scholarly journals Caplacizumab for Acute Thrombotic Thrombocytopenic Purpura

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Katherine V. Katsivalis, PharmD ◽  
Jaime Thomas, PharmD
Keyword(s):  
Plasma Exchange ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Thromboembolic Event ◽  
Immunosuppressive Agents ◽  
Standard Of Care ◽  
Thrombocytopenic Purpura ◽  
Specialty Pharmacy ◽  
A1 Domain ◽  
Von Willebrand ◽  
Willebrand Factor

Acute thrombotic thrombocytopenic purpura (aTTP) is a rare microangiopathic hemolytic anemia. Standard of care currently includes plasma exchange and immunosuppressive agents, including glucocorticoids, vincristine, and rituximab. Even with these therapies, relapse occurs in 36% of patients, and mortality ranges from 10% to 20%. Caplacizumab is a novel agent approved for the treatment of adult patients with aTTP in conjunction with plasma exchange and immunosuppressive therapies. It works by binding to the A1 domain of von Willebrand factor (VWF), blocking platelets from binding to VWF and aggregating. In clinical trials, patients who received caplacizumab compared with placebo were more likely to have a normalization of their platelet count, a lower rate of recurrence, and a lower incidence of the composite of aTTP-related death, recurrence, or major thromboembolic event. The side effect profile is rather benign and includes epistaxis, headache, and gingival bleeding. Caplacizumab is only available through specialty pharmacy services due to its high cost. Providers should be aware of and prepared for the prior authorization process required to assist their patients in gaining access to the medication. Currently, there is no formal consensus regarding caplacizumab’s place in therapy for patients with aTTP, but it remains an option for refractory cases.

Recovery and Half-Life of von Willebrand Factor-Cleaving Protease after Plasma Therapy in Patients with Thrombotic Thrombocytopenic Purpura

1999 ◽  
Vol 81 (01) ◽  
pp. 8-13 ◽  
Author(s):  
Rodolfo Robles ◽  
Beat Morselli ◽  
Pierre Sandoz ◽  
Bernhard Lämmle ◽  
Miha Furlan
Keyword(s):  
Plasma Exchange ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Von Willebrand Factor ◽  
Half Life ◽  
Protease Activity ◽  
Plasma Therapy ◽  
Thrombocytopenic Purpura ◽  
Plasma Infusion ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryPlasma exchange using fresh-frozen plasma (FFP) for replacement was given to two brothers during a relapse of thrombotic thrombocytopenic purpura (TTP). A constitutional deficiency of von Willebrand factor(vWF)-cleaving protease had been previously established in both patients. No inhibitor of vWF-cleaving protease was present in patients’ plasmas. They received plasma exchange for four and three consecutive days, respectively. In both patients, the activity of vWF-cleaving protease after the first plasmapheresis session was evaluated and was found to be virtually identical to anticipated activity calculated from predicted patient plasma volume and volume of exchanged plasma. Pathologic platelet counts and lactate dehydrogenase levels were normalized in both patients within 4-6 days. The biologic half-life of vWF-cleaving protease was determined in these patients following the last plasma exchange. The respective half-lives of 3.3 and 2.1 days represent the lowest known clearance rates of proteases in circulating human plasma.Another patient with relapsing TTP was treated with plasma exchange and/or plasma infusion for 10 consecutive days during the first relapse, 221-231 days after the initial TTP event. Pharmacokinetic studies of vWF-cleaving protease were performed after plasma exchange on day 221 and after plasma infusion on day 231. High level of an IgG in patient plasma, capable of completely inhibiting protease activity in an equal volume of normal plasma, had been established prior to first plasmapheresis. There was no measurable protease activity at any time during plasma therapy. Following plasma exchange, the level of the inhibitor was transiently slightly depressed. After 10 days of plasma therapy, the concentration of the inhibitor in patient plasma was increased about 5-fold. We suggest that, in contrast to protease deficient patients without circulating inhibitor, complementary therapy including immunosuppressive treatment, vincristine and/or splenectomy is indicated in patients with acquired inhibitors of vWF-cleaving protease. Testing for vWF-cleaving protease inhibitor may be useful in predicting the response to plasma exchange in patients with TTP.

scholarly journals Acquired Deficiency of von Willebrand Factor-Cleaving Protease in a Patient With Thrombotic Thrombocytopenic Purpura

