Update on iron supplementation in patients with cancer-related anemia.

INTRODUCTION: Numerous clinical trials affirm the efficacy and safety of IV iron to treat cancer-related anemia (CRA). Nonetheless, evaluation and treatment of CRA remains suboptimal. AREAS COVERED: This review summarizes CRA therapy with a focus on iron deficiency and its treatment. The literature search was conducted using the National Library of Medicine (PubMed) database from 2004 to 2024. Topics reviewed include CRA pathophysiology, laboratory diagnosis of iron deficiency, a summary of clinical trial results using IV iron to treat CRA, and safety aspects. EXPERT OPINION: Despite overwhelming positive efficacy and safety data, IV iron remains underutilized to treat CRA. This is likely due to persistent (unfounded) concerns about IV iron safety and lack of physician awareness of newer clinical trial data. This leads to poor patient quality of life and patient exposure to anemia treatments that have greater safety risks than IV iron. Solutions to this problem include increased educational efforts and considering alternative treatment models in which other providers separately manage CRA. The recent availability of new oral iron therapy products that are effective in treating anemia of inflammation has the potential to dramatically simplify the treatment of CRA.

Targeting a higher plasma VWF level at time of delivery in pregnant individuals with von Willebrand disease: Outcomes at a single-institution cohort study.

INTRODUCTION: Guidelines on the management of pregnant individuals with von Willebrand disease (VWD) at the time of delivery recommend that von Willebrand factor (VWF) and factor VIII:C (FVIII:C) levels be ≥50% to prevent postpartum haemorrhage (PPH). Yet, high PPH rates persist despite these levels or with prophylactic factor replacement therapy to achieve these levels. AIMS: The current practice at our centre has been to target peak plasma VWF and FVIII:C levels of ≥100 IU/dL at time of delivery. The objective of this study was to describe obstetric outcomes in pregnant individuals with VWD who were managed at our centre. METHODS: Demographics and outcomes on pregnant individuals with VWD who delivered between January 2015 and April 2023 were collected. RESULTS: Forty-seven singleton deliveries (among 41 individuals) resulting in 46 live births and one foetal death were included. Twenty-one individuals had at least one prior birth by the start date of this study, of which 11 (52.4%) self-reported a history of PPH. Early PPH occurred in 12.8% (6/47) of deliveries. Two individuals required blood transfusion, of which one also had an unplanned hysterectomy and transfer to ICU. There were no thrombotic events reported. CONCLUSION: The strategy of targeting higher peak plasma VWF and FVIII:C levels (≥100 IU/dL) at the time of delivery may be effective in reducing the risk of delivery-associated bleeding complications in VWD patients. Yet, the rate of early PPH remains unsatisfactory compared to the non-VWD population.

Antithrombin Therapy: Current State and Future Outlook.

Antithrombin (AT) is a natural anticoagulant pivotal in inactivating serine protease enzymes in the coagulation cascade, making it a potent inhibitor of blood clot formation. AT also possesses anti-inflammatory properties by influencing anticoagulation and directly interacting with endothelial cells. Hereditary AT deficiency is one of the most severe inherited thrombophilias, with up to 85% lifetime risk of venous thromboembolism. Acquired AT deficiency arises during heparin therapy or states of hypercoagulability like sepsis and premature infancy. Optimization of AT levels in individuals with AT deficiency is an important treatment consideration, particularly during high-risk situations such as surgery, trauma, pregnancy, and postpartum. Here, we integrate the existing evidence surrounding the approved uses of AT therapy, as well as potential additional patient populations where AT therapy has been considered by the medical community, including any available consensus statements and guidelines. We also describe current knowledge regarding cost-effectiveness of AT concentrate in different contexts. Future work should seek to identify specific patient populations for whom targeted AT therapy is likely to provide the strongest clinical benefit.

Prolonged Exposure to Caplacizumab as Rescue Therapy in Refractory Immune Thrombotic Thrombocytopenic Purpura.

