Treatment of refractory thrombotic thrombocytopenic purpura with <i><scp>N</scp></i>‐acetylcysteine: a case report

Li, Gloria W.; Rambally, Siayareh; Kamboj, Jasmine; Reilly, Sean; Moake, Joel L.; Udden, Mark M.; Mims, Martha P.

doi:10.1111/trf.12440

Cited by 58 publications

(45 citation statements)

References 16 publications

(32 reference statements)

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“…NAC was recently evaluated as adjunctive TTP therapy, and was used to manage a PEX and corticosteroid-treated patient who had persistent thrombocytopenia, neurologic, and cardiac symptoms. 70,72 Despite the initiation of rituximab, the patient continued to deteriorate with coma, low blood pressure, and continued fever. NAC was initiated at 150 mg/kg IV over 1 hour after PEX, and daily NAC infusions were continued for 10 days at 150 mg/kg given over 17 hours after PEX.…”

Section: N-acetylcysteinementioning

confidence: 99%

How I treat refractory thrombotic thrombocytopenic purpura

Sayani¹,

Abrams

2015

Blood

143

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Acquired thrombotic thrombocytopenic purpura (TTP) is characterized by thrombocytopenia and microangiopathic hemolytic anemia (MAHA) without an obvious cause, and may include fever, mild renal failure, and neurologic deficits. It is characterized by a deficiency of the von Willebrand factor (VWF) cleaving enzyme, ADAMTS13 (a disintegrin and metalloproteinase, with a thrombospondin type 1 motif, member 13), resulting in formation of microthrombi in the high sheer environment of the microvasculature. This causes microvascular occlusion, MAHA, and organ ischemia. Diagnosis is based on the presence of clinical symptoms, laboratory aberrations consistent with MAHA, decreased ADAMTS13 activity, and possibly presence of anti-ADAMTS13 autoantibodies. Upfront treatment of acute TTP includes plasma exchange and corticosteroids. A significant number of patients are refractory to this treatment and will require further interventions. There are limited data and consensus on the management of the refractory TTP patient. Management involves simultaneously ruling out other causes of thrombocytopenia and MAHA, while also considering other treatments. In this article, we describe our management of the patient with refractory TTP, and discuss use of rituximab, increased plasma exchange, splenectomy, and immunosuppressive options, including cyclophosphamide, vincristine, and cyclosporine. We also review recent evidence for the potential roles of bortezomib and N-acetylcysteine, and explore new therapeutic approaches, including recombinant ADAMTS13 and anti-VWF therapy. (Blood. 2015;125(25):3860-3867) Case A 25-year-old previously healthy woman presented with a 3-day history of fatigue, nausea, abdominal pain, and easy bruising. She was alert, oriented, afebrile, had mild abdominal tenderness, and purpura on her extremities. Her hemoglobin was 8.4 g/dL; platelets, 15 3 10 9 /L; creatinine, 1.1 mg/dL; and her lactate dehydrogenase and reticulocytes were increased. Schistocytes and nucleated red blood cells were easily seen on her peripheral blood smear. In the absence of other obvious precipitators of thrombocytopenia and microangiopathic hemolytic anemia (MAHA), she was diagnosed with acquired thrombotic thrombocytopenic purpura (TTP). Blood samples were sent for ADAMTS13 (a disintegrin and metalloproteinase, with a thrombospondin type 1 motif, member 13) activity and inhibitor levels, and the patient was immediately started on plasma exchange (PEX) and prednisone 1 mg/kg per day. She responded well initially, and her platelets rose to 105 000/mL on day 4. However, on day 5, she was febrile and her platelets dropped to 40 000/mL. BackgroundAcquired TTP was initially characterized by thrombocytopenia, MAHA, renal failure, neurologic deficits, and fever. However, it is now well accepted that neither renal failure nor high fevers are key diagnostic features. Thrombocytopenia and MAHA are required for diagnosis when TTP is suspected. TTP is a hematologic emergency, with a mortality of 90% if untreated. Treatment with PEX and cortico...

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Section: N-acetylcysteinementioning

confidence: 99%

How I treat refractory thrombotic thrombocytopenic purpura

Sayani¹,

Abrams

2015

Blood

143

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“…17 This compound, which is clinically used for chronic obstructive lung disease, reduces the size of VWF multimers by selective breakage of intermolecular disulfide bonds.…”

Section: Discussionmentioning

confidence: 99%

“…16 A recent case report described the successful treatment of an acquired TTP patient who was unresponsive to plasma exchange with N-acetylcysteine. 17 This compound, which is clinically used for chronic obstructive lung disease, reduces the size of VWF multimers by selective breakage of intermolecular disulfide bonds. 18 Furthermore, inhibition of the VWF-platelet glycoprotein Ib interaction using inhibitory anti-VWF antibodies was successful in preventing and treating acquired TTP in baboons.…”

Section: Discussionmentioning

confidence: 99%

Potential for Recombinant ADAMTS13 as an Effective Therapy for Acquired Thrombotic Thrombocytopenic Purpura

