Gastrointestinal Bleeding in Hereditary Hemorrhagic Telangiectasia Accompanied with Very Severe Thrombocytopenia

Introduction

Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, is a rare autosomal-dominant disease. The global average prevalence of HHT is estimated to range from 1: 5000 to 1: 8000 [1]. The most common genetic mutations associated with the development of HHT are observed in the endoglin (ENG) and activin A receptor like type 1 (ACVRL1) genes [2]. These mutations disrupt the transforming growth factor-β signaling pathway, leading to telangiectasia and arteriovenous malformations (AVMs) in various organs [3]. Recurrent epistaxis, often accompanied with gastrointestinal bleeding (GIB), is a common clinical manifestation observed in HHT patients. Furthermore, the lesions may also involve the lungs, liver, and central nervous system.

The gastrointestinal tract, as the second most common site of bleeding in HHT patients, is highly susceptible to involvement, with symptoms presenting as hematemesis and melena. Brinjikji et al reported that the prevalence of concurrent GIB was as high as 10.8% among 10 293 HHT patients [4]. The use of capsule endoscopy has also provided additional evidence supporting the high co-occurrence rate of HHT and GIB [5]. The majority of HHT patients exhibit iron-deficiency anemia following GIB, characterized by decreased hemoglobin levels while maintaining normal platelet counts. If the platelet count in HHT patients decreases, which is a dangerous condition, it may be attributed to infection, primary hematologic disorders, or adverse drug reactions, among others [6]. To our knowledge, GIB induced by HHT accompanied with thrombocytopenia is rarely reported, with only 1 case, documented in 2022 [7].

The most effective treatment for GIB induced by HHT is symptomatic management. However, due to the presence of vascular abnormalities (such as telangiectasia and AVMs), combined with the extensive nature of the lesions and the difficulty in improving vascular structure in the short term, endoscopic treatment or surgical intervention may exacerbate vascular damage [8]. This makes the management of HHT complicated by GIB particularly challenging, and the presence of thrombocytopenia further increases the complexity of treatment.

Hence, we report a woman admitted to our hospital due to upper-GIB caused by HHT who suffered a life-threatening thrombocytopenia during treatment and survived thanks to the comprehensive analysis of her condition and timely and appropriate application of various treatments.

Case Report

A 66-year-old woman had suffered from recurrent epistaxis for more than 5 years, during which multiple nasal packing procedures and electrocautery treatments were performed for hemostasis. The genetic testing revealed a pathogenic mutation in the ACVRL1 associated with HHT-2, leading to diagnosis of HHT. Subsequently, she received intermittent bevacizumab infusion therapy, but the clinical response was suboptimal. A gastroscopy showed multiple telangiectasias in the stomach and duodenum 2 years ago. Two weeks ago, she developed hematemesis and melena following ingestion of hard food. She received supportive treatments, such as fasting for solids and liquids, acid suppression, and rehydration. However, the symptoms showed no significant improvement. From her medical history, we also learned that her father and sister had similar symptoms of recurrent epistaxis.

Upon admission, her vital signs were: body temperature, 36.5°C; heart rate, 71 beats per min; respiratory rate, 18 breaths per min; blood pressure, 115/51 mmHg. The physical examination showed an anemic face with no signs of abdominal tenderness, rebound pain, muscular tension, or palpable masses. Other physical examination results were normal.

The laboratory tests revealed white blood cells of 2.60×109/L, red blood cells of 2.27×1012/L, platelets of 152×109/L, hemoglobin of 65 g/L, granulocyte ratio of 68.1%, C-reactive protein of 4.10 mg/L, D-dimer of 1.43 ug/ml, and N-terminal pro-brain natriuretic peptide of 383.0 pg/ml. The prothrombin time (PT) and activated partial thromboplastin time (APTT) were normal.

The computed tomography (CT) scan of her chest suggested the possibility of pulmonary hypertension, accompanied with multiple pulmonary nodules, global cardiac enlargement, and a small quantity of pericardial effusion. The abdominal enhanced CT scan revealed the enhanced nodule in S6 of the liver, hepatic S1 cyst, and parapelvic cyst in the left kidney.