We describe a case of refractory thrombotic thrombocytopenic purpura (7 lines of therapy) in which caplacizumab was used over a 6-month period as rescue therapy. Caplacizumab maintained the patient in clinical remission until successful immunosuppression was achieved resulting in normal ADAMTS13 levels. This case illustrates the utility of caplacizumab therapy in treating refractory TTP.

Five Challenging Cases of Hereditary Antithrombin Deficiency Characterized by Thrombosis or Complicated Pregnancy.

Hereditary antithrombin deficiency (ATD) is a rare autosomal dominant condition (estimated prevalence 1:500-1:5000). Most ATD patients have AT activity levels 40-60% of normal. We present treatments for venous thromboembolism (VTE) in five cases of hereditary ATD. Four patients had a family history of ATD, and one had a de novo mutation. The majority of patients had a VTE while on prophylactic anticoagulation. AT concentrate augmentation was added in these cases to treat the VTE and for prophylaxis against further episodes. Two patients had significant bleeding events, one had permanent physical sequelae. Two of the patients were pregnant. VTE is a common cause of morbidity and mortality during pregnancy. Although low molecular weight heparins are the drugs of choice during pregnancy, this treatment was inadequate in one patient (developed VTE on therapy). These cases emphasize the need to screen for ATD in young patients (<55 years) presenting with VTE. AT augmentation therapy may be necessary in patients inadequately treated with conventional anticoagulants. Careful monitoring and individualized care are needed in ATD patients, especially those with demonstrated bleeding tendencies.

Acquired von Willebrand syndrome in monoclonal gammopathy - A scoping review on hemostatic management.

BACKGROUND: Acquired von Willebrand syndrome (AVWS) has been associated with monoclonal gammopathy of undetermined significance (MGUS), with limited data on its management. METHODS: We conducted a systematic literature search in Medline (Ovid), Embase, and Scopus up to September 11, 2019, for studies reporting on the management of AVWS associated with MGUS (AVWS-MGUS). Data on patient characteristics, laboratory parameters at presentation, and clinical and laboratory outcomes were extracted. OBJECTIVES: To describe the clinical presentation and outcomes of different therapeutic approaches. RESULTS: Seventy-five studies were included in the final review, for a total of 137 patients. Most patients had von Willebrand factor ristocetin cofactor activity <30 IU/dL (86.6%) and factor VIII levels <50 IU/dL (91.8%). Bleeding severity ranged from no bleeding (16.1%) to minor bleeding (46.4%) and major bleeding (37.5%). The overall clinical success rates for 1-deamino-8-D-arginine vasopressin (DDAVP), factor replacement therapy, and intravenous immunoglobulin (IVIG) were 43.8%, 33.3%, and 85.4%, respectively. The laboratory response rates for DDAVP, factor replacement therapy, and IVIG were 39.0%, 62.9%, and 88.6%, respectively. Several other treatments were also reported in small numbers, out of which myeloma-directed therapies, plasma exchange, recombinant factor VIIa, and antifibrinolytics appeared most successful, while immunosuppressive agents were largely ineffective. CONCLUSION: IVIG appears to be an effective treatment for AVWS-MGUS bleeding, conferring a high clinical success rate with measurable laboratory outcomes; albeit temporary. DDAVP and factor replacement therapy may be partially successful in controlling minor bleeds, but not major bleeds. Other less commonly used agents may be effective in certain cases, although data are limited.

High prevalence of overweight/obesity in adult persons with hemophilia in Utah and a review of the literature.

: The objectives of this study were firstly to determine the prevalence of overweight/obesity in adult persons with hemophilia in Utah, and to explore the association between age, disease severity and race with body mass index (BMI), and secondly to provide recent data on the prevalence of overweight/obesity in the hemophilia population via a review of the literature. We conducted a retrospective cross section study of adult persons with hemophilia who were seen at a Utah hemophilia treatment center from 1 January 2017 to 31 December 2019. The electronic database PubMed was searched for studies with observation periods from 1 January 2012 to 31 December 2019. The age-adjusted prevalence for overweight/obesity in the adult Utah hemophilia population was higher than the overall Utah population and the general US population. After adjusting for race and age, mild hemophilia was associated with a 7.7% higher BMI (95% confidence interval, 0.023-15.98%, P < 0.05). Review of the literature demonstrated high levels of overweight/obesity in hemophilia communities globally with considerable heterogeneity between studies. Despite increasing awareness, prevalence of overweight/obesity in the hemophilia population remains high in comparison with the general population. There is a critical need to address this issue acutely at hemophilia treatment centers due to the considerable burden of obesity.