Blood ◽  
1998 ◽  
Vol 91 (8) ◽  
pp. 2839-2846 ◽  
Author(s):  
Miha Furlan ◽  
Rodolfo Robles ◽  
Max Solenthaler ◽  
Bernhard Lämmle
Keyword(s):  
Platelet Count ◽  
Plasma Exchange ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Von Willebrand Factor ◽  
Protease Activity ◽  
Temporary Increase ◽  
Severe Thrombocytopenia ◽  
Thrombocytopenic Purpura ◽  
Von Willebrand ◽  
Willebrand Factor

Plasma of patients with thrombotic thrombocytopenic purpura (TTP) has been shown to contain unusually large von Willebrand factor (vWF) multimers that may cause platelet agglutination in vivo. Fresh frozen plasma infusions and plasma exchange represent the most efficient therapy of acute TTP. A specific protease responsible for cleavage of vWF multimers has been recently isolated from normal human plasma and was found to be deficient in four patients with chronic relapsing TTP. We examined the activity of the vWF-cleaving protease in plasma samples collected over a period of 400 days from a further patient with recurrent episodes of TTP who was treated by plasma exchange, plasma infusion, vincristine, corticosteroid therapy, and splenectomy. Complete deficiency of the vWF-cleaving protease was established during the first episode of TTP. The ensuing normalization of the platelet count was associated with the appearance of the protease activity. Three months after remission from the initial TTP event, the vWF-cleaving protease again disappeared and the platelet count gradually decreased. Relapses of severe thrombocytopenia occurred 7 and 11 months after the first acute episode of TTP. Deficient protease activity was associated with the presence in the patient plasma of an inhibitor that was found to be an IgG. Plasma exchange/infusion was followed by a temporary increase in the antibody titer, whereas treatment with vincristine led to a recovery of the platelet count without affecting the inhibitor concentration. Splenectomy and corticosteroid treatment resulted in disappearance of the autoantibody and normalization of the protease activity and of the platelet count. Our data suggest that the thrombocytopenia in this patient with TTP was associated with a lack of the vWF-cleaving protease activity depleted by an autoimmune mechanism. This case, together with our previously reported patients, leads us to conclude that acquired as well as constitutional deficiency of the vWF-cleaving protease may predispose to TTP.

scholarly journals Caplacizumab in adult patients with acquired thrombotic thrombocytopenic purpura

2020 ◽  
Vol 11 ◽  
pp. 204062072090290 ◽  
Author(s):  
Ashley Hanlon ◽  
Ara Metjian
Keyword(s):  
Clinical Trials ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Immune Suppression ◽  
Fatal Disease ◽  
Thrombocytopenic Purpura ◽  
A1 Domain ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Adhesion Of Platelets ◽  
Novel Agent

Thrombotic thrombocytopenic purpura (TTP) is usually a fatal disease caused by a deficiency of the metalloproteinase, ADAMTS13, often due to autoimmunity. This leads to the development of pathogenic multimers of von Willebrand factor (vWF), causing an inappropriate interaction of platelets and vWF. This results in a thrombotic microangiopathy, which is treated with therapeutic plasma exchange and immune suppression. Although this treatment has reduced the mortality of TTP to only about 20%, there have been no recent significant advances in the treatment of TTP. Recently, a novel agent has been approved for use in TTP. Caplacizumab, which binds to the A1 domain of vWF, prevents the adhesion of platelets to vWF. It is a first in-class ‘nanobody’, that in clinical trials has shown marked efficacy in treating TTP and its complications. This review will discuss the development and implications of caplacizumab in the treatment of TTP.

scholarly journals Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura

Blood ◽  
2008 ◽  
Vol 112 (1) ◽  
pp. 11-18 ◽  
Author(s):  
J. Evan Sadler
Keyword(s):  
Plasma Exchange ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Von Willebrand Factor ◽  
Unanswered Question ◽  
Thrombocytopenic Purpura ◽  
The Past ◽  
Adamts13 Deficiency ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Intensive Immunosuppressive Therapy

Abstract Discoveries during the past decade have revolutionized our understanding of idiopathic thrombotic thrombocytopenic purpura (TTP). Most cases in adults are caused by acquired autoantibodies that inhibit ADAMTS13, a metalloprotease that cleaves von Willebrand factor within nascent platelet-rich thrombi to prevent hemolysis, thrombocytopenia, and tissue infarction. Although approximately 80% of patients respond to plasma exchange, which removes autoantibody and replenishes ADAMTS13, one third to one half of survivors develop refractory or relapsing disease. Intensive immunosuppressive therapy with rituximab appears to be effective as salvage therapy, and ongoing clinical trials should determine whether adjuvant rituximab with plasma exchange also is beneficial at first diagnosis. A major unanswered question is whether plasma exchange is effective for the subset of patients with idiopathic TTP who do not have severe ADAMTS13 deficiency.

