Platelet defects in patients and mice with Ehlers-Danlos syndrome, 2026, Kumskova et al.

[SNT Gatchaman]

Platelet defects in patients and mice with Ehlers-Danlos syndrome

Spoiler: Authors

Kumskova, Mariia; Flora, Gagan D; Nayak, Manasa K; Budnik, Ivan; Jain, Aditi; Patel, Rakesh B; Jha, Abhishek B; Ghatge, Madankumar; Chauhan, Neelam; Michael, James V; McKenzie, Steven E; Sharathkumar, Anjali; Staber, Janice M; Lentz, Steven R; Chauhan, Anil K

Ehlers-Danlos syndrome (EDS) is a group of connective tissue disorders characterized by joint hypermobility, skin hyperelasticity, perivascular tissue fragility, easy bruising, and increased bleeding risk. Abnormal bleeding in EDS ranges from mild ecchymoses to life-threatening hemorrhage. Platelet function abnormalities have been reported in people with EDS, but the broad nature and extent of these defects remain poorly defined.

Herein, we evaluated blood samples from people with the hypermobile, classical, classical-like, and vascular types of EDS, and used a Col5a1+/− mouse model of classical EDS to characterize the extent of platelet dysfunction. Our findings suggest that platelet dysfunction in EDS is an outcome of reduced integrin αIIbβ3 activation resulting from decreased phosphorylation of talin-1, leading to defects in aggregation and spreading.

The observed platelet dysfunction was associated with reduced expression of the platelet surface receptors glycoprotein VI (GPVI) and proteinase-activated receptor 1 (PAR1) and impaired downstream signaling. Col5a1+/− mice demonstrated increased tail bleeding time, reproduced the signaling defects observed in platelets from people with EDS, and exhibited decreased susceptibility to FeCl3-induced carotid artery thrombosis.

Collectively, our data indicate that platelet dysfunction in EDS is likely contributing to hemorrhagic complications.

KEY POINTS
Platelets in EDS exhibit reduced integrin αIIbβ3 activation, leading to impaired aggregation and spreading.

Platelet dysfunction in EDS is associated with decreased GPVI and PAR1 receptor expression and their impaired downstream signaling.

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[SNT Gatchaman]

Open access commentary in —

EDS: from Hippocrates to hyporeactive platelets

Spoiler: Authors

McFadyen; James D

In this issue of Blood, using a mouse model of classical Ehlers-Danlos syndrome (EDS) and platelets from patients with EDS, Kumskova et al have begun to uncover the extent and nature of platelet dysfunction in patients with EDS.

Web | DOI | PDF | Blood | Open Access

Quotes —

the recognition of EDS as a distinct clinical entity emerged in the early 20th century when Edvard Ehlers and Henri-Alexandre Danlos described patients with joint hypermobility, lax skin, and a propensity for easy bruising. Their early description led to the eponymous name of EDS, which is now recognized as a heterogeneous group of inherited connective tissue disorders. Indeed, there are currently 14 recognized subtypes of EDS, 13 of which have been defined at a molecular level.

Given that most subtypes of EDS are due to mutations in genes encoding fibrillar collagens or other molecules that play an important role in regulating the physical properties of the extracellular matrix, it has long been assumed that the bleeding symptoms observed in patients with EDS are simply due to vascular fragility.

However, more recently it has become appreciated that the cause of bleeding in EDS is almost certainly multifactorial, and not solely due to defects in vascular or connective tissue.

The authors initially thoroughly characterized the platelet phenotype of a large cohort of patients with EDS. Significantly, platelets from patients with EDS exhibited significant reductions in platelet aggregation in response to stimulation with either collagen-related peptide (CRP) or thrombin receptor activating peptide-6 (TRAP-6).

the authors demonstrated that this inhibition of platelet aggregation was due to impaired integrin αIIbβ3 activation, and diminished glycoprotein VI (GPVI) and protease-activated receptor 1 (PAR1)–linked downstream signaling.

In contrast, other platelet functional responses, such as alpha granule or dense granule exocytosis and phosphatidylserine exposure, were preserved. Interestingly, EDS platelets showed a reduction in both GPVI and PAR1 expression.

Because the patient cohort was comprised of patients with various subtypes of EDS, the authors then corroborated their findings in a mouse model of classic EDS (cEDS). cEDS is associated with haploinsufficiency of the collagen type V alpha 1 chain gene (Col5a1) in 30% to 50% of cases; therefore, the authors used a Col5a1+/− mouse model of EDS. […] it was striking how similar the phenotypes of platelets from Col5a1+/− mice were to patients with EDS. Indeed, platelets from Col5a1+/− mice demonstrated a reduction in integrin αIIbβ3 activation in response to CRP or protease-activated receptor 4–activating peptide stimulation and defects in platelet spreading, without any detectable differences in alpha granule exocytosis. Moreover, akin to human EDS platelets, Col5a+/− platelets demonstrated a reduction in PAR4 and GPVI expression and impaired downstream signaling events.

However, it must be noted that mouse platelets do not share the same repertoire of PAR receptors as human platelets […] Accordingly, whether human platelets demonstrate a reduction in PAR4 expression or signaling will require further investigation.

mouse platelets also demonstrated impaired functional responses to ADP stimulation, which suggests that the platelet defect, at least in Col5a1+/− mice, may be associated with a more global signaling defect. Therefore, further investigation will be required to fully unravel the precise mechanisms leading to the hyporeactive platelet phenotype in EDS, and perhaps more fundamentally to understand how a heterogenous clinical entity such as EDS gives rise to platelets with a reduction in the expression of key platelet receptors and/or pivotal signaling pathways.

these findings confirm that platelet dysfunction is common in EDS and contributes to the bleeding observed in this patient cohort. […] Second, the accurate detection of platelet dysfunction in patients with EDS may require platelet assays that use lower agonist concentration than commonly used in diagnostic laboratories. Lastly, this study nicely serves to illustrate that the causes of bleeding are often complex and multifactorial, yet by taking seemingly simple observations from the bedside to the bench, we can begin to resolve the often enigmatic nature of bleeding.

 

[Utsikt]

Herein, we evaluated blood samples from people with the hypermobile, classical, classical-like, and vascular types of EDS

How did they define the different types of EDS?

 

[Jonathan Edwards]

How did they define the different types of EDS?

On a brief look through the paper I did not see any specific genetics.

It seems odd to lump together a whole range of different genetic disorders of collagen and related proteins and use one mouse model of one particular defect. I am not sure why all these different defects should affect platelets the same way.

 

[Murph]

So EDS is linked to POTS, EDS shows reduced platelet aggregation, but Iwasaki and company were proposing increased platelet aggregation in ME/CFS?

It doesn't make sense yet, but not in a way that I'm dismissive of: I'm certainly paying attention.

This measurement they are making - integrin αIIbβ3 activation and phosphorylation of talin-1 - is one they could roll out in new disease cohorts. Fund them to do it on POTS, ME/CFS with POTS, ME/CFS no POTS, LC, etc.