How I treat cancer-associated anemia.

Despite increasing use of targeted therapies to treat cancer, anemia remains a common complication of cancer therapy. Physician concerns about the safety of intravenous (IV) iron products and erythropoiesis-stimulating agents (ESAs) have resulted in many patients with cancer receiving no or suboptimal anemia therapy. In this article, we present 4 patient cases that illustrate both common and complex clinical scenarios. We first present a review of erythropoiesis and then describe our approach to cancer-associated anemia by identifying the contributing causes before selecting specific treatments. We summarize clinical trial data affirming the safety and efficacy of currently available IV iron products used to treat cancer-associated anemia and illustrate how we use commonly available laboratory tests to assess iron status during routine patient management. We compare adverse event rates associated with IV iron vs red cell transfusion and discuss using first-line IV iron monotherapy to treat anemic patients with cancer, which decreases the need for ESAs. A possible mechanism behind ESA-induced tumor progression is discussed. Finally, we review the potential of novel therapies such as ascorbic acid, prolyl hydroxylase inhibitors, activin traps, hepcidin, and bone morphogenetic protein antagonists in treating cancer-associated anemia.

ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder.

PURPOSE: To identify the molecular cause in five unrelated families with a distinct autosomal dominant ocular systemic disorder we called ROSAH syndrome due to clinical features of retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache. METHODS: Independent discovery exome and genome sequencing in families 1, 2, and 3, and confirmation in families 4 and 5. Expression of wild-type messenger RNA and protein in human and mouse tissues and cell lines. Ciliary assays in fibroblasts from affected and unaffected family members. RESULTS: We found the heterozygous missense variant in the ɑ-kinase gene, ALPK1, (c.710C>T, [p.Thr237Met]), segregated with disease in all five families. All patients shared the ROSAH phenotype with additional low-grade ocular inflammation, pancytopenia, recurrent infections, and mild renal impairment in some. ALPK1 was notably expressed in retina, retinal pigment epithelium, and optic nerve, with immunofluorescence indicating localization to the basal body of the connecting cilium of the photoreceptors, and presence in the sweat glands. Immunocytofluorescence revealed expression at the centrioles and spindle poles during metaphase, and at the base of the primary cilium. Affected family member fibroblasts demonstrated defective ciliogenesis. CONCLUSION: Heterozygosity for ALPK1, p.Thr237Met leads to ROSAH syndrome, an autosomal dominant ocular systemic disorder.

The Role of Intravenous Iron in the Treatment of Anemia Associated with Cancer and Chemotherapy.

Cancer-related anemia (CRA) is a commonly occurring problem for patients with cancer regardless of whether they are receiving treatment with chemotherapy or immunotherapy. It may result from one or more processes (decreased production, increased destruction, or increased loss of red blood cells, RBC). Perturbations in iron availability form the primary basis for anemia in many patients with cancer-related anemia. Functional iron deficiency (FID) anemia is a condition in which the patient has adequate or increased iron stores, but this iron pool is not available for erythropoiesis. Erythropoiesis-stimulating agents (ESAs) were the original treatment for FID; over time, however, if the supply of iron cannot keep pace with increased RBC synthesis driven by ESAs, FID may eventually lead to the lack or loss of ESA responsiveness. Subsequent clinical trials reported that intravenous (IV) iron could enhance the erythropoietic response to ESAs. This chapter reviews the pathogenesis of FID and summarizes the literature on the treatment of cancer- and chemotherapy-induced anemia. Clinical trials using IV iron with or without ESAs are reviewed in addition to the currently available IV iron products. The consensus conclusions from these trials, as well as guideline recommendations, support the use of IV iron in these patients to enhance ESA responsiveness, decrease ESA dosage, and reduce RBC transfusions. Little data have been published on the long-term safety of IV iron or its impact on tumor growth. This paper also briefly explores novel approaches for the treatment of FID anemia, which has relevance in treating not only cancer patients but also patients with benign inflammatory disorders.

