Refractory anaemia in a patient with end-stage heart failure secondary to aortic stenosis

Anaemia is common in patients with cardiovascular disease, particularly in those with heart failure (HF). Approximately one third of these patients present with anaemia, which has been associated with increased all-cause and cardiovascular mortality.¹ Iron deficiency anaemia is the most common type, accounting for about half of all anaemia cases.² The pathogenesis of anaemia in HF is multifactorial, involving iron deficiency, abnormalities in erythropoietin synthesis and responsiveness, chronic inflammation leading to bone marrow dysfunction, gastrointestinal bleeding, and the adverse effects of various medications, among other factors.³ As a result, anaemia in HF patients is often regarded as an explainable phenomenon. However, in some cases, the cause of anaemia may be unexpected and complex. Here, we report a patient with HF who presented with refractory anaemia and was ultimately treated successfully. This case may provide insights into potential underlying causes of anaemia in patients with HF.

A 78-year-old woman admitted due to worsened dyspnoea. She was diagnosed with rheumatic heart disease (RHD) complicated by mitral stenosis 32 years ago. Surgical mechanical mitral valve replacement (MVR) was performed and the symptoms improved post-operation. She has been taking warfarin ever since with international normalized ratio ranging between 1.8 and 2.2. During follow-up period, the complete blood count (CBC) indicated haemoglobin (Hb) was around 110 g/L.

Twenty years after MVR, when she had routine checkup, the echocardiography showed a mild aortic valve stenosis (AS); however, she had no symptoms. Five years later, the patient began to feel dyspnoea again and CBC indicated a decreased Hb of 65 g/L. The patient reported she had intermittent black stool, and therefore received gastrointestinal endoscopy examination; however, there were no obvious ulcer, cancers, or vascular malformation. Besides, bone marrow aspiration showed an active erythroid hyperplasia with iron deficiency and serum iron was also significantly reduced. Therefore, she was prescribed with oral iron supplementation, but anaemia still worsened gradually and a transfusion was needed every 2–4 weeks to maintain the Hb around 80 g/L.

Meanwhile, her exercise tolerance was progressively reduced. When she was 74 years old, echocardiography revealed a moderate to severe AS with orifice area 0.8 cm² and 2 years later it progressed to severe AS with orifice area 0.5 cm². The patient's exercise tolerance continued to worsen despite aggressive therapy, including daily administration of 40–80 mg of furosemide to maintain a dry weight status, as well as beta-blockers to control the heart rate within the range of 70–80 b.p.m. Meanwhile, the Hb decreased to 60 g/L, and it needed transfusing 200–400 mL red blood cell every other day to maintain the Hb around 80 g/L despite the use of oral polysaccharide iron complex and intermittent administration of ferric carboxymaltose. Other medications included spironolactone 20 mg daily, bisoprolol 2.5 mg daily and rabeprazole 20 mg daily. During the course, the patient did not complain of black stool, haematochezia, haematuria or cola-coloured urine.

At admission, the patient was obviously anaemic and breathless, had jugular vein distention, low respiratory sound in the right lung. Cardiac auscultation revealed atrial fibrillation rhythm with heart rate of 72 b.p.m. and 3/6 systolic murmur in the aortic valve area. Abdominal examination found an enlarged liver with positive hepatojugular reflux sign. The lower extremity was edematous. Laboratory tests showed an Hb of 70 g/L, mean corpuscular volume of 72.1 fL, and serum iron was significantly decreased (2.8 μmol/L) with increased reticulocyte (4.3%). Faecal occult blood test (FOBT) was positive. The serum folate and Vitamin B12 levels were within normal range. Echocardiography displayed a severe AS with orifice area 0.5 cm² and serious calcification of the aortic valve. The left ventricular ejection fraction was 61% and the mechanical mitral valve worked well.

Upon admission, the patient presented with severe anaemia, necessitating the administration of 100–200 mL red blood cell every other day. Intravenous diuretic therapy with furosemide (80–100 mg per day) was administered to relieve symptoms of HF. The patient was also initiated on appropriate anticoagulation with warfarin, targeting an international normalized ratio of 1.8 to 2.5, and received intravenous proton pump inhibitor (PPI) therapy due to the potential gastrointestinal bleeding.

The patient's AS had progressed into end-stage HF. Therefore, surgical aortic valve replacement was deemed highly risky and transcatheter aortic valve replacement (TAVR) was considered an alternative option. After aggressive anti-HF therapy including 80–100 mg of intravenous diuretics daily to enhance diuresis, intravenous recombinant human brain natriuretic peptide to relieve HF symptoms and sacubitril/valsartan, the symptoms significantly improved; meanwhile, the Hb remained around 90 g/L after repeated transfusion. The patient finally received TAVR successfully. The symptoms of HF were further relieved and the Hb began to keep stable around 105 g/L until discharge.

After discharge, the patient continued to use warfarin anticoagulation, combination diuretic therapy with furosemide and bumetanide, and oral PPI therapy to minimize the risk of gastrointestinal bleeding, as well as intermittent intravenous iron supplement and the Hb kept around 105 g/L without transfusion. During the three-year follow-up period, her had no rehospitalization due to HF and the Hb kept stable at 100–110 g/L. The dynamic change of HB was shown in Figure 1 and the timetable of the diagnosis and treatment was shown in Figure 2.

The two most challenging aspects of this patient's management were to find out the causes of refractory anaemia and to deal with the AS.

