Warfarin and heterotopic ossification: good, bad or ugly?

Gallieni, Maurizio; Martini, A; Fusaro, Maria

doi:10.1038/sc.2010.141

Cited by 5 publications

(7 citation statements)

References 3 publications

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“…It is a pleasure to be able to respond to thoughtful responses. We agree with the comments of Gallieni et al 1 on the possible mechanism of warfarin treatment in preventing HO post SCI. The authors suggest that the positive effect of warfarin may be in response to its block on osteocalcin.…”

supporting

confidence: 91%

“…The letters by Gallieni et al 1 and Silver 2 regarding our paper 3 both provided interesting insights into heterotopic ossification (HO) post spinal cord injury (SCI). It is a pleasure to be able to respond to thoughtful responses.…”

mentioning

confidence: 93%

“…We also agree with the authors' comment that there is an increased risk of cardiovascular calcification due to warfarin; however, this is a complex relationship. 1 This risk has been shown to occur in certain individuals with specific genetic variations in their carboxylation enzymes. 7 As cited by the letter of Gallieni et al 1 and our article, 3 this may lead to increased risk of hemorrhage.…”

mentioning

confidence: 99%

“…1 This risk has been shown to occur in certain individuals with specific genetic variations in their carboxylation enzymes. 7 As cited by the letter of Gallieni et al 1 and our article, 3 this may lead to increased risk of hemorrhage. Our review of the literature was based upon our welldefined methodology.…”

mentioning

confidence: 99%

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Reply to Gallieni et al. and Silver

Mehta

Teasell

2010

Spinal Cord

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supporting

confidence: 91%

mentioning

confidence: 93%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Reply to Gallieni et al. and Silver

Mehta

Teasell

2010

Spinal Cord

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“…However since then no one showed clinical benefit from warfarin use in heterotopic ossification, moreover a few reports demonstrated increase in vascular calcification and osteoporosis [61].…”

Section: Pharmacological Treatmentmentioning

confidence: 99%

Understanding heterotopic ossification after spinal cord injury

Kulina¹

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Neurological heterotopic ossification (NHO) is a frequent complication of spinal cord and traumatic brain injuries (15-25% of patients) and manifests as abnormal ossification of soft tissues near joints. NHO is very debilitating and further delays rehabilitation as it causes pain, joint deformation and ankylosis and vascular and nerve compression. In the absence of an animal model the mechanisms leading to NHO are unknown and consequently there is no preventive treatment. The only effective approach to eliminate HO is complicated and expensive surgical resection. However these surgeries are delicate and can be challenging as they are performed once the NHO are mature, often large and incapacitating entrapping large blood vessels and nerves.To elucidate NHO pathophysiology, we have developed the first animal model of NHO in genetically unmodified mice. Mice underwent a spinal cord transection (SCI); muscular inflammation was induced by intramuscular injection of cardiotoxin in limbs (IM-CTX).Formation of NHO was followed by μCT and immunohistology.SCI alone or muscular inflammation alone did not induce NHO in mice. The combination of both SCI and muscular inflammation was necessary to induce NHO. This is consistent with clinical observations as NHO incidence is higher in patients with severe trauma or concomitant infection. Abundant F4/80 + macrophages, which can provide pro-anabolic support in bone formation, were detected within the inflamed muscle and associated with areas of intramuscular bone formation (confirmed by von Kossa and collagen type 1 staining). In vivo depletion of phagocytic macrophages with clodronate-loaded liposomes prevented NHO formation whereas Zoledronate treatment exacerbated NHO. This supports our hypothesis that macrophage-mediated inflammation is a key activator of NHO following SCI. To further identify the source and type of macrophages, involved in the bone formation after SCI and test some potential treatment options different knock-out mouse models were investigated. My data suggest that local muscle residential macrophages potentially play an important role in NHO.In addition we identified several populations of muscle progenitor cells that are prone to osteogenic differentiation in vitro. These data suggest that the mesenchymal progenitors that differentiate into osteoblasts in HO following spinal cord injury are already present in healthy muscles and therefore can be derived from local muscle progenitor cells rather than being recruited from the remote site, such as bone marrow.iii Finally we investigated why SCI was necessary for NHO development. My hypothesis was that SCI causes release of systemic factors priming NHO. In support of this, I showed that NHO developed in non-paralysed inflamed front limbs of mice with SCI. Also, blood plasma from mice with SCI and IM-CTX induced osteogenic differentiation of cultured muscle mesenchymal progenitor cells (mMPC) sorted from naïve mice. This suggests that systemic factors facilitating NHO, such as substance P and G-CSF are ...

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