The D-dimer assay.

D-dimer is an indirect marker of fibrinolysis and fibrin turnover; this molecule exhibits unique properties as a biological marker of hemostatic abnormalities as well as an indicator of intravascular thrombosis. D-dimer is a soluble fibrin degradation product that results from the systematic degradation of vascular thrombi through the fibrinolytic mechanism. Because of this, the D-dimer serves as a valuable marker of activation of coagulation and fibrinolysis in a number of clinical scenarios. Most commonly, D-dimer has been extensively investigated for excluding the diagnosis of venous thromboembolism (VTE) and is used routinely for this indication. In addition, D-dimer has been evaluated for determining the optimal duration of anticoagulation in VTE patients, for diagnosing and monitoring disseminated intravascular coagulation, and for monitoring other conditions in which the patient is at high risk of bleeding or thrombosis. Limitations of the assay include D-dimer elevation in a constellation of clinical scenarios (age, pregnancy, and cancer) and lack of clinical standardization.

Dynamic dosing of romiplostim in patients with immune thrombocytopenia purpura: Two case reports.

Romiplostim is a thrombopoietin receptor agonist approved for the treatment of immune thrombocytopenia purpura. When following FDA-approved romiplostim prescribing recommendations to withhold treatment for platelet counts above 400k/µL, some patients exhibit a precipitous decline in their platelet count potentially causing patient harm. We present two cases where stable platelet counts were achieved only through persistent weekly dosing of romiplostim despite platelet counts above 400k/µL on the day of administration. Therefore, continuous weekly dosing of romiplostim despite platelet count being above 400k/µL combined with twice weekly vigilant monitoring is an alternative method of romiplostim dosing that mitigates severe fluctuations in platelets. We also discuss important details, postulated mechanisms, and evidence-based mitigation strategies.

Evaluation of Coagulation in the Neurosurgery Patient.

Normal hemostasis provides for balanced interactions between the blood vessel wall, coagulation proteins, and platelets. After vascular injury, primary hemostasis and secondary hemostasis function in a coordinated fashion to stop bleeding. Standard coagulation tests have been shown in multiple studies to predict bleeding and mortality in neurosurgical patients. Emerging coagulation tests are useful point-of-care assays that guide transfusion therapy and diagnose patients with hyperfibrinolysis. This article provides an overview of hemostasis, a summary of standard coagulation testing and point-of-care tests, and a brief review of coagulation test usefulness in neurosurgery, focusing on studies in patients with traumatic brain injury.

Erythropoiesis-Stimulating Agents in the Management of Anemia in Chronic Kidney Disease or Cancer: A Historical Perspective.

Anemia is common in patients with cancer or with chronic kidney disease (CKD). Although the introduction of erythropoiesis-stimulating agents (ESAs) has transformed the management of anemia, their use has been complicated by a number of factors including frequent guideline updates, safety concerns and, in the United States, a Risk Evaluation and Mitigation Strategy (REMS) program, which aimed to ensure that the benefits of ESAs outweigh the risks. Many previous concerns around ESA use in cancer and CKD have been addressed by the reassuring results of post-approval studies, and biosimilar ESAs have been used in Europe for many years, with safety and efficacy profiles similar to originator products. This review describes the evolution of the use of ESAs from approval to the present day, discussing results from clinical studies of ESAs in cancer and CKD, and the influence of these findings on product labeling and guideline updates. We also discuss the impact of the introduction of ESA biosimilars in Europe, bringing cost savings and increased access to patients.

SCF-KIT signaling induces endothelin-3 synthesis and secretion: Thereby activates and regulates endothelin-B-receptor for generating temporally- and spatially-precise nitric oxide to modulate SCF- and or KIT-expressing cell functions.