Tersteeg

Schiviz

Meyer

et al. 2015

ATVB

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Objective-The metalloprotease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) regulates the size of von Willebrand factor multimers. A deficiency in ADAMTS13 activity is associated with the life-threatening disease thrombotic thrombocytopenic purpura (TTP). The vast majority of patients have acquired TTP, where circulating anti-ADAMTS13 autoantibodies are causative for the decreased ADAMTS13 activity. Current treatment consists of plasma exchange, but improved therapies are highly warranted. Approach and Results-We have developed a new rat model mimicking various aspects of acquired TTP to investigate the therapeutic efficacy of human recombinant ADAMTS13. A polyclonal antibody against ADAMTS13 completely blocked endogenous rat ADAMTS13 activity in Sprague-Dawley rats. When TTP was triggered using recombinant von Willebrand factor, the animals displayed severe TTP-like symptoms, such as thrombocytopenia, hemolytic anemia, and von Willebrand factor-rich thrombi in the kidneys and brain. Subsequent injection of 400, 800, or 1600 U/kg recombinant ADAMTS13 prevented full development of these symptoms. Analysis of plasma samples confirmed that recombinant ADAMTS13 was able to override circulating anti-ADAMTS13 inhibitory antibodies, resulting in restoration of ADAMTS13 activity and degradation of ultralarge von Willebrand factor multimers. Conclusions-Recombinant ADAMTS13 was shown to be effective in averting severe acquired TTP-like symptoms in rats and holds promising value for the treatment of this severe and life-threatening disease in humans. rADAMTS13 therapy seems to be a promising treatment opportunity for this patient group. In the presented study, we developed a rat model mimicking various aspects of acquired TTP, with which we further explored the feasibility of rAD-AMTS13 treatment in acquired TTP. Materials and MethodsMaterials and Methods are available in the online-only Data Supplement. Results Establishing a Rat Model Resembling Acquired TTPFirst, rats were injected with polyclonal anti-ADAMTS13 antibodies (650 U/kg) to block endogenous rat ADAMTS13 activity and to establish a robust inhibitor titer of ≈10 BU/ mL. Then, animals were administered 2000 U/kg recombinant VWF (rVWF) to trigger TTP symptoms.11 Control animals received either control IgG instead of anti-ADAMTS13 antibodies or saline instead of rVWF. Animals were followed for 24 h, and blood samples were analyzed after 3 and 24 h. The normal platelet count at baseline was 650±177×10 3 platelets/μL blood ( Figure 1A). Rats injected with anti-ADAMTS13 antibodies and triggered with rVWF developed thrombocytopenia, with a platelet count of 427±111×10 3 /μL after 3 h and 218±40×10 3 /μL after 24 h ( Figure 1A). Neither injection of anti-ADAMTS13 antibodies without additional rVWF nor injection of control IgG with rVWF resulted in thrombocytopenia (652±146×10 3 /μL and 766±63×10 3 /μL after 24 h, respectively; Figure 1A). Hemoglobin levels also decreased significantly after 24 h when rats developed TTP ...

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“…60,61 Finally, N-acetylcyteine was shown to reduce the size and activity of VWF in human and mouse plasma, 62 and has been successfully used in refractory TTP in one patient. 63 In conclusion, we have uncovered an important role for ADAMTS13 in preventing TMA following systemic VEGF inhibition. Therefore, we suggest the evaluation of ADAMTS13 activity as a predictor for the development of TMA under antiangiogenic therapy and of pregnancy-related TMA.…”

Section: /2mentioning

confidence: 99%

ADAMTS13 Endopeptidase Protects against Vascular Endothelial Growth Factor Inhibitor–Induced Thrombotic Microangiopathy

Erpenbeck

Demers

Zsengellér

et al. 2016

Journal of the American Society of Nephrology

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Thrombotic microangiopathy (TMA) is a life-threatening condition that affects some, but not all, recipients of vascular endothelial growth factor (VEGF) inhibitors given as part of chemotherapy. TMA is also a complication of preeclampsia, a disease characterized by excess production of the VEGF-scavenging soluble VEGF receptor 1 (soluble fms-like tyrosine kinase 1; sFlt-1). Risk factors for VEGF inhibitor-related TMA remain unknown. We hypothesized that deficiency of the VWF-cleaving ADAMTS13 endopeptidase contributes to the development of VEGF inhibitor-related TMA. ADAMTS13 2/2 mice overexpressing sFlt-1 presented all hallmarks of TMA, including thrombocytopenia, schistocytosis, anemia, and VWF-positive microthrombi in multiple organs. Similar to VEGF inhibitor-related TMA in humans, these mice exhibited severely impaired kidney function and hypertension. In contrast, wild-type mice overexpressing sFlt-1 developed modest hypertension but no other features of TMA. Recombinant ADAMTS13 therapy ameliorated all symptoms of TMA in ADAMTS13 2/2 mice overexpressing sFlt-1 and normalized BP in wild-type mice. ADAMTS13 activity may thus be a critical determinant for the development of TMA secondary to VEGF inhibition. Administration of recombinant ADAMTS13 may serve as a therapeutic approach to treat or prevent thrombotic complications of VEGF inhibition.

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Treatment of refractory thrombotic thrombocytopenic purpura with N‐acetylcysteine: a case report

Abstract: This is the first complete report of a TTP patient treated with NAC. NAC was a safe and effective supplementary treatment for refractory TTP in this patient.

Cited by 58 publications

References 16 publications

How I treat refractory thrombotic thrombocytopenic purpura

How I treat refractory thrombotic thrombocytopenic purpura

Potential for Recombinant ADAMTS13 as an Effective Therapy for Acquired Thrombotic Thrombocytopenic Purpura

ADAMTS13 Endopeptidase Protects against Vascular Endothelial Growth Factor Inhibitor–Induced Thrombotic Microangiopathy

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