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Jewish Home > Cholesterol and Metabolism Center > Research > Osteonecrosis
Osteonecrosis
Jewish Hospital Cholesterol Center, Charles J. Glueck MD, Director, James E. Lang MD, Associate Director, LeAnn Coberly MD
Assistant Medical Director. Jewish Hospital Cholesterol Center, 3200 Burnet Ave, Cincinnati, Ohio 45229.
Phone: 513-585-7800 Fax: 513-585-7950
E-mail: glueckch@healthall.com or cglueck@fuse.net
web: http://www.jewishhospitalcincinnati.com/cholesterol/index.html
Thrombophilia and Hypofibrinolysis: Reversible etiologies of osteonecrosis.
Thrombophilia (increased tendency to develop thrombosis) and hypofibrinolysis (reduced ability to lyse thrombi) may be
pathogenetic for osteonecrosis of the head of the femur (1-5, 10, 12-16) and jaw (6, 7) in adults and with osteonecrosis of the femur in children
(Legg-Perthes disease) (8, 9, 11). In adults and children, thrombophilia or hypofibrinolysis may predispose to thrombotic venous occlusion in bone
which leads to intramedullary hypertension, anoxia, and ischemic bone death characteristic of osteonecrosis.
Thrombophilia and hypofibrinolysis are transmitted as autosomal dominant traits, although their effects can be amplified by
diseases and drugs (3,4,14,15). The major heritable thrombophilic and hypofibrinolytic disorders pathogenetic for osteonecrosis are as follows(1-16):
Thrombophilic Disorders:
Resistance to activated protein C:
Resistance to activated protein C is the most common currently recognized heritable
thrombophilic factor, found in 3-7% of the general population and in 11% to 50% of patients with venous thrombosis (11). Heritable resistance to
activated protein C is caused by a CGA-->CAA substitution at position 1691 of the Factor V Leiden gene which blocks binding of activated protein C
to the prothrombotic Factor V, producing thrombophilia. Activated protein C resistance (APCR) can be amplified by exogenous estrogens (oral
contraceptives, post-menopausal estrogen supplementation) (7).
Protein C deficiency:
When protein C is deficient, factor Va 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 Va is not adequately
suppressed, leading to increased procoagulant activity and increased risk of venous and arterial thrombosis.
Protein C and S deficiency have been found in 2-5% and 5-9% of patients with venous thrombosis. Protein C is activated by an
endothelial cell surface thrombin-thrombomodulin complex, and along with its cofactor protein S inhibits the prothrombotic factors V and VIII; hence
deficiency in protein C and/or S leads to thrombophilia.
Anticardiolipin Antibodies:
Anticardiolipin antibodies (ACLA) belong to a family of antiphospholipid autoantibodies which
are directed against negatively charged phospholipid antigens. Anticardiolipin antibodies 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 are associated with both venous and arterial thrombi.
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 triglycerides can increase PAI-Fx, causing a decrease in tPA-Fx.
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.
Thrombophilia and/or hypofibrinolysis have been found in 76% of 289 patients with osteonecrosis (17). In studies of
osteonecrosis of the hip, provided that therapy is begun prior to irreversible segmental collapse of the head of the femur (5, 17), treatment of
thrombophilia and hypofibrinolysis can reverse or retard the progression of osteonecrosis. Two adults with early, potentially reversible osteonecrosis
of the hip (Ficat stages I, II) had thrombophilia (resistance to activated protein C, protein C deficiency) and were treated respectively with
Coumadin (targeted INR of 2-2.5) and with Winstrol (an anabolic-androgenic steroid) 6 mg/day (6,7,11). On therapy, thrombophilia was normalized,
severe hip pain resolved, and the progression of their osteonecrosis was reversed/retarded, as shown by MRI/X-ray. Two adults with osteonecrosis of
the hip (Ficat stages I, II) had hypofibrinolysis (high PAI-1, high Lp[a]). Winstrol (6 mg/day) normalized fibrinolytic activity, resolved their
severe hip pain, and reversed/retarded their osteonecrosis, as shown by MRI and X-ray. In 4 hypofibrinolytic adults (high PAI-1, high Lp[a]) with more
advanced osteonecrosis (segmental collapse of the head of the femur-Ficat stages III, IV), Winstrol (6 mg/day) normalized fibrinolysis but had no
effect on hip pain, MRI, or X-ray.
Discussion:
Our studies in 289 adults and children with osteonecrosis of the hip, knee, or jaw have begun to illuminate the pathogenetics of
osteonecrosis (1-17). The majority (about 80%) of patients with osteonecrosis have heritable thrombophilia (increased likelihood of thrombosis) and/or
hypofibrinolysis (reduced ability to lyse thrombi).
References:
Abstract and Articles in press:
THROMBOPHILIA AND HYPOFIBRINOLYSIS: PATHOGENETIC ETIOLOGIES OF OSTEONECROSIS.
