Hereditary hemorrhagic telangiectasia may be the most morbid inherited bleeding disorder of women.

Hereditary hemorrhagic telangiectasia (HHT) is the second-most-common inherited bleeding disorder worldwide and remains without approved therapies. HHT causes serious mucosal bleeding resulting in severe iron deficiency anemia, major psychosocial complications, and visceral arteriovenous malformations in brain, lung, and liver that can cause life-threatening hemorrhagic complications. No study has examined the relative morbidity of HHT and von Willebrand disease (VWD), the most common inherited bleeding disorders in women. We performed an observational cohort study of women with HHT or VWD, comparing a representative sample of 100 randomly selected women with HHT to 100 randomly selected age-matched women with VWD. In HHT versus VWD, recurrent epistaxis and GI bleeding were more likely (OR [95% CI]=32.73 [13.81-71.80], P<0.0001 and 5.69 [2.59-12.89], P<0.0001) and heavy menstrual bleeding was less likely (OR 0.32 [0.18-0.57], P<0.0001). Iron deficiency anemia was significantly more likely, and lowest hemoglobin significantly lower, in HHT versus VWD. Odds of iron infusion dependence, requirement for red cell transfusion, and hemostatic surgical procedures were significantly higher-17-fold, 3-fold, and 8-fold higher, respectively-and hospital admissions to manage disease complications were both approximately 14 times more frequent in women with HHT versus VWD. In conclusion, much higher disease-related morbidity, mortality, and healthcare utilization was observed in women with HHT versus VWD, providing evidence that HHT may be the most clinically significant inherited bleeding disorder of women. Given the vast gap in research funding for HHT compared with both hemophilia (a disease primarily of men) and VWD, these findings have significant implications for gender equity in hematology.

Avatrombopag for adults with early versus chronic immune thrombocytopenia.

Avatrombopag is a newer thrombopoietin receptor agonist (TPO-RA) currently approved to treat chronic ITP (duration >12 months). No studies have yet evaluated the safety and effectiveness of avatrombopag in newly diagnosed ITP (duration <3 months) or persistent ITP (duration 3-12 months), and so its use in these populations is presently off-label worldwide. We hypothesize that avatrombopag has similar safety and effectiveness irrespective of ITP disease phase. To evaluate this, we performed a multicenter observational cohort study of adults with ITP treated with avatrombopag, comparing patient outcomes by disease phase (newly diagnosed/persistent versus chronic). Seventy-five patients were included, 23 with newly diagnosed/persistent ITP (17.7 patient-years of avatrombopag treatment) and 52 with chronic ITP (65.3 patient-years of avatrombopag treatment). On avatrombopag, 91% of newly diagnosed/persistent patients versus 96% of chronic patients (p = .58) achieved a platelet response (≥50 × 109 /L) and 86% versus 81% of patients (p = .78) achieved a complete response (≥100 × 109 /L). Median platelet counts on avatrombopag were similar between the two groups (165 × 109 /L vs. 129 × 109 /L, p = .57). Response durability was high and similar in both groups. No patients in the newly diagnosed/persistent group had a major bleeding event, thromboembolic event or avatrombopag discontinuation for adverse events, compared with 4, 1, and 2, respectively, in the chronic group. Thrombocytosis (platelets ≥400 × 109 /L) incidence was similar in the two groups. No other drug-related adverse events occurred in either group. Avatrombopag was safe and effective in patients with newly diagnosed and persistent ITP, with outcomes numerically, statistically, and clinically similar to patients receiving avatrombopag for chronic ITP.

Cardiac Sarcoidosis and a Likely Pathogenic TTN Variant in a Patient Presenting With Ventricular Tachycardia.

Rare variants in TTN are the most common monogenic cause of early-onset atrial fibrillation and dilated cardiomyopathy. Whereas cardiac sarcoidosis is very underdiagnosed, a common presentation can be ventricular arrhythmias. This report presents a patient with a likely pathogenic TTN variant and cardiac sarcoidosis. (Level of Difficulty: Intermediate.).

Antithrombotic therapy for atrial fibrillation in hereditary hemorrhagic telangiectasia.

