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Thromb Haemost 2010; 103(05): 1053-1064
DOI: 10.1160/TH09-10-0689
Platelets and Blood Cells
Schattauer GmbH

Novel integrin-dependent platelet malfunction in siblings with leukocyte adhesion deficiency-III (LAD-III) caused by a point mutation in FERMT3

Kerstin Jurk
1   Department of Anaesthesiology and Intensive Care, Experimental and Clinical Haemostasis, University-Hospital of Münster, Münster, Germany
,
Ansgar S. Schulz
2   Department of Pediatrics and Adolescent Medicine, University Clinic of Ulm, Ulm, Germany
,
Beate E. Kehrel
1   Department of Anaesthesiology and Intensive Care, Experimental and Clinical Haemostasis, University-Hospital of Münster, Münster, Germany
,
Daniel Räpple
3   Department of Medicine I, University of Freiburg, Freiburg, Germany
,
Harald Schulze
4   Laboratory of Pediatric Molecular Biology, Department of General Pediatrics, Charité – University of Berlin, Berlin, Germany
,
Dieter Möbest
3   Department of Medicine I, University of Freiburg, Freiburg, Germany
,
Wilhelm W. Friedrich
2   Department of Pediatrics and Adolescent Medicine, University Clinic of Ulm, Ulm, Germany
,
Heymut Omran
8   Department of General Pediatrics, University Hospital Muenster, Germany
,
Erika Deak
6   Institute of Transfusion Medicine and Immune Hematology German Red Cross Blood Donor Service, Johann Wolfgang Goethe University Medical School, Frankfurt, Germany
,
Reinhard Henschler
1   Department of Anaesthesiology and Intensive Care, Experimental and Clinical Haemostasis, University-Hospital of Münster, Münster, Germany
,
Jürgen S. Scheele
3   Department of Medicine I, University of Freiburg, Freiburg, Germany
7   Department of Pharmacology, University of Freiburg, Freiburg, Germany
,
Barbara Zieger
5   Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany
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Publikationsverlauf

Received: 07. Oktober 2009

Accepted after major revision: 09. Januar 2010

Publikationsdatum:
22. November 2017 (online)

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Summary

Leukocyte adhesion deficiency-III (LAD-III) also called leukocyte adhesion deficiency-1/variant (LAD1v) is a rare congenital disease caused by defective integrin activation of leukocytes and platelets. Patients with LAD-III present with non-purulent infections and increased bleeding symptoms. We report on a novel integrin-dependent platelet dys-function in two brothers with LAD-III syndrome caused by a homozygous mutation 1717C>T in the FERMT3 gene leading to a premature stop codon R573X in the focal adhesion protein kindlin-3. Stimulation of patients´ platelets with all used agonists resulted in a severely decreased binding of soluble fibrinogen indicating a defect in inside-out activation of the integrin αIIbβ3 (GPIIb/IIIa). Patients´ platelets did not respond to the α2β1-integrin agonist aggretin-A at all. Our data on granula secretion indicate for the first time that the thrombin receptor PAR-4 but not PAR-1 may be important in integrin-triggered granule secretion in response to thrombin. In contrast, collagen mediated platelet granule secretion was not affected in LAD-III-patients. Thus, integrin-signalling may be not essential in collagen-induced granule secretion. The patients’ peripheral blood mononuclear cells showed a severe loss of adhesion capacity to VCAM-1 and to endothelial cells compared to cells from healthy donors. Rap-1 activation after PMA stimulation could be observed in controls´ but not in patients´ cells. After haematogenesis stem cell transplantation (HSCT) the brothers showed no symptoms of bleeding or immunodeficiency and the integrin-dependent platelet and leukocyte functions normalised.

Keywords

Leukocyte adhesion deficiency - platelets - integrin - kindlin-3
 

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