ATHN Transcends: A Natural History Cohort Study of the Safety, Effectiveness, and Practice of Treatment in People With Non-Neoplastic Hematologic Disorders
In parallel with the growth of American Thrombosis and Hemostasis Network's (ATHN) clinical studies, the number of new therapies for all congenital and acquired hematologic conditions, not just those for bleeding and clotting disorders, is increasing significantly. Some of the recently FDA-approved therapies for congenital and acquired hematologic conditions have yet to demonstrate long-term safety and effectiveness beyond the pivotal trials that led to their approval. In addition, results from well-controlled, pivotal studies often cannot be replicated once a therapy has been approved for general use.(1,2,3,4) In 2019 alone, the United States Food and Drug Administration (FDA) has issued approvals for twenty-four new therapies for congenital and acquired hematologic conditions.(5) In addition, almost 10,000 new studies for hematologic diseases are currently registered on www.clinicaltrials.gov.(6) With this increase in potential new therapies on the horizon, it is imperative that clinicians and clinical researchers in the field of non-neoplastic hematology have a uniform, secure, unbiased, and enduring method to collect long-term safety and efficacy data. ATHN Transcends is a cohort study to determine the safety, effectiveness, and practice of therapies used in the treatment of participants with congenital or acquired non-neoplastic blood disorders and connective tissue disorders with bleeding tendency. The study consists of 7 cohorts with additional study arms and modules branching off from the cohorts. The overarching objective of this longitudinal, observational study is to characterize the safety, effectiveness and practice of treatments for all people with congenital and acquired hematologic disorders in the US. As emphasized in a recently published review, accurate, uniform and quality national data collection is critical in clinical research, particularly for longitudinal cohort studies covering a lifetime of biologic risk.(7)
⁃ Any age
⁃ Having a congenital or acquired non-neoplastic hematologic disorder; or
⁃ Having a bleeding phenotype as indicated by an age adjusted abnormal ISTH Bleeding Assessment Tool score with an unknown diagnosis; or
⁃ Connective tissue disorder with bleeding tendency as indicated by an age adjusted abnormal ISTH Bleeding Assessment Tool score.
‣ Participants who meet any of the following inclusion criteria are eligible for enrollment into this cohort:
⁃ Factor VIII or factor IX activity \< 50%, without another explanation for low clotting factor other than congenital hemophilia or being a known carrier for congenital hemophilia; OR
⁃ Being a known carrier for congenital hemophilia with a factor VIII or factor IX activity greater than or equal to 50% with or without a bleeding phenotype as indicated by an age-adjusted abnormal ISTH Bleeding Assessment Tool score; OR
⁃ Known congenital hemophilia that have a factor level \>50% after receiving vector; OR
⁃ Acquired hemophilia
‣ Participants who meet the following inclusion criteria are eligible for enrollment into this cohort:
‣ 1\. Meeting the definition of VWD or low VWF per most recent international guidelines
‣ Participants who meet the following inclusion criteria are eligible for enrollment into this cohort:
⁃ Abnormalities of platelet function
∙ Glanzmann thrombasthenia (GPIIb or GPIIIa)
‣ Bernard-Soulier syndrome (GPIbalpha, GPIbbeta, or GPIX)
⁃ Abnormalities of platelet granules
⁃ Abnormalities of platelet signal transduction
⁃ Abnormalities of platelet secretion
⁃ Collagen Receptor Defect
⁃ ADP Receptor Defect
⁃ Thromboxane Receptor Defect
⁃ Giant Platelet Disorder
⁃ Abnormalities in platelet aggregation testing due to another or unknown cause (not drug related)
‣ Participants who meet the following inclusion criteria are eligible for enrollment into this cohort:
‣ 1\. Have an established Rare Coagulation Disorder (RCD) diagnosis of one of the following:
⁃ PAI-1 deficiency
⁃ Factor I, II, V, VII, X, XI, XIII deficiencies
⁃ Combined FV and FVIII deficiency
⁃ Plasminogen deficiency
⁃ Decreased tissue plasminogen activator
⁃ Afibrinogenemia/hypofibrinogenemia/dysfibrinogenemia
‣ Participants who meet the following inclusion criteria are eligible for enrollment into this cohort:
⁃ Have a bleeding phenotype as indicated by an age-adjusted abnormal ISTH Bleeding Assessment Tool score with an unknown diagnosis; OR
⁃ Connective tissue disorder with bleeding tendency as indicated by an age-adjusted abnormal ISTH Bleeding Assessment Tool score
‣ Participants who meet the following inclusion criteria are eligible for enrollment into this cohort:
⁃ Have a prior history of arterial or venous thrombosis
⁃ Patients with a known congenital or acquired thrombophilia with or without a thrombosis a. Common congenital thrombophilias:: i. Protein C deficiency ii. Protein S deficiency iii. Antithrombin deficiency iv. Factor V Leiden v. Prothrombin gene mutation b. Rare genetic factors i. Hyperhomocysteinemia c. Indeterminate genetic factors i. Elevated factor VIII ii. Elevated factor IX iii. Elevated factor XI iv. Elevated lipoprotein (a) d. Acquired thrombophilias i. Lupus anticoagulant ii. Anti-cardiolipin antibodies/Beta2 glycoprotein antibodies iii. Antiphospholipid syndrome
‣ Participants who meet the following inclusion criteria are eligible for enrollment into this cohort:
‣ 1\. Having any congenital or acquired non-neoplastic hematologic disorder not included in any other cohort
⁃ Age \<18 years at time of enrollment
⁃ Parent or authorized guardian or legally authorized representative (LAR) can provide informed consent
⁃ Care established at one of the participating HTCs
⁃ Diagnosis of severe factor VIII deficiency with baseline factor VIII level \<1%
⁃ Initiating or plan to initiate prophylaxis with emicizumab or factor replacement
⁃ Factor exposure, plasma/FFP, cryo, and single donor platelets ≤3 EDs
⁃ ≤5 years of age
• People with severe HA with a baseline FVIII activity of less than 1%. (While inclusion for participation in ATHN Transcends lists \<5% FVIII activity, this proposed module will limit enrollment to people with FVIII activity levels of \<1%)
• \<18 years of age
• No history of FVIII inhibitor
• Sex at birth of male, female, or intersex
• Participants may be exposed to unfractionated blood components, no more than one dose of FVIII concentrate other than efanesoctocog alfa and up to three doses of efanesoctocog alfa prior to enrollment
• Potential participants who have a history of bleeding will be eligible for participation if they meet all other inclusion criteria
‣ 1\. Congenital hemophilia A or B of any severity with or without inhibitors receiving a current therapy, a non-factor product, or for whom use of a non-factor product is a possibility.