CJ Glueck, R Freiberg, R Gruppo,
A Crawford. Jewish Hosp, Cincinnati, Ohio., In Press, Thrombosis and Haemostasis, 1997
Thrombophilia and hypofibrinolysis may be pathogenetic for osteonecrosis (ON) of the femur in adults and children, causing
thrombotic venous occlusion in bone, intramedullary hypertension, and ischemic bone death. Thrombophilia and hypofibrinolysis were assessed in 291
patients with ON, 103 adults in 3 cohorts with ON of the hip (n=30,31,42), 64children with ON of the hip, and 124 adults with ON of the jaw in 2 cohorts
(n=49, n=55). Of the 291 patients, 75% had familial thrombophilia /hypofibrinolysis. Only 14 of 64 (22%) children with ON had normal coagulation
measures. In 64 children with ON, the mutant Factor V gene was found in 13% vs 4% of healthy normal children (p=.02), low protein C in 28% vs 3%
(p=.005), and low stimulated tissue plasminogen activator activity (tPA-Fx) in 36% vs 14% (p=.05). In 3 cohorts comprising 103 adults with ON of the
hip, only 13%, 26%, and 33% respectively had normal coagulation measures. In these 103 patients, low tPA-Fx (usually with high plasminogen activator
inhibitor activity [PAI-Fx]) was found in 28% vs 6% of normal controls (p=.02), and high Lp(a) in 40% vs 22% (p=.001). In the 42 patients where
anticardiolipin antibodies (ACLA) were measured, 22% had high IgG vs 5% of controls (p=.02), 22% had high IgA vs 3% of controls (p=.008). Of 124
patients with ON of the jaw, only 27% had normal coagulation measures. The mutantFactor V gene was found in 22% of patients vs 0% of controls (p=.001),
low protein C in 14% vs 0% (.02), and high PAI-Fx in 18% vs 8% (p=.03). Most (75%) children and adults with ON have heritable thrombophilia and/or
hypofibrinolysis which, we postulate, facilitate thrombotic blockage of venous drainage of bone, subsequent increase in bone venous pressure, reduced
arterial perfusion, anoxia, and subsequent ischemic bone death (osteonecrosis).
AMELIORATION OF OSTEONECROSIS BY TREATMENT OF THROMBOPHILIA AND HYPOFIBRINOLYSIS.
R Freiberg, CJ Glueck.
Jewish Hospital, Cincinnati, Ohio, USA. In Press. Thrombosis and Haemostasis, 1997.
Thrombophilia and hypofibrinolysis may be pathogenetic for osteonecrosis of the femur, causing thrombotic venous occlusion in
bone, intramedullary hypertension, anoxia, and ischemic bone death (osteonecrosis [ON]). We assessed whether treatment of thrombophilia
/hypofibrinolysis would ameliorate ON. Familial thrombophilia or hypofibrinolysis in 9 adults with osteonecrosis were treated with Coumadin (target INR
2.5) or Winstrol (6 mg/day) (anabolic-andro genicsteroid), with follow-up of thrombophilia/ hypofibrinolysis for about 1 year on therapy. Two adults
with early ON of the hip (Ficat stages I, II) had familial thrombophilia (resistance to activated protein C, protein C deficiency). On Coumadin and
Winstrol, respectively, thrombophilia was normalized, severe hip pain resolved with resumption of usual activities, and was reversed/retarded, as shown
by MRI/X-ray. Three adults with early ON (Ficat stages I, II) had hypofibrinolysis (high plasminogen activator inhibitor activity [PAI-Fx], high Lp[a]).
Winstrol normalized fibrinolytic activity, completely resolved severe hip pain with resumption of usual activity, and reversed/retarded ON, by
MRI/X-ray. In 4 hypofibrinolytic adults (high PAI-Fx, high Lp[a]) with more advanced ON (segmental collapse of the head of the femur (Ficat III, IV),
Winstrol normalized fibrinolysis without improving hip pain, activity restriction, or MRI/X-ray progression of ON. If therapy to normalize
thrombophilia/ hypofibrinolysis is begun early in ON, before irreversible collapse of the head of the femur, progression of ON can be stopped and often
reversed. Normalization of thrombophilia/hypofibrinolysis cannot improve ON, if started after collapse of the head of the femur. Most patients with
osteonecrosis have thrombophilia and/or hypofibrinolysis as a major underlying pathoetiology. When assessing a patient with osteonecrosis one should
measure the major determinants of thrombophilia: resistance to activated protein C (and, if abnormal, do the PCR assay for the Mutant Factor V Leiden
gene), protein C, protein S, anticardiolipin antibodies IgG and IgM, and the lupus anticoagulant. Also, one should measure the major determinants of
hypofibrinolysis: plasminogen activator inhibitor 1 and stimulated tissue plasminogen activator activity, and lp(a). With these measures in hand, the
underlying coagulation defect can be treated and if the osteonecrosis is Ficat I or II, it can be reversed by treatment of the coagulation defect.
Glueck CJ, Freiberg R, Gruppo R et al. Thrombophilia and hypofibrinolysis: Reversible pathogenetic etiologies of osteonecrosis
in adults and children.
