Bleeding risks for uncharacterized platelet function disorders

Abstract

Background The bleeding risks for nonsyndromic platelet function disorders (PFDs) that impair aggregation responses and/or cause dense granule deficiency (DGD) are uncertain. Objectives Our goal was to quantify bleeding risks for a cohort of consecutive cases with uncharacterized PFD. Methods Sequential cases with uncharacterized PFDs that had reduced maximal aggregation (MA) with multiple agonists and/or nonsyndromic DGD were invited to participate along with additional family members to reduce bias. Index cases were further evaluated by exome sequencing, with analysis of RUNX1 ‐dependent genes for cases with RUNX1 sequence variants. Bleeding assessment tools were used to estimate bleeding scores, with bleeding risks estimated as odds ratios (ORs) relative to general population controls. Relationships between symptoms and laboratory findings were also explored. Results Participants with uncharacterized PFD (n = 37; 23 index cases) had impaired aggregation function (70%), nonsyndromic DGD (19%) or both (11%), unlike unaffected relatives. Probable pathogenic RUNX1 variants were found in 2 (9%) index cases/families, whereas others had PFD of unknown cause. Participants with PFD had increased bleeding scores compared to unaffected family members and general population controls, and increased risks for mucocutaneous (OR, 4‐207) and challenge‐related bleeding (OR, 12‐43), and for receiving transfusions for bleeding (OR, 100). Reduced MA with collagen was associated with wound healing problems and bruising, and more severe DGD was associated with surgical bleeding ( P < .04). Conclusions PFDs that impair MA and/or cause nonsyndromic DGD have significantly increased bleeding risks, and some symptoms are more common in those with more severe DGD or impaired collagen aggregation.

Thrombin generation abnormalities in commonly encountered platelet function disorders

“…3 While some of these PFD are caused by pathogenic RUNX1 mutations (PFD-RUNX1), others are caused by uncharacterized molecular defects that manifest with nonsyndromic DGD (PFD-DGD) or impaired aggregation responses to multiple agonists (PFD-OTH). 3 At present, there are uncertainties about how these PFD affect TG.…”

“…First, platelet aggregation influences TG 4 and in some PFD (including PFD-RUNX1), platelet activation and aggregation are impaired. 3,5 Second, TG by normal platelets is increased by platelet-activating agonists. 6 Third, platelet DG store and release constituents that affect TG, including ADP that enhances TG by promoting platelet activation and polyphosphate that directly accelerates TG.…”

“…[10][11][12][13][14][15] Accordingly, we used CAT with PRP and PPP to conduct a pilot study of a well-characterized, PFD cohort, with increased risks for mucocutaneous and challenge-related bleeding. 3 This cohort included persons with PFD-DGD, PFD-RUNX1, and PFD-OTH. 3,16 We also assessed other parameters that are known to influence TG, including (a) tissue factor pathway inhibitor (TFPI) 17,18 which influences TG in Quebec platelet disorder (QPD), 14 coagulation factor deficiencies, 17,19 and bleeding of unknown cause (BUC) 20 ;…”

“…3 This cohort included persons with PFD-DGD, PFD-RUNX1, and PFD-OTH. 3,16 We also assessed other parameters that are known to influence TG, including (a) tissue factor pathway inhibitor (TFPI) 17,18 which influences TG in Quebec platelet disorder (QPD), 14 coagulation factor deficiencies, 17,19 and bleeding of unknown cause (BUC) 20 ;…”

“…22,23 We postulated that characterizing ANO6 expression in our cohort might provide new insights as PFD-RUNX1 are known to alter the expression of many genes. 3,24 Finally, we looked for potential relationships between findings and bleeding, using data on symptoms and bleeding scores for our PFD cohort. 3…”