Factor VIII stimulants and other novel therapies for the treatment of von Willebrand disease: what's new on the horizon?

INTRODUCTION: Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting about 0.6% to 1.3% of the population, and is characterized primarily by mucocutaneous bleeding secondary to defective platelet adhesion and aggregation. Current therapeutic options for those with severe disease are limited and require frequent intravenous infusions. AREAS COVERED: This review discusses the current and recently completed clinical trials involving pathways to FVIII augmentation for the treatment of VWD. Clinical trials registered on clinicaltrials.gov and published data via PubMed searches through June 2024 were included. EXPERT OPINION: Available treatment options to those with VWD are limited in part due to limited clinical trials, the complexity of VWD types, and the pharmacokinetics of current treatment options. The development of therapeutic options that reduce treatment burden is necessary to improve quality of life and reduce bleeding complications and in recent years there has been an increased interest from industry to apply novel therapeutics for VWD. The FVIII mimetic, emicizumab, has demonstrated early success in patients with severe VWD and is a promising treatment option for those who require prophylaxis. Furthermore, products like efanesoctocog alfa (Altuviiio®) and BT200 have achieved enhanced VWF/FVIII half-life extension could expand the current treatment landscape while concurrently minimizing treatment burden.

Early stage clinical trials for the treatment of hemophilia A.

INTRODUCTION: Hemophilia A is a severe bleeding disorder affecting about 1 in 5,000 males. The gold standard for prophylaxis and treatment of acute bleeding has been factor (F) VIII concentrate. A multitude of treatment modalities are now available and under clinical investigation. AREAS COVERED: This review discusses ongoing/recently completed early-phase clinical trials registered on ClinicalTrials.gov in patients with hemophilia A through April 2022. These new pipeline therapies are focused on addressing the safety and efficacy of new factor-related products, non-factor related products, and gene therapy options for hemophilia. EXPERT OPINION: Current standard of care effectively prevents and treats acute bleeding and has significantly improved the quality of life in hemophilia. The biggest challenges in the improvement of care are treatment-related burden and the burden of cost in developing countries. New drugs under development are likely to enter practice by the end of this decade and address many of the unmet needs particularly of those with severe disease. Data is limited in unique populations (e.g. congenital/inherited FVIII inhibitors, non-severe hemophilia A, women/girls with hemophilia and children) which are important areas for future research; additional clinical trials and long-term outcome data are necessary prior to incorporating these new therapies in our treatment arsenal.

Extracorporeal Membrane Oxygenation in Critically Ill Children.

Neonatal and pediatric extracorporeal membrane oxygenation (ECMO) has evolved over the past 50 years. Advances in technology, expertise, and application have increased the number of centers providing ECMO with expanded indications for use. However, increasing the use of ECMO in recent years to more medically complex critically ill children has not changed overall survival despite increased experience and improvements in technology. This review focuses on ECMO history, circuits, indications and contraindications, management, complications, and outcome data. The authors highlight important areas of progress, including unintubated and awake patients on ECMO, application during the COVID-19 pandemic, and future directions.

Viscoelastic Testing in Pediatric Mechanical Circulatory Support.

Pediatric mechanical circulatory support can be lifesaving. However, managing anticoagulation is one of the most challenging aspects of care in patients requiring mechanical circulatory support. Effective anticoagulation is even more difficult in pediatric patients due to the smaller size of their blood vessels, increased turbulent flow, and developmental hemostasis. Recently, viscoelastic testing (VET) has been used as a qualitative measure of anticoagulation efficacy in patients receiving extracorporeal membrane oxygenation (ECMO) and ventricular assist devices (VAD). Thromboelastography (TEG®) and thromboelastometry (ROTEM®) provide a global qualitative assessment of hemostatic function from initiation of clot formation with the platelet-fibrin interaction, platelet aggregation, clot strength, and clot lysis. This review focuses on the TEG®/ROTEM® and important laboratory and patient considerations for interpretation in the ECMO and VAD population. We summarize the adult and pediatric ECMO/VAD literature regarding VET values, VET-platelet mapping, utility over standard laboratory monitoring, and association with outcome measures such as blood product utilization, bleeding, and thrombosis.

Developmental Hemostasis: The Evolution of our Coagulation System.

Developmental hemostasis describes the evolution of the coagulation system from the neonatal period through adulthood. Neonates have lower levels of coagulation factors and elevated screening levels at birth. These levels can be influenced by various circumstances including gestational age, labor effects, and clinical status. The most commonly used screening tests for coagulopathy are the prothrombin time, partial thromboplastin time, and fibrinogen level. These values can be difficult to interpret as every laboratory has its own age-specific reference ranges. An understanding of developmental hemostasis is important when evaluating, diagnosing, and treating clinical manifestations, including vitamin K deficiency, surgical needs, infections, inherited thrombophilias, and inherited bleeding disorders. The mainstay of treatment for bleeding or hemorrhage is platelet and fresh frozen plasma transfusions. For the treatment of thrombosis, unfractionated heparin and low-molecular-weight heparin are the 2 most commonly used anticoagulants in the neonatal setting.

Managing Severe Hemophilia A in Children: Pharmacotherapeutic Options.

