Diagnostic Challenges in Atypical Hemolytic Uremic Syndrome: A Case of Artificial Mitral Valve Dysfunction as a Possible Trigger for Severe Thrombotic Microangiopathy

Introduction

Hemolytic uremic syndrome (HUS) is a severe, life-threatening thrombotic microangiopathy characterized by the triad of acute kidney injury, non-immune microangiopathic hemolytic anemia, and thrombocytopenia [1]. The global incidence of HUS ranges from 6.3 to 14.2 cases per million annually, with pediatric cases being more common [2]. HUS is broadly classified into 2 subtypes: typical HUS, caused mainly by Shiga toxin–producing Escherichia coli (STEC), and atypical HUS (aHUS), which is further subdivided into primary and secondary subgroups [3]. While STEC-HUS is relatively more common, aHUS is ultra-rare disease and often presents diagnostic challenges [4]. The most common underlying cause of aHUS is an inherited defect of complement proteins or formation of autoantibodies against complement regulatory proteins, which are included in the primary subgroup [5]. Other causes, including pregnancy, viral infections, and sepsis, belong to the secondary subgroup [3]. Moreover, in patients with aHUS, comorbidities often play an important role in the onset and course of the disease. Conditions such as cardiovascular disease, autoimmune disorders, malignancies, or chronic infections can act as co-factors that exacerbate complement dysregulation or endothelial damage [6].

The clinical presentation of HUS varies, ranging from mild symptoms, such as fatigue and malaise, to severe renal failure requiring dialysis [1,3]. In particular, aHUS is known for its more aggressive clinical course and frequent relapses, often leading to long-term renal complications [3]. Diagnosis of HUS and its subtypes requires a comprehensive evaluation, including blood tests, measurement of ADAMTS-13 activity, microbiological tests for STEC, and genetic and serological analyses for complement system abnormalities [3,7].

Treatment strategies for HUS have evolved significantly. While plasma exchange and supportive care remain the mainstay for typical HUS, the introduction of complement-inhibiting monoclonal antibodies, such as eculizumab and ravulizumab, has significantly improved outcomes in patients with aHUS [1,7,8]. These therapies are approved by both the U.S. Food and Drug Administration and European Medicines Agency specifically for the treatment of patients with complement-mediated thrombotic microangiopathy [9,10].

Identifying the underlying cause of HUS is crucial for proper management of the disease, especially with its various etiologies and clinical presentations. Infections and genetic mutation are well-known causes; however, the cause is still unknown in 30% of aHUS cases [11]. Mechanical factors related to cardiovascular interventions are not frequently associated with thrombotic microangiopathy; therefore, the effect of this phenomena is not excessively described in the medical literature. In this report, we describe a case of 70-year-old woman presenting with thrombotic microangiopathy and perivalvular leakage of an artificial mitral valve prosthesis.

Case Report

A 70-year-old woman with a history of artificial mitral valve replacement, performed in 1998, was referred from a district hospital to the tertiary nephrology center with suspicion of thrombotic microangiopathy – HUS. On admission, the patient was in poor condition, experiencing malaise, dyspnea, recurrent episodes of bleeding from oral mucosa, and hematuria. Physical examination revealed significant edema of the lower extremities, muffled breath sounds, and crepitations. Laboratory test results showed anemia (hemoglobin, 7.5 g/dL), mild thrombocytopenia (platelet count, 111 G/L), evidence of hemolysis with numerous schistocytes in the blood smear, and elevated serum markers: lactate dehydrogenase (4578.8 U/L), bilirubin (39.6 μmol/L), urea (29.32 mmol/L), creatinine (2.14 mg/dL), and international normalized ratio (4.12), as well as undetectable haptoglobin. The findings led to an initial diagnosis of acute liver, kidney, and heart dysfunction (Figure 1A–1E).

The patient was on long-term warfarin therapy due to previous mechanical valve implantation, which likely accounted for the elevated international normalized ratio. Activated partial thromboplastin time (APTT) was 74.4 seconds, and liver enzymes were only mildly elevated (alanine aminotransferase=39.1 U/L; aspartate aminotransferase=57 U/L). Fibrinogen levels were within the reference range, and D-dimer was not significantly elevated, making disseminated intravascular coagulation unlikely. To investigate the cause of the elevated APTT, antiphospholipid antibodies were tested, including lupus anticoagulant, anticardiolipin, and anti-β2 glycoprotein I antibodies, all of which returned negative. These results helped rule out antiphospholipid syndrome as a contributing factor, further supporting the exclusion of rheumatologic or autoimmune triggers for aHUS in this case. Additionally, there was no clinical evidence of sepsis, malignancy, or coagulopathy, further supporting the exclusion of chronic disseminated intravascular coagulation as a primary cause of thrombotic microangiopathy.

