Causes and Severity of Anemia in Hereditary Hemorrhagic Telangiectasia

Introduction: Hereditary hemorrhagic telangiectasia (HHT) is characterized by the abnormal development of blood vessels leading to the formation of mucocutaneous telangiectasias and arteriovenous malformations (AVMs) in visceral organs. Anemia is a frequent complication of HHT secondary to blood loss from recurrent epistaxis, gastrointestinal bleeding, or both. The purpose of this study was to determine presence and severity of anemia at initial evaluation for HHT, and identify predictors of anemia.

Methods: We conducted a retrospective chart review of HHT patients evaluated at the University of North Carolina HHT Center of Excellence from 2008-2015. Data abstracted from the medical record included diagnosis of anemia, hemoglobin, source of bleeding, HHT genotype, epistaxis severity score (ESS), presence of visceral organ AVMs, history of treatment of AVMs, iron therapy, and need for blood transfusions. All data were collected from the patient's first visit to the HHT center. Source of bleeding was recorded as epistaxis, GI bleeding, or both. Epistaxis severity was determined by the ESS, with a higher score indicating more severe bleeding. GI bleeding had to be confirmed by patient history, presence of bleeding telangiectasias on endoscopy, or ongoing symptoms (bright red or dark stools). Presence of anemia required verification with complete blood count results. Anemia severity was defined as mild if hemoglobin ≥ 10, moderate if 8-10, and severe if <8 g/dl. Screening for visceral organ AVMs was conducted as per the international guidelines for management of HHT. All patients were screened for pulmonary (pAVM) and brain (bAVM) AVMs, and screening for GI and liver (lAVM) AVMs was pursued only in symptomatic patients. Cramer's V and chi squared goodness of fit test determined if overall source or severity was linked to gender, genotype, and AVM location. A test of multinomial proportions determined statistical significance between individual gender, genotype, and AVM location with source and severity.

Results: A total of 168 patients were included, of which 84 had documented anemia. In patients with anemia, the majority were female (72%), Caucasian (79%), and had ALK-1 genotype (50%). Mild anemia was most common (52%), followed by moderate (37%), and severe anemia (11%). Neither gender nor genotype was significantly associated with anemia severity. In patients with mild anemia, pAVMs were the most common visceral organ affected (45%), while GI telangiectasias were most common in the severe anemia group (67%). In moderate anemia, there was an equal proportion of GI and pAVM involvement (44%). Overall the presence of AVMs was linked to anemia severity (p-value: 0.0006), but there was no association between individual AVM site and anemia severity. The majority of patients with mild anemia were or had been on oral iron (76%), while patients with moderate (75%) and severe anemia (100%) had or were currently on IV iron replacement.

Epistaxis was the most common cause of anemia in the mild and moderate groups (75% and 59% respectively), while both GI bleeding and epistaxis were present in the majority of patients with severe anemia (44%). The mean ESS in patients with mild anemia was 5.18 compared to 6.93 in those with moderate anemia. The ALK-1 genotype was a significant predictor of anemia related to epistaxis. LAVMs also significantly increased the risk for anemia from recurrent epistaxis while GI telangiectasias were associated with anemia from both GI bleeding and epistaxis.

Conclusion:Iron deficiency anemia can be associated with significant morbidity. This is the first study to analyze the causes and severity of anemia in HHT patients at the time of initial evaluation to an HHT Center of Excellence. A high prevalence of anemia was found in this HHT population, with 50% of patients having documented anemia. We found that patients with ALK-1 mutations and liver AVMs are more likely to have epistaxis as the source of their anemia. Further, we demonstrate that patients with severe anemia more frequently present with GI AVMs. Understanding disease related predictors of anemia could help identify patients that are at highest risk and thereby facilitate aggressive screening in high-risk groups. Our findings are timely given the increasing awareness of HHT within the hematology community.