Hemophilia A is the most common severe inherited bleeding disorder in males. Initial treatment strategies focused on the use of factor concentrates to prevent joint bleeding and the development of long-term crippling arthropathy. The current standard of care has evolved from regular replacement of factor VIII concentrates which has significantly improved the quality of life for those with severe disease to include and consider novel therapies that augment or bypass the hemostatic pathway (ie, emicizumab, Mim8). Other pipeline therapies that suppress specific natural anticoagulant pathways (ie, antithrombin, TFPI) to reestablish hemostatic balance are under Phase 3 trial investigation. These novel therapeutics have allowed providers more variety in dosing regimens and ease of administration while also maintaining effective bleeding prevention. The possibility of "curative" gene therapy is under exploration, with ongoing clinical trials in adult males.

Distinctive phenotypes in two children with novel germline RUNX1 mutations - one with myeloid malignancy and increased fetal hemoglobin.

RUNX1 associated familial platelet disorder (FPD) is a rare autosomal dominant hematologic disorder characterized by thrombocytopenia and/or altered platelet function. There is an increased propensity to develop myeloid malignancy (MM) - acute myeloid leukemia, myeloproliferative neoplasms or myelodysplastic syndrome often in association with secondary somatic variants in other genes. To date, 23 FPD-MM pediatric cases have been reported worldwide. Here, we present two new kindreds with novel RUNX1 pathogenic variants in which children are probands. The first family is a daughter/mother diad, sharing a heterozygous frameshift variant in RUNX1 gene (c.501delT p.Ser167Argfs*9). The daughter, age 13 years, presented with features resembling juvenile myelomonocytic leukemia - severe anemia, thrombocytopenia, high white cell count with blast cells, monocytosis, increased nucleated red cells and had somatic mutations with high allele burden in CUX1, PHF6, and SH2B3 genes. She also had increased fetal hemoglobin and increased LIN28B expression. The mother, who had a long history of hypoplastic anemia, had different somatic mutations- a non-coding mutation in CUX1 but none in PHF6 or SH2B3. Her fetal hemoglobin and LIN28B expression were normal. In the second kindred, the proband, now 4 years old with thrombocytopenia alone, was investigated at 3 months of age for persistent neonatal thrombocytopenia with large platelets. Molecular testing identified a heterozygous intragenic deletion in RUNX1 encompassing exon 5. His father is known to have increased bruising for several years but is unavailable for testing. These two cases illustrate the significance of secondary mutations in the development and progression of RUNX1-FPD to MM.

Reversible Cerebral Vasoconstriction Syndrome and Sickle Cell Disease: A Case Report.

Reversible cerebral vasoconstriction syndrome (RCVS), is rare in the pediatric population and is characterized by severe headaches and other neurologic symptoms. We present a case of RCVS occurring concomitantly with posterior reversible encephalopathy syndrome in an 8-year-old African American child with sickle cell disease (HbSS). Imaging studies including computed tomography, magnetic resonance imaging and cerebral angiography of the brain showed acute hemorrhagic stroke and a beaded appearance of peripheral cerebral vessels. In this report, we focus on the typical features of RCVS and discuss the underlying risk factors that may increase the risk in patients with HbSS disease.

Bivalirudin during thrombolysis with catheter-directed tPA in a heparin-refractory patient: A case report.

Venous thromboembolism has increasing significance in hospitalized pediatric patients. Patients who have life-threatening or limb-threatening thrombotic events require thrombolysis in addition to anticoagulation. In patients who show signs of heparin resistance or heparin-induced thrombocytopenia, it is imperative to identify alternative therapeutic options. We present a child in whom bivalirudin was used for systemic anticoagulation during catheter-directed thrombolysis along with tissue plasminogen activator (Alteplase® ) for the treatment of a near-occlusive organ-threatening thrombus. We also review the currently available literature on the use of combination therapy of an intravenous direct thrombin inhibitor with alteplase.

Utility of thromboelastography for the diagnosis of von Willebrand disease.

Von Willebrand disease (VWD) is an inherited bleeding disorder that is caused by a quantitative or qualitative deficiency of von Willebrand factor (VWF). The National Heart, Lung, and Blood Institute (NHLBI) guidelines for the diagnosis of VWD state that a VWF activity (VWF:RCo) of <30 IU/dL or <50 IU/dL with symptoms of clinical bleeding are consistent with the diagnosis of VWD. However, current gold-standard diagnostic testing takes days to have complete results. Thromboelastography (TEG) is a testing method that provides a graphical trace that represents the viscoelastic changes seen with fibrin polymerization in whole blood, therefore providing information on all phases of the coagulation process. This study describes the TEG characteristics in 160 patients who presented for workup of a bleeding disorder and a subset of those were subsequently diagnosed with VWD. The TEG parameters, K-time (representing the dynamics of clot formation) and the maximal rate of thrombus generation (MRTG), were found to be sensitive in detecting patients with VWF:RCo <30 IU/dL. The TEG, unlike VWF:RCo, can be done in real time, and results are available to the clinician within an hour. This will definitely be beneficial in acute situations such as evaluation of and management of acute bleeding in patients with acquired deficiencies of VWF and may play an important role in the surgical management of patients with VWD.