or hypofibrinolysis as major pathoetiologies of their disease. Provided that the coagulation disorder can be diagnosed before segmental collapse of the head of the femur (i.e., in Ficat stages I or II), then weeks of low molecular weight heparin therapy is effective in stopping the progression of the osteonecrosis and even in reversing it. Hence, low molecular weight heparin therapy for early osteonecrosis of the hip has the potential to stop and reverse the osteonecrosis medically in 82% of cases, thus saving the hip from surgical replacement. Most recently, we have shown in subjects with the Factor V Leiden mutation, that long term continuous anticoagulation (up to 16 years) can stop the progression of osteonecrosis and prevent the need for total hip replacement. Glueck CJ, Freiberg RA, Wang P. Treatment of osteonecrosis of the hip and knee with Enoxaparin. In Koh, KH editor: Osteonecrosis, Diagnosis and Treatment, In Press, B. Objectives: Our first specific aim in adults only, is to determine whether and to what degree anticoagulant therapy with low molecular weight heparin (Enoxaparin 1.5 mg/kg/day in two divided doses) followed by Xarelto will ameliorate avascular necrosis of the hip or prevent its progress, in adults with thrombophilic disorders (cf Time Line, page 20) We will continue to examine the efficacy and safety of therapy for thrombophilia and hypofibrinolysis in adults for arresting the progress of and reversing osteonecrosis. Although Enoxaparin therapy is equally effective in therapy of osteonecrosis of the jaw, endpoints of therapy (change in pain, change in bone scan, X-ray, etc) are 7

8 harder to judge 49, and we will focus on osteonecrosis of the hip and knee, as well as multifocal osteonecrosis. 50,51 A second specific aim of this pilot study will be to gather enough data on safety, efficacy, and the time course of improvement with Enoxaparin followed by Xarelto to allow a subsequent placebo-controlled, multicenter, controlled clinical trial of anticoagulation therapy in osteonecrosis of the hip. 8 2C. Methods 2C1: Study Design: The overall study design is summarized in the attached timeline (page 20). 2C1A, Patients: Over the next 48 months, we plan to continue our study of the safety and efficacy of Enoxaparin in the therapy of osteonecrosis in patients before segmental collapse of the head of the femur (Ficat Stages I, II), or segmental collapse of the knee.. In all patients, we will measure thromophilic and hypofibrinolytic variables. 1-22,44-51 In new patients, we will use the following protocol: 2C1B: First, a single blood sample taken (30 ml, about 7 teaspoonsful). Then, laboratory tests will be done on this blood sample to see if there is a clotting problem which might be causing the osteonecrosis. If there is no clotting problem which might be causing the osteonecrosis, then participation in the research protocol is finished. Only in those adults who have both osteonecrosis of the hip or knee, which has not collapsed (Ficat Stages III-IV) and a specific blood clotting problem, we may recommend the following: 2C1C: Low Molecular Weight Heparin (Lovenox) Therapy: The following dose schedule will be used, linked to patient weight: 1.5 mg/kg/day in two divided doses. As in the past, this will be given for 3 months, with baseline X-ray and MRI, and follow-up X-ray and MRI after 3 months therapy If, after 3 months on Lovenox, there is no improvement in pain, or if there is progression to Ficat stage III or IV (joint collapse), then there will be no further anticoagulant therapy (Time line, page 20). If, after 3 months of Lovenox, pain is substantially reduced, and if there is no progression to Ficat stage III or IV, then we will follow-up with 3 months therapy with Xarelto 20 mg. X ray and MRI will be repeated after the 3 8

