DDAVP Response in Symptomatic Carriers


Status: Recruiting
Keywords: Hemophilia , Carrier
IRB Number: 00062253
Specialty: Hematology/BMT
Sub Specialties:

Brief Summary

Study Objectives:

AIM 1: To determine if DDAVP response correlates with genotype in Symptomatic Carriers of Hemophilia A(SCHA).

Female carriers of hemophilia A, a bleeding disorder with decrease or absence of the clotting factor VIII, can experience bleeding symptoms when their factor VIII level is low, usually less than 40% of normal (0.4 IU mL-1). Desmopressin Acetate (1-deamino-8-D-arginine-vasopressin, DDAVP) is an important therapy in patients with mild hemophilia A (MHA) and SCHA to prevent bleeding symptoms after trauma or minor surgical procedures and to treat bleeding symptoms such as menorrhagia or epistaxis. DDAVP is a synthetic analog of vasopressin, a potent natural antidiuretic hormone that also has the property, at supraphysiologic levels, of causing release of body stores of factor VIII and Von Willebrand Factor (VWF) which boosts circulating levels between 2-5 times baseline levels. This rapid, but transient, release of the patients own factor can raise factor levels sufficiently to promote hemostasis(make a good clot) in many individuals.[5] A trial of DDAVP prior to first use is recommended because not all patients respond to DDAVP nor is it tolerated in all individuals or sufficient for all bleeding or surgical interventions. Recent publications have shown a correlation between the genotype responsible for FVIII deficiency and the response to DDAVP in MHA (discussed below).[6, 7] It is unknown if these responses can be generalized to include SCHA.

The laboratory testing schedule after screening and meeting inclusion criteria will be a standard, FDA approved DDAVP trial with the intranasal preparation of DDAVP (300ug for patients >50kg and 150mg for patients ≤50 kg) and to be administered once during days 1-4 of the menstrual cycle, if patient is menstruating, otherwise at the convenience of the patient. In women, FVIII:C and VWF levels are known to be at their lowest during days 1-4 of the menstrual cycle, therefore, testing during this phase of the cycle should capture the lowest level and reflect the greatest bleeding risk. The DDAVP trial laboratory testing set would include a standard set of coagulation parameters: pre-infusion CBC, FVIII:C, FVIII:Ag, PTT, VWF:RCo, VWF:Ag, basic metabolic panel (serum sodium, potassium, chloride, carbon dioxide, creatinine, blood uria nitrogen, and calcium), and ferritin; 60 min post-infusion FVIII:C, FVIII:Ag, PTT, VWF:RCo, VWF:Ag; and 4 hr post-infusion FVIII:C, FVIII:Ag, PTT, VWF:RCo, VWF:Ag. In the event of a failed DDAVP test, or inconsistent results, the DDAVP testing would be repeated. If factor testing is within the normal range, then additional testing of platelet aggregation and other factor levels may be offered as part of standard of care. These results would be recorded as part of the study data.

Phenotype of the male relative and genotype (if known) would be recorded and tabulated against the magnitude and duration of response to DDAVP. 

AIM 2: To assess if DDAVP response changes during the reproductive years in SCHA.

Many women experience changes in their factor levels during the reproductive years. Oral contraceptive pills and pregnancy typically increase clotting factor levels. No studies have looked at the changes in factor levels in SCHA according to their reproductive status, or if their response to DDAVP might also change (get better or worse). The reproductive status of the patient will be recorded with the response to DDAVP and results among patients will be grouped according to the reproductive status (ie, patients who are currently menstruating, on oral contraceptives, currently pregnant or pre or post menopausal). If the reproductive status of a patient changes, ie she begins taking hormonal therapy, becomes pregnant or undergoes menopause, then a repeat DDAVP challenge would be considered, depending on the clinical scenario and appropriateness of therapy.

AIM 3: To assess frequency of bleeding symptoms in SCHA, presence of anemia, and clinical response to DDAVP, subjective (patient perceived reduction in bleeding symptoms) and objective (reduced need for additional hemostatic therapy after the use of DDAVP).

This AIM will be achieved through the administration of a standard questionnaire through a 30 to 45 minute interview focused on bleeding symptoms that the woman has experienced in her past with emphasis on gynecologic and obstetric bleeding and surgical bleeding. If the patient has utilized DDAVP in the past for treatment of a bleeding symptom, her perception of efficacy will be recorded along with the need for any additional treatments if it was not efficacious. If she utilizes DDAVP during the study period, then her perception of efficacy (subjective) as well as any additional treatments required (objective) will be recorded.

Principal Investigator: Danielle Nance
Department: Hematology
Co Investigator: George Rodgers

Contact Information

Name:Danielle Nance
Phone: 801-585-2626
Email: danielle.nance@hsc.utah.edu

Inclusion Criteria

Females of male relatives with a diagnosis of hemophilia A.

Number of patients and rationale: The initial goal of enrollment would be for 60 patients, 20 from each mutation severity type, as classified according phenotype of male relative (some mutations can have severe to moderate [FVIII:C <0.01-0.04 IU mL-1] or moderate to mild [FVIII:C 0.01-0. 04 IU mL-1 or greater] phenotype). Patients would be identified within the Intermountain Thrombosis and Hemophilia Treatment Center at Primary Children’s Medical Center and the University of Utah Health Sciences Medical Center. Patients would be enrolled until the goals for enrollment were met or until July 2014. The goal of enrollment of 60 patients is arbitrary, based on the number of mutations that can cause hemophilia A (~2100 so far discovered).

  1. Proven female carrier of a mutation in the F8 gene (by direct F8 mutation analysis, haplotype analysis or obligate carrier/father with F8 deficiency),
  2. Baseline FVIII:C level <0.4 IU mL-1, or symptomatic bleeding.
  3. Age >12 – 64 years old, and
  4. Documented informed consent obtained prior to enrollment in the study and prior to any study procedures. For patients under the age of 16, both informed consent from the guardian/parent and assent from the patient would be obtained prior to study enrollment.

Potential study subjects who have already had FVIII:C testing would go on to the consenting process. Patients who have no previous FVIII:C level would be offered a blood test for FVIII:C testing. The process of screening female relatives of male patients may also serve to identify additional females who are at risk of bleeding and enable an educative session by a trained hemophilia treatment center staff regarding risk of bleeding and appropriate treatments for bleeding symptoms that otherwise may have gone unrecognized and untreated. Patients who meet inclusion criteria and agree to participate will also have a ferritin level checked to assess presence or absence of anemia (objective measure of degree of symptomatic involvement).

Exclusion Criteria

  1. Subjects with any other bleeding disorder besides hemophilia A
  2. Age <12 or >65
  3. A condition that would be contraindicated with DDAVP administration (ie hypersensitivity to DDAVP, preexisting hyponatremia or previous history of hyponatremia, renal impairment moderate to severe, uncontrolled hypertension, heart failure, previous intracranial hemorrhage).
  4. Physiologic abnormality or condition of the nasal passages and/or mucosa that would interfere with optimal intranasal delivery of DDAVP.
  5. Baseline FVIII:C levels ≤0.04 IU mL-1.
  6. Subjects who are unwilling to comply with any of the treatments or visits.
  7. Subjects who are not suitable for participation in this investigation for any reason according to the investigator.