Anaemia is a common comorbidity in patients with AS, with reported prevalence ranging from 20% to 64%.^4-8 In the CURRENT AS registry, among 3403 patients diagnosed with severe AS, 835 (25%) had mild anaemia and 1282 (38%) had moderate to severe anaemia at the time of diagnosis.⁴ Furthermore, the 5-year cumulative incidence of aortic valve-related death and HF hospitalization increased progressively with the severity of anaemia, reaching 56% in patients with moderate to severe anaemia.⁴ Therefore, identifying the causes of anaemia in patients with AS is of great significance for both treatment and improving prognosis.

There are some underlying interpretable causes of anaemia in the patient. Iron deficient anaemia was diagnosed accurately; however, the causes of iron deficient anaemia are multifactorial. First, long-term gastrointestinal congestion and loss of appetite led to iron ingestion and absorption disorders. Second, long-term warfarin use could cause occult gastrointestinal bleeding especially in the setting of gastrointestinal congestion. Third, anaemia of chronic disease is usually prevalent in patients with HF⁹ and interacts with HF, leading to a vicious cycle. Moreover, a chronic illness and repeated transfusion resulted in immune and inflammation activation, which inhibited haematopoietic function in bone marrow.¹⁰ However, the anaemia in this patient was refractory and it needed frequent transfusion to maintain a minimally acceptable Hb level. Therefore, haemolytic anaemia was suspected due to hydrodynamic shearing of the erythrocytes by turbulent flow could cause mechanical haemolysis¹¹; however, tests associated with haemolysis (haemoglobinuria, urobilinogen, Coombs and schistocyte tests) were negative, indicating haemolysis was not responsible for her anaemia. In addition, bone marrow aspiration did not exhibit hypoplastic or myelodysplastic signs. Other potential causes such as cancers, recurrent rheumatism, and autoimmune disease were excluded. Subsequently, genetic testing revealed that she had a SEA heterozygote of α-thalassaemia, which is a type of thalassaemia caused by disorder of globin generation. The symptoms of anaemia in such patients are usually mild or absent especially in young individuals.

Notably, this patient presented with iron deficiency accompanied by an elevated reticulocyte count, a finding that is somewhat atypical, as iron deficiency is generally associated with reduced red blood cell production. Several possible explanations may account for this discrepancy. First, the patient had coexisting thalassaemia, which could lead to compensatory erythropoiesis in the bone marrow; even in the presence of iron deficiency, this compensatory response may lead to elevated reticulocyte levels. Second, the patient was receiving iron supplementation, which could have triggered a transient increase in reticulocyte production as the bone marrow responded to improved iron availability.

In patients with AS and recurrent gastrointestinal bleeding, Heyde syndrome should be considered. It is a gastrointestinal bleeding from angiodysplasia in the presence of AS caused by cleavage of von Willebrand factor (vWF) due to high shear stress forces associated with AS.¹² Although the patient was too feeble to receive colonoscopy examination, the gastroscope did not reveal angiodysplasia in the upper gastrointestinal tract, and the patient had no typical presentation of gastrointestinal bleeding. The vWF level was also within the normal range, indicating Heyde syndrome was less likely.

It is worth noting that throughout the disease course, the patient reported intermittent melena, and faecal occult blood testing returned a positive result. However, a contemporaneous gastrointestinal endoscopy revealed no evidence of active bleeding, ulcers, malignancy, or vascular malformations. While significant upper gastrointestinal bleeding was ruled out, minor or intermittent bleeding episodes could not be excluded, potentially related to gastrointestinal congestion from HF or the effects of warfarin therapy.

For the treatment of iron deficiency anaemia in patients with HF, current ESC guidelines recommend routine screening for anaemia and iron deficiency in all patients with HF, along with the identification of underlying causes.^{13, 14} Given the often suboptimal response to oral iron supplementation and its limited efficacy in improving exercise capacity, intravenous iron supplementation with ferric carboxymaltose is the preferred therapeutic approach for HF patients with documented iron deficiency.¹³ The patient in this case presented with classic iron deficiency anaemia, characterized by reduced serum iron and transferrin saturation. For this patient, despite treatment with both oral iron supplementation and intravenous iron infusions, the therapeutic response remained poor, suggesting that in addition to iron deficiency, there may be other causes contributing to the patient's anaemia.

Another unanswered question is the aetiology of AS. Although the patient had a history of RHD, it remained unclear whether AS was a progression of RHD. However, there was no evidence of active rheumatic processes and anti-streptolysin ‘o’ titre was within normal range, indicating AS was probably non-rheumatic. It is worth noting the patient had chronic use of warfarin, which can cause calcification of the valve and stenosis.¹⁵ In addition, degeneration was also a possible cause for the patient's AS. However, regardless of the underlying cause, TAVR is a useful treatment option to relieve symptoms and improve the outcome.

Although the precise mechanisms of anaemia in this patient are not well understood, it is probably multifactorial (Figure 3). Among these factors associated with anaemia, AS played a central role, which was demonstrated by the improvement in both anaemia and HF after TAVR.

In conclusion, anaemia in patients with end-stage HF is multifactorial, and identifying its accurate cause can be challenging. Biochemical, haematologic, imaging tests and sometimes genetic tests could clarify the potential causes of anaemia. In patients with AS complicated by HF and anaemia, TAVR is an effective strategy to improve the prognosis.

None declared.