Long-term Prophylaxis Research Articles

Patient outcomes associated with subcutaneous C1INH prophylaxis for hereditary angioedema: a retrospective analysis

BackgroundReal-world data on subcutaneous C1INH (C1INH[SC]) usage and patient-level impacts on hereditary angioedema (HAE)-related outcomes and quality of life (QoL) are both lacking and challenging to generate using conventional study methodologies. Using a hybrid study design involving patient interviews supplemented by retrospective medical chart data review, we conducted a real-world assessment of the impact of C1INH(SC) prophylaxis on HAE attack patterns, QoL, and on-demand medication use.MethodsThe study was conducted at seven US sites and included 36 adults with HAE who had been treated with C1INH(SC) long-term prophylaxis following ≥ 12 months of on-demand management only. Patients underwent 30-min interviews, facilitated and analyzed by a trained qualitative research specialist. Medical records were reviewed for 12 months before (pre-index) and after (post-index) initiation of C1INH(SC). Using interview data with descriptive terms converted to numerical values, we compared pre- versus post-index attack frequency, severity, and rescue medication usage.ResultsMean (SD) annualized attack frequency per patient decreased 82.0%, from 38.8 (38.8) attacks/year pre-index to 7.0 (15.3) attacks/year (P < 0.001); the median number of attacks decreased by 97.0% (30 pre-index to 1 post-index). For 20 patients, the annualized attack rate after starting C1INH(SC) prophylaxis was ≤ 1 attack/year; 12 of these patients reported 0 attacks. Mean (SD) attack severity (scale: 0 = none/mild to 4 = very severe) decreased from 2.3 (0.7) pre-index to 0.9 (0.9) post-index (P < 0.001). Mean/median rescue medication use decreased by 77.2%/96.3%. Improved QoL was narratively described for many domains.ConclusionsThese real-world findings indicate that long-term prophylaxis with C1INH(SC) markedly improves important factors that contribute to the goal of achieving total disease control and normalization of patients’ lives, including fewer and less severe attacks, less rescue medication usage, and improved QoL.

Delay in diagnosis is the most important proximate reason for mortality in hereditary angio-oedema: our experience at Chandigarh, India.

Hereditary angio-oedema (HAE) is a rare autosomal dominant disorder characterized clinically by recurrent episodes of nonpruritic subcutaneous and/or submucosal oedema. Laryngeal oedema is the commonest cause of mortality in patients with HAE. Prior to the availability of first-line treatment options for the management of HAE, mortality was as high as 30%. Mortality has significantly declined in countries where first-line treatment options are available and patients can access these therapies. There is a paucity of literature on the outcomes of patients with HAE in developing countries where availability of and access to first-line treatment options are still a challenge. To report our experience on mortality in patients with HAE and to report factors associated with the death of these patients. We carried out a record review of all patients diagnosed with HAE between January 1996 and August 2022. Families with HAE who had reported the death of at least one family member/relative from laryngeal oedema were studied in detail. Of the 65 families (170 patients) registered in the clinic, 16 families reported the death of at least one family member/relative from laryngeal oedema (total of 36 deaths). Of these 16 families, 14 reported that 1 or more family members had experienced at least 1 attack of laryngeal oedema. One patient died during follow-up when she was taking long-term prophylaxis with stanozolol and tranexamic acid, while the remaining 35 patients were not diagnosed with HAE at the time of their death. At the time of death of all 36 patients, at least 1 other family member had symptoms suggestive of HAE, but the diagnosis was not established for the family. To our knowledge, this is the largest single-centre cohort of patients with HAE in India reporting mortality data and factors associated with death in these families. The delay in diagnosis is the most important reason for mortality.

Value of Prophylactic Plasma Treatment and Incidence of Acute Episodes in Patients Enrolled in the International Hereditary Thrombotic Thrombocytopenic Purpura Registry

Background: Hereditary thrombotic thrombocytopenic purpura (hTTP), or Upshaw-Schulman syndrome, is a rare thrombotic microangiopathy due to a severe congenital deficiency of ADAMTS13 resulting from bi-allelic ADAMTS13 mutations. As in other plasma factor deficiencies, treatment consists of replacement of the missing ADAMTS13, which can currently be attempted with fresh frozen plasma, solvent/detergent plasma or plasma-derived factor VIII/Von Willebrand factor concentrates. Although prophylactic plasma infusions prevent acute episodes in many but not all hTTP patients, current treatment guidelines state conditional recommendations for prophylaxis outside of pregnancy, because evidence supporting the burdensome plasma prophylaxis in hTTP patients is scarce. Aims: Prospective evaluation of the incidence of acute episodes occurring in hTTP patients during periods with and without prophylactic plasma treatment. Methods: All patients with a confirmed diagnosis of hTTP enrolled in the International hTTP Registry between January 01, 2006 and December 31, 2021 were eligible for study. Diagnosis of hTTP was based on persisting ADAMTS13 activity &amp;lt;10%, bi-allelic ADAMTS13 mutations, and/or an infusion trial with full recovery and a half-life of plasma ADAMTS13 of around 60 hours. We recorded the patients' detailed medical history at enrollment and then collected prospective data on the clinical course, treatment modalities and laboratory values through site-visits and case report forms completed by treating physicians during annual visits or at occurrence of acute TTP episodes. Patients were followed until December 31, 2022 (database lock), death, or loss to follow-up, whatever came first. This post-hoc analysis evaluated acute TTP episodes during follow-up, stratified by periods on prophylaxis and without prophylaxis. Patients could contribute follow-up time to both periods (strata), but never simultaneously and gestation periods were excluded. Minimum criterion for long-term prophylaxis was defined as at least one monthly plasma infusion over a period of ≥ 6 months. Results were reported using descriptive statistics without formal statistical comparison and incident rates of acute TTP events were calculated per 1000 person-years with corresponding 95% confidence intervals (CIs). Results: At the end of December 2021, the International hTTP Registry had 182 confirmed hTTP patients eligible for this analysis that were followed for a median period of 3.6 (range, 0-18.5) years. The gender distribution showed more female (n=98, 53.8%) than male (n= 84, 46.2%) patients enrolled, a disparity likely related to a surge of diagnosis in women due to pregnancy complications. During prospective follow-up, 47 (25.8%) hTTP patients never had prophylactic treatment, while 135 (74.2%) received any form of prophylactic treatment, including long-term prophylaxis in 117 (86.7%). Patients who received any prophylactic treatment during follow-up had an incidence rate (95% CI) of acute TTP episodes of 272.4 (230.8-319.3) per 1000 person-years while receiving prophylaxis and of 520.4 (401.6-663.3) per 1000 person-years during periods without prophylaxis (Table 1). In the patients on long-term prophylaxis, the incidence rate of acute TTP episodes was 267.1 (226.0-313.6) per 1000 person-years in periods with prophylaxis, and 879.6 (664.4-1142.2) per 1000 person-years without prophylaxis. Irrespective of treatment interval, about half of patients on prophylaxis had break-through events, with the highest incidence rate observed in the group of patients receiving plasma products weekly, possibly reflecting their more precarious or severe disease course. Conclusions: In this large hTTP patient cohort observed for five years on average, we confirm the incidence rate of acute events as reported by Tarasco et al. (Blood 2021;137;3563-75). Here, we demonstrate for the first time that hTTP patients with disease courses requiring prophylaxis benefit from this burdensome treatment, which was most evident in patients on long-term prophylaxis. Current treatment options are however insufficient to suppress residual disease activity leading to break-through events observed in half of the patients on prophylaxis. Novel therapies, such as recombinant ADAMTS13, with the potential of reaching higher plasma levels, will likely overcome limitations of current treatment options.