We demonstrate that SCF-KIT signaling induces synthesis and secretion of endothelin-3 (ET3) in human umbilical vein endothelial cells and melanoma cells in vitro, gastrointestinal stromal tumors, human sun-exposed skin, and myenteric plexus of human colon post-fasting in vivo. This is the first report of a physiological mechanism of ET3 induction. Integrating our finding with supporting data from literature leads us to discover a previously unreported pathway of nitric oxide (NO) generation derived from physiological endothelial NO synthase (eNOS) or neuronal NOS (nNOS) activation (referred to as the KIT-ET3-NO pathway). It involves: (1) SCF-expressing cells communicate with neighboring KIT-expressing cells directly or indirectly (cleaved soluble SCF). (2) SCF-KIT signaling induces timely local ET3 synthesis and secretion. (3) ET3 binds to ETBR on both sides of intercellular space. (4) ET3-binding-initiated-ETBR activation increases cytosolic Ca2+, activates cell-specific eNOS or nNOS. (5) Temporally- and spatially-precise NO generation. NO diffuses into neighboring cells, thus acts in both SCF- and KIT-expressing cells. (6) NO modulates diverse cell-specific functions by NO/cGMP pathway, controlling transcriptional factors, or other mechanisms. We demonstrate the critical physiological role of the KIT-ET3-NO pathway in fulfilling high demand (exceeding basal level) of endothelium-dependent NO generation for coping with atherosclerosis, pregnancy, and aging. The KIT-ET3-NO pathway most likely also play critical roles in other cell functions that involve dual requirement of SCF-KIT signaling and NO. New strategies (e.g. enhancing the KIT-ET3-NO pathway) to harness the benefit of endogenous eNOS and nNOS activation and precise NO generation for correcting pathophysiology and restoring functions warrant investigation.

siRNA-knockdown of ADAMTS-13 modulates endothelial cell angiogenesis.

ADAMTS-13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13, is a zinc-containing metalloprotease that cleaves von Willebrand factor (vWf). Previous publications by our laboratory have shown that ADAMTS-13 may also be involved in angiogenesis. For this study, we report the successful transient knockdown of endogenous ADAMTS-13 in human umbilical vein endothelial cells (HUVEC) via siRNA and the effects of reduced endogenous ADAMTS-13 on HUVEC angiogenesis functions. 15nM of ADAMTS-13 siRNA reduced HUVEC ADAMTS-13 protein levels by 90% after 24h incubation, whereas control siRNA did not affect endogenous ADAMTS-13 levels. Furthermore, this transfection did not affect the HUVEC endogenous protein level of ADAMTS-1, a related family member of ADAMTS-13 indicating the specificity of the siRNA. Transfection of HUVEC with 15nM of ADAMTS-13 siRNA resulted in a 21% decrease in proliferation after 24h incubation. The effects of ADAMTS-13 knockdown on migration of HUVEC across a scratch wound were also evaluated. 24h after transfection with control siRNA, there was increased cell migration across the scratch wound. This dramatic migration did not occur with ADAMTS-13 knockdown cells. Decreased protein levels of endogenous ADAMTS-13 also affected angiogenesis as measured by endothelial cell tube formation using a Matrigel matrix method. The tube lengths, sizes and junction numbers of the ADAMTS-13 knockdown cells were all significantly lower compared to control cells by about 40%. The protein level of vascular endothelial growth factor (VEGF), a well-known regulator of angiogenesis, was significantly decreased by 45% upon knockdown of ADAMTS-13. Moreover, activity of the AKT pathway, one of the VEGF angiogenesis downstream signaling pathways was down-regulated by ADAMTS-13 siRNA. These data indicate that in cultured endothelial cells, one role of endogenous ADAMTS-13 is regulation of angiogenesis, mediated through VEGF and AKT signaling pathway. Overall, our data suggest an additional model of endogenous ADAMTS-13 functionality, beyond that of cleaving von Willebrand factor.