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Platelet function in genetic immune deficiencies
in FERMT3 (kindlin-3) resulted in impaired thrombus for- mation and a clear bleeding phenotype.33 Furthermore, both ORAI1-deficient and ORAI1R93W mouse platelets were found to be partly defective in procoagulant activity (PS exposure), along with the annulled SOCE activity.8,11,29
In the present study, we observed even more variable platelet phenotypes in the 9 patients/relatives with a
mutation in ORAI1, STIM1 or FERMT3. Heatmap analy- sis indicated extensive but distinct patterns of reduced thrombus formation between patients, compared to blood from cohorts of healthy control subjects. Blood analysis further indicated that most patients/relatives carrying such a mutation had platelet counts below or near the lower range of normal. Low platelet count was found to corre-
A
B
C
Figure 5. Integrated analysis of thrombus formation for patients with ORAI1, STIM1 or FERMT3 mutations. Thrombus formation on three microspots was measured with blood from home controls (HC1-12), travel controls (C1-6) and indicated patients/relatives with a genetic mutation in ORAI1 (P1-5), STIM1 (P6) or FERMT3 (P7- 9), at wall-shear rate of 1600 s-1, as for Figure 4. Coding of microspots: Sp1, collagen type I; Sp2, von Willebrand Factor (VWF)/rhodocytin; Sp3, VWF/fibrinogen. Coding of outcome parameters: V1, thrombus morphological score (scale 0-5); V2, platelet surface area coverage (% SAC); V3, thrombus contraction score (scale 0- 3); V4, thrombus multilayer score (scale 0-3); V5, phosphatidylserine (PS) exposure (% SAC); V6, P-selectin expression (% SAC); V7, αIIbβ3 activation (% SAC). Data were scaled per parameter from 0-10. (A) Heatmap of scaled values for control groups HC1-12 and C1-6 (means); and of scaled values for individual patients (*) and relatives. (B) Subtraction heatmap of scaled values, compared to those from HC1-12. (C) Subtraction heatmap after filtering for differences considered to be relevant, i.e. outside the range of mean ± 2 SD (HC1-12).
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