Cost-Effectiveness of Long-Term Prophylaxis with Plasma-Derived Vs. Recombinant Von Willebrand Factor in Severe Von Willebrand Disease

Introduction: von Willebrand disease (VWD) is the most common inherited bleeding disorder and exhibits significant variability in bleeding phenotype across patients. International guidelines conditionally recommend long-term prophylaxis to reduce bleeding events for patients with a severe phenotype: all patients with type 3 VWD and a subset of patients with severe phenotypes of types 1 and 2 VWD. At the time of this conditional recommendation, only 10% of patients with severe VWD are treated prophylactically, unlike patients with severe hemophilia (~45%). In the United States, there are currently two approved factor replacement therapies: plasma-derived von Willebrand factor (pdVWF) and recombinant von Willebrand factor (rVWF). The cost-effectiveness of prophylaxis options for patients with VWD in the United States is not known. We sought to fill this gap by determining the cost-effectiveness of pdVWF versus rVWF prophylaxis treatment options for patients with severe VWD. Methods: In this independent analysis free of industry influence, we constructed a Markov model of adult patients with severe VWD to compare the cost-effectiveness of long-term prophylaxis with pdVWF versus rVWF. Transition probabilities for patients' breakthrough bleeding events while on prophylaxis with each factor replacement product, and product utilization, were derived from an open-label, prospective, phase 3 clinical trial that employed a pdVWF versus rVWF switch design (NCT 02973087). Costs of prophylaxis and costs of VWD-specific breakthrough bleed health resource utilization in the United States (US) accounted for bleed category, severity, and bleed-specific mortality, and were sourced from previously published literature and the Centers for Medicare &amp; Medicaid Services. For effectiveness measured in quality-adjusted life-years (QALY), utilities for patients with severe VWD on prophylaxis were informed from EQ-5D-specific utility data for patients with severe hemophilia on prophylaxis. The primary outcome was the incremental cost-effectiveness ratio (ICER) or the incremental net monetary benefit (iNMB) if the intervention (rVWF) was found to be cost-saving, reported over a lifetime time-horizon across a range of accepted willingness-to-pay (WTP) thresholds in US dollars per QALY. The two secondary outcomes were threshold analyses for 1) the breakthrough bleed rate and 2) frequency of infusions necessary for the non-favored product (i.e., in the base-case) to become favored. In addition, we conducted a scenario analysis assuming the non-significant reduction in bleeding with rVWF (0.55 [95% confidence interval 0.086-3.523]) otherwise nullified in the base-case analysis, was significant. We proceeded with deterministic sensitivity analyses, varying all parameter estimates across the largest of their known 95% confidence intervals or +/-20% of absolute value. We concluded with a probabilistic sensitivity analysis, capturing uncertainty in all parameters simultaneously over 10,000 Monte Carlo simulations. Results: In the base-case, treatment with prophylactic pdVWF versus prophylactic rVWF yielded discounted lifetime costs of $21.2 million and $19.8 million, with both accruing 20.6 discounted QALYs. The average incremental net monetary benefit across accepted WTP thresholds of $50,000-$150,000/QALY was $1.38 million [95% credible interval $1.10-1.67 million], in favor of rVWF. Deterministic sensitivity analysis showed that the model was most sensitive to the frequency and cost of pdVWF infusions. In all three probabilistic sensitivity analyses across all WTP thresholds, rVWF was favored over pdVWF in 100% of 10,000 Monte Carlo iterations. Threshold analyses revealed that 1) the bleeding rate on pdVWF prophylaxis would have to reduce by at least 43% and, 2) the average frequency of pdVWF infusions would need to decrease from 3 to 2.75 infusions per week for pdVWF to be favored over rVWF prophylaxis. Scenario analysis revealed similar significant improvement in incremental net monetary benefit with rVWF. Conclusion: Twice-weekly rVWF versus thrice-weekly pdVWF demonstrated similar quality-adjusted life-expectancy, while rVWF was cost-saving due to its longer half-life requiring fewer lifetime infusions. At current pricing in the United States, prophylactic rVWF is a cost-saving option for patients averaging more than 2.75 weekly pdVWF infusions.

Efficacy of Regular Prophylaxis with a Plasma-Derived Von Willebrand Factor/Factor VIII Concentrate in Reducing Heavy Menstrual Bleeding in Females with Von Willebrand Disease