Serological tests for autoimmune markers (ANA, ANCA, anti-GBM, direct antiglobulin) were negative. Complement factors (C3, C4) remained at the normal level, but the terminal pathway products sC5b-9 were increased, at 402 ng/mL (reference range, 110–252 ng/mL), suggesting complement overactivation without consumption. Homocysteine levels were in the normal range and stool examination for Shiga toxin was negative. ADAMTS-13 activity was 19%, which is considered mildly deficient but not in the range typical for thrombotic thrombocytopenic purpura (TTP), which is below 10%.

Genetic tests (MLPA and Sanger sequencing) revealed no pathogenic or likely pathogenic variants of complement factors (CFH, CFI, CD46, C3, CFB, THBD). Also, no variants of uncertain significance were found.

Initial management included supportive care with fluid balance monitoring, blood pressure control, and transfusion of 2 units of leukocyte-depleted packed red blood cells. Plasma exchange was not performed, and renal replacement therapy was not required. Anticoagulation with warfarin was maintained, and no immunosuppressive therapy was administered.

Considering the evidence of massive hemolysis, along with the exclusion of rheumatological, hematological, and cardiac causes, the patient was initially qualified for treatment with eculizumab at a dose of 900 mg IV for 1 week, followed by 8 subsequent 1200 mg doses. The treatment led to a rapid improvement in hemolysis and resolution of clinical symptoms.

Due to the history of complicated artificial mitral valve replacement and lack of another possible explanation for the patient’s serious clinical condition, a more thorough cardiac workup was performed. Repeated echocardiograms, including transesophageal, were suggestive of perivalvular leakage and confirmed severe dysfunction of the mitral valve prosthesis (suggestion of prosthetic dehiscence). Sepsis and infective endocarditis were considered as potential contributors to thrombotic microangiopathy but were excluded through negative blood cultures and lack of vegetations or valvular involvement on transesophageal echocardiography.

Due to multiple comorbidities, the patient was disqualified from urgent cardiac surgery and was referred to the invasive cardiology department where a 2-step intravascular mitral valve repair was performed. Combined with C5 inhibition, these procedures resulted in complete resolution of thrombotic microangiopathy. The resolution of hemolysis and thrombotic microangiopathy following complement inhibition before the cardiac procedure supported the diagnosis of aHUS rather than mechanical microangiopathic hemolytic anemia from valvular dysfunction. After 3 months of the therapy, eculizumab was discontinued, and the patient remained symptom-free. However, the patient died a month later because of an exacerbation of heart failure.

Discussion

This case report underscores the diagnostic complexity of thrombotic microangiopathy in patients with overlapping clinical factors, such as mechanical heart valve dysfunction and signs of complement activation.

The patient’s clinical and laboratory improvement following eculizumab therapy prior to surgical intervention strongly supports the diagnosis of an aHUS-type thrombotic microangiopathy, rather that hemolysis caused solely by prosthetic valve dysfunction. These findings emphasize the need for careful and thorough examination of patients with thrombotic microangiopathy, especially those with a complex medical history. Specifically, it highlights the diagnostic challenges in determining the thrombotic microangiopathy cause, especially in distinguishing whether the underlying mechanism is primarily mechanical, immune-mediated, or multifactorial.

Our patient was a 70-year-old woman who presented with severe hemolysis, thrombocytopenia, and schistocytes in blood smear, meeting the diagnostic criteria for thrombotic microangiopathy [12]. Further investigations ruled out TTP and typical HUS, as ADAMTS-13 activity did not reach the diagnostic threshold, and microbiological testing for STEC was negative. The exclusion of TTP and typical HUS, along with the presence of acute renal failure, led to the diagnosis of aHUS. Genetic testing did not reveal any pathogenic variants in genes of complement-regulatory proteins, indicating a secondary cause of aHUS. However, it is important to note that up to 30% of patients with aHUS who respond to complement inhibition therapy may not have a detectable mutation [13]. Therefore, the absence of such mutations may not exclude the genetic causes of aHUS. Moreover, the most common causes of secondary aHUS were excluded, such as malignancy, autoimmune and glomerular diseases, and infections [14]. It is important to note that apart from chronic warfarin therapy, the patient did not receive any other drugs that could induce thrombotic microangiopathy, such as immunosuppressants, chemotherapeutics, or VEGF inhibitors. Supportive treatment included fluid management, blood pressure control, and blood transfusions. This limitation of potential confounding factors supports the thesis that clinical improvement may had been primarily related to treatment with eculizumab. Increased levels of terminal sC5b-9 complex implied complement overactivation, suggesting an endothelial injury. However, increased sC5b-9 levels can occur in many cardiac conditions, and while suggestive, are not diagnostic for aHUS on their own [15]. Additionally, complement factors remained within normal ranges, which may appear atypical for classic aHUS presentation, in which the level of C3 is decreased and level of C4 is normal or elevated. Nevertheless, a normal level of C3 and C4 does not exclude the diagnosis of aHUS, as this pattern may occur in about 20% of cases responsive to anti-C5 drugs [13].

