The role of GP Ib-IX complexes in platelet adhesion was discovered from studies on patients with the Bernard-Soulier Syndrome (BSS). In this inherited disorder, the bulk of the platelets are round and giant. Furthermore, the platelet count is decreased, often severely so. The relationship between these abnormalities and the deficiency of GP Ib-IX is not well understood. In normal discoid platelets, the bulk of GP Ib-IX is found on the plasma membrane. After platelet activation by thrombin, this distribution changes and the majority of GP Ib-IX complexes are located within the surface-connected canalicular system (SCCS). The platelets now possess pseudopods and are spheroid. Cytoskeletal modifications accompany these changes. We now report that platelets of a BSS variant with a qualitative defect of GP Ib show no translocation of GP Ib in response to thrombin, suggesting that the linkage with the cytoskeleton is impaired. Morphological studies of megakaryocytes (MK) from BSS patients show an altered maturation and an abnormal development of the membrane systems, implying a role for GP Ib-IX in megakaryocytopoiesis. In a case of Epstein syndrome, where giant platelets and thrombocytopenia are associated with deafness and renal dysfunction, platelets possess the bulk of GP Ib-IX inside the SCCS but without signs of platelet activation as assessed by P-selectin expression. This patient also shows an impaired megakaryocytopoiesis and an irregular development of the demarcation membranes within the MK. As collagen IV mutations are a feature of the related Alport syndrome, we hypothesize that defects in the link between extracellular matrix proteins, membrane receptors and the cytoskeleton could be a common cause of giant platelet syndromes.