Background: Heavy menstrual bleeding (HMB) is the dominant symptom affecting ~80-90% of women with VWD and is a common cause of outpatient visits and hospitalizations. Long-term prophylaxis with a von Willebrand factor (VWF) concentrate is recommended in von Willebrand disease (VWD) patients with a history of severe, frequent bleeds, and for women with VWD who experience HMB. A recent prospective study found that recombinant VWF was not superior to tranexamic acid at reducing HMB in women with VWD. The WIL-31 study demonstrated the efficacy of prophylaxis with a plasma-derived VWF/factor VIII (pdVWF/FVIII) concentrate containing VWF and FVIII in a 1:1 activity ratio (wilate ®) in adults and children with VWD of all types. The primary endpoint was met, showing a decrease of 84% in the mean total annualized bleeding rate (ABR) compared with prior on-demand treatment. The impact of pdVWF/FVIII prophylaxis on HMB was evaluated as a secondary endpoint of the WIL-31 study. Aims: To investigate the efficacy of regular prophylaxis with a pdVWF/FVIII concentrate in reducing the incidence of HMB in females with VWD who had previously been treated on demand. Methods: WIL-31 (NCT04052698) was a prospective, non-controlled, international, multicenter phase 3 trial that enrolled male/female patients, aged ≥6 years old with VWD type 1 (VWF:RCo &amp;lt;30 IU/dL), type 2 (except 2N) or type 3. Prior to entering the WIL-31 study, all patients had received on-demand treatment with a VWF-containing product during a 6-month, prospective, observational, run-in study (WIL-29). Patients in WIL-31 received regular pdVWF/FVIII prophylaxis 2-3 times per week at a dose of 20-40 IU/kg for 12 months. Exploratory analyses included comparison of heavy menstrual ABR (HMABR). HMB was defined as any menstrual bleed that impeded the ability to perform daily activities (such as work, housework, exercise, or social activities) during menstrual periods. Criteria for HMB included changing pads more frequently than hourly, menstrual bleeding lasting 7 or more days, or the presence of clots &amp;gt;1 cm combined with a history of flooding or a Pictorial Blood Assessment Chart (PBAC) score ≥185. PBAC scores were reviewed from patient diaries at each study visit. Results: Of the 33 patients included in the overall population, 14 (42%) were female and half (n=7; 13-43 years old) were of childbearing age. In these females, all VWD types were represented: type 1 (n=2), type 2 (n=1); and type 3 (n=4). Six (86%) females were on hormonal birth control during WIL-31. Prophylaxis with pdVWF/FVIII reduced the mean HMABR by 64% compared with on-demand treatment (3.0 vs 8.3 in WIL-31 and WIL-29, respectively). During on-demand treatment, 86% (6/7) of females experienced ≥1 HMB episode, which was reduced to 29% (2/7) during prophylaxis with four patients experiencing no HMB (Figure 1). During on-demand treatment, 6 females experienced 32 HMB episodes; of these, 7 (22%) required further treatment with pdVWF/FVIII and 2 (6%) required concomitant medication. Under prophylaxis, two patients (aged ≥17 years), experienced 12 HMBEs; of these, only one (8%) impeded daily activity and none required additional pdVWF/FVIII treatment, hospitalization, or concomitant medication. Mean (SD) intra-individual median PBAC scores (N=4) decreased by 43% from 227 (91.7) during on-demand treatment to 131 (59.9) with prophylaxis, a 96-point reduction. Conclusion: Prophylaxis with pdVWF/FVIII was efficacious in reducing HMB compared with on-demand treatment in 7 female patients with VWD. None of the cases of HMB during prophylaxis was severe enough to require additional treatment. Among women with VWD, HMB remains a major burden and further research is required.

Design of an Observational Study (PROVE) to Assess the Long-Term Effects of Prophylaxis with Simoctocog Alfa or Emicizumab on Joint and Bone Health in Hemophilia a Patients

Background: Arthropathy caused by repeated joint bleeding is a major complication in patients with severe hemophilia A and is associated with long-term morbidity. Factor VIII (FVIII) prophylaxis has proven benefits for prevention of bleeding, including joint bleeding, in these patients. Alongside preservation of joint health, FVIII prophylaxis may preserve bone mineral density (BMD) and reduce the risk of fractures. Emicizumab is a bi-specific monoclonal antibody with no structural homology to FVIII and is approved for prophylaxis in hemophilia A patients. However, data on the long-term impact of emicizumab on joint and bone health are limited. Aims: To assess the impact of long-term prophylaxis with simoctocog alfa (Nuwiq ®; a fourth generation recombinant FVIII) versus emicizumab on joint and bone health in people with hemophilia A. Methods: PROVE is a multinational, prospective, two-arm, low-interventional study that will collect clinical data on joint and bone health in patients receiving prophylaxis with simoctocog alfa or emicizumab in routine clinical practice. Approximately 200 male participants (100 in each treatment arm) at least 12 years of age with severe hemophilia A (FVIII activity [FVIII:C] &amp;lt;1%) will be enrolled. Written, informed consent will be obtained from each patient or their legal representative. The primary objective of the study is to evaluate the long-term effect of simoctocog alfa versus emicizumab on joint health as measured by magnetic resonance imaging (MRI). The primary endpoint will be a between-group comparison of the change in total score on the extended MRI (eMRI) scale (Table 1). Secondary and exploratory endpoints include the impact of simoctocog alfa vs emicizumab on bleeding rates, joint and bone health, physical activity, quality of life and safety (Table 1). Study treatments will be defined by the treating physician prior to inclusion of a patient into the study. Patients will not be randomized to the treatment groups but will continue with their current prophylactic regimen (simoctocog alfa or emicizumab). Patients will be provided with an electronic diary (eDiary) in which to record study related data, including treatment-related data, bleeding event details, fracture details, concomitant medications and adverse drug reactions. Each patient will be followed for up to 4 years. An interim analysis is planned after 2 years. Conclusion: ThePROVE study aims to generate real-world data on the long-term effects of prophylaxis with simoctocog alfa or emicizumab on joint and bone health in hemophilia A.

Efficacy of Regular Prophylaxis with a Plasma-Derived Von Willebrand Factor/Factor VIII Concentrate in Reducing Nose Bleeds in Children and Adults with Von Willebrand Disease

Background: The use of a von Willebrand factor (VWF) concentrate for long-term prophylaxis is recommended for individuals with von Willebrand disease (VWD) who have a history of frequent and severe bleeds, regardless of their age or the type of VWD. Bleeding from the nose (epistaxis) is one of the most common types of bleeding in VWD patients. The WIL-31 study demonstrated the efficacy of prophylaxis with a plasma-derived VWF/factor VIII (pdVWF/FVIII) concentrate containing VWF and FVIII in a 1:1 activity ratio (wilate ®) in adults and children with VWD of all types. The primary endpoint was met, showing a decrease of 84% in the mean total annualized bleeding rate (ABR) compared with prior on-demand treatment. Aims: To investigate the efficacy of regular prophylaxis with a pdVWF/FVIII concentrate in reducing nose bleeds in people with VWD, compared with previous on-demand treatment. Methods: WIL-31 (NCT04052698) was a prospective, non-controlled, international, multicenter phase 3 trial that enrolled male/female patients, aged ≥6 years with VWD type 1 (VWF:RCo &amp;lt;30 IU/dL), type 2 (except 2N) or type 3. Prior to entering the WIL-31 study, all patients had received on-demand treatment with a VWF-containing product during a 6-month, prospective, observational, run-in study (WIL-29); patients who experienced at least 6 bleeding episodes, excluding menstrual bleeds, of which ≥2 were treated with a VWF-containing product, were eligible to enter WIL-31. Patients in WIL-31 received regular prophylaxis with pdVWF/FVIII 2-3 times per week at a dose of 20-40 IU/kg for 12 months. In this post-hoc analysis, nose bleeds during WIL-29/-31 were described, and the mean ABRs were compared. Results: The study population included 33 patients with a median (range) age of 18 (7-61) years; 9 (27.3%) patients were 6-11 years old, 6 (18.2%) were 12-16 years old, and 18 (54.5%) were ≥17 years old. All VWD types were represented: type 1 (n=6), type 2 (n=5); and type 3 (n=22). There were 173 breakthrough bleeds in total during WIL-31, of which nose bleeds were the most common (89/173; 51.4%). Nose bleeds occurred in 16 of 33 patients during prophylaxis vs 26 of 33 during on-demand treatment. Of the 89 nose bleeds, 17 were traumatic, 69 spontaneous, and 3 due to allergic reaction (not product related). The mean number of spontaneous nose bleeds per patient during prophylaxis was 2.1, 2.3, 1.2, and 2.2, for the overall population, and the 6-11, 12-16, and ≥17 years age groups, respectively. Eight nose bleeds (9.0%) were major (all in the same patient). The mean nose ABR was reduced by 76% during prophylaxis vs on-demand treatment. The reduction was consistent across age groups (74-77%, Figure 1) but not across VWD types, with mean nose ABR reductions of 48, 89, and 80% for VWD type 1, type 2, and type 3 patients, respectively. During prophylaxis, a higher number of VWD type 3 patients, compared with type 1 and type 2 patients, experienced nose bleeds (12 vs 3 vs 1). The mean duration of nose bleeds decreased during prophylaxis vs on-demand for 12-17 years old, ≥17 years old, type 2 and type 3 VWD patients, but increased for 6-11 years old and severe type 1 patients. No relationship was observed between the number of nose bleeds and patient age (R 2=0.082). The majority (80.9%; 72/89) of nose bleeds were treated with pdVWF/FVIII with 86.1% (62/72) requiring only a single infusion; two required concomitant treatment with tranexamic acid. All treated nose bleeds were rated as “successfully treated”. Conclusion: The data indicate thatprophylaxis with pdVWF/FVIII was effective at reducing nose bleeds in patients with VWD type 2 and 3, and across all age groups.

