Clinical characteristics of pulmonary hypertension associated with hereditary hemorrhagic telangiectasia treated with bevacizumab: a single-center case series

Introduction

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by abnormal proliferation of blood vessels throughout several organs, including small telangiectasias in the skin and mucosal membranes, as well as large arteriovenous malformations (AVMs), predominantly in the brain, liver, and lungs.

Pulmonary hypertension (PH) is a severe complication of HHT. The prevalence of PH associated with HHT (HHT-PH) varies widely between studies, ranging from 5.5–31% (1-4). The mechanisms underlying HHT-associated PH (HHT-PH) are heterogeneous. In HHT, PH may develop as a consequence of high output cardiac failure (HOCF) associated with systemic AVMs or pulmonary vascular remodeling similar to the changes of pulmonary arterial hypertension (PAH) (5). This pathophysiological heterogeneity creates substantial challenges for diagnosis and treatment selection.

Previous studies have reported that anti-angiogenic treatments such as bevacizumab can effectively relieve symptoms in HHT patients with HOCF, or severe epistaxis and gastrointestinal bleedings (6-8). The International HHT Guidelines also recommend intravenous bevacizumab for HHT patients with symptomatic HOCF due to hepatic AVMs or severe bleeding who failed to respond sufficiently to first-line management (9,10). In previous studies, cardiac output (CO) exceeding 8 L/min or cardiac index (CI) exceeding 4 L/min/m² was adopted as the most common criterion to predict HOCF (11,12).

Previous studies have reported that the normal CI in healthy adults ranges from approximately 2.5 to 4.0 L/min/m² (13) and declines with aging (14). A systematic review showed that the mean CI in healthy individuals older than 60 years ranged from 2.1 to 3.2 L/min/m² (14). These findings suggest that some HHT-PH patients may already exhibit a clinically relevant high-output state even when the CI does not reach the conventional threshold of 4.0 L/min/m². Therefore, absolute CO/CI thresholds alone may not adequately reflect the heterogeneous hemodynamic characteristics of HHT-PH. Because cardiac reserve and circulatory adaptation vary substantially among individuals, some patients without markedly elevated CI may still exhibit clinically significant AVM-related hemodynamic abnormalities and potentially benefit from bevacizumab therapy. Further characterization of bevacizumab-treated HHT-PH patients may provide additional insight into the clinical and hemodynamic heterogeneity underlying treatment responses and help inform clinical decision-making regarding bevacizumab therapy.

Here, we have outlined the characteristics, managements and therapeutic responses of the bevacizumab treated HHT-PH. Our study’s objective was to provide our single-center experience with the use of bevacizumab in patients with HHT-PH, in order to improve the understanding of the clinical management of patients with HHT-PH. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0764/rc).

Methods

We retrospectively reviewed the clinical data of HHT-PH patients who received bevacizumab treatment between September 2021 and June 2024 at Beijing Anzhen Hospital, Capital Medical University. To better contextualize the hemodynamic characteristics of HHT-PH, age- and sex-matched patients with PAH and PH associated with left heart disease (PH-LHD) were additionally included as reference groups at a ratio of 2:1. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the ethics board of Beijing Anzhen Hospital, Capital Medical University (No. 2026243x) and individual consent for this retrospective analysis was waived.

All HHT-PH patients had to meet the following inclusion criteria: (I) adult patients with definite HHT diagnosis according to the Curaçao criteria (15); (II) PH was defined as a mean pulmonary artery pressure (mPAP) of >20 mmHg at rest obtained by right heart catheterization (RHC) (16); (III) patients received bevacizumab treatment because of symptomatic HOCF, severe epistaxis or gastrointestinal bleeding (11).

The PAH was defined as mPAP >20 mmHg, pulmonary arterial wedge pressure (PAWP) ≤15 mmHg, and pulmonary vascular resistance (PVR) >2 Wood units (WU). The PH-LHD diagnosis was established by mPAP >20 mmHg and PAWP >15 mmHg, or mPAP >20 mmHg with PAWP between 13–15 mmHg, followed by confirmed diagnosis through exercise or fluid challenge during RHC (16,17).

