Novel antiplatelet strategies targeting VWF and GPIb.

Von Willebrand factor has a pivotal role in primary hemostasis. Its role in thrombotic microangiopathies (TMA), as well as cardiovascular disease, has been demonstrated. Thrombotic thrombocytopenic purpura (TTP), a thrombotic microangiopathy, is a life-threatening condition with a high mortality rate if untreated. Current management strategies comprise plasma exchange to remove autoantibodies and replenish ADAMTS13, along with immunosuppressive agents in immune TTP. This review focuses on novel antiplatelet strategies that target VWF and GPIb. The benefits of the nanobody caplacizumab in achieving faster normalization of platelet count, as well as reduced thromboembolic events were shown through TITAN and HERCULES trials, and these findings have been practice changing. The use of caplacizumab in patients with immune TTP (iTTP) has now become well established. Potential benefits of ARC1779 and N-acetylcysteine have also been shown on a small scale in iTTP, however these lack evidence through larger randomized controlled trials. Further therapies, some in early phase, others in clinical practice, target platelet aggregation within arteries and their utility is presented with cerebrovascular disorders.

Acquired immune-mediated von Willebrand syndrome accompanied by antiphospholipid syndrome.

Acquired von Willebrand syndrome (AvWS) is a rare bleeding disorder with laboratory findings resembling those of congenital von Willebrand disease. AvWS usually occurs in association with a variety of underlying disorders, such as lymphoproliferative disease or cardiovascular disease, but autoimmune AvWS is very rare. We now describe the case of a 42-year-old woman with autoimmune AvWS with concurrent antiphospholipid syndrome (APS). The patient was suffering from epistaxis and menorrhagia from few years prior to referral. She was referred to our hospital because of Activated Partial Thromboplastin Time (APTT) prolongation. Autoimmune AvWS was diagnosed as hemostatic and immunological analyses showed very low (<6%) levels of vWF ristocetin cofactor activity, low (6%) levels of vWF antigen and the presence of anti-vWF antibodies (IgG1 and IgG2) as well as antiphospholipid antibodies. Steroid therapy led to prompt AvWS remission, but deep vein thrombosis occurred in the left leg, on day 36 and APS was diagnosed. A combination of steroid and anti-coagulant was given for approximately 3 years. Thrombosis has not recurred; but AvWS re-exacerbated with steroid tapering. This is the first case report of autoimmune AvWS concurrent with APS, and the long-term disease course described here can be beneficial to clinicians.

Phage display broadly identifies inhibitor-reactive regions in von Willebrand factor.

BACKGROUND: Correction of von Willebrand factor (VWF) deficiency with replacement products containing VWF can lead to the development of anti-VWF alloantibodies (i.e., VWF inhibitors) in patients with severe von Willebrand disease (VWD). OBJECTIVE: Locate inhibitor-reactive regions within VWF using phage display. METHODS: We screened a phage library displaying random, overlapping fragments covering the full-length VWF protein sequence for binding to a commercial anti-VWF antibody or to immunoglobulins from three type 3 VWD patients who developed VWF inhibitors in response to treatment with plasma-derived VWF. Immunoreactive phage clones were identified and quantified by next-generation DNA sequencing (NGS). RESULTS: Next-generation DNA sequencing markedly increased the number of phages analyzed for locating immunoreactive regions within VWF following a single round of selection and identified regions not recognized in previous reports using standard phage display methods. Extending this approach to characterize VWF inhibitors from three type 3 VWD patients (including two siblings homozygous for the same VWF gene deletion) revealed patterns of immunoreactivity distinct from the commercial antibody and between unrelated patients, though with notable areas of overlap. Alloantibody reactivity against the VWF propeptide is consistent with incomplete removal of the propeptide from plasma-derived VWF replacement products. CONCLUSION: These results demonstrate the utility of phage display and NGS to characterize diverse anti-VWF antibody reactivities.

A critical evaluation of caplacizumab for the treatment of acquired thrombotic thrombocytopenic purpura.

Introduction: Acquired thrombotic thrombocytopenic purpura (aTTP) is a thrombotic microangiopathy caused by inhibitory autoantibodies against ADAMTS13 protein. Until recently, the combination of plasma exchange (PEX) and immunosuppression has been the standard front-line treatment in this disorder. However, aTTP-related mortality, refractoriness, and relapse are still a matter of concern. Areas covered: The better understanding of the pathophysiological mechanisms of aTTP has allowed substantial improvements in the diagnosis and treatment of this disease. Recently, the novel anti-VWF nanobody caplacizumab has been approved for acute episodes of aTTP. Caplacizumab is capable to block the adhesion of platelets to VWF, therefore inhibiting microthrombi formation in the ADAMTS13-deficient circulation. In this review, the characteristics of caplacizumab together with the available data of its efficacy and safety in the clinical setting will be analyzed. Besides, the current scenario of aTTP treatment will be provided, including the role of other innovative drugs. Expert opinion: With no doubt, caplacizumab is going to change the way we treat aTTP. In combination with standard treatment, caplacizumab can help to significantly reduce aTTP-related mortality and morbidity and could spare potential long-term consequences by minimizing the risk of exacerbation.