In Urbaniak JR, Jones, TP Jr(eds). Osteonecrosis: etiology, diagnosis, and treatment. Rosemony, IL. Amer. Acad. Orthopedic
surgeons. 1997;pp105-110.
Recent progress in amelioration of osteonecrosis by treatment of thrombophilia and hypofibrinolysis.
AMELIORATION OF OSTEONECROSIS BY TREATMENT OF THROMBOPHILIA AND HYPOFIBRINOLYSIS.
CJ Glueck, RA Freiberg, R Gruppo, P Kirk, RN Fontaine, A Gupta, T Tracy, P Wang. Cholesterol Center, Jewish Hospital, Cincinnati, Ohio. J Invest Med 1998;46:227A
Fifteen patients with Ficat stage I or II osteonecrosis (ON), 5 with thrombophilia, and 10 with hypofibrinolysis, were treated to
determine the effect of therapy (Rx) on the symptomatic and radiographic progression of ON. To assess symptomatic relief, pain was rated daily by 5
numeric scores. MRI scans were done initially and at 6-8 months on Rx. Of the 5 thrombophilic patients, 2 had homocysteinemia, 1 was heterozygous for
the mutant Factor V Leiden gene, 1 had high anticardiolipin antibody (IgG). They were treated for 26 weeks (range 6-42) with folic acid/B6 (n=2), or
coumadin (n=2), or low molecular weight heparin (n=1). Twenty-two of 25 (88%) pain scores were improved on Rx (p<.001). On Rx, 4 of 5 patients became
pain free. MRIs in 3 improved after 30, 38, and 39 weeks on Rx. Of the 10 hypofibrinolytic patients, 7 had high plasminogen activator inhibitor activity
(PAI-Fx), 4 were homozygous and 3 heterozygous for the mutant PAI-1 gene, 4 had high Lp(a). They were treated with the anabolic-androgenic steroid,
Winstrol (6 mg/day) for 11 weeks (range 3-31). Sixteen of 46 (35%) of pain scores were improved on Rx (p<.001), 23 (50%) were unchanged, and 7 (15%)
worsened. On Rx, 1 of 10 patients became pain free; MRIs in 4 patients were unchanged after 4, 10, 12, and 31 weeks on Rx. Rx for thrombophilia was more
successful than for hypofibrinolysis with 100% improvement in overall pain score vs 40%, p=.04, and 100% vs 33% improvement in mood score, p=.028. After
covariance adjusting for severity of pain before Rx, pain relief in the thrombophilic group was greater than in the hypofibrinolytic group (p=.02). Rx
of thrombophilia and hypofibrinolysis ON before segmental collapse of the head of the femur shows promise in amelioration of ON.
HERITABLE THROMBOPHILIA AND HYPOFIBRINOLYSIS: COMMON PATHOETIOLOGIES OF RETINAL VEIN THROMBOSIS.
L
Vadlamani, CJ Glueck, H Bell, A Gupta, RN Fontaine, P Wang, T Tracy, R Gruppo, D Stroop. Cholesterol Center, Jewish Hospital, Cincinnati, Ohio
In 17 patients, our specific aim was to determine whether heritable thrombophilias and hypofibrinolyses were pathoetiologic risk
factors for retinal vein thrombosis (RVT). Coagulation measures in 17 patients with RVT were compared to those in healthy normal controls. Three of 17
patients (18%) were heterozygous for the thrombophilic Factor V Leiden G1691A mutation versus 7 of 233 controls (3%), p=.023. Two of 17 (12%) patients
had normal alleles (5G/5G) for the plasminogen activator inhibitor (PAI) gene promoter; 88% were heterozygous or homozygous for the 4G polymorphism. Of
234 controls, 85 (36%) had 5G/5G; 149 (64%) were either heterozygous or homozygous for the 4G polymorphism, p=.03. Of 14 RVT patients with measures of
dilute Russel's viper venom time, a thrombophilic antiphospholipid antibody, 6 (43%) were abnormal (>38.8 sec) vs 1/30 (3.3%) controls p=.002.
Patients were more likely (8/16, 50%) to have high levels of hypofibrinolytic Lp(a) (>35 mg/dl) than controls (5/40, 13%), X2=9, p=.003.
Patients were more likely to have high levels of the major determinant of hypofibrinolysis, plasminogen activator inhibitor activity (PAI-Fx). PAI-Fx
was high (>22 U/L) in 6/16 patients (38%) vs 1/40 controls (2.5%), X2=12.8, p=.001. Hypofibrinolytic disorders often occurred in clusters.
Median Lp(a) in patients with the 4G/4G genotype was 62 mg/dL vs 5.3 in 4G/4G controls (p=.048). Patients with retinal vein thrombosis commonly have
both thrombophilia and hypofibrinolysis, opening avenues to protection of the contralateral eye by anticoagulant therapy, and to prevention of
thrombosis in other venous and arterial beds.
E-mail: glueckch@healthall.com
or cglueck@fuse.net
Fax: 513-585-7950
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