9 months on Xarelto, 6 months from the start of the study (Time line, page 20). 9 2C1D: In cases where medical insurance will not cover the cost of Lovenox, or there are practical difficulties with Lovenox injections twice per day, then we will use Xarelto 20 mg/day. 2C1E: Inclusion Criteria: Patients must have the following: I. Primary osteonecrosis of the hip, i.e., not associated with alcoholism, sickle cell disease, Gaucher's disease, trauma, post-radiation syndromes. II. Osteonecrosis graded at Ficat Stage I or II by MRI and X-ray. Ficat Stages I or II means that the head of femur (the major bone of the upper leg) has not collapsed. This is very important, because our previous work has shown that if segmental collapse of the head of the femur has already occurred (Ficat Stages III, IV), then medical therapy with low molecular weight heparin will not stop or reverse the osteonecrosis. III. A well defined blood clotting disorder. The coagulation disorders which will be measured, and which will warrant inclusion, are > 1 of the following: Thrombophilic disorders: Hetero- or homozygosity for the Factor V Leiden mutation or the prothrombin gene mutation, homozygosity for the MTHFR mutation. Anticardiolipin antibodies or the Lupus anticoagulant, deficiency in proteins C, S, or antithrombin III. Hypofibrinolytic disorders: Homozygosity for the 4G/4G mutation of the PAI-1 gene and/or plasminogen activator inhibitor activity (PAI-Fx) levels > normals' 95th percentile (>22 U/L); Lp(a) >35 mg/dl. IV. Ability and willingness to participate in the 12 week Lovenox or Xarelto treatment period, 3 outpatient visits (every 4 weeks) over a 12 week period, with a subsequent 12 Xarelto follow-up period for those subjects with a positive response to Lovenox and familial thrombophilia (Time line, page 20). 2C1F: Exclusion Criteria: Any medical condition which would contraindicate anticoagulation with 9

10 Lovenox or Xarelto including the following: uncontrolled hypertension, uncontrolled diabetes, active esophageal, stomach, or duodenal ulcers, active Crohn's disease, active ulcerative colitis, any known bleeding disorder of the bowel (diverticulitis, colonic polyposis), deficiency of platelets, any intracranial mass lesions, cancer, metastatic cancer, uncontrolled severe psychiatric disease (major depression, schizophrenia, etc). 10 2C1G: Evaluation methods: At the first visit, a full battery of coagulation tests will be obtained, along with physical examination, and laboratory safety tests. It is anticipated that diagnostic X rays and MRIs will have been obtained by the referring Orthopedist before the first visit to the Cholesterol Center. After completion of Visit 1, and assessment of the coagulation and safety data, and review of inclusion and exclusion criteria, patients who are eligible for Lovenox intervention will return for Visit 2, three weeks after Visit 1. At Visit 2, Lovenox will be started in eligible patients who will then return for re-evaluation every 4 weeks for 12 weeks. At each of the 3 follow-up visits, blood will be obtained for complete blood count and platelet count. Weight and blood pressure will be measured; a brief history and physical examination will be carried out. After 12 weeks on Lovenox, repeat X rays and MRIs of both hips or knees will be obtained to allow an anatomic comparison between pre- and posttreatment bone architecture (Time line, page 20). For those subjects transitioning on to Xarelto, after a positive response to Lovenox, after 12 weeks on Xarelto, repeat X rays and MRIs will be obtained (Time line, page 20). 2C1H: Endpoints-efficacy: After the initial 12 weeks on Lovenox a second X ray and MRI of both hips and knees will be obtained to assess the anatomic status of the osteonecrosis. For those subjects transitioning to 12 weeks therapy with Xarelto, repeat X rays and MRIs will be done after 12 weeks on Xarelto, and then X rays will be repeated once a year thereafter for a total of 5 years (Time line, page 20). 2C1I: Endpoints-safety: 1. Complete blood count and platelet count. Development of medically 10