Rates and Predictors of Prophylaxis in Women with Von Willebrand Disease and Heavy Menstrual Bleeding

Background: Women with von Willebrand disease (vWD) suffer from heavy menstrual bleeding (HMB) often complicated by iron deficiency anemia (IDA) and reduced quality of life. Despite the American Society of Hematology (ASH) recommendations for long-term prophylaxis in patients with severe frequent bleeds, prophylaxis remains under-utilized in women with severe HMB. Given the scarcity of data on management of gynecological bleeding, it is critical to examine our practice patterns and identify factors associated with prophylaxis use. Aims: 1) To evaluate the management and outcomes of gynecological bleeding in vWD, including rates of desmopressin (DDAVP) and vWF prophylaxis for HMB and predictors of their use. 2) To examine the association between prophylaxis and severe HMB. Methods: This retrospective cohort study included women ≥18 years diagnosed with vWD in the Northern Alberta Bleeding Disorders Program. We assessed the rates of HMB, severe HMB and IDA, along with their management strategies. Prophylaxis rates with DDAVP and vWF concentrates, as well as predictors of their use, were examined. Severe HMB was defined as HMB requiring Emergency Department (ED) visits, hospitalizations, blood transfusions, or surgical management (dilation &amp; curettage [D&amp;C], endometrial ablation or hysterectomy). IDA was defined as ferritin &amp;lt;30 mcg/L and hemoglobin &amp;lt;120 g/L. Logistic regression was used to examine factors associated with severe HMB. Variables with P-value &amp;lt;0.20 on univariate regression were included in multivariable regression. Results: 168 women were evaluated with a median age of vWD diagnosis of 27 years (IQR 18-38): 140 (81%) type 1, 23 (13%) type 2, and 5 (3%) type 3 vWD. Among those with type 1 vWD, 43 (31%) had baseline vWF levels &amp;lt;0.30 IU/ml, 94 (67%) had vWF levels of 0.30-0.49 IU/ml, and 3 (2%) had missing values. DDAVP response was assessed in 124/140 (89%) type 1 vWD and 13/23 (57%) type 2 vWD. There were 145 (86%) women with HMB, managed most commonly by tranexamic acid (TXA) (112; 77%), followed by hormonal therapy (73; 50%), subcutaneous DDAVP (40; 28%), and levonorgestrel intrauterine system (39; 26%). vWF prophylaxis was used in only 11 (8%) women. Surgical procedures for HMB were common including hysterectomy (28; 19%), endometrial ablation (15; 10%) and D&amp;C (15; 10%). Over a quarter (39; 27%) received iron infusions. Of the 65 (45%) women with a history of IDA, 6 (9%) had persistent IDA &amp;gt;5 years, 6 (9%) had IDA lasting 2-5 years and 53 (65%) had IDA corrected within 2 years. Prophylaxis rates did not differ between the 68 (40%) women with severe HMB and the 77 (53%) with non-severe HMB, with comparable rates of VWF use (9% vs 6%, P=0.60). Compared with women who never received prophylaxis, those who received DDAVP or vWF prophylaxis were more likely to have received TXA (93% vs 70%, P=0.003), iron infusions (43% vs 19%, P=0.004) and to have been diagnosed before 2000 (22% vs 7%, P=0.03) (Table 1). Though non-significant, a higher proportion of type 3 vWD (9% vs 1%, P=0.06) and higher ISTH-BAT (median 8 vs 7, P=0.07) were observed in prophylaxis recipients. On multivariable logistic regression, time from first bleeding symptom to diagnosis (adjusted odds ratio [aOR] 1.04, 95% CI 1.01-1.07) and prophylactic DDAVP use (aOR 2.4, 95% 1.01-5.6) were associated with severe HMB. There was a non-significant trend towards lower odds of severe HMB in patients diagnosed in 2000-2010 and 2011-2021 as compared to pre-2000 (aOR 0.3, 95% 0.1-1.0). Diagnosis before age 18, vWD type and baseline vWF activity were not associated with severe HMB. Conclusion: Women with vWD experience high rates of HMB and its associated complications. In our study, there was a relatively high uptake of DDAVP prophylaxis, however vWF prophylaxis was under-utilized even in those with severe HMB. We failed to demonstrate an impact of either prophylactic therapy on severe HMB, though this may be due to confounding by indication. There was a significant association between prophylactic DDAVP and vWF with other quality of care indicators including TXA and iron infusions. It is unclear if this association is related to practice patterns or patient factors such as access to care or preference for early definitive treatment. Overall, our findings highlight a need to further understand the barriers to prophylaxis use and to consider earlier prophylaxis for severe HMB to decrease bleeding complications and the need for resource-intensive therapies.