After admission, she received supportive treatments such as fasting for solids and liquids, esomeprazole for acid suppression, octreotide for vasoconstriction, rehydration, and blood transfusion. The hemoglobin level remained stable at approximately 60 g/L. On the fourth day after admission, there was a sudden worsening of hematemesis and melena, accompanied with decreased blood pressure and increased heart rate. Concurrently, the hemoglobin level decreased to 53 g/L and platelet count dropped to 6×109/L. However, the coagulation-related indexes were still in normal ranges. At that time, she was in poor general condition, which posed a high risk for bone marrow procedures, leading to refusal by the patient’s family. After careful consideration, we discontinued the intravenous administration of esomeprazole. Since the active upper-GIB still required a proton pump inhibitor (PPI), we switched to an omeprazole sodium for injection named Losec, which the patient had used before. The patient received intermittent platelets transfusion in combination with a subcutaneous injection of recombinant human interleukin-11 (3 mg qd). She was also intermittently treated with plasma, red blood cells, human serum albumin transfusions, and hemostatic drugs infusion, including hemocoagulase, tranexamic acid, etamsylate, and human prothrombin complex, along with the administration of Losec (at a rate of 8 mg/h intravenous pumping continually) and octreotide (at a rate of 25 ug/h intravenous pumping continually). On the fifth day after admission, the hemoglobin level continued to decline to 41 g/L and the platelet count dropped to 1×109/L. The decline in the hemoglobin level and platelet count stopped on the sixth day after admission, subsequently exhibiting a slight increase.

A gastroscopy was performed on the eighth day after admission, when her hemoglobin level reached 62 g/L and platelet count reached 23×109/L. The gastroscopy revealed over 50 angioectatic sites with active bleeding in the esophagus, stomach, and duodenum (Figure 1A). Ultimately, the patient’s diagnosis of upper-GIB in HHT accompanied with thrombocytopenia was confirmed, and argon plasma coagulation (APC) was planned as an intervention for hemostasis. The bleeding from angioectatic sites were stopped by APC (Figure 1B). APC was performed at an output of 45 W and with an argon gas flow rate of 1.5 L/min. On the second day after endoscopic treatment, her vital signs remained stable. Intravenous pumping of Losec and octreotide were discontinued. She was given intravenous infusion of Losec (40 mg bid), while continuing to receive a subcutaneous injection of recombinant human interleukin-11 for injection (3 mg qd). The hemoglobin level and platelet count showed a gradual recovery. On the seventh day after endoscopic treatment, the hemoglobin level was 65 g/L and the platelet count was 119×109/L, without any manifestations of GIB. Subsequently, she was discharged. During hospitalization, her cumulative volume of hematemesis reached 700 ml and melena was 2400 ml. The changes in hemoglobin levels and platelet counts during hospitalization are shown in Figure 2.

After a 6-month period following discharge, the patient’s symptoms were significantly improved and she mostly returned to a normal life. Her hemoglobin level had improved to 102 g/L, and the platelet count had increased to 284×109/L. The gastroscopy and colonoscopy images indicated only a few telangiectasia with old bloodstains in the stomach, duodenal bulb, ascending colon, and transverse colon (Figure 1C, 1D). The magnetic resonance imaging, diffusion-weighed imaging, and susceptibility-weighted imaging of the brain revealed a small ischemic lesion in the left frontal lobe, along with findings suggestive of empty sella and cerebral arteriosclerosis with stenosis, without evidence of AVMs or intracranial hemorrhage.

After 20 months, capsule endoscopy revealed no typical telangiectasia in the small intestine.

Discussion

To our knowledge, the most prominent symptom of HHT is recurrent epistaxis, often accompanied with GIB and AVMs in various organs. While epistaxis typically begins in childhood, GIB predominantly occurs in advanced stages, particularly among individuals aged 50–60 years [9,10]. GIB is more prevalent in the stomach and small intestine than in the colon [11]. Our patient exhibited similar clinical symptoms. Additionally, pulmonary hypertension and hepatic involvement, such as hepatic artery dilatation and nodular hyperplasia, are common in HHT patients [12,13]. In this case, CT scans suggested pulmonary hypertension and an enhanced nodular lesion in segment S6 of the liver, which are typical manifestations of HHT. Therefore, GIB, along with recurrent epistaxis and organ lesions, should be considered a potential indicator of HHT.

Symptomatic treatment based on hemostasis is the main management for HHT patients with GIB. According to the second international guidelines, chronic GIB can result in iron-deficiency anemia, necessitating iron infusion and red blood cells transfusion if deemed necessary [14]. In terms of pharmacological interventions, somatostatin analogues (eg, octreotide), PPI, and other hemostatic agents (such as hemocoagulase, tranexamic acid, etamsylate, and human prothrombin complex) have been widely used in clinical practice for the management of GIB in HHT patients [15]. In recent years, bevacizumab, thalidomide, and emerging combination therapies have demonstrated promising efficacy in the treatment of refractory GIB in HHT patients [16–18]. However, due to inconsistent clinical outcomes and potential adverse effects, further comprehensive cohort studies are warranted to establish their long-term safety and efficacy [19,20]. Furthermore, APC has been shown to play a pivotal role in the management of HHT-related GIB, as supported by long-term follow-up studies conducted by Kwan et al [21]. Despite these advances, the management of GIB in HHT patients remains highly challenging due to the underlying vascular abnormalities and the relapsing nature of the disease.

