Bleeding is known to be a common complication in HHT, from nasal telangiectasia-related epistaxis, to bleeding from gastrointestinal (GI) telangiectasias or AVMs, or even from cutaneous telangiectases. Pericacho and colleagues (O10) used two murine models of HHT (both heterozygous mutations in Eng± or Alk±) to evaluate hemostasis. Both models showed abnormalities in endothelial-dependent hemostasis. In Eng deficiency, platelet-endothelial adhesion was impaired, with a resultant reduction in thrombus stability; while in Alk1 deficiency, alterations in fibrinolysis were noted with decreased plasma PAI-1 and increased t-PA, resulting in accelerated thrombus breakdown. These differential mechanisms could suggest genotype-dependent treatment of bleeding, with potential increased effectiveness of antifibrinolytics for HHT2.

Joyce and colleagues (O44) performed whole genome sequencing on 104 participants with HHT in order to search for variants in 75 genes of interest associated with bleeding or hemolytic disorders [19]. 56 gene variants were identified within the cohort, however all were rare with allele frequencies < 0.003. Those patients with higher bleeding severity, previously attributed to HHT alone, were found to have more deleterious variants in platelet and coagulation genes, suggesting that more severe HHT bleeding phenotypes may have additional genetic predisposition, and might benefit from further hematologic workup.

Kasthuri et al. (O11) presented new evidence regarding an increased prevalence of heavy menstrual bleeding (HMB) in women with HHT. Data was collected via a survey distributed by Cure HHT to assess menstrual bleeding and quality of life. Among the 633 responses, HMB was reported by 74% of women with HHT as compared to 53% in the general female population; among women with HHT of childbearing age, 49% had sought care for HMB and 56% felt that it had a negative impact on their quality of life. Anemia in the past year was reported by 67%, with 79% of these receiving oral iron, 27% IV iron infusion, and 10% blood transfusion.

While it is widely accepted that HHT-related bleeding can lead to development of iron-deficiency anemia, it is possible that other mechanisms are at work. Sharma et al. (O45) compared iron deficiency parameters amongst the HHT genotypes. While hemoglobin was not statistically different, higher serum ferritin was found in ALK1 as compared to ENG (median 31 vs 25, p = 0.006) or to SMAD4 (median 26, p = 0.03) patients. Mean corpuscular volume was lower in SMAD4 than in ALK1 median 75 vs 90, p < 0.0001) or ENG (median 89, p < 0.0001). Red blood cell counts were higher in SMAD4 than in ALK1 or ENG, presumably to compensate for the smaller cell size. The authors speculate that these differences are due to SMAD4 role as a hepcidin regulator [20], which might dictate differential responses to iron replacement therapy based on molecular genotype.

Kasthuri et al. (O14) assessed thrombotic risk in HHT and its relation to iron-deficiency anemia (IDA), by comparing patients with HHT and IDA to those with HHT only, IDA only, and healthy controls. Patients with HHT and IDA had a statistically significant increase in D-dimer as compared to control subjects (516.52 vs 210.19, p = 0.049). VEGFA levels were increased in both HHT groups; E-selectin levels appeared higher in the HHT groups but did not reach statistical significance. An angiogenesis protein array assay (performed on 2 patients from each of the groups) revealed a fivefold increase in tissue factor in the HHT groups, with several other proteins showing ≥ 50% differential expression. These findings suggest a procoagulant state in HHT, and the differentially expressed proteins may represent potential targets for therapies in the future.

Al-Samkari and colleagues (O9) performed an extensive scoping review of the literature to assess use of anticoagulation and antiplatelet therapy in patients with HHT. Complications included worsening HHT-related bleeding in 41% of patients, with early discontinuation of antithrombotic therapy in 40% of these (23% overall). Therapies to control bleeding – local ablative therapy or systemic therapies – were attempted in 8.6% of cases.

Next, Al-Samkari and colleagues (O15) from 5 centers prospectively observed outcomes of anticoagulation and antiplatelet therapies in patients with HHT. Together they followed 119 patients through 187 antithrombotic therapy episodes: 59 patients (48%) dose-reduced or discontinued therapy prematurely due to worsening bleeding; similar rates of reduction or discontinuation were seen regardless of antithrombotic medication (44–48%), with only single-agent antiplatelet therapy showing a slightly lower likelihood of bleeding (37%). A history of prior GI bleeding was predictive of discontinuation (3.25-fold odds, p = 0.001). Across the board, hemoglobin levels were lower, IV iron infusions and pRBC transfusions increased, and ED visits and admissions increased in the 3 months after starting antithrombotic therapies as opposed to the 3 months prior, confirming that such therapy remains challenging in patients with HHT.

Whitehead et al. (O13) presented safety and efficacy of left atrial appendage occlusion (LAAO) for stroke protection in the setting of atrial fibrillation (AF) in patients with HHT, who might not tolerate long-term anticoagulation. In their cohort of 329 consecutive adult patients with a definite diagnosis of HHT, 31 had atrial fibrillation. Eleven of these patients underwent LAAO; 20 control patients did not. Three in each group used anticoagulation. There were 7 ischemic strokes related to AF, with 3 in control patients and 4 in the LAAO group prior to procedure; no strokes were observed in the treatment group post-procedure, though 2.96 would have been expected based on prior frequency. The approach may be particularly useful for those patients who have significantly increased bleeding with anticoagulation therapy.