Hereditary angioedema outcomes in US patients switched from injectable long-term prophylactic medication to oral berotralstat

BackgroundBerotralstat, a first-line, once-daily, oral plasma kallikrein inhibitor for long-term prophylaxis of hereditary angioedema (HAE), is an effective and well-tolerated treatment option. ObjectiveTo summarize the safety, effectiveness, and impact on treatment satisfaction in patients who switched from injectable long-term prophylactics to oral berotralstat monotherapy (150 mg daily) at US sites in the international open-label APeX-S study. MethodsAPeX-S was an open-label, Phase II study of berotralstat conducted in 22 countries. Here, we focus on APeX-S patients enrolled at US sites who switched from injectable long-term prophylactics to berotralstat 150 mg once-daily monotherapy. ResultsA total of 34 patients discontinued lanadelumab (n = 21), subcutaneous C1 esterase inhibitor (n = 11), or intravenous C1 esterase inhibitor (n = 2) and switched to berotralstat 150 mg monotherapy. Vomiting, diarrhea, and upper respiratory tract infection were the most common adverse events (each 11.8%). Mean monthly attack rates were consistently low after the switch to berotralstat. The mean (SEM) monthly attack rate was 0.29 (0.11) at Month 1, 0.48 (0.15) at Month 6, and 0.58 (0.23) at Month 12. The median attack rate was 0 attack/mo throughout 12 months of treatment. Improvements were observed in the Treatment Satisfaction Questionnaire for Medication from baseline to Month 12 after the switch to berotralstat monotherapy, with the greatest improvements in convenience. ConclusionThe transition from injectable prophylactic medication to berotralstat was generally well tolerated. Patients switching to berotralstat monotherapy maintained good control of their HAE symptoms and reported improved treatment satisfaction. Trial RegistrationClinicalTrials.gov Identifier: NCT03472040.

To Boost or to Reset: The Role of Lactoferrin in Energy Metabolism.

Many pathological conditions, including obesity, diabetes, hypertension, heart disease, and cancer, are associated with abnormal metabolic states. The progressive loss of metabolic control is commonly characterized by insulin resistance, atherogenic dyslipidemia, inflammation, central obesity, and hypertension, a cluster of metabolic dysregulations usually referred to as the "metabolic syndrome". Recently, nutraceuticals have gained attention for the generalized perception that natural substances may be synonymous with health and balance, thus becoming favorable candidates for the adjuvant treatment of metabolic dysregulations. Among nutraceutical proteins, lactoferrin (Lf), an iron-binding glycoprotein of the innate immune system, has been widely recognized for its multifaceted activities and high tolerance. As this review shows, Lf can exert a dual role in human metabolism, either boosting or resetting it under physiological and pathological conditions, respectively. Lf consumption is safe and is associated with several benefits for human health, including the promotion of oral and gastrointestinal homeostasis, control of glucose and lipid metabolism, reduction of systemic inflammation, and regulation of iron absorption and balance. Overall, Lf can be recommended as a promising natural, completely non-toxic adjuvant for application as a long-term prophylaxis in the therapy for metabolic disorders, such as insulin resistance/type II diabetes and the metabolic syndrome.

Immunogenicity of a Plasma-Derived Von Willebrand Factor/Factor VIII Concentrate during the Wil-31 Prophylaxis Study in Patients with Von Willebrand Disease

Background: Long-term prophylaxis with a von Willebrand factor (VWF) concentrate is recommended in people with von Willebrand disease (VWD) with a history of frequent and severe bleeds. The WIL-31 study demonstrated the efficacy of prophylaxis with a plasma-derived VWF/factor VIII (pdVWF/FVIII) concentrate containing VWF and FVIII in a 1:1 activity ratio (wilate ®) in adults and children with VWD of all types. The primary endpoint was met, showing a decrease in mean total annualized bleeding rate (ABR) of 84% compared with prior on-demand treatment. Aim: To assess the immunogenicity of pdVWF/FVIII when used during the WIL-31 study in children and adults with VWD of all types. Methods: WIL-31 (NCT04052698) was a prospective, non-controlled, international, multicenter phase 3 trial that enrolled male/female patients aged ≥6 years with VWD type 1 (VWF: RCo &amp;lt;30 IU/dL), type 2 (except 2N) or type 3. Prior to entering the WIL-31 study, all patients had received on-demand treatment with a VWF-containing product during a 6-month, prospective, observational, run-in study (WIL-29); patients who experienced at least 6 bleeding episodes (BEs), excluding menstrual bleeds, of which ≥2 were treated with a VWF-containing product, were eligible to enter WIL-31. During WIL-31, patients received regular pdVWF/FVIII (containing VWF and FVIII in a 1:1 activity ratio) prophylaxis 2-3 times per week at a dose of 20-40 IU/kg for 12 months. FVIII (chromogenic and one-stage assays) and VWF (VWF:RCo assay) activities were assessed at baseline and throughout the study. Retention samples were collected at screening and baseline visits for possible later inhibitor testing (to be performed at a central laboratory using the Nijmegen-Bethesda assay for FVIII inhibitors and the mixing study based on VWF:RCo for VWF inhibitors). Inhibitor testing was also performed if inhibitor development was suspected. Results: Inhibitor testing was performed in 2 of 33 patients because of unusual pharmacokinetic results at the 6-month visits, even though neither patient had any clinical signs of an inhibitor. The VWF inhibitors were detected in samples from two brothers taken at their 6-month visits. However, when retained blood samples from the screening visits of both boys were tested, both samples tested inhibitor-positive, demonstrating that both boys had developed the inhibitors prior to starting prophylaxis during WIL-31. During and before the WIL-29 run-in study, both boys had been treated on demand with another pdVWF/FVIII concentrate. The boys had both been diagnosed with VWD shortly after birth, and it was suspected that they had type 2A based on family history and were 15 (patient A) and 11 years old (patient B) at the start of WIL-31. They had a family history of VWD (both parents were diagnosed with VWD), but no family history of inhibitors. After the completion of WIL-31, both patients were reclassified to type 3 VWD following further investigation including next-generation sequencing. Baseline VWF activity indicated low VWF:RCo levels (Patient A: 0.092 IU/mL and Patient B: 0.65 IU/mL; Figure 1). The boys received 38 (patient A) and 34 IU/kg (patient B) pdVWF/FVIII respectively, twice weekly during WIL-31, and their mean total ABRs decreased by 85% and 91%, respectively, during WIL-31 compared with WIL-29. All bleeding episodes during WIL-31 were spontaneous nose bleeds. Both boys continued the same prophylactic regimen until the end of WIL-31. In one patient the inhibitor titer was negative by the end of the study. Conclusion: VWF inhibitors were detected in 2 of the 33 patients on prophylaxis with pdVWF/FVIII in the WIL-31 study and subsequent investigation revealed that both patients were already positive for VWF inhibitors prior to the study start. In one of the patients, the inhibitor resolved during continued prophylaxis. Despite the inhibitors, prophylaxis was effective in both patients with an ≥85% reduction in ABR compared to on demand treatment.