Antithrombotic therapy reduces stroke risk in patients with atrial fibrillation but at the cost of increased bleeding risk. Patients with hereditary hemorrhagic telangiectasia (HHT) are at increased bleeding risk due to fragile mucocutaneous telangiectasias and visceral arteriovenous malformations. These patients are simultaneously at elevated thrombotic risk due to the vascular abnormalities of HHT. Managing atrial fibrillation in patients with HHT represents an understudied and challenging clinical scenario. We present a retrospective cohort study investigating antithrombotic therapy in patients with HHT and atrial fibrillation. We found that antithrombotic therapy was poorly tolerated, leading to premature dose-reduction or discontinuation of therapy in a majority of patients and in a majority of treatment episodes. Five patients undergoing left atrial appendage procedures did well despite difficulties completing the prescribed course of post-procedure antithrombotic therapy. Left atrial appendage occlusion or simultaneous administration of systemic anti-angiogenic therapy may represent alternatives but require additional study in patients with HHT.

Anticoagulation and antiplatelet therapy in hereditary hemorrhagic telangiectasia: A scoping review.

INTRODUCTION: Data describing safety and tolerability of anticoagulation and antiplatelet therapy in hereditary hemorrhagic telangiectasia (HHT), the second-most-common inherited bleeding disorder, is limited. METHODS: We performed a scoping review, searching MEDLINE and EMBASE from inception to March 2023 for eligible studies reporting detailed clinical data describing antithrombotic use in HHT. Data extracted included study design, patient population, and characteristics and outcomes of antithrombotic therapy. RESULTS: Of 625 unique manuscripts identified through database search, 77 were included: 64 case reports/case series describing 65 patients and 13 cohort studies. Data were extracted on a total of 466 patients with HHT, covering 587 episodes of antithrombotic therapy. The most common reasons for antithrombotic therapy were venous thromboembolism (VTE) (44.6 %), atrial arrhythmias (17.8 %) and stroke (10.5 %). anticoagulation was used in in 356 episodes (61.9 %), antiplatelet therapy in 140 episodes (24.3 %), and both together in 50 episodes (8.7 %). Complications of therapy included worsened HHT-associated bleeding (primarily epistaxis and gastrointestinal bleeding) in 198 antithrombotic treatment episodes (38.9 %) and premature antithrombotic therapy discontinuation in 142 episodes (28.9 %). Bleeding-directed therapy (local ablative therapy and systemic therapies) were employed to address worsening bleeding in 14.6 % of episodes. No specific complications of therapy were reported in 322 total antithrombotic events (58.4 %). Rates of bleeding (8.3 % to 80 %), therapy discontinuation (14.3 % to 57.1 %), and other complications ranged considerably from study to study. CONCLUSION: Current publications vary widely on the outcomes and tolerability of antithrombotics in HHT, but confirm the clinical challenge of adequate antithrombotic therapy in this population. More formal studies are needed to better guide optimal antithrombotic use in HHT.

Safety, tolerability, and effectiveness of anticoagulation and antiplatelet therapy in hereditary hemorrhagic telangiectasia.

BACKGROUND: Antithrombotic therapy (anticoagulation and antiplatelet therapy) is frequently needed in patients with hereditary hemorrhagic telangiectasia (HHT); however, data describing and guiding its use are very limited. OBJECTIVES: To investigate the safety, tolerability, and effectiveness of antithrombotic therapy in HHT in a cohort large enough to compare agents, evaluate for baseline predictors of premature discontinuation, and evaluate hematologic support requirements and healthcare utilization before and after antithrombitc therapy initiation. METHODS: We performed a multicenter observational cohort study characterizing the outcomes of antithrombic therapy in adults with HHT. RESULTS: A total of 119 patients with HHT with 187 discrete antithrombotic therapy episodes were included. Of these, 59 patients (50%) dose-reduced and/or prematurely discontinued therapy (including 52 patients [44%] who discontinued) due to worsened bleeding complications. Initiation at reduced dose intensity had a similar premature discontinuation rate (49%) as initiation at standard dose intensity (43%). In a multivariable logistic model, a history of gastrointestinal bleeding was associated with 3.25-fold odds of discontinuation (p = .001). Hemoglobin was significantly lower (10.8 g/dL vs 12.2 g/dL, p < .001), and the need for hematologic support (intravenous iron and/or red blood cell transfusion) was significantly higher (29 patients vs 12 patients, p = .004) in the 3 months after antithrombotic therapy initiation vs the 3 months before; emergency department visits and hospital admissions due to bleeding also increased. The rates of dose-reduction and/or premature discontinuation were similar regardless of the anticoagulant class (warfarin, 46%; heparin-based, 48%; direct oral anticoagulants, 44%) or with multiple simultaneous agents (44%) but were slightly lower with single-agent antiplatelet therapy (37%). Thromboembolism despite receiving antithrombotic therapy was common (18 patients, 15%) with varying outcomes. CONCLUSION: Antithrombotic therapy is challenging in HHT, resulting in objectively higher morbidity and health care utilization from worsened bleeding. Discontinuation rates approached 50% regardless of the dose intensity at initiation or type of antithrombotic agent used and were higher in patients with a gastrointestinal bleeding history.