Clinical data were retrospectively collected from electronic medical records, including demographic characteristics, HHT manifestations, underlying diseases, medication history, laboratory findings, echocardiographic parameters and hemodynamic data. Information regarding bevacizumab treatment, including treatment indications, dosing schedules, treatment duration and clinical changes after treatment, was also reviewed. Bevacizumab was administered intravenously at a dose of 5 mg/kg every 2 weeks for 6 cycles during the induction phase. Clinical evaluations were performed after completion of the induction phase, including symptoms, World Health Organization functional class (WHO-FC), 6-minute walking distance (6MWD), laboratory findings, and echocardiographic parameters and repeat hemodynamic evaluation. Following induction therapy, patients could choose whether to receive maintenance treatment according to their willingness and clinical condition. Maintenance therapy consisted of either scheduled administration every 3 months or as-needed treatment according to clinical status. During the maintenance phase, patients were followed every 3 months through outpatient visits or telephone interviews. Repeat RHC was performed 6–12 months after initiation of maintenance bevacizumab therapy.

Statistical analysis

SPSS 26.0 software was used for the statistical analysis of relevant data. Categorical variables are expressed in absolute counts or percentages (%), and the χ²-test or Fisher’s exact test was used to make comparison between groups. If the continuous variables conformed to a normal distribution, expressed by mean ± standard deviation, and the group differences were compared using the t-test. If not, they would be expressed by the median (P25, P75), and the group differences compared using the Mann-Whitney U test. For continuous data, between-group differences were compared using one-way analysis of variance (ANOVA) test or a Kruskal-Wallis test with least significant difference analysis. Paired-samples t-tests were carried out to analyze any differences in the same group of patients before and after treatment. Cases with missing data were excluded from the relevant analyses. Efforts to reduce potential sources of bias included the use of predefined eligibility criteria, inclusion of all eligible participants, and standardized data collection from medical records.

Results

Baseline characteristics and clinical features

A total of 6 newly diagnosed HHT-PH patients, as well as 12 patients with PAH and 12 with PH-LHD were recruited for this study. The baseline characteristics of HHT-PH patients are summarized in Table 1. All HHT-PH patients were female. The mean age of patients at inclusion was 55.00±15.99 years. The median time from symptoms onset to diagnosis was 78.00 (8.50, 165.00) months.

All HHT-PH patients had dyspnea and mucocutaneous telangiectasia. And they all had epistaxis. All HHT-PH patients had hepatic AVMs and four of them had pulmonary AVMs. Typical radiologic features of pulmonary and hepatic AVMs are shown in Figure 1 and ultrasound features of hepatic AVMs are shown in Figure 2. Anemia was present in five out of six patients. Their mean 6MWD was 309.67±190.93 meters and 3 patients had WHO-FC III/IV. The median brain natriuretic peptide (BNP) levels were 261.50 (168.00, 371.15) pg/mL. The mean tricuspid annular plane systolic excursion (TAPSE) and TAPSE/systolic pulmonary arterial pressure (sPAP) were 16.83±1.60 mm and 0.28±0.06 mm/mmHg, respectively. There were no significant differences in WHO-FC, 6MWD, BNP levels and TTE-related data among HHT-PH, PAH and PH-LHD patients (Table 2).

Figure 1 The radiologic features of pulmonary and liver AVMs. (A,B) Three-dimensional volume rendered and arterial phase images of the liver in a patient with HHT (patient 5). There are dilated and tortuous hepatic vessels (white arrows), multiple telangiectasias (black arrow) and a perfusion abnormality (white arrowhead). (C,D) Arteriovenous malformations of the left lingular pulmonary artery were shown (white arrows). AVMs, arteriovenous malformations; HHT, hereditary hemorrhagic telangiectasia.

Figure 2 The ultrasonic features of liver AVMs. (A,B) Hepatic vascular malformations on Doppler ultrasound in a patient with HHT (patient 1) before the bevacizumab treatment. (C,D) After bevacizumab treatment, hepatic vascular malformations were relieved obviously. AVMs, arteriovenous malformations; HHT, hereditary hemorrhagic telangiectasia.

