Page 45 - Haematologica March 2020

HISTORY, a plasminogen deficiency registry
Table 3. Details of the study visits. Assessments
Informed consent
Re-consent (if minor reaches 18 years)
Eligibility criteria
Demographics
Laboratory investigations Plasminogen antigen level Plasminogen activity level Genetic testing
Family history
Baseline
X
X X
X X X
X
Year One
Year Two
Year Three Unscheduled*
6 months
12 months
18 months
24 months
30 months
36 months
X
X XX
X
Medical history
Initial comprehensive history/review
of systems
Medical history since last visit (procedures, pregnancy, treatment, other symptoms or complications, etc.)
Concurrentmedications X
X
XXXXXXX
X X X X X X X
*Additional data will be collected at the time of an unscheduled visit for re-consent, illness, pregnancy (plasminogen activity level and banked plasma will be collected at con- firmation of pregnancy,during the third trimester and at delivery),and development of lesions.
should be used, or how frequently clinical visits should occur to monitor for symptoms to ensure early interven- tion and prevent sequelae. Furthermore, it is unknown if treatment should be lifelong, intermittent, or may be withdrawn over time and how this varies by patient, dis- ease severity, and affected system.
All non-specific therapeutic interventions to treat acute and chronic manifestations of PLGD will be recorded, along with efficacy, safety and complications. Specific treatments, including ophthalmological plasminogen drops and systemic intravenous plasminogen replace- ment therapy are currently under clinical investigation;14,34 any use of these investigational agents will also be record- ed. Currently, data to support wider real-world optimal therapeutic regimens are lacking. There are no standard dosing regimens for intravenous plasminogen replace- ment therapy and the required minimal plasminogen plasma levels to treat or prevent specific manifestations are unknown; treatment for each patient must be individ- ualized based on their pharmacokinetic profile.14 HISTO- RY will explore development of a population pharmaco- kinetic model46 for the investigational intravenous plas- minogen concentrate14 to estimate plasma levels and adjust doses if symptoms emerge.
Factors that correlate with disease expression and severity
No screening test for PLGD exists; specific plasminogen activity/antigen levels are required, but assays are not uniformly available. This study will collect methodologi- cal details of locally performed tests to review their diag- nostic utility; testing will be repeated centrally to confirm diagnosis and local assay utility. Peyvandi et al. demon- strated that clotting level activity in some rare bleeding disorders does not correlate with clinical bleeding severi- ty.43 Published data suggest that this may also be true for PLGD; therefore, global coagulation assays (including thrombin generation, thromboelastography, simultane- ous thrombin/plasmin generation and fibrinolytic poten- tial)47-50 will be performed to evaluate their utility in phe- notypic prediction and clinical management.
Table 4. Demographics of the initial 51 enrolled subjects.
Demographics
Gender Male
Female
Subjects with plasminogen deficiency
9 15
Unaffected family members
11 16
Age
<18years 14 8 ≥18 years 10 19
Ethnicity
White 21 22 Hispanic/Latino 3 5
Consanguineous parentage
Yes 0 0 No 22 27
Unknown
Endogenous plasminogen activity Median (%)
Range (%)
Endogenous plasminogen antigen Median (mg/dL)
Range (mg/dL)
n/a: not applicable.
2 0
18.5 n/a 1 - 42 n/a
3.4 n/a
1 - 12 n/a
The true prevalence of PLGD is not well established and likely depends on the population in any particular region or country; similarly, the genetic alterations influ- encing disease expression and severity are not well defined. A genome-wide association study conducted by Ma et al. determined genetic modifiers of plasminogen levels in normal adults;51 the study revealed that four sin- gle nucleotide polymorphisms were associated with vari- ations in plasminogen levels. How these variations affect the severity or progression of PLGD is unknown. The PLG(K38E) mutation is known to result in a milder clini- cal course;12,13 conversely, other mutations are known to not be predictive (for example, in one family with the conserved W597C mutation, one member was asympto- matic, another had ligneous periodontitis, and a third had
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