It is noteworthy that iron-deficiency anemia induced by HHT normally has no impact on platelet counts. However, our patient exhibited a significant and unexplained decline in platelet counts. Thrombocytopenia is defined as the platelet count of less than 100×109/L [22]. Our patient fulfilled the diagnostic criteria of HHT, GIB, and thrombocytopenia. Although cases of these disorders have been reported previously, the overlapping case of HHT, GIB, and thrombocytopenia is rare. We further analyzed the etiology of thrombocytopenia in this patient. Firstly, we ruled out infection as a potential cause. The patient received anti-infective therapy with normal or mildly decreased white blood cells during hospitalization, and no clinical signs of infection were observed. Secondly, normal PT and APTT effectively excluded thrombocytopenia secondary to coagulation disorders, such as disseminated intravascular coagulation. Additionally, the absence of splenomegaly on the abdominal enhanced CT scan ruled out hypersplenism as a contributing factor. Finally, we systematically excluded the possibility of thrombocytopenia caused by typical hematologic disorders, including idiopathic thrombocytopenic purpura, aplastic anemia, or lymphoma. Although bone marrow aspiration and biopsy were not performed, the patient had no prior history of hematologic diseases, and she was able to achieve a short-term normalization of the platelet count simply by discontinuing esomeprazole and receiving symptomatic treatment, which is almost impossible to achieve in these hematologic disorders. Furthermore, these hematologic disorders usually exhibit a high recurrence rate within 3 months after treatment, but the clinical manifestations and platelet counts of this patient showed a favorable prognosis after 6 months, effectively excluding thrombocytopenia caused by these hematologic conditions [23]. After excluding these causes of thrombocytopenia, we considered the possibility of PPI-induced thrombocytopenia.

Several studies have shown that certain PPIs, such as pantoprazole and lansoprazole, can induce thrombocytopenia during the treatment of GIB [24,25]. PPI-induced thrombocytopenia is considered a type of drug-induced thrombocytopenia (DIT). Based on the evaluation criteria proposed by George et al, our patient could be diagnosed as having DIT [26]. Considering that esomeprazole is the most likely cause of thrombocytopenia, we discontinued it immediately. Then, we applied another PPI, Losec, which the patient had previously used. The platelet count stopped falling and gradually returned to the normal level. Although esomeprazole was not the only medication taken before the development of thrombocytopenia, the persistence of other medications and Losec did not result in further decline in platelet counts. We also excluded other causes of thrombocytopenia. Finally, due to ethical constraints, the patient did not receive esomeprazole again for a trial diagnosis after her platelet count normalized. The patient fulfilled 3 criteria of DIT. Therefore, we speculate that the administration of esomeprazole had induced thrombocytopenia. However, this phenomenon appears to exhibit significant interindividual variability, as not all patients treated with esomeprazole develop thrombocytopenia. For this reason, switching to another PPI with a different chemical structure is a good strategy for continuing the treatment. The specific mechanisms underlying PPI-induced thrombocytopenia remain incompletely understood. Based on current evidence, we hypothesize that certain PPI exert their effects through 2 primary pathways: by suppressing megakaryocyte production in the bone marrow or by accelerating the destruction of circulating platelets [27]. The latter mechanism likely involves both immune-mediated and non-immune-mediated processes. Immune-mediated mechanisms may include the formation of drug-dependent antibodies or immune complexes, while non-immune-mediated mechanisms could involve direct cytotoxic effects or the induction of platelet apoptosis. However, these hypotheses require further research to be confirmed.

Conclusions

This case shows a rare confluence of HHT, GIB, and very severe thrombocytopenia, providing valuable insights into the uncommon phenomenon of PPI-induced thrombocytopenia and offering systematic clinical management recommendations for such complex cases. In the context of PPI therapy, a sharp decline in platelet counts should prompt consideration of PPI-induced thrombocytopenia after excluding other potential causes. Immediately discontinuing the involved PPI is advised. For patients with active bleeding or a high risk of hemorrhage, platelet transfusion should be initiated when the platelet count falls below 20×109/L, supplemented with recombinant human interleukin-11 to stimulate platelet production. If continued PPI therapy for GIB is necessary, switching to a PPI with a different chemical structure is recommended, with close monitoring of platelet counts to ensure timely intervention.