Hemodynamic characteristics

All the enrolled HHT-PH patients had confirmed PH, with mPAP 29.89±10.51 mmHg, PAWP 13.83±5.98 mmHg and PVR 189.94 (54.46, 289.89) dyn·s·cm^–5. Four patients had significantly increased CI (≥4.0 L/min/m²). Based on the hemodynamic data, two patients (patients 1 and 6) were typical post-capillary PH caused by a high-flow state. One patient (patient 4) was diagnosed with HHT-PH combined with connective tissue disease (CTD)-PAH. Another patient (patient 3) was diagnosed with unclassified PH and high CO. Subsequent exercise RHC revealed the presence of heart failure with preserved ejection fraction, suggesting that she should also be diagnosed as Group 2 PH as a consequence of high CO. In the other two cases (patients 2 and patient 5), the hemodynamic data showed pre-capillary PH and the CI did not meet the diagnostic criteria for high CO.

There were significant differences in hemodynamics among HHT-PH, PAH and PH-LHD patients. The hemodynamics of HHT-PH were different from those of the other two groups of patients. Compared with HHT-PH patients, PAH patients had lower CI [2.37 (1.92, 3.03) vs. 6.10 (3.77, 7.60) L/min/m², P=0.003] as well as higher PVR [886.70 (705.18, 1,278.68) vs. 189.94 (54.46, 289.89) dyn·s·cm^–5, P=0.005] and higher systemic vascular resistance (SVR) (1,836.07±673.64 vs. 740.93±333.06 dyn·s·cm^–5, P=0.001); PH-LHD patients showed lower CI [2.38 (1.91, 2.63) vs. 6.10 (3.77, 7.60) L/min/m², P=0.002] as well as similar PVR [229.48 (179.15, 416.60) vs. 189.94 (54.46, 289.89) L/min/m², P>0.99] and higher SVR (1,667.78±453.84 vs. 740.93±333.06 dyn·s·cm^–5, P=0.002) (Table 2).

Therapeutic response to bevacizumab of HHT-PH patients

All of the HHT-PH patients we included received bevacizumab therapy. All six HHT-PH patients completed the induction phase of bevacizumab therapy. One patient (patient 4) was subsequently lost to follow-up before post-treatment hemodynamic reassessment and therefore was not included in the efficacy analysis. Consequently, five patients with complete follow-up hemodynamic data were included in the subsequent therapeutic response analysis. Although formal post-treatment hemodynamic reassessment was unavailable, this patient reported symptomatic improvement after induction therapy.

Four patients subsequently received maintenance therapy. Three patients underwent follow-up hemodynamic reassessment during maintenance treatment. Among them, three used a continuous regimen (regularly-scheduled bevacizumab maintenance doses at 5 mg/kg each time), while one used an intermittent regimen (as-needed) (Table 1). Two patients received pulmonary vasodilator therapy. One patient has already used targeted drugs before referral to our hospital and another patient was treated because of coexisting CTD-PAH (Table 1).

Five patients with available follow-up data were included in the efficacy analysis. All five patients experienced significant symptoms (WHO-FC) relief. Significant improvements of BNP levels, TAPSE/sPAP and hemoglobin (Hb) were observed in all five patients. Four patients experienced improvements in 6MWD, mPAP and mixed venous oxygen saturation (SvO₂) except patient 3. Patient 3 reported a marked enhancement in hemodynamics and exercise tolerance during the maintenance treatment (Table S1). In addition to patient 5, CI also declined significantly in the other four patients. The increase CI in patient 5 may be related to the use of targeted therapy, which reduced PVR. This patient showed notable enhancements in symptoms, as well as other hemodynamic and transthoracic echocardiography parameters, demonstrating the effectiveness of the treatments (Figure 3).

Figure 3 Treatment responses after the induction therapy of bevacizumab. Five patients completed the induction phase of bevacizumab. All five patients experienced significant symptoms (WHO-FC) relief. Significant improvements of BNP levels, TAPSE/sPAP and Hb were observed in all five patients. (A) WHO-FC; (B) mPAP; (C) CI; (D) BNP; (E) 6MWD; (F) SvO₂; (G) Hb; (H) TAPSE/sPAP. 6MWD, 6-minute walking distance; BNP, brain natriuretic peptide; CI, cardiac index; Hb, hemoglobin; mPAP, mean pulmonary arterial pressure; sPAP, systolic pulmonary artery pressure; SvO₂, mixed venous oxygen saturation; TAPSE, tricuspid annular plane systolic excursion; WHO-FC, World Health Organization functional class.

