A Pilot Study of N-acetylcysteine in Thrombotic Thrombocytopenia Purpura
| Status: | Enrolling by invitation |
|---|---|
| Conditions: | Hematology |
| Therapuetic Areas: | Hematology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 4/21/2016 |
| Start Date: | May 2013 |
| End Date: | March 2017 |
A Pilot Study of N-acetylcysteine in Suspected Thrombotic Thrombocytopenia Purpura
In this study, the investigators want to determine if N-acetylcysteine(NAC), given
intravenously, will decrease complications in patients with Thrombotic Thrombocytopenia
Purpura (TTP) who are receiving treatment with therapeutic plasma exchange (TPE). The
investigators want to determine, through anti-oxidant activity, if NAC will have additional
efficacy in TTP by improving cleavage of the patients' VWF by ADAMTS13, and preventing
propagation of platelet/VWF strings. This will be manifest by a more rapid improvement in
the patient's platelet count, decrease in number of days requiring TPE, and decrease in
microvascular thrombotic complications. The investigators will additionally: 1) Assess
safety of NAC by evaluating subjects for adverse events and significant adverse events 2)
Determine effects on TTP by measuring clinical and research laboratory values 3) Determine
drug effects by measuring clinical and research laboratory values.
intravenously, will decrease complications in patients with Thrombotic Thrombocytopenia
Purpura (TTP) who are receiving treatment with therapeutic plasma exchange (TPE). The
investigators want to determine, through anti-oxidant activity, if NAC will have additional
efficacy in TTP by improving cleavage of the patients' VWF by ADAMTS13, and preventing
propagation of platelet/VWF strings. This will be manifest by a more rapid improvement in
the patient's platelet count, decrease in number of days requiring TPE, and decrease in
microvascular thrombotic complications. The investigators will additionally: 1) Assess
safety of NAC by evaluating subjects for adverse events and significant adverse events 2)
Determine effects on TTP by measuring clinical and research laboratory values 3) Determine
drug effects by measuring clinical and research laboratory values.
Thrombotic thrombocytopenic purpura (TTP) is a rare hemostatic disorder with life
threatening consequences secondary to microvascular thrombosis. While the use of therapeutic
plasma exchange (TPE) has greatly improved survival, end organ damage, resistance to
therapy, and relapses occur in many patients. Ultra-large von Willebrand factor multimers
(ULVWF) are pathogenic in TTP. The investigators have found that N-acetylcysteine (NAC)
cleaves ULVWF in vitro and in vivo in the ADAMTS13 deficient mice that are at increased risk
of TTP. NAC is well tolerated in humans at intravenous doses used for treatment of
acetaminophen overdose. This dosage correlates with that producing an effect in the murine
studies noted above, and thus is an attractive treatment for patients with TTP. By cleaving
VWF and preventing propagation of platelet/VWF strings, the investigators hypothesize that
NAC treatment will decrease complications in patients with TTP receiving treatment with TPE.
This will be manifest by a more rapid improvement in platelet count, decrease in number of
days requiring plasma exchange, and decrease in microvascular thrombotic complications. To
prepare for a larger trial the investigators propose a pilot study in 3 patients with
suspected TTP at the University of Washington (UW) Medical Center. The study will be
approved by the UW IRB prior to study initiation. Patients who consent to the study will
receive daily NAC infusions beginning after the first TPE, in doses used for acetaminophen
overdose. Blood samples will be collected for laboratory assays to determine optimal timing
for sample collection in the larger multicenter trial, and to pilot the data collection
forms. The investigators will also evaluate safety and patient tolerability.
threatening consequences secondary to microvascular thrombosis. While the use of therapeutic
plasma exchange (TPE) has greatly improved survival, end organ damage, resistance to
therapy, and relapses occur in many patients. Ultra-large von Willebrand factor multimers
(ULVWF) are pathogenic in TTP. The investigators have found that N-acetylcysteine (NAC)
cleaves ULVWF in vitro and in vivo in the ADAMTS13 deficient mice that are at increased risk
of TTP. NAC is well tolerated in humans at intravenous doses used for treatment of
acetaminophen overdose. This dosage correlates with that producing an effect in the murine
studies noted above, and thus is an attractive treatment for patients with TTP. By cleaving
VWF and preventing propagation of platelet/VWF strings, the investigators hypothesize that
NAC treatment will decrease complications in patients with TTP receiving treatment with TPE.
This will be manifest by a more rapid improvement in platelet count, decrease in number of
days requiring plasma exchange, and decrease in microvascular thrombotic complications. To
prepare for a larger trial the investigators propose a pilot study in 3 patients with
suspected TTP at the University of Washington (UW) Medical Center. The study will be
approved by the UW IRB prior to study initiation. Patients who consent to the study will
receive daily NAC infusions beginning after the first TPE, in doses used for acetaminophen
overdose. Blood samples will be collected for laboratory assays to determine optimal timing
for sample collection in the larger multicenter trial, and to pilot the data collection
forms. The investigators will also evaluate safety and patient tolerability.
Inclusion Criteria:
1. Age >= 18 years of age
2. Diagnosis of suspected TTP (lab evidence of hemolysis, platelet count <120,000,
schistocytes on peripheral smear)
3. Plans for or just initiated therapeutic plasma exchange (TPE), and before 3rd TPE
4. Normal baseline prothrombin time (PT) and activated partial thromboplastin time
(aPTT)
5. Anticipated TPE for > 5 days
Exclusion Criteria:
1. Asthma
2. Life expectancy < 1 week
3. Liver function tests abnormal- (ALT, direct bilirubin > three times upper normal
limit)
4. Known underlying bleeding disorder
5. Pregnancy or nursing
6. Known allergy to NAC
7. Phosphodiesterase Type 5 inhibitors, nitroglycerin, or carbamazepine current use
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