Systemic bevacizumab as salvage therapy for persistent severe bleeding and anemia in heyde syndrome following aortic valve replacement.

Heyde syndrome is characterized by the co-occurrence of aortic stenosis and bleeding gastrointestinal angiodysplasias, often with acquired von Willebrand syndrome. Current management for bleeding includes hematologic support with red cell transfusion and intravenous iron and correction of aortic stenosis with valve replacement. However, persistent Heyde syndrome after valve replacement occurs in a significant minority of cases, and there is no accepted therapy for these patients. Given that the pathophysiology of angiodysplasia formation in Heyde syndrome involves dysregulated angiogenesis, targeting angiogenesis may be an effective therapeutic option. We describe two cases of persistent Heyde syndrome with severe bleeding and anemia in patients following aortic valve replacement who were treated with systemic bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor. In both cases, treatment was successful, with resolution of bleeding, liberation from hematologic support, and normalization of hemoglobin. In addition to responding to therapy, neither patient had treatment-related adverse events (and both had recurrent anemia upon treatment discontinuation, further evidence of the therapeutic impact of bevacizumab). Additional investigation into the use of systemic antiangiogenic therapy for treatment of Heyde syndrome is warranted.

Predictors of mortality and outcomes of liver transplant in spur cell hemolytic anemia.

Spur cell hemolytic anemia (SCHA) is a rare, acquired, nonimmune hemolytic anemia of decompensated cirrhosis. Data describing prognostic impact, outcomes of liver transplant, and clinical hematologic characteristics of SCHA are absent or limited. We performed a multicenter, 24-year observational cohort study of patients with SCHA, retrospectively analyzing hepatic and hematologic parameters, independent predictors of mortality, and long-term outcomes of liver transplant. Sixty-nine patients with SCHA met eligibility for inclusion. The median (interquartile range) age was 53 (42-59) years; 46.4% were female, and 11 (15.9%) received liver transplant. Thirty-nine patients (56.5%) were red blood celltransfusion-dependent. All 11 patients undergoing transplant had rapid and complete resolution of SCHA, with improvement in median hematocrit from 22.1% to 34.6% post-transplant (p = .001) and excellent post-transplant outcomes. In multivariable logistic models adjusting for age, sex, etiology of cirrhosis, active/recent variceal bleeding, and Child-Turcotte-Pugh score, transfusion dependence had an odds ratio (OR) for 90-day mortality of 9.14 (95% CI, 2.46-34.00) and reduced pre-transfusion hematocrit had an OR of 4.73 (95% CI, 1.42-15.82) per 6% decrease; increased red cell transfusion requirement, reduced hemoglobin, increased lactate dehydrogenase, and increased indirect bilirubin were also independently predictive of higher 90-day mortality. Model for end-stage liver disease (MELD)-Na and Child-Turcotte-Pugh scores consistently significantly underestimated 90-day mortality, with standardized mortality ratios (SMRs) >1 across all scores/classes [MELD-Na 20-29, SMR 2.42 (1.18-4.44); Child-Turcotte-Pugh class B, SMR 4.46 (1.64-9.90)]. In conclusion, SCHA is associated with substantial excess mortality than predicted by MELD-Na or Child-Turcotte-Pugh scores and uniformly resolves with liver transplant, without recurrence. Multiple parameters of hemolytic anemia severity independently predict higher 90-day mortality.

Laboratory-Generated Urine Toxicology Interpretations: A Mixed Methods Study.