Recombinant ADAMTS13 for the Treatment of Acute TTP Events in Patients with Congenital Thrombotic Thrombocytopenic Purpura: Results from the Phase 3 Randomized, Controlled, Crossover Study and the Phase 3b Continuation Study

Background Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, life-threatening thrombotic microangiopathy caused by an inherited deficiency of the enzyme ADAMTS13. An ongoing phase 3 study (NCT03393975) and phase 3b continuation study (NCT04683003) are investigating the safety and efficacy of recombinant ADAMTS13 (rADAMTS13; TAK-755; Takeda Development Center Americas, Inc., Lexington, MA, USA) for prophylaxis and on-demand treatment of acute events in patients with cTTP. Aims To assess the efficacy and safety of rADAMTS13 for the treatment of acute TTP events and long-term prophylaxis in patients with severe cTTP. Methods The phase 3 prospective, randomized, controlled, open-label, multicenter, crossover study (NCT03393975) is open to enroll patients 0-70 years old with severe cTTP (ADAMTS13 activity &amp;lt;10%). Upon completion of the phase 3 study, patients could enroll into the phase 3b prospective, open-label, multicenter, single treatment arm continuation study (NCT04683003). In the phase 3 study, patients were randomized 1:1 at enrollment to receive prophylaxis with either rADAMTS13 or standard of care (SoC). SoC was determined by the treating physician and could include fresh frozen plasma, pooled solvent/detergent-treated plasma, or factor VIII/von Willebrand factor concentrates. Patients in the phase 3b continuation study received open-label rADAMTS13 treatment. In both studies, patients could be enrolled and receive treatment on demand for acute TTP events. Per protocol, rADAMTS13 was to be administered at 40 IU/kg on Day 1, 20 IU/kg on Day 2 and 15 IU/kg daily from Day 3 onwards until 2 days after resolution of the acute event (defined as platelet count either ≥150,000/μL or within 25% of baseline; and elevation of LDH levels ≤1.5× of baseline or ≤1.5× the upper limit of normal). Data are presented from a pre-planned interim analysis (data cutoff: August 12, 2022) and focus on the treatment of acute TTP events in both studies. Results At the time of the data cutoff, 8 acute TTP events were reported in 7 patients ( Table), all of whom were ≥18 years old. None of the events occurred while the patient was receiving rADAMTS13 prophylaxis. Six events occurred in 5 patients (median age: 20.0 years; sex: 3 male, 2 female) who received on-demand treatment in the phase 3 study; 2 of these patients were randomized to receive rADAMTS13 and 3 to receive SoC. One event also occurred in the phase 3 study while the patient was receiving prophylaxis with SoC. One event occurred in the screening period prior to the patient starting rADAMTS13 prophylaxis in the phase 3b continuation study; this event was treated with rADAMTS13. Platelet counts observed during the first 3 days of treatment for all 8 acute TTP events are shown in the Figure. Prior to study treatment, on Day 0, the mean platelet counts were similar between the rADAMTS13 and SoC cohorts. Over the first 3 treatment days, the mean platelet count increased more than ~5-fold with rADAMTS13, and ~3-fold with SoC. All three acute TTP events treated with rADAMTS13 resolved without requiring the administration of any other treatment containing ADAMTS13. Based on pharmacokinetics (PK) data available in 5 patients (3 received treatment with rADAMTS13 and 2 with SoC), the post-infusion ADAMTS13 activity levels ~1 hour after administration were between 80% to 270% of normal with rADAMTS13 and between 10% to 48% with SoC. These observed ADAMTS13 activity levels were as expected based on the linear PK observed following single dose PK assessments in the phase 3 study. Of the 4 patients who received SoC for the treatment of an acute TTP event, 2 experienced a mild treatment-emergent adverse event (TEAE) that was considered related to the SoC (nausea and pruritis). Of the 3 patients who received rADAMTS13, 1 patient experienced 3 mild TEAEs (feeling hot, nausea, and thrombocytosis) that were considered related to rADAMTS13. No serious TEAEs related to rADAMTS13 were reported and no neutralizing antibodies against ADAMTS13 were observed. Conclusions The resolution of acute TTP events and an improvement in platelet count in patients with cTTP following treatment with rADAMTS13 was closely related to higher ADAMTS13 activity exposure. No serious TEAEs related to rADAMTS13 were reported.

Effect of Factor VIII and Von Willebrand Factor Activities on Number of Bleeding Events in Previously Treated Patients with Von Willebrand Disease on Regular Prophylaxis with a Plasma-Derived Von Willebrand Factor/Factor VIII Concentrate

Background: von Willebrand disease (VWD) is characterized by a deficiency or reduction of activity in von Willebrand factor (VWF). As VWF has a role in stabilizing coagulation factor VIII (FVIII), VWD patients often suffer from secondary FVIII deficiency. Current guidelines recommend that VWD patients with a history of severe and frequent bleeds should use long-term prophylaxis with factor replacement therapy. The WIL-31 study demonstrated the efficacy of prophylaxis with a plasma-derived VWF/factor VIII concentrate containing VWF and FVIII in a 1:1 activity ratio (pdVWF/FVIII; wilate ®) in adults and children with VWD. The primary endpoint was met, showing a decrease of 84% in the mean total annualized bleeding rate (ABR). As elevated levels of FVIII are associated with an increased risk for thrombosis, it is important to determine whether repeated dosing with pdVWF/FVIII leads to accumulation of FVIII over time. Aims: To investigate the activity levels of VWF and FVIII in patients with VWD receiving regular prophylaxis with pdVWF/FVIII. Methods: WIL-31 (NCT04052698) was a prospective, non-controlled, international, multicenter phase 3 trial that enrolled male/female patients, aged ≥6 years old with VWD type 1 (VWF:RCo &amp;lt;30 IU/dL), type 2 (except 2N) or type 3. Prior to entering the WIL-31 study, all patients had received on-demand treatment with a pdVWF/FVIII concentrate during a 6-month, prospective, observational, run-in study (WIL-29). Patients in WIL-31 received regular pdVWF/FVIII prophylaxis 2-3 times per week at a dose of 20-40 IU/kg for 12 months. VWF activity (VWF:RCo) and FVIII activity (measured by the chromogenic [Chr] and one-stage [OS] assays) were performed at baseline and throughout the study. Full pharmacokinetic (PK) analyses were performed in all patients aged 6-16 years, a single dose of 60 ± 10 IU/kg pdVWF/FVIII was administered. Samples were collected at up to 1 hour prior to injection and then at multiple time points post-injection (1-72 hours). Safety, including the occurrence of thrombotic events, was monitored throughout the study. Results: The overall study population included 33 patients, with a median age of 18 years consisting of 9 (27.3%) patients aged 6-11 years, 6 (18.2%) patients aged 12-16 years, and 18 (54.5%) patients aged ≥17 years. Six (18.2%) patients had severe type 1 VWD, 5 (15.2%) patients had type 2, and 22 (66.7%) patients had type 3. Baseline FVIII and VWF activities in WIL-31 were similar regardless of age group, and as expected were lower in patients with type 3 VWD compared with severe type 1 and type 2 (Figure 1). There was a negative correlation of baseline FVIII and VWF activity with the number of spontaneous bleeding episodes (BEs) during prophylaxis. Patients who had no spontaneous BEs during prophylaxis had higher baseline FVIII and VWF levels compared with those who had spontaneous BEs. Mean peak and trough FVIII and VWF activity levels remained consistent during the study and there was no accumulation of either factor over the 12-month prophylaxis period (Figure 2). Full PK assessments were performed according to protocol in 13 patients aged 6-16 years. The mean ± standard deviation in vivo half-life was 16.1±6.7, 16.2±7.7, and 9.8±7.7 hours, for FVIII Chr, FVIII OS, and VWF:RCo, respectively. No thrombotic events were observed. Conclusion: No accumulation of FVIII or VWF in the plasma was reported in 33 patients who received regular prophylaxis with pdVWF/FVIII for 12 months, regardless of VWD type and age.

