Medical Treatment of Osteonecrosis of the Knee Associated With Thrombophilia-Hypofibrinolysis

Abstract

In 6 patients with stage II knee osteonecrosis, all 6 with thrombophilia and 4 with concurrent hypofibrinolysis, the authors prospectively determined whether anticoagulation with enoxaparin could prevent collapse and progression to osteoarthritis, ameliorate pain, and restore function. The 6 patients were treated with enoxaparin (40 to 60 mg/d for 3 or more months) as mandated by a US Food and Drug Administration-approved protocol. In post-enoxaparin prospective follow-up, patients were reassessed clinically every 4 to 6 months, and radiographs were obtained every year. The 6 patients followed up at 15.1, 7.5, 3.9, 2.25, 2, and 1 year, respectively. None progressed to joint collapse or severe osteoarthritis. Four became and remained asymptomatic at 2-, 3.9-, 7.5-, and 15.1-year follow-up, respectively. A fifth patient did not progress to collapse or severe osteoarthritis but had residual pain at 2.25-year follow-up. The sixth patient had no symptomatic benefit on enoxaparin but improved on rivaroxaban at 1-year follow-up. Two patients had recurrences of knee pain 1 and 4 years after their initial treatment with enoxaparin. One resolved after a second course of enoxaparin, and the other, with a second recurrence 1 year after the second course, resolved after a third course. Pretreatment, all 6 patients required canes, crutches, or wheelchairs, but after enoxaparin, no patient required them, and walking was unrestricted. Thrombophilia-hypofibrinolysis contributes to the pathogenesis of knee osteonecrosis. Thrombophilic-hypofibrinolytic patients with stage II knee osteonecrosis treated with enoxaparin have had no collapse or progression to severe osteoarthritis, and most have had resolution of pain and restoration of full function. This represents a major improvement compared with the natural history of untreated spontaneous knee osteonecrosis.

Osteonecrosis in children and adolescents with acute lymphoblastic leukemia: a therapeutic challenge

“…According to the data reported by Glueck et al, 29,30 LMW heparin holds promise to prevent ON progression from early-to late-stage ON in primary ON associated with thrombophilia or hypofibrinolysis, but not in secondary ON caused by glucocorticoid treatment. The latter is thought to represent the major pathogenic mechanism in the development of ON in adolescents with ALL.…”

“…Lowmolecular-weight (LMW) heparin might positively affect intravascular clotting, especially in patients with a prothrombotic underlying disease. 29,30 Prostacyclin analogs have antiedema, anti-inflammatory, vasodilatory, and antiaggregant effects. [31][32][33][34] To reduce the adverse effects of steroids on lipid metabolism and lipocyte proliferation resulting in increased marrow pressure, lipid-clearing agents such as statins can reduce lipid levels in blood and tissues during high-dose glucocorticoid therapy.…”

Case report: primary osteonecrosis associated with thrombophilia-hypofibrinolysis and worsened by testosterone therapy

“…Primary ON [6] is not a common cause of arthralgia [24], and the diagnosis and therapy of ON remains poorly understood by many clinicians. While the prevalence of early-stage (pre-joint collapse) primary ON appears to be relatively low [25], it is important to diagnose, because, as we have shown, treatment with long-term anticoagulation in patients with familial or acquired thrombophilia-hypofibrinolysis and with primary ON (Ficat [13] stage I-II, pre-joint collapse) often results in complete symptomatic relief and long-term joint preservation of both knees [7] and hips [26], and may ameliorate osteonecrosis of the jaw [27]. The major clinical barrier to reaching this therapeutic benefit is the lack of awareness of the association between thrombophilia- hypofibrinolysis with primary ON [1, 3, 14, 28–31] which we are addressing in the current report.…”

“…The development of primary ON appears to follow a sequence of events initiated by familial or acquired thrombophilia [2–4], venous occlusion causing osseous venous outflow obstruction, leading to increased intraosseous venous pressure, reduced arterial flow, ischemia, bone infarction and eventual joint collapse [3–7]. Venous occlusion is the initiating event in experimental models of ON [8], and enoxaparin can prevent steroid induced ON [9].…”

“…Venous occlusion is the initiating event in experimental models of ON [8], and enoxaparin can prevent steroid induced ON [9]. Heritable or acquired thrombophilia-hypofibrinolysis alone, or augmented by testosterone therapy (TT) [9, 10] or clomiphene given to raise testosterone (in men) [10] are thought to lead to thrombotic venous occlusion and thence to osteonecrosis [3, 5–7]. In the current report, our specific aim was to describe the association of familial thrombophilia (Factor V Leiden heterozygosity), acquired thrombophilia (lupus anticoagulant, high anticardiolipin [ACLA] antibody IgM), and hypofibrinolysis (4G4G homozygosity for the plasminogen activator inhibitor −1 mutation) with hip and jaw ON, and the interaction of TT with familial thrombophilia in ON.…”