BACKGROUND: Clinicians frequently order urine drug testing (UDT) for patients on chronic opioid therapy (COT), yet often have difficulty interpreting test results accurately. OBJECTIVES: To evaluate the implementation and effectiveness of a laboratory-generated urine toxicology interpretation service for clinicians prescribing COT. STUDY DESIGN: Type II hybrid-convergent mixed methods design (implementation) and pre-post prospective cohort study with matched controls (effectiveness). SETTING: Four ambulatory sites (2 primary care, 1 pain management, 1 palliative care) within 2 US academic medical institutions. METHODS: Interpretative reports were generated by the clinical chemistry laboratory and were provided to UDT ordering providers via inbox message in the electronic health record (EHR). The Partners Institutional Review Board approved this study.Participants were primary care, pain management, and palliative care clinicians who ordered liquid chromatography-mass spectrometry UDT for COT patients in clinic. Intervention was a laboratory-generated interpretation service that provided an individualized interpretive report of UDT results based on the patient's prescribed medications and toxicology metabolites for clinicians who received the intervention (n = 8) versus matched controls (n = 18).Implementation results included focus group and survey feedback on the interpretation service's usability and its impact on workflow, clinical decision making, clinician-patient relationships, and interdisciplinary teamwork. Effectiveness outcomes included UDT interpretation concordance between the clinician and laboratory, documentation frequency of UDT results interpretation and communication of results to patients, and clinician prescribing behavior at follow-up. RESULTS: Among the 8 intervention clinicians (median age 58 [IQR 16.5] years; 2 women [25%]) on a Likert scale from 1 ("strongly disagree") to 5 ("strongly agree"), 7 clinicians reported at 6 months postintervention that the interpretation service was easy to use (mean 5 [standard deviation {SD}, 0]); improved results comprehension (mean 5 [SD, 0]); and helped them interpret results more accurately (mean 5 [SD, 0]), quickly (mean 4.67 [SD, 0.52]), and confidently (mean 4.83 [SD, 0.41]). Although there were no statistically significant differences in outcomes between cohorts, clinician-laboratory interpretation concordance trended toward improvement (intervention 22/32 [68.8%] to 29/33 [87.9%] vs. control 21/25 [84%] to 23/30 [76.7%], P = 0.07) among cases with documented interpretations. LIMITATIONS: This study has a low sample size and was conducted at 2 large academic medical institutions and may not be generalizable to community settings. CONCLUSIONS: Interpretations were well received by clinicians but did not significantly improve laboratory-clinician interpretation concordance, interpretation documentation frequency, or opioid-prescribing behavior.

The Impact of Outpatient Laboratory Alerting Mechanisms in Patients with AKI.

Background: AKI is an abrupt decrease in kidney function associated with significant morbidity and mortality. Electronic notifications of AKI have been utilized in patients who are hospitalized, but their efficacy in the outpatient setting is unclear. Methods: We evaluated the effect of two outpatient interventions: an automated comment on increasing creatinine results (intervention I; 6 months; n=159) along with an email to the provider (intervention II; 3 months; n=105), compared with a control (baseline; 6 months; n=176). A comment was generated if a patient's creatinine increased by >0.5 mg/dl (previous creatinine ≤2.0 mg/dl) or by 50% (previous creatinine >2.0 mg/dl) within 180 days. Process measures included documentation of AKI and clinical actions. Clinical outcomes were defined as recovery from AKI within 7 days, prolonged AKI from 8 to 89 days, and progression to CKD with in 120 days. Results: Providers were more likely to document AKI in interventions I (P=0.004; OR, 2.80; 95% CI, 1.38 to 5.67) and II (P=0.01; OR, 2.66; 95% CI, 1.21 to 5.81). Providers were also more likely to discontinue nephrotoxins in intervention II (P<0.001; OR, 4.88; 95% CI, 2.27 to 10.50). The median time to follow-up creatinine trended shorter among patients with AKI documented (21 versus 42 days; P=0.11). There were no significant differences in clinical outcomes. Conclusions: An automated comment was associated with improved documented recognition of AKI and the additive intervention of an email alert was associated with increased discontinuation of nephrotoxins, but neither improved clinical outcomes. Translation of these findings into improved outcomes may require corresponding standardization of clinical practice protocols for managing AKI.

A case of statin-associated immune-mediated necrotizing myopathy with atypical biopsy features.

Statin-associated immune-mediated necrotizing myopathy (IMNM) is a rare presentation of a statin-associated myopathy. Patients usually present with muscle weakness and pain in the setting of statin use with elevated creatine kinase (CK) levels and a positive anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) antibody. Muscle biopsies typically show necrosis, CD68+ macrophages, and minimal lymphocytes. We present a case of a 67-year-old woman who had 2 months of progressive weakness and bilateral lower extremity pain after initiating atorvastatin therapy with symptoms persisting after statin cessation. She was found to have high anti-HMGCR antibody titers, and the biopsy of the rectus femoris muscle showed a prominent endomysial inflammatory cell infiltrate with necrotic and regenerative fibers and an atypical extensive inflammatory infiltrate composed of both CD4+ helper T cells and CD8+ cytotoxic T cells. She showed symptom resolution and normalization of CK levels and inflammatory markers with treatment involving a prolonged prednisone taper and a brief course of azathioprine, which was stopped because of the adverse effects.