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Identification of platelet function defects by multi-parameter assessment of thrombus formation.

de Witt SM, Swieringa F, Cavill R, Lamers MM, van Kruchten R, Mastenbroek T, Baaten C, Coort S, Pugh N, Schulz A, Scharrer I, Jurk K, Zieger B, Clemetson KJ, Farndale RW, Heemskerk JW, Cosemans JM - Nat Commun (2014)

Bottom Line: Three types of thrombus formation can be identified with a predicted hierarchy of the following receptors: glycoprotein (GP)VI, C-type lectin-like receptor-2 (CLEC-2)>GPIb>α6β1, αIIbβ3>α2β1>CD36, α5β1, αvβ3.Application with patient blood reveals distinct abnormalities in thrombus formation in patients with severe combined immune deficiency, Glanzmann's thrombasthenia, Hermansky-Pudlak syndrome, May-Hegglin anomaly or grey platelet syndrome.We suggest this test may be useful for the diagnosis of patients with suspected bleeding disorders or a pro-thrombotic tendency.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.

ABSTRACT
Assays measuring platelet aggregation (thrombus formation) at arterial shear rate mostly use collagen as only platelet-adhesive surface. Here we report a multi-surface and multi-parameter flow assay to characterize thrombus formation in whole blood from healthy subjects and patients with platelet function deficiencies. A systematic comparison is made of 52 adhesive surfaces with components activating the main platelet-adhesive receptors, and of eight output parameters reflecting distinct stages of thrombus formation. Three types of thrombus formation can be identified with a predicted hierarchy of the following receptors: glycoprotein (GP)VI, C-type lectin-like receptor-2 (CLEC-2)>GPIb>α6β1, αIIbβ3>α2β1>CD36, α5β1, αvβ3. Application with patient blood reveals distinct abnormalities in thrombus formation in patients with severe combined immune deficiency, Glanzmann's thrombasthenia, Hermansky-Pudlak syndrome, May-Hegglin anomaly or grey platelet syndrome. We suggest this test may be useful for the diagnosis of patients with suspected bleeding disorders or a pro-thrombotic tendency.

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Contribution of platelet-adhesive receptors to formation of type I–III thrombi.Schematic representation of thrombus type formed at high shear rate on surfaces capturing platelets via adhesive receptors (GPIb, and integrins α2β1, α6β1) as well as signalling-linked receptors (GPVI, CLEC-2).
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f7: Contribution of platelet-adhesive receptors to formation of type I–III thrombi.Schematic representation of thrombus type formed at high shear rate on surfaces capturing platelets via adhesive receptors (GPIb, and integrins α2β1, α6β1) as well as signalling-linked receptors (GPVI, CLEC-2).

Mentions: By combining the analysis of thrombus types and the receptor assignment matrix per surface (Fig. 1), we then evaluated the combinations of receptors contributing to formation of type III thrombi. First, computational analysis was performed for the high-shear condition of the surfaces binding GPIb (vWF, vWF-BP) in combination with the key integrins α2β1/α6β1 and the signalling receptors GPVI/CLEC-2. In combination, these three receptor/ligand classes consistently produced type III thrombi (Fig. 7). Integrins seemed to have a stimulatory but not essential role, with α6β1 being more active than α2β1. This was also clear from the mean scores of laminin-containing surfaces (α6β1 binding), which performed better than GFOGER- or decorin-containing surfaces (α2β1 binding) (Supplementary Table 2).


Identification of platelet function defects by multi-parameter assessment of thrombus formation.

de Witt SM, Swieringa F, Cavill R, Lamers MM, van Kruchten R, Mastenbroek T, Baaten C, Coort S, Pugh N, Schulz A, Scharrer I, Jurk K, Zieger B, Clemetson KJ, Farndale RW, Heemskerk JW, Cosemans JM - Nat Commun (2014)

Contribution of platelet-adhesive receptors to formation of type I–III thrombi.Schematic representation of thrombus type formed at high shear rate on surfaces capturing platelets via adhesive receptors (GPIb, and integrins α2β1, α6β1) as well as signalling-linked receptors (GPVI, CLEC-2).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4109023&req=5

f7: Contribution of platelet-adhesive receptors to formation of type I–III thrombi.Schematic representation of thrombus type formed at high shear rate on surfaces capturing platelets via adhesive receptors (GPIb, and integrins α2β1, α6β1) as well as signalling-linked receptors (GPVI, CLEC-2).
Mentions: By combining the analysis of thrombus types and the receptor assignment matrix per surface (Fig. 1), we then evaluated the combinations of receptors contributing to formation of type III thrombi. First, computational analysis was performed for the high-shear condition of the surfaces binding GPIb (vWF, vWF-BP) in combination with the key integrins α2β1/α6β1 and the signalling receptors GPVI/CLEC-2. In combination, these three receptor/ligand classes consistently produced type III thrombi (Fig. 7). Integrins seemed to have a stimulatory but not essential role, with α6β1 being more active than α2β1. This was also clear from the mean scores of laminin-containing surfaces (α6β1 binding), which performed better than GFOGER- or decorin-containing surfaces (α2β1 binding) (Supplementary Table 2).

Bottom Line: Three types of thrombus formation can be identified with a predicted hierarchy of the following receptors: glycoprotein (GP)VI, C-type lectin-like receptor-2 (CLEC-2)>GPIb>α6β1, αIIbβ3>α2β1>CD36, α5β1, αvβ3.Application with patient blood reveals distinct abnormalities in thrombus formation in patients with severe combined immune deficiency, Glanzmann's thrombasthenia, Hermansky-Pudlak syndrome, May-Hegglin anomaly or grey platelet syndrome.We suggest this test may be useful for the diagnosis of patients with suspected bleeding disorders or a pro-thrombotic tendency.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.

ABSTRACT
Assays measuring platelet aggregation (thrombus formation) at arterial shear rate mostly use collagen as only platelet-adhesive surface. Here we report a multi-surface and multi-parameter flow assay to characterize thrombus formation in whole blood from healthy subjects and patients with platelet function deficiencies. A systematic comparison is made of 52 adhesive surfaces with components activating the main platelet-adhesive receptors, and of eight output parameters reflecting distinct stages of thrombus formation. Three types of thrombus formation can be identified with a predicted hierarchy of the following receptors: glycoprotein (GP)VI, C-type lectin-like receptor-2 (CLEC-2)>GPIb>α6β1, αIIbβ3>α2β1>CD36, α5β1, αvβ3. Application with patient blood reveals distinct abnormalities in thrombus formation in patients with severe combined immune deficiency, Glanzmann's thrombasthenia, Hermansky-Pudlak syndrome, May-Hegglin anomaly or grey platelet syndrome. We suggest this test may be useful for the diagnosis of patients with suspected bleeding disorders or a pro-thrombotic tendency.

Show MeSH
Related in: MedlinePlus