This case provides clinical evidence of a potential link between perivalvular leak and the development of thrombotic microangiopathy. However, these findings indicate an association rather than confirmed relationship. Thrombotic microangiopathy may have contributed to and exacerbated cardiac dysfunction. Previous studies suggest that cardiovascular diseases, such as hypertension, can lead to a form of thrombotic microangiopathy through complement activation [16,17]. A retrospective analysis by Khalil et al indicated that another variant of thrombotic microangiopathy, TTP, can lead to cardiac damage, most often due to microvascular clotting [18]. These findings underscore the complexity of the association between cardiac pathology and thrombotic microangiopathy.

The pathophysiology of aHUS triggered by artificial valve dehiscence remains unclear but may involve turbulence-induced microangiopathy. In our case report, the presence of perivalvular leakage probably led to mechanical hemolysis, then to an endothelial activation and local complement dysregulation, resulting in systemic thrombotic microangiopathy. Previous studies have shown that mechanical hemolysis is linked to a valvular regurgitation and perivalvular leakage; however, there are no data of aHUS cases in this setting [19–21]. The literature describes cases of thrombotic microangiopathy associated with other heart conditions, including heart transplantation, in which both the procedure itself and the effect of post-transplant drugs, such as calcineurin inhibitors, may contribute [22,23]. TTP can also occur as a complication after open heart surgery [24]. However, the mentioned cases associate thrombotic microangiopathy with the surgery, not with the cardiac pathology itself.

One of the few cases of aHUS associated with cardiac valve replacement was reported by Markakis et al, in which thrombotic microangiopathy was associated with aortic valve implantation [25]. However, in their case, aHUS appeared 10 days after surgery, while in our case, the patient had undergone artificial valve implantation surgery more than 25 years earlier. This time interval between the surgery and an onset of thrombotic microangiopathy in our patient’s case suggests that aHUS was not directly caused by the operation itself, but rather by the long-term effects of perivalvular leakage and chronic hemolysis. Importantly, the topography of the valve leak in our case may represent unique mechanical trauma that has not been previously associated with aHUS. Therefore, such atypical valve dysfunction may act as a chronic complement activating factor.

Considering the rapid resolution of aHUS symptoms after eculizumab admission, it can be concluded that inhibition of the complement system had a major role in this case. Nevertheless, it should be emphasized that our observations indicate a correlation rather than a clear causation between valve dysfunction and the development of aHUS. The improvement in hemolysis parameters after the initiation of eculizumab suggests the involvement of complement-dependent mechanisms; however, the patient’s multiple comorbidities warrant careful interpretation of the results.

The introduction of complement inhibitors, such as eculizumab or ravolizumab, has significantly improved the prognosis of patients with aHUS. These drugs have considerably reduced the mortality and morbidity of patients, both in primary and secondary causes of this disease [7,26,27]. However, the long-term prognosis remains uncertain, especially in patients with multiple comorbidities. The complement inhibitors may stop the progression of a secondary thrombotic microangiopathy, but they do not address the underlying cause that may impact patient health. Our case is an example of this problem. Despite successful resolution of thrombotic microangiopathy after C5 inhibition with eculizumab and valve repair, the patient died from an exacerbation of heart failure, which was not related to aHUS. Therefore, multidisciplinary care is essential in managing such complex cases [28].

Conclusions

This case emphasizes the need for comprehensive evaluation and a multidisciplinary approach in diagnosing and treating aHUS, especially in patients with multiple comorbidities and complicated medical history. The findings in our case support the diagnosis of complement-mediated aHUS, while suggesting that mitral valve dysfunction may have acted as a co-factor rather than a direct cause.