11 significant anemia or a below normal platelet count will lead to discontinuation of therapy. Development of clinically significant bleeding for any reason (gastric, colon, urinary tract, etc) will lead to discontinuation of therapy. 2. Brief interval history and physical examination. Evidence of clinically significant internal or external bleeding will lead to discontinuation of therapy. 3. Allergy to the low molecular weight heparin or Xarelto will lead to discontinuation of therapy. 11 2C1J: Risks and Precautions: The following foreseeable risks and discomforts are involved in this study. One minor potential risk of the study involves the process of taking blood. This includes commonly, the occurrence of discomfort and/or bruise at the site of puncture; and less commonly, the formation of a small blood clot or swelling of the vein and surrounding tissue, and bleeding from the puncture site. The risks of bruising at the site of venipuncture may be slightly increased during the Lovenox or Xarelto therapy. There is a risk that during Lovenox or Xarelto therapy bleeding from skin or the gastrointestinal system could occur. Should increased bleeding occur, it should be brought immediately to the attention of the participating physician, and after evaluation of blood clotting, either the dose of Lovenox or Xarelto will be adjusted (downward), or anticoagulant will be discontinued. Very rarely, the low molecular weight heparin is associated with a reduced platelet count, which itself, could cause bleeding. Platelet counts will be carefully checked throughout the study, and if the platelet count falls below normal, having been normal before Lovenox was started, then the Lovenox will be stopped. All of the coagulation measurements have been quantitated by us before in published papers. 1-23, C1K, Definitions: Lp(a): Lipoprotein(a) is a unique lipoprotein which incorporates the major apolipoprotein of LDL cholesterol (apo B 100) and a highly glycosulated apoprotein, apolipoprotein(a), attached to the apo B by a disulfide bridge

12 tpa-fx: tpa-ag: PAI: PAI-Ag: PAI-Fx: Tissue plasminogen activator, the major endogenous, in vivo activator of the fibrinolytic system. Measured after 10 minutes venous occlusion in the arm at 100 mg Hg. Tissue plasminogen activator inhibitor antigen, bound to PAI and not activated. Plasminogen activator inhibitor, the major endogenous, in-vivo inhibitor of the fibrinolytic system. Plasminogen activator inhibitor antigen, the inactive protein antecedent of PAI. Plasminogen activator inhibitor activity, the body's major active inhibitor of tpa-fx. 12 Resistance to activated protein C: A genetic defect in the prothrombotic Factor V, Factor V Leiden, does not allow Factor V to be bound by the antithrombotic activated protein C. In patients homozygous or heterozygous for the Factor V Leiden defect, venous thrombosis is very common, and this defect is the most common coagulation defect causing Legg-Perthes disease. Anticardiolipin antibodies: Antiphospholipid antibodies which promote arterial and venous thrombosis. Lupus Anticoagulant: Antiphospholipid antibodies which promote arterial and venous thrombosis. Homocysteine: A thrombophilic amino acid. Levels are predominantly governed by homozygosity for the MTHFR gene. MTHFR mutation: A mutation in the C677T methylenetetrahydrofolate reductase (MTHFR) gene which governs (to a large degree), serum homocysteine levels. Homozygosity for this mutation is associated with increased risk of thrombosis. Homozygosity in unselected populations for this mutation is common, 11% in our studies. Prothrombin gene mutation: The 20210A mutation of the prothrombin gene governs prothrombin levels. Heterozygosity for this mutation is associated with increased risk of thrombosis. Heterozygosity for this mutation in unselected populations is common, 4% in our studies. Mutant Factor V Leiden gene: Associated with resistance to activated protein C. 12