Rituximab prevents recurrence of thrombotic thrombocytopenic purpura: a case report

Blood ◽  
2005 ◽  
Vol 106 (3) ◽  
pp. 925-928 ◽  
Author(s):  
Miriam Galbusera ◽  
Elena Bresin ◽  
Marina Noris ◽  
Sara Gastoldi ◽  
Daniela Belotti ◽  
...  
Keyword(s):  
Plasma Exchange ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Therapeutic Option ◽  
Close Monitoring ◽  
Thrombocytopenic Purpura ◽  
Small Vessels ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Substantial Morbidity

AbstractThrombotic thrombocytopenic purpura (TTP) is a rare disorder of small vessels that is associated with deficiency of the von Willebrand factor–cleaving protease, ADAMTS13. The presence of anti-ADAMTS13 autoantibodies is considered a factor predisposing to relapses. Despite close monitoring and intensive plasma treatment, in these patients acute episodes are still associated with substantial morbidity and mortality rates, and the optimal therapeutic option should be prevention of relapses. This study was conducted in a patient with recurrent TTP due to high titers of ADAMTS13 inhibitors, who used to have 2 relapses of TTP a year. The study compared the standard treatment plasma exchange with rituximab. Results documented that plasma exchange had only a small transient effect on ADAMTS13 activity and inhibitors; on the contrary, prophylaxis with rituximab was associated with disappearance of anti-ADAMTS13 antibodies, a progressive recovery of protease activity, and it allowed the patient to maintain a disease-free state during a more than 2-year follow-up.

scholarly journals How I treat refractory thrombotic thrombocytopenic purpura

Blood ◽  
2015 ◽  
Vol 125 (25) ◽  
pp. 3860-3867 ◽  
Author(s):  
Farzana A. Sayani ◽  
Charles S. Abrams
Keyword(s):  
Plasma Exchange ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Clinical Symptoms ◽  
Thrombocytopenic Purpura ◽  
New Therapeutic Approaches ◽  
Number Of Patients ◽  
A Disintegrin And Metalloproteinase ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract 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.

Caplacizumab: an anti–von Willebrand factor antibody for the treatment of thrombotic thrombocytopenic purpura

2020 ◽  
Vol 77 (15) ◽  
pp. 1201-1207
Author(s):  
Alyssa L Hollifield ◽  
Justin R Arnall ◽  
Donald C Moore
Keyword(s):  
Adverse Events ◽  
Plasma Exchange ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Von Willebrand Factor ◽  
Antibody Fragment ◽  
Self Administration ◽  
Phase 3 ◽  
Thrombocytopenic Purpura ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Purpose The pharmacology, pharmacokinetics, efficacy, safety, dosing and administration, and place in therapy of caplacizumab, a novel antibody fragment that inhibits von Willebrand factor, for the treatment of acquired thrombotic thrombocytopenic purpura (TTP) are summarized. Summary Caplacizumab is a humanized anti–von Willebrand factor monoclonal antibody fragment that inhibits the interaction between ultralarge von Willebrand factor multimers and platelets. Caplacizumab is indicated for use in combination with standard-of-care modalities such as plasma exchange and immunosuppressive therapy for the treatment of adults with acquired TTP. By inhibiting von Willebrand factor, caplacizumab offers a new approach to the management of TTP by preventing the development of potentially life-threatening microvascular thrombosis that can occur in the disease process. In a randomized, placebo-controlled phase 3 trial, patients with acquired TTP treated with caplacizumab had more rapid platelet level normalization than placebo users; caplacizumab use also resulted in lower rates of disease recurrence and TTP-related death. The most common adverse events associated with caplacizumab use are bleeding-related events. In a phase 3 trial, serious bleeding-related adverse events were reported in 8 patients (11%) in the caplacizumab group and 1 patient (1%) in the placebo group. Caplacizumab is administered as an 11-mg intravenous loading dose 15 minutes prior to plasma exchange, followed by administration of 11 mg subcutaneously daily after plasma exchange. Once-daily caplacizumab administration can be continued for 30 days after the last plasma exchange. The medication and supplies for administration are provided as a single-use kit; patients should be trained on proper reconstitution and self-administration technique prior to the use of caplacizumab in the ambulatory setting. Conclusion Caplacizumab is a first-in-class von Willebrand factor inhibitor approved for the treatment of adults with acquired TTP.

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