‣ Participants who meet the following inclusion criteria at the time of screening are eligible to enroll in the study module.
‣ Rebinyn® Cohort
⁃ Has provided signed written consent for the Rebinyn® Module before any study-related activities.
⁃ Male participants, at any age with hemophilia B, naïve or minimally exposed (up to 3 EDs) to nonacog beta pegol treatment at time of study enrollment.
⁃ Decision to initiate treatment with commercially available nonacog beta pegol has been made by the participant(s)/Legally Authorized Representative(s) (LAR(s)) and the treating physician before and independently from the decision to include the participant in this study.
‣ Rebinyn® RWE Cohort
⁃ Has provided signed written consent for ATHN Transcends Study before any study-related activities.
⁃ Currently treated with nonacog beta pegol
⁃ Any age
⁃ Hemophilia A or B of any severity with or without inhibitors having received or will receive a hemophilia gene transfer product in the next 6 months.
⁃ Age 18 years and older
⁃ Able to give informed consent.
⁃ HEMGENIX Cohort • Age 18 years of age or older
⁃ • Treatment with commercial HEMGENIX
⁃ • Have provided signed written informed consent within 3 months before or within 6 months after HEMGENIX treatment, or within 6 months of when the study is initiated at the treating site.
‣ <!-- -->
⁃ Platelet adhesion defect
∙ Bernard Soulier syndrome (Defective GPIb-IX-V receptor, impaired adhesion to VWF)
‣ Velocardio-facial syndrome/DiGeorge syndrome (Defective GPIb-IX-V receptor)
‣ Platelet type vWD (Defective GPIb-IX-V, gain of function interaction between VWF-GP1bα)
⁃ Platelet aggregation defect
∙ Glanzmann thrombasthenia (Defective integrin αIIbβ3 (GPIIb/IIIa)
‣ Platelet aggregation defect, NOS
⁃ Agonist receptor defects
∙ Epinephrine
‣ ADP
‣ Collagen
‣ Thromboxane A2
⁃ Platelet signaling defects
∙ Cyclooxygenase deficiency (PTGS1 mutation)
‣ Phospholipase A2 deficiency
‣ Thromboxane synthase deficiency (TBXAS1 mutation)
‣ G protein activation defect (GNAS mutation)
‣ Scott syndrome (defect in phosphatidyl serine translocation)
⁃ Platelet Granule disorders
∙ Dense granule storage pool disorder • Hermansky Pudlak syndrome
⁃ Chediak Higashi syndrome
• Griscelli syndrome
‣ Alpha granule storage pool disorder
∙ • Grey platelet syndrome
• Arthrogryposis-Renal Dysfunction-Cholestasis (ARC) syndrome
• Quebec platelet disorder
• Paris-Trousseau syndrome
‣ Combined alpha delta granule deficiency
⁃ Platelet cytoskeletal structure defects
∙ Wiskott Aldrich syndrome
‣ MYH9 associated disorders (myosin heavy chain)
∙ • May Hegglin syndrome
∙ • Fechtner syndrome
• Sebastian syndrome
• Epstein syndrome
‣ Other mutations • FLNA mutations (Filamin) • DIAPH1 (Actin and microtubules) • ACTN1 (alpha actinin) • TPM4 (tropomyosin)
⁃ TUBB1 (beta tubulin)
⁃ Other Congenital thrombocytopenias
∙ Familial platelet disorders and predisposition to AML (RUNX1)
‣ X linked thrombocytopenia with dyserythropoiesis (GATA1)
‣ Congenital amegakaryocytic thrombocytopenia (MPL)
‣ 1\. Participant has signed the informed consent/assent form 2. Participant has flow cytometry or aggregometry or genetics confirmed GT 3. Participant is willing to perform study procedures, including daily bleed tracking for 3 months