13 2C1L:. Hetero- and homozygosity for this mutation are associated with increased risk of thrombosis. This is the most common cause of venous thrombosis. Heterozygosity for this mutation in unselected populations is common, 3% in our studies. 4G/5G Mutation of the Plasminogen activator inhibitor-1 (PAI-1) gene: Homozygosity for the mutation is associated with increased risk of thrombosis via high PAI-1 activity levels and inhibition of fibrinolysis. Homozygosity for this mutation in unselected populations is very common, 20% in our studies. Sample Size: Based on our best clinical judgment and on previous data on safety and efficacy of enoxaparin in patients with osteonecrosis, as summarized above, 7,16,18,22,44-49 we plan to study 50 patients. 2C1M. Statistical section Sample Size: The sample size is based on our best clinical judgment and on previous data on safety and efficacy of enoxaparin in patients with osteonecrosis, as summarized above 7,16,18,22, The proposed pilot study should be the basis of a larger, more definitive, randomized trial. Coagulation abnormalities at baseline: Serologic coagulation measures and PCR assays will be compared to healthy normal controls by non-parametric tests of difference (since most of the data will not be normally distributed), and by X 2 analysis. Descriptive statistics at baseline: 1. Descriptive statistics will be calculated to describe the mean, median, and distribution of all coagulation measures and all laboratory safety tests (platelet count, CBC, etc) at pre-treatment baseline. Similarly, the major components of the pain summary form will be summarized for each patient and for the patient group at pre-treatment baseline. We have already studied measures of thrombophilia and hypofibrinolysis in 197 healthy normal children and in 40 healthy normal adults 42,43. Data in patients will be compared with healthy normal controls, after matching for age, sex, and race. Since most of this data is not normally distributed, non parametric Wilcoxon tests of difference and Chi Square analyses will be used. Baseline X rays and MRIs with repeat studies taken after 12 and 24 weeks after initiation of therapy, and then subsequently once a year for 4 years, will be compared by Dr Richard Freiberg, our primary Orthopedic consulting principal investigator. These comparisons will be made blinded in regards to time and clinical response to therapy. Dr Freiberg will grade each X ray and MRI as to Ficat Stage (I-IV), and will quantitate the percent of the femoral head femur-tibia-fibula involved with osteonecrosis and the 13 13

14 presence or absence of segmental collapse of the femoral head. After he has completed his grading, then paired comparisons of X-ray and MRI appearance pre-therapy and at the end of the first 12 weeks, and the second 12 weeks after therapy, along with yearly evaluations, will be made by non-parametric Wilcoxon tests of difference, two-way analysis of variance, and Chi-Square analyses. 14 2C1N. References. 1. Glueck CJ, Glueck HI, Mieczkowski, Tracy T, Speirs J, Stroop D. Familial high plasminogen activator inhibitor with hypofibrinolysis, a new pathophysiologic cause of osteonecrosis. Thrombosis Haemostasis, 69: , Glueck CJ, Glueck HI, Tracy T, Speirs J, McCray C, Stroop D. Inheritance conjointly contributing to fibrinolysis and hyperlipidemia. Metabolism, 1993;42: Glueck CJ, Glueck HI, Tracy T, Speirs J, McCray C, Stroop D. Relationship between Lp(a), lipids, apolipoproteins, and fibrinolytic activity in 191 hyperlipidemic patients. Metabolism 42: , Glueck CJ, Glueck HI, Stroop D, Speirs J, Tracy T. Endogenous testosterone, fibrinolysis, and coronary heart disease risk in men. J Lab Clin Med, 1993;122(#4): Glueck CJ, Glueck HI, Freiberg R, Henderson C, Stroop D, Hamer T, Tracy T, Sosa F, Levy M. High plasminogen activator inhibitor activity and hypofibrinolysis, a major cause of idiopathic osteonecrosis. Am J Hematology, 1994;45: Glueck CJ, Glueck HI, Tracy T, Speirs J, Stroop D. Fibrinolytic Activity, Lipids, Lipo- Apo-Lipoproteins, and Top Tertile Lp(a). The Journal of Military Med Lab Science, 1992;21(#1): Glueck CJ, Freiberg R, Glueck HI, Tracy T, Stroop D, Hamer T. Idiopathic osteonecrosis, hypofibrinolysis, high plasminogen activator inhibitor, high lipoprotein (a), and therapy with Stanozolol. Amer J Hematology 48: , Glueck CJ, Glueck HI, Tracy T, Speirs J, Stroop D. Basal and stimulated fibrinolytic activity. Clinical Research, 1992;40:752A. 9. Glueck CJ, Glueck HI, Welch M, Freiberg R, Tracy T, Hamer T, Stroop D. Familial Idiopathic Osteonecrosis mediated by familial hypofibrinolysis with high levels of plasminogen activator inhibitor. Thrombosis-Haemostasis, 1994;71:

