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Carpal Tunnel Syndrome Is Associated With High Fibrinogen and Fibrinogen Deposits

Utrobičić, Ivan MD‡,*; Novak, Ivana PhD§,*; Marinović-Terzić, Ivana MD, PhD§,*; Matić, Katarina MD; Lessel, Davor MD; Salamunić, Ilza PhD#; Babić, Mirna Saraga MD, PhD**; Kunac, Nenad MD‡‡; Mešin, Anka Koštić MD§§; Kubisch, Christian MD; Maček, Boris PhD; Terzić, Janoš MD, PhD§

doi: 10.1227/NEU.0000000000000422
Research-Human-Clinical Studies

BACKGROUND: Idiopathic carpal tunnel syndrome (ICTS) is a common entrapment neuropathy. Some cases of ICTS are linked to mutations of the transthyretin gene, whereas others are associated with systemic amyloidosis. The majority of ICTS cases are of unknown etiology.

OBJECTIVE: To study molecular mechanisms of ICTS development.

METHODS: A total of 71 ICTS patients and 68 control subjects were included in the study. The fibrinogen level was determined before surgery and its deposition in the transversal carpal ligament (TCL) was detected by immunohistochemistry, Western blot, and mass spectrometry. Fibrinogen interaction with other proteins was studied by immunoprecipitation assay.

RESULTS: Plasma levels of the proinflammatory and hemostatic protein fibrinogen are elevated in ICTS patients. Other measured systemic inflammatory markers were not affected, and local inflammatory responses in TCL were absent. ICTS patients have shorter bleeding times, probably because of the elevated plasma levels of fibrinogen. Polymorphisms of the fibrinogen B promoter region were previously associated with increased plasma fibrinogen, but this association was not observed among patients with ICTS. Interestingly, we detected fibrinogen deposits in the TCL, whereas transcriptional activity of the fibrinogen genes was low. Amyloidogenic proteins, including transthyretin and α-synuclein, were also found in the TCL, whereas their local transcriptional activity was rather high. Finally, we demonstrated that fibrinogen interacts with transthyretin and α-synuclein in TCL lysates.

CONCLUSION: Our data indicate that fibrinogen and other aggregation-prone proteins have potentially important roles in the pathogenesis of ICTS.

ABBREVIATIONS: CTS, carpal tunnel syndrome

ENG, electroneurography

ICTS, idiopathic carpal tunnel syndrome

PCR, polymerase chain reaction

SNP, single-nucleotide polymorphism

TCL, transversal carpal ligament

TTR, transthyretin

Department of Plastic Surgery, University Hospital Split, and University of Split School of Medicine, Split, Croatia;

§University of Split School of Medicine, Split, Croatia;

Proteome Center Tübingen, Tübingen, Germany;

Institute of Human Genetics, University of Ulm, Ulm, Germany;

#Department of Laboratory Diagnostics, University Hospital Split, and University of Split School of Medicine, Split, Croatia;

**Department of Anatomy and Histology, University Hospital Split, and University of Split School of Medicine, Split, Croatia;

‡‡Department of Pathology, University Hospital Split, Split, Croatia;

§§Unit for Family Practice, Split, Croatia

Correspondence: Janoš Terzić, MD, PhD, University of Split, School of Medicine, Soltanska 2, HR-21000, Split, Croatia. E-mail:

* These authors have contributed equally to this article.

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Received February 07, 2014

Accepted April 21, 2014

Copyright © by the Congress of Neurological Surgeons