322.

DISORDERS OF COAGULATION OR FIBRINOLYSIS: POSTER I | NOVEMBER 29, 2018

Procoagulant Platelet Potential Is Inversely Correlated

with Bleeding and Joint Disease in Severe Hemophilia A
1,2 3,4 *,5
Shawn M. Jobe, MD PhD, Amy L. Dunn, MD, Traci Leong, PhD
1
Pediatrics, Medical College of Wisconsin, Milwaukee, WI
2
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI
3
Division of Hematology/Oncology/BMT, Nationwide Childrens Hospital, Columbus, OH
4
The Ohio State University, Columbus, OH
5
Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA

Blood (2018) 132 (Supplement 1) : 1185.

http://doi.org/10.1182/blood-2018-99-117989

Abstract
The variability of clinical phenotype in patients with severe hemophilia A (factor VIII activity < 1%)
has been well established, currently and in the era prior to wide-spread prophylaxis. The introduction
of prophylaxis as a treatment modifier of the natural history of severe hemophilia A has led to the
introduction of composite scores to assist in the assessment of disease severity. Perhaps the most
prominent of these is that proposed by Schulman et al (J Thromb Haem 2008;6(7):1113-21) which utilizes
three domains of phenotypic presentation to characterize a patient's clinical phenotype, acute (annualized
bleeding rate), chronic (joint status), and treatment intensity (normalized factor usage). However, the
biologic mechanisms driving this variability in clinical phenotype continue to remain largely uncertain.
Procoagulant platelet potential is an individual's ability to generate procoagulant platelets in response
to a standard concentration of agonist. This response, which generates platelets capable of intensely
supporting coagulation, tends to remain relatively constant and varies substantially between individuals.
A few small case-control studies have investigated the role of procoagulant platelet potential or platelet-
supported thrombin generation in mediating the phenotypic variability with discordant results.

The relationship of procoagulant platelet potential and platelet-supported thrombin generation to

phenotypic severity was investigated in a single-center cohort of 92 pediatric and adult severe hemophilia
A patients without active inhibitors. Procoagulant platelet potential (defined as the ratio of procoagulant
platelets / all activated platelets following stimulation with thrombin (0.5 units/mL) and convulxin (250 ng/
mL)) and the expression of other platelet activation markers, including P-selectin (granule release) and
PAC-1 (integrin activation) were investigated in washed platelets. Platelet-dependent thrombin generation
was investigated in a limited cohort (45) of these patients. Phenotypic data was collected in regard to
reported bleeding events over the past 5 years, joint health using the hemophilia joint health score,
intensity of factor therapy, and therapeutic intent (prophylaxis or on-demand). Correlations were assessed
as continuous variables using regression analysis with p <0.05 deemed significant.

Procoagulant platelet potential was inversely correlated with both acute (annualized bleeding rate) (r =
-0.47, p = 0.0006) and chronic measures (joint score) (r = -0.38, p = 0.0001) of phenotypic severity. In
contrast, when platelet-dependent thrombin generation or other markers of thrombin or GPVI-dependent
platelet activation potential were assessed i.e. P-selectin expression or PAC-1, no correlation was
identified with either acute or chronic measures of phenotypic severity or with the HSS composite
score. Surprisingly, when the composite score of HSS as defined by Schulman (acute + chronic +
factor utilization) was utilized to assess a potential relationship this correlation was not observed.
Further analysis revealed that this lack of correlation was due to the fact that therapeutic intensity (factor
utilization) was directlycorrelated with procoagulant platelet potential (r = 0.54, p = 0.0006).

Here we have identified a potentially critical role for procoagulant platelets as biologic modifiers of
hemophilia A. Furthermore, we have identified a risk associated with the use of a composite score in
assessing disease severity in hemophilia. Utilization of a composite score as the sole measure would
have missed the significant effects noted in each of the individual domains. Procoagulant platelets both
support thrombin generation and inflammatory cell recruitment. Thus, one potential hypothesis for these
opposing effects on the domains of the composite score is that increased procoagulant platelet formation
supports stable hemostatic plug formation (reduced bleeding rate) or increases inflammatory presentation
resulting in therapy intensification or both. Finally, our results here point towards new tools and pathways
for risk stratification and therapeutic modulation in patients with hemophilia A based on assessment of
procoagulant platelet potential.

Disclosures

Jobe: Shire: Consultancy; Octapharma: Consultancy; CSL: Consultancy.

Author notes
* Asterisk with author names denotes non-ASH members.

© 2018 by the American Society of Hematology