15 10. Glueck CJ, Freiberg R, Glueck HI, Stroop D, Tracy T. High plasminogen activator inhibitor activity and antigen and hypofibrinolysis, a cause of osteonecrosis? Clinical Research, Abstract, 41:309A, Presented. National AFCR, ASCI, AAP Meetings, Washington DC, 4/29-5/1/ Glueck CJ, Glueck HI, Welch M, Freiberg R, Tracy T, Hamer T, Stroop D. Familial Idiopathic Osteonecrosis mediated by familial hypofibrinolysis with high levels of plasminogen activator inhibitor. Thrombosis-Haemostasis, 1994;71: Gruppo R, Glueck CJ, McMahon RE, Bouquot J, Becker A, Tracy T, Wang P. Anticardiolipin antibodies, thrombophilia, and hypofibrinolysis. Pathophysiology of osteonecrosis of the jaw. J Lab Clin Med 1996;127: Pierre-Jacques H, Glueck CJ, Mont MA, Hungerford DS. Familial heterozygous protein S deficiency: a pathophysiologic cause of osteonecrosis. Journal of Bone and Joint Surgery 1997;79A: Glueck CJ, Glueck HI, Greenfield D, Freiberg R, et a. Protein C deficiency, protein S deficiency, thrombophilia, and hypofibrinolysis. Pediatric Research 1994;35: Glueck CJ, Crawford A, Roy D, Freiberg R, et al. Association of antithrombotic factor deficiencies and hypofibrinolysis with Legg-Perthes disease. J Bone Joint Surg 78A:3-13, Glueck CJ, Freiberg R, Tracy T, Stroop D, Wang P. Thrombophilia, hypofibrinolysis, and osteonecrosis. Clinical Orthopedic 1997;334: Glueck CJ, Rorick MH, Schmerler M, Anthony JJ, Feibel JH, Bishir M, Glueck HI, Stroop D, Hamer AT, Tracy T. Hypofibrinolytic and atherogenic risk factors for stroke. J Lab Clin Med. 1995;125: Glueck CJ, Freiberg, R, Gruppo R, Crawford A, Roy D, Brandt G, McMahon RE, Bouquot J, Tracy T, Stroop D, Wang P, Becker A. Thrombophilia and Hypofibrinolysis: Reversible Pathogenetic Etiologies of Osteonecrosis in Adults and in Children (Legg-Perthes Disease). AOA International Symposium on Osteonecrosis. In Urbaniak JR, Jones JP Jr (eds). Osteonecrosis: Etiology, diagnosis, and treatment. Rosemont IL, American Academy of Orthopedic Surgeons, 1997;pp Pacheco I, Glueck CJ, Wang P, Mont M, Hungerford D, Petri M. CLINICAL CHARACTERISTICS OF PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS ASSOCIATED WITH OSTEONECROSIS. Journal of Investigative Medicine, 44(#3):252A, Presented, AAP/ASCI/AFCR National 15 15

