Osteonecrosis and Thrombophilia: Pathophysiology, Diagnosis, and Treatment

Factor V Leiden

PTG TC

PAIG 4G4G

MTHFR TT

Factor VIII >150%

Factor XI >150%

Homocysteine high^a

Idiopathic osteonecrosis

20/220

10/213

59/210

44/211

39/161

10/154

24/196

(n = 221)

(9%)

(5%)

(28%)

(21%)

(24%)

(6%)

(12%)

Normal control

2/109

3/107

26/104

32/109

7/103

3/101

5/107

(n = 110)

(2%)

(3%)

(25%)

(29%)

(7%)

(3%)

(5%)

Idiopathic vs controls Fisher’s p

.017

.0002

.04

Secondary osteonecrosis

9/111

3/109

31/109

32/110

10/69

3/61

17/108

(n = 113)

(8%)

(3%)

(28%)

(29%)

(14%)

(5%)

(16%)

Normal control

2/109

3/107

26/104

32/109

7/103

3/101

5/107

(n = 110)

(2%)

(3%)

(25%)

(29%)

(7%)

(3%)

(5%)

Secondary vs controls Fisher’s p

.059

.012

	ACLA IgG high^b	ACLA IgM high^c	Antigenic Protein C <73%	Antigenic Protein S <63%	Antigenic Free S <66%	Antithrombin III <80%	Lupus positive
Idiopathic osteonecrosis	11/194	22/193	9/190	1/192	8/173	7/188	2/188
(n = 221)	(6%)	(11%)	(5%)	(0.5%)	(5%)	(4%)	(1%)
Normal control	6/109	2/109	6/96	4/96	2/96	2/96	2/110
(n = 110)	(6%)	(2%)	(6%)	(4%)	(2%)	(2%)	(2%)
Idiopathic vs controls Fisher’s p	NS	.003	NS	.04	NS	NS	NS
Secondary osteonecrosis	5/106	10/106	3/100	3/99	16/95	2/97	5/101
(n = 113)	(5%)	(9%)	(3%)	(3%)	(17%)	(2%)	(5%)
Normal control	6/109	2/109	6/96	4/96	2/96	2/96	2/110
(n = 110)	(6%)	(2%)	(6%)	(4%)	(2%)	(2%)	(2%)
Secondary vs controls Fisher’s p	NS	.018	NS	NS	.0004	NS	NS

PTG prothrombin G20210A mutation, PAIG PAI-1 4G/5G promoter polymorphism, MTHFR methylenetetrahydrofolate reductase C677T/A1298C, Free S protein S free, TT homozygous mutant, TC heterozygote mutant, CC wild type normal

^aDated cut point for Homocysteine high: ≥13.5 umol/l (before 3/20/2005); ≥12 (3/21/05–3/27/06); ≥10.4 (3/28/06–4/14/08); ≥11.4 (4/15/08–11/14/08); ≥15 (after 11/15/08)(6/9/15 revised)

^bDated cut point for IgG high: ≥23 GPL (before 10/31/12); ≥15 (after 11/1/12)

^cDated cut point for IgM high: ≥10 MPL (before 4/30/12); ≥13 (after 5/1/12)

Sonography of leg veins revealed no signs of deep venous thrombosis.

Management

The estrogen-testosterone patch was immediately discontinued. In the absence of contraindications to anticoagulation, enoxaparin 1.5 mg/kg/day in two divided doses was started. After completion of a 3-month course of enoxaparin, standard in our initial study protocol as required by the FDA [5], ambulation was pain-free. After being asymptomatic for an additional 8 months, right hip pain returned, and enoxaparin was restarted. After 3 months on the second course of enoxaparin, she again became asymptomatic. A repeat MRI revealed Ficat stage I osteonecrosis, without change from the pretreatment study.

Xarelto, 10 mg/day, was then started. She remained asymptomatic for the subsequent 9 months. Repeat MRI revealed no change, still Ficat stage I osteonecrosis.

Outcome

She remains entirely asymptomatic 3 years after initial diagnosis, being maintained on Xarelto 10 mg/day. In patients with major gene thrombophilias and Ficat stages I–II osteonecrosis at the time of first beginning anticoagulation, progression to joint collapse can usually be prevented, pain ameliorated, and function maintained [6]. Long-term anticoagulation also carries increased bleeding risk, but this is much less with the new Xa inhibitors than Coumadin [7–9].

Case Presentation 2

In January 2008, this 54-year-old Caucasian male developed increasing fatigue and loss of libido. Workup revealed low testosterone levels. A diagnosis of hypogonadism was made. He was then started on a testosterone patch (50 mg/ day) in February 2008. Six months after starting the testosterone patch, he developed severe bilateral hip pain. X-rays revealed bilateral osteonecrosis of the hips, right hip Ficat stage II and left Ficat stage I. On our evaluation of thrombophilia-hypofibrinolysis (Table 1.1), he was found to be heterozygous for the factor V Leiden mutation and homozygous for the MTHFR C677T mutation (associated with abnormal homocysteine metabolism). There were no risk factors for secondary osteonecrosis, and we attributed the development of the osteonecrosis to an interaction between the thrombophilic factor V Leiden mutation and exogenous testosterone therapy [4, 10].

Management

Testosterone was stopped. Enoxaparin, 1.5 mg/kg/day in two divided doses, was started and maintained for 3 months as usual. Four months later, MRI and X-ray showed no change from pretreatment, but his pain was much less. Because of persistent pain, a second 3-month course of enoxaparin was given, and he became asymptomatic. Eight months later, there was no change in his X-ray or MRI. Three years from initial treatment with enoxaparin, MRIs were unchanged. There were no new areas of osteonecrosis or marrow edema compared to pretreatment. Because of symptomatic improvement on enoxaparin and stable X-rays and magnetic resonance images (MRIs), chronic long-term anticoagulation was started 3 years after diagnosis with Pradaxa 150 mg twice per day.

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