Quantitative System Pharmacology Modeling of the Effect of Recombinant ADAMTS13 on Platelets in Patients with Congenital Thrombotic Thrombocytopenic Purpura

Background: Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, thrombotic microangiopathy due to an inherited deficiency of the von Willebrand factor (VWF)-cleaving protease, ADAMTS13.Accumulation of ultra-large VWF multimers increases blood clot formation in small blood vessels, leading to a low platelet count (thrombocytopenia). Treatment of cTTP consists of ADAMTS13 replacement with infusions of plasma-based therapies (PBT). Recombinant ADAMTS13 (rADAMTS13; Takeda Development Center Americas, Inc., Lexington, MA, USA) is in development for patients with cTTP.The ultra-rare nature of cTTP limits the sample size for a formally powered study to assess the impact of ADAMTS13 supplementation on efficacy outcome. This study was a proof-of-principle that model-based clinical trial simulations can be used to supplement clinical trial data in ultra-rare indications. Aims: To calibrate and validate a quantitative system pharmacology (QSP) model describing a mechanistic relationship between ADAMTS13, VWF and platelet numbers in patients with cTTP who received long-term prophylaxis with rADAMTS13 or PBT (fresh frozen or solvent/detergent treated plasma). In addition, to evaluate the treatment benefits of rADAMTS13 versus PBT using clinical trial simulations in virtual patients with cTTP as a supplement to the cTTP phase 3 study (NCT03393975) data. Methods: A QSP model was built using i) in vitro enzyme kinetic data and preclinical experimental data following administration of recombinant VWF and rADAMTS13 in ADAMTS13 knockout (KO) mice, and ii) data from the literature including platelet count and VWF activity from healthy human and untreated patients with cTTP. These data were used to calibrate the parameters corresponding to interactions between ADAMTS13 activity, VWF activity, and platelets. The model was validated against literature data from patients with cTTP treated with PBT and with data from a phase 2 study of patients with immune-mediated TTP treated with rADAMTS13 (NCT03922308). The model was then calibrated to longitudinal platelet data from the cTTP phase 3 study, in which patients with cTTP received prophylaxis for 6 months with PBT (exposure equivalent to ~10 IU/kg ADAMTS13 in the form of 10-20 mL/kg doses) and rADAMTS13 (40 IU/kg) either once every week (Q1W) or once every 2 weeks (Q2W) dosing intervals . The model was used to provide 1-year clinical trial simulations of isolated thrombocytopenia occurrences in a population of 1,000 virtual patients, phenotype-matched to patients in the cTTP phase 3 study. Results:Virtual clinical trial simulations using the QSP model suggested that rADAMTS13 administered over 1 year with a Q1W or Q2W schedule results in significantly fewer patients experiencing occurrences of thrombocytopenia (platelet count threshold of &amp;lt;150 x 10 9/L) compared to patients treated with PBT (hazard ratio [HR] relative to Q2W PBT: Q1W PBT, HR = 0.62; Q2W rADAMTS13, HR = 0.47; Q1W rADAMTS13, HR = 0.18). The treatment difference between rADAMTS13 and PBT was even more pronounced when a thrombocytopenia threshold of &amp;lt;100 x 10 9/L was used (Figure and Table). Simulations also predicted a prophylactic carry-over effect on platelets, with approximately 20 days taken to reach 90% of the long-term average platelet count when switching from rADAMTS13 to PBT or from PBT to rADAMTS13. A correlation analysis for a Q2W dosing of rADAMTS13 demonstrated that ADAMTS13 trough activity (C trough, Spearman ρ = 0.96) and time with ADAMTS13 activity above 10% (Spearman ρ = 0.93) showed stronger correlations with increased platelet count than the maximum plasma ADAMTS13 activity level (C max, Spearman ρ = 0.68). A correlation analysis for a Q1W dosing frequency produced similar results.Mean time above 10% ADAMTS13 activity was higher following rADAMTS13 versus PBT administration (5.2 vs 1.7 days). Conclusions: This model-based virtual clinical trial simulation predicts that dosing with rADAMTS13 would provide &amp;gt;50% reduction in the HR of thrombocytopenia occurrences over PBT. Patients may also have a higher level of protection for 2-3 weeks when switching from rADAMTS13 to PBT. These findings supplement the assessment of clinical benefit of rADAMTS13 in the cTTP phase 3 study and show that increased ADAMTS13 activity following rADAMTS13 administration is likely to reduce occurrences of thrombocytopenia in cTTP.

Emicizumab: the hemophilia A game-changer.

In hemophilia, the unmet needs regarding adherence to prophylaxis and lack of effective long-term prophylaxis regimens, especially in patients with inhibitors, led to the production of emicizumab, the first non-factor medicine for subcutaneous administration in patients with severe and moderate hemophilia A with or without factor VIII inhibitors. This review describes the research steps behind the development of this game-changing medication as well as its success in the prophylaxis of bleeding episodes, as witnessed by the results of pivotal clinical trials but also by real-life use in the frame of a still expanding global market. We also discuss potential and actual adverse events and the nuances related to clinical use, such as laboratory monitoring, development of neutralizing antidrug antibodies, risk of thrombosis/hypercoagulability and role in the management of surgical operations. The potential of emicizumab to prevent bleeding in other congenital and acquired coagulation disorders is also outlined.

Long-term prophylaxis for hereditary angioedema: Initial experiences with garadacimab and lanadelumab.