16 Biomedicine 96 Meetings, Washington DC, May 3-6, Glueck CJ, Hungerford D, Freiberg R, Tracy T, Wang P. FAMILIAL HETEROZYGOUS PROTEIN S DEFICIENCY: A PATHOPHYSIOLOGIC CAUSE OF OSTEONECROSIS. Journal of Investigative Medicine, 44(#3):233A, Presented, AAP/ASCI/AFCR National Biomedicine 96 Meetings, Washington DC, May 3-6, Glueck CJ, McMahon R, Bouquot J, Tracy T, Gruppo R, Wang P.THROMBOPHILIA AND HYPOFIBRINOLYSIS: PATHOPHYSIOLOGIC CAUSES OF OSTEONECROSIS OF THE JAWS. Journal of Investigative Medicine, 44(#3):213A, Glueck CJ, McMahon RE, Bouquot JE, Tracy T, Sieve-Smith L, Wang P. A Preliminary pilot study of treatment of thrombophilia and hypofibrinolysis and amelioration of the pain of osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;85: Glueck CJ, Stevens D, Freiberg R, Tracy T, Gruppo R, Wang P. THROMBOPHILIA AND HYPOFIBRINOLYSIS: PATHOPHYSIOLOGIC CAUSES OF LEGG-PERTHES DISEASE. Journal of Investigative Medicine, 44(#3):213A, Presented, AAP/ASCI/AFCR National Biomedicine 96 Meetings, Washington DC, May 3-6, Silberman S, Armentrout M, Vella F, Saha A. Macra Lp(a) for quantitation of human lipoprotein (a) by enzymes. Clin Chem 1990;36(6):961. Macra Lp(a) Enzyme Immunoassay Kit. Catalog #D306. Terumo Medical Corp. Elkton MD Glueck CJ, McCray C, Stroop D, Tracy T, Speirs J. Measurement of Lp(a): Comparison of Terumo and Imubind methods. Clinical Research 1992;40:414A. 26. Allain C, Poon LS, Chan CSG, Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem 1974;20: McGowan MW, Artiss JD, Strandbergh DR, Zak B. A peroxidase-coupled method for the calorimetric determination of serum triglycerides. Clin Chem 1983;29: Assman G, Schriewer H, Schmitz G, Hagele EO. Quantification of high density lipoprotein cholesterol by precipitation with phosphotungstic acid/mgcl 2. Clin Chem 1983;29: Glueck CJ, McCray C, Speirs J. Measurement of serum Apo A1 and Apo B: comparison of immunoturbindimetric and rate nephelometric techniques. Clin Chim 16

17 Acta 1991;197: Glimcher MJ, Kenzora JE. The biology of osteonecrosis of the human femoral head and its clinical implications. III. Discussion of the etiology and genesis of the pathological sequela; comments on treatment. 5/1992;14: Golding JS. Conditions of the hip associated with hemoglobinopathies. Clin- Orthop. Jan-Feb 1973;90: Slichter SJ, Stegall P, Smith K, Huang TW, Harker LA. Dysbaric osteonecrosis: a consequence of intravascular bubble formation, endothelial damage, and platelet thrombosis. J-Lab-Clin-Med. 10/1981;98(4): Gregosiewicz A, Okonski M, Stoecka D, Kandzierski G, Szponar M. Ischemia of the femoral head in Perthes' disease: is the cause intra- or extravascular? J-Pediatr- Orthop. Mar-Apr 1989;9(2): Snedecor GW, Cochran WG. Statistical Methods, (ed 7), Ames IA, Iowa State University Press, Byard PJ, Glueck CJ, Borecki IB, et al. A genetic study of hypoalphalipoproteinemia. Genetic Epidemiology 1984;1: Borecki IB, Rao DC, Third JHLC, Laskarzewski P, Glueck CJ. A major gene for primary hypoalphalipoproteinemia. Am J Human Genetics 1986;38: Nurmohamed MT, Verhaeghe R, Haas S, Iriarte JA, Vogel G, Van Rij AM, Prentice CR, TenCate JW. A comparative trial of a low molecular weight heparin (enoxaparin) versus standard heparin for the prophylaxis of postoperative deep vein thrombosis in general surgery. Am J Surg. 1995;169(6): Levine MN, Hirsh J, Gent M, Turpie AG, Leclerc J, Powers PJ, Jay RM, Neemeh J. Prevention of deep vein thrombosis after elective hip surgery. A randomized trial comparing low molecular weight heparin with standard unfractionated heparin. Ann Intern Med 1991;114(7): Spiro TE, Johnson GJ, Christie MJ, Lyons RM, MacFarlane DE, Blasier RB, Tremaine MD. Efficacy and safety of enoxaparin to prevent deep venous thrombosis after hip replacement surgery. Enoxaparin clinical trial group. Ann Intern Med 1994;121(2): Colwell CW Jr, Spire TE. Efficacy and safety of enoxaparin to prevent deep vein thrombosis after hip arthroplasty. Clin Orthop 1995;Oct(319): Carter CA, Skoutakis VA, Spir TE, E\West ME, Tooms RE, Joe RH, Knutson TJ. 17