Discussion

The diagnosis and management of HHT-PH is extremely challenging. The present study described the demographic, clinical and hemodynamic characteristics of bevacizumab-treated HHT-PH patients.

As is well known, early diagnosis is important in determining appropriate outcomes for HHT patients. However, there is still a concern about the difficulty in establishing a timely accurate diagnosis in HHT (18). A questionnaire by Pierucci et al. observed a long diagnostic delay in patients with HHT and only 88/233 patients received a correct diagnosis at first counseling (19). Our study reflected a similar issue. The median time from symptoms onset to diagnosis in HHT-PH was 78 months. The prolonged diagnostic time reflected the insidious onset of HHT, making it difficult to diagnose. In our study, six patients suffered recurrent epistaxis over several years, but HHT wasn’t diagnosed until they developed severe dyspnea. These findings highlight the importance of paying attention to subtle clinical features such as epistaxis and telangiectasias in these patients.

In this study, all patients received bevacizumab due to HOCF associated with hepatic AVMs or severe bleeding, and significant improvements were observed in hemodynamic and clinical indicators. The hemodynamic profile of HHT-PH benefiting from bevacizumab treatment differed significantly from that of PAH and PH-LHD. HHT-PH patients were characterized by high CO/CI along with low PVR. In contrast, typical PAH patients presented with low CO or CI and markedly elevated PVR, while typical PH-LHD patients had low CO/CI and low PVR. A high-output, low-resistance hemodynamic profile may raise suspicion for HHT-related PH, particularly in patients with clinical features suggestive of HHT. These findings also suggest that the treatment should focus on controlling the high-output state rather than using targeted therapies to reduce PVR in HHT-PH patients with high CO/CI and low PVR.

In HHT, mutations involving the Endoglin or activin receptor-like kinase 1 (ALK1) signaling pathways lead to dysregulated angiogenesis and abnormal vascular formation, resulting in the development of telangiectasias and AVMs (20). In patients with hepatic AVMs, excessive arteriovenous shunting may lead to elevated CO and subsequently HOCF and PH. The mechanisms differ from the classical vascular remodeling observed in PAH, which is predominantly characterized by progressive obliterative remodeling of the pulmonary arterioles and markedly elevated PVR (21). HHT-PH in our study was mainly characterized by a high-output, low-resistance hemodynamic profile associated with abnormal angiogenesis and AVM-related shunting.

Bevacizumab, a monoclonal antibody that targets vascular endothelial growth factor (VEGF), may partially improve this pathophysiological process by reducing abnormal angiogenesis and hepatic shunting, thereby decreasing the high-flow state and alleviating PH (22). Previous studies reported significant improvements in CI and HOCF symptoms in most patients treated with bevacizumab and adverse events were uncommon in HHT-PH (23-25). However, the use of bevacizumab in HHT is not a standard or approved treatment. Bevacizumab is recommended in HHT guidelines for the treatment of severe epistaxis or HOCF due to hepatic AVM (9,10). In our study all six patients received bevacizumab, and achieved significant improvements in symptoms, Hb, BNP levels and TAPSE/sPAP after the induction therapy. Except for patient 3, the other four patients experienced improvements in hemodynamics and 6MWD after the induction therapy. Of note, patient 3 reported a marked enhancement in hemodynamics and exercise tolerance during the maintenance treatment. No serious adverse events were reported in the bevacizumab treatment group. These findings suggest that bevacizumab may be a potential treatment option for selected HHT-PH patients with high-flow state; however, the results should be interpreted cautiously because of the limited sample size and retrospective case-series design.