With no approved long-term prophylaxis (LTP) for the prevention of hereditary angioedema (HAE) attacks in Hong Kong, patients rely on compassionate use programs and drug trials. Moreover, studies regarding the use and efficacy of LTP in Asia are lacking. Our aim was to assess 2 LTP medications for HAE in Hong Kong: lanadelumab and garadacimab. A prospective study was performed. Adult patients with a diagnosis of type I or type II HAE with 1 or more expert-confirmed attacks per month were consecutively recruited. The patients had been receiving treatment for at least 6 months. Clinical data were obtained, and questionnaires were administered before treatment periodically for at least 6 months following initiation of LTP. Almost one-third of the patients with HAE experienced frequent attacks and began receiving LTP (8 of the 11 received garadacimab and 3 of the 11 received lanadelumab). At baseline, the time-normalized number of HAE attacks was 2.5 plus or minus 1.3 per month. At month 6, there was an overall reduction of time-normalized number of attacks per month of -2.4 attacks per month (95% CI= -3.3 to -1.5. [P< .01]). The time-normalized number of HAE attacks at month 6 was 0.1 plus or minus 0.1 per month. More than 70% of the patients (8 of 11) were completely attack-free during the 6-month period while receiving LTP, and no patients required hospitalization. LTP improved patients' scores of the Angioedema Quality-of-Life Questionnaire (P < .001) and reduced activity impairment due to health (P= .008). Patients experienced significant improvement across all dimensions of the Treatment Satisfaction for Medication Questionnaire (54.5%-76.8% [P= .002]), and no adverse events were reported. The patients receiving LTP with garadacimab and lanadelumab experienced a significant reduction in number of HAE attacks and improvement in quality of life, and they were satisfied with treatment.

Epidemiology and treatment of children with hereditary angioedema in Germany: A retrospective database study.

Hereditary angioedema (HAE) is a potentially life-threatening inherited disease that causes recurrent, serious, and debilitating episodes of swelling. While evidence has improved in adult patients, data on the epidemiology and treatment of pediatric patients with HAE remain very limited. The aim of this study was to determine the incidence and prevalence of pediatric patients with HAE aged <12years, as well as treatment patterns, co-medication, and specialties involved. In this retrospective study (2016-2021), the German IQVIATM pharmacy claims (LRx) database was used to analyze prescriptions of HAE-specific treatments and co-medications. We found an HAE prevalence in pediatric patients aged <12years of 2.51:100,000 and a 12-month prevalence of up to 1.02:100,000 between 2016 and 2021. Most HAE treatments were prescribed by outpatient clinics and pediatricians, with an increasing proportion of icatibant as an on-demand treatment and low rates of long-term prophylaxis (LTP). The prescription rate of analgesics as the most common co-medication decreased notably after HAE diagnosis. Our findings provide insights into the epidemiology and current pediatric HAE treatment landscape in Germany. The obtained HAE prevalence in pediatric patients aged <12years was even higher than the previously reported average of overall cohorts, whereas the LTP rate was low, which might indicate an unmet need for newer LTP treatment options in pediatric patients.

Pneumocystis jirovecii Pneumonia after Heart Transplantation: Two Case Reports and a Review of the Literature.

Post-transplant Pneumocystis jirovecii pneumonia (PcP) is an uncommon but increasingly reported disease among solid organ transplantation (SOT) recipients, associated with significant morbidity and mortality. Although the introduction of PcP prophylaxis has reduced its overall incidence, its prevalence continues to be high, especially during the second year after transplant, the period following prophylaxis discontinuation. We recently described two cases of PcP occurring more than one year after heart transplantation (HT) in patients who were no longer receiving PcP prophylaxis according to the local protocol. In both cases, the disease was diagnosed following the diagnosis of a viral illness, resulting in a significantly increased risk for PcP. While current heart transplantation guidelines recommend Pneumocystis jirovecii prophylaxis for up to 6-12 months after transplantation, after that period they only suggest an extended prophylaxis regimen in high-risk patients. Recent studies have identified several new risk factors that may be linked to an increased risk of PcP infection, including medication regimens and patient characteristics. Similarly, the indication for PcP prophylaxis in non-HIV patients has been expanded in relation to the introduction of new medications and therapeutic regimens for immune-mediated diseases. In our experience, the first patient was successfully treated with non-invasive ventilation, while the second required tracheal intubation, invasive ventilation, and extracorporeal CO2 removal due to severe respiratory failure. The aim of this double case report is to review the current timing of PcP prophylaxis after HT, the specific potential risk factors for PcP after HT, and the determinants of a prompt diagnosis and therapeutic approach in critically ill patients. We will also present a possible proposal for future investigations on indications for long-term prophylaxis.

The role of anxiety in patients with hereditary angioedema during oral treatment: a narrative review.

The present study investigated the clinical potential of managing anxiety during dental procedures to reduce acute attacks in patients with hereditary angioedema (HAE). HAE is a rare disease, little known to physicians and dentists, but with an increased hospitalization rate over the years. HAE is due to a deficiency/dysfunction of the C1 esterase inhibitor, leading to increased vascular permeability. Recommendations for HAE management include long-term and short-term prophylaxis and treatment of acute attacks, but the importance of anxiety control is underestimated. The authors reviewed the literature to provide the scientific community with an overview of possible protocols for managing anxiety in dental practice and their effectiveness. Management can be used in prosthetics, periodontal and implant surgery, endodontics, and oral surgery. Our analysis shows that although there are few articles in the indexed literature, protocols for managing anxiety in HAE patients in dentistry will become increasingly prevalent in the daily clinical practice of dentists due to its benefits. The benefits and better control of intraoperative complications and risks may lead clinicians to use sedation, assessment, or anxiety control techniques in daily clinical practice to reduce such attacks. Clinical relevance: This study suggests that controlling and managing anxiety can help prevent and reduce acute angioedema attacks.

Evolution of Guidelines for the Management of Hereditary Angioedema due to C1 Inhibitor Deficiency.

Hereditary angioedema (HAE) is a severe and disabling condition characterized by recurrent episodes of subcutaneous or mucosal swelling in the skin and respiratory and gastrointestinal tracts. HAE due to C1-esterase inhibitor deficiency (C1-INH-HAE) is the most prevalent subtype. The present Iberian study compared C1-INH-HAE treatment guidelines published between 2010 and 2022 to identify the main differences in therapeutic approaches for on-demand treatment and short- and long-term prophylaxis (LTP). HAE guidelines evolved with the availability of new treatments and with a change in the management paradigm towards an individualized, patient-centered approach, where quality of life (QOL) is central. A parallel trend was observed towards increasingly frequent home-based treatment, which potentially facilitates timely interventions, provides greater flexibility and convenience, and is associated with increased QOL, enabling patients to lead more normal lives. Most innovations over the years were made for LTP, together with the advent of new therapies and awareness of patients' needs. Several prophylactic therapies with a high level of evidence became available, although formal head-to-head comparisons are lacking. The treatment goals became more ambitious, ranging from a reduction in the frequency, severity, and duration of attacks to achieving total disease control and normalization of patients' lives. The document also addresses relevant items such as changes in terminology (eg, the introduction of designations as "first-line") and the introduction of patient-reported outcome measures to assess patients' perceptions of their self-experienced QOL and well-being. Unmet needs in the management of C1-INH-HAE are identified.