18 Enoxaparin: the low-molecular-weight heparin for prevention of postoperative thromboembolic complications. Ann Pharmacother 1993;27(10): Balasa VV, Gruppo R, Glueck CJ, Stroop D, Becker A, Pillow A, Wang P. The relationship of mutations in the Methylenetetrahydrofolate Reductase, Prothrombin, and Plasminogen Activator Inhibitor-1 Genes to plasma levels of Homocysteine, Prothrombin, and Plasminogen Activator Inhibitor-1 levels in Children and Adults. Thrombosis-Haemostasis Presented, Pediatric Hematology Society, July 1, Balasa VV, Gruppo R, Glueck CJ, Stroop D, Becker A, Pillow A, Wang P. The relationship of mutations in the Methylenetetrahydrofolate Reductase, Prothrombin, and Plasminogen Activator Inhibitor-1 Genes to plasma levels of Homocysteine, Prothrombin, and Plasminogen Activator Inhibitor-1 levels in Children and Adults. Thrombosis Haemostasis, 1999;81: 44. Glueck CJ, Freiberg RA, Gruppo R, Kirk P, Fontaine R, Gupta A, Tracy T, Wang P. Amelioration of osteonecrosis by treatment of thrombophilia. Journal of Investigative Medicine, 1998;46:227A. Presented, Biomedicine 98, Washington DC, May 2, Glueck CJ, Brandt G, Gruppo R, Crawford A, Roy D, Becker A, Tracy T, Stroop D. Resistance to activated protein C, Legg-Perthes Disease, and Thrombosis. Clinical Orthopedics 1997;338: Glueck CJ, Freiberg R, Crawford A, Roy D, Tracy T, Sieve-Smith L, Wang P.Secondhand smoke, hypofibrinolysis, and childhood osteonecrosis of the hip, Legg-Perthes disease. Clinical Orthopedics 1998;352: Brandt G, Gruppo R, Glueck CJ, Stroop D, Becker A, Pillow A, Wang P. Sensitivity, specificity, and predictive value of modified assays for activated protein C resistance in children. Thrombosis Haemostasis 1998;79: Gruppo R, Glueck CJ, Wall E, Roy D, Wang P. Legg-Perthes disease in three siblings, 2 heterozygous and 1 homozygous for the Factor V Leiden Mutation. Journal of Pediatrics 1998;132: Glueck CJ, McMahon RE, Bouquot JE, Tracy T, Sieve-Smith L, Wang P. A Preliminary pilot study of treatment of thrombophilia and hypofibrinolysis and amelioration of the pain of osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;85: Glueck CJ, Freiberg RA, Swank M, Kirk P, Fontaine R, Tracy T, Wang P. Amelioration of osteonecrosis of the hip by treatment of thrombophilia and hypofibrinolysis: A pilot study. Clinical Orthopedics, In Review 1/13/

19 51. Glueck CJ, Wang P, Tracy T, Sieve-Smith L. Amelioration of osteonecrosis by treatment of thrombophilia and hypofibrinolysis. J Invest Med, In press, Antman EM TIMI IIB. American Heart J. 1998;135:S

20 TIME LINE for Lovenox and Xarelto therapy of osteonecrosis of the hip and/or knees 20 X X X X X- Week -3 Week 0 Week 4 Week 8 Week 12 X-ray X-ray MRI MRI Start Lovenox Stop Lovenox CBC and differential x x x x History and physical x x x x examination If no progression of osteonecrosis at week 12 by X-ray or MRI, and/or improvement of symptoms, then start second anticoagulation session, 12 weeks on Xarelto 20 mg X X X X--- Week 12 Week 16 Week 20 Week 24, repeat X ray, MRI Start Xarelto Stop Xarelto CBC and differential x x x- History and physical x x x If progression of osteonecrosis at week 12 by X-ray or MRI, or worsening of symptoms, then, no further anticoagulation. Repeat X rays and MRIs at years 1 (week 52), 2, 3, and 4. If worsening of symptoms or progression of osteonecrosis at yearly X rays and MRIs then start third anticoagulation session, 12 weeks on Xarelto 20 mg. 20

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