Inhibition of von Willebrand factor–platelet glycoprotein Ib interaction prevents and reverses symptoms of acute acquired thrombotic thrombocytopenic purpura in baboons

Feys, Hendrik B.; Roodt, Jan; Vandeputte, Nele; Pareyn, Inge; Mottl, Harald; Hou, Sam; Lamprecht, Seb; Rensburg, Walter Janse van; Deckmyn, Hans; Vanhoorelbeke, Karen

doi:10.1182/blood-2012-04-421248

Cited by 39 publications

(43 citation statements)

References 12 publications

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“…82 An aptamer (ARC1779), a humanized mAb (GBR600), and a bivalent singlechained antibody (ALX-0681) all bind to the VWF A1 domain and impair VWF binding to platelets in vitro. [83][84][85] The aptamer, ARC1779, has been the most studied of the anti-VWF agents, and preliminary studies have shown improvement in the platelet count and LDH in patients with acquired TTP. 86,87 In a double-blind placebo-controlled trial that closed prematurely, ARC1779 together with PEX suppressed VWF activity, and was well tolerated.…”

Section: Anti-vwf Therapymentioning

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: Anti-vwf Therapymentioning

confidence: 99%

How I treat refractory thrombotic thrombocytopenic purpura

Sayani¹,

Abrams

2015

Blood

143

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“…36 Therefore, missing ADAMTS13 activity, by neutralizing autoantibodies or by reduced protein expression, represents the pathophysiological correlate for TTP and the appearance of ULVWF multimers in those patients. [37][38][39] However, since 1982, the formation of these ULVWF multimers has never been shown in human vessels.…”

Section: Discussionmentioning

confidence: 99%

von Willebrand factor fibers promote cancer-associated platelet aggregation in malignant melanoma of mice and humans

Bauer

Suckau

Frank

et al. 2015

Blood

121

128

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Key Points• Tumor-derived VEGF-A mediates endothelial cell activation, VWF release, and platelet aggregation provoking coagulation in tumor patients.• Local ADAMTS13 inhibition promotes VWF fiber formation in tumor microvessels.Tumor-mediated procoagulatory activity leads to venous thromboembolism and supports metastasis in cancer patients. A prerequisite for metastasis formation is the interaction of cancer cells with endothelial cells (ECs) followed by their extravasation. Although it is known that activation of ECs and the release of the procoagulatory protein von Willebrand factor (VWF) is essential for malignancy, the underlying mechanisms remain poorly understood. We hypothesized that VWF fibers in tumor vessels promote tumor-associated thromboembolism and metastasis. Using in vitro settings, mouse models, and human tumor samples, we showed that melanoma cells activate ECs followed by the luminal release of VWF fibers and platelet aggregation in tumor microvessels. Analysis of human blood samples and tumor tissue revealed that a promoted VWF release combined with a local inhibition of proteolytic activity and protein expression of ADAMTS13 (a disintegrinlike and metalloproteinase with thrombospondin type I repeats 13) accounts for this procoagulatory milieu. Blocking endothelial cell activation by the low-molecular-weight heparin tinzaparin was accompanied by a lack of VWF networks and inhibited tumor progression in a transgenic mouse model. Our findings implicate a mechanism wherein tumor-derived vascular endothelial growth factor-A (VEGF-A) promotes tumor progression and angiogenesis. Thus, targeting EC activation envisions new therapeutic strategies attenuating tumor-related angiogenesis and coagulation. (Blood. 2015;125(20):3153-3163) IntroductionTo form new metastatic lesions, circulating melanoma cells have to interact with endothelial cells (ECs) and migrate through the vessel wall.1,2 In this context, our own in vitro studies show that melanoma cells activate ECs by an indirect, tissue factor (TF)-mediated thrombin generation.3 Next to this indirect melanoma-induced EC activation, recent findings identified melanoma-derived vascular endothelial growth factor-A (VEGF-A) as main mediator of direct EC activation. 4,5 Both the thrombin-and the VEGF-A-dependent pathways induce EC activation followed by Weibel-Palade body (WPB) exocytosis and the release of inflammatory cytokines and the highly procoagulatory glycoprotein von Willebrand factor (VWF), linking inflammation and coagulation. 6 On the one hand, luminally released VWF fibers are involved in hemostasis and vessel repair as mediators of platelet adhesion to the endothelium. 7,8 On the other hand, we showed that tumor cell-induced ultra-large VWF (ULVWF) fibers have the highest potential for platelet binding and aggregation.9,10 This effect may contribute not only to pathophysiologic vessel occlusion, 11 but also to the establishment of metastasis as platelets facilitate tumor cell extravasation. 12-14Indeed, it is well-known that cancer pati...

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“…Jelenleg erre 3-féle kísérleti gyógyszer -aptamer (ARC1779) [55], humanizált mAb (GBR600) [56], bivalens nanobody (ALX-0681) [57] -vizsgálatai folynak.…”

Section: A Jövő Terápiás Lehetőségeiunclassified

Egészségügyi szakmai irányelv – A thromboticus thrombocytopeniás purpura (TTP) és a haemolyticus uraemiás syndroma (HUS) kezeléséről

…¹

2017

Orvosi Hetilap

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Inhibition of von Willebrand factor–platelet glycoprotein Ib interaction prevents and reverses symptoms of acute acquired thrombotic thrombocytopenic purpura in baboons

Cited by 39 publications

References 12 publications

How I treat refractory thrombotic thrombocytopenic purpura

How I treat refractory thrombotic thrombocytopenic purpura

von Willebrand factor fibers promote cancer-associated platelet aggregation in malignant melanoma of mice and humans

Egészségügyi szakmai irányelv – A thromboticus thrombocytopeniás purpura (TTP) és a haemolyticus uraemiás syndroma (HUS) kezeléséről

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