Importantly, the effects of VEGF inhibition on the pulmonary vasculature are likely to be very complex. VEGF signaling is also involved in pulmonary vascular homeostasis and endothelial repair (26). Inhibition of VEGF activity in pulmonary endothelial cells may disrupt vascular formation and neovascularization, potentially leading to the remodeling of the pulmonary vascular structure, ultimately resulting in the development of PAH (27,28). Therefore, although bevacizumab may improve high-flow physiology in selected HHT-PH patients, its use should be approached with caution, particularly in patients with markedly elevated PVR or features suggestive of intrinsic pulmonary vascular disease. Previous studies have suggested that patients with HOCF are the subgroup most likely to benefit from bevacizumab. In the present study, although HHT-PH was characterized by a high-output, low-resistance hemodynamic profile, some patients with CI <4 L/min/m² still exhibited favorable responses to bevacizumab. This observation indicates that CI alone should not be used as the sole criterion for identifying candidates for bevacizumab therapy with HHT-PH. In clinical practice, treatment decisions should be based on the overall hemodynamic and clinical profile. Larger studies are needed to define better the subgroup of HHT-PH patients most likely to benefit from bevacizumab therapy.

There is currently no unified regimen for the use of bevacizumab (23). Treatment is usually divided into induction phase and maintenance phases. Induction treatment is relatively consistent, but maintenance treatment varies significantly among previous studies. Some centers used a continuous maintenance strategy (regularly-scheduled bevacizumab maintenance doses) and others used an intermittent (as needed) maintenance strategy (23). In the present study, four out of six patients received maintenance treatment. Three cases (patients 3, 5, 6) received a continuous treatment regimen (with an interval of 1 or 2 months) and one case (patient 1) received an intermittent regimen. Additionally, the optimal duration of continuous maintenance therapy and the criteria for temporary discontinuation of bevacizumab remain unclear. In our study, the longest duration of bevacizumab use exceeded 2 years. Al-Samkari et al. reported an 8-year use of bevacizumab without any complications (8). Nevertheless, the effects of indefinite use of bevacizumab in patients with HHT remain unknown. Furthermore, experience from our single center suggested that it might depend on whether the symptoms were relieved and the high CO was controlled. To sum up, the data regarding the maintenance regimens of bevacizumab are limited, and the well-controlled prospective studies will be essential for determining the optimal maintenance strategy.

At present, there are no randomized control trials for PAH-specific therapy in HHT. The experience with PAH-specific therapy in HHT is sparse and limited to case reports. PAH-specific therapy is generally recommended only for patients with HHT-PAH (2,29-31). However, in patients with HHT-PH due to a high flow state, PAH-specific therapy should be used with caution, as pulmonary vasodilator therapy may increase venous return and thereby exacerbate left heart failure. In our study, two patients were given targeted therapies. Patient 4 had the complications of CTD disease. Patient 5 had already received targeted drug (ambrisentan) before referral to our hospital. Due to the obviously elevated PVR and the patient’s sustained symptoms relief, we maintained the targeted therapy. These two patients achieved significant improvements in hemodynamics and exercise tolerance. Of note, several studies have posed concerns about the increased bleeding risk when HHT-PH patients are treated with pulmonary vasodilator therapy (5,32). In our two cases, we also did not observe worsening of bleeding or anemia. Nevertheless, before initiating PAH-specific therapy in HHT-PH patients, a detailed hemodynamic assessment and a thorough investigation of other potential causes of PH should be conducted.

The present study had certain limitations. First, the sample size was limited and therefore the findings should be interpreted cautiously and will require confirmation in larger studies. Second, patients with a CI below 4 L/min/m² may still benefit from bevacizumab treatment, but the threshold for CI requires further validation through large-scale cohort studies. Finally, only a few patients received maintenance therapy of bevacizumab during this study, the effectiveness and safety of maintenance therapy therefore needs to be investigated in future studies.

Conclusions

In this single-center study, HHT-PH patients treated with bevacizumab showed a distinct hemodynamic profile compared with patients with PAH and PH-LHD. After bevacizumab induction therapy, clinical improvement was observed in most patients with available follow-up data. Notably, some patients with a baseline CI below 4 L/min/m² also showed improvement, suggesting that the conventional CI threshold may need further evaluation.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0764/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0764/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0764/prf

Funding: The study was supported by the Capital Funds for Health Improvement and Research (No. 2024-2-2067), Beijing Anzhen Hospital High Level Research Funding (No. 2024AZC2005), Noncommunicable Chronic Diseases-National Science and Technology Major Project (No. 2026ZD0556205), and The National Key Research and Development Program of China (No. 2023YFC2507205).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0764/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the ethics board of Beijing Anzhen Hospital, Capital Medical University (No. 2026243x) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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