Resolution of Severe Thrombocytopenia and Candida parapsilosis Infective Endocarditis With Fourth Open-Heart Surgery

Abstract

Background

Surgical treatment for infective endocarditis (IE) with severe thrombocytopenia is considered high risk and is often avoided.

Case Summary

A 67-year-old man with a history of 3 open-heart surgeries presented with fever and severe thrombocytopenia accompanied by a bleeding tendency. Blood cultures and transthoracic echocardiography confirmed IE of the aortic bioprosthetic valve caused by Candida parapsilosis. Despite appropriate antifungal medical therapy, blood cultures remained persistently positive, severe thrombocytopenia persisted, and the vegetation continued to enlarge, resulting in medially refractory IE. Surgical intervention was deemed essential, and the patient underwent a fourth open-heart surgery. Shortly after the procedure, blood cultures turned negative, and platelet counts improved dramatically. The patient was discharged home.

Discussion

Severe thrombocytopenia in this case was likely caused by the fungal infection and vegetation formation.

Take-Home Message

Surgical treatment for medically refractory fungal IE can aid in infection control and result in significant improvement in platelet count.

Graphical Abstract

History of Presentation

A 67-year-old Japanese man was admitted to our hospital with a few days of fever and severe thrombocytopenia, accompanied by a bleeding tendency, including brownish urine and occasional epistaxis. At the visit 2 weeks before his admission, the patient complained of occasional epistaxis, and a blood test showed a decrease in platelet count slightly below the reference range (Figure 1). His body temperature on admission was elevated at 37.8 °C, with an oxygen saturation of 98% on room air. His heart rate was 93 beats/min, and blood pressure was 92/79 mm Hg. Physical examination revealed a Levine grade 3 of 6 systolic murmur and purpura on the lower legs. No significant lymphadenopathy was observed.

Figure 1.

Clinical Course of the Patient

Despite medical treatment, the platelet count (orange line) remained low, and the vegetation increased in size. However, shortly after surgery, the platelet count showed a dramatic recovery. ¶The point in time 2 months before the admission. F-FLCZ = fosfluconazole; L-AMB = liposomal amphotericin B; MCFG = micafungin; PC = platelet concentrate; Plt = platelet counts; SBT/CPZ = sulbactam/cefoperazone.

Past Medical History

He had previously undergone 3 open-heart surgeries because of mitral valve prolapse and bicuspid aortic valve: the first at 48 years of age, involving mitral valve repair; the second at 54 years of age, which included bioprosthetic replacement of the aortic and mitral valves, ascending aortic replacement, and tricuspid valve repair; and the third surgery, performed 8 months before his admission, comprising mitral valve mechanical replacement, left atrial size reduction, and pacemaker implantation for postoperative atrioventricular block.

Differential Diagnosis

The initial differential diagnosis included blood disorders such as idiopathic thrombocytopenic purpura and lymphoma, disseminated intravascular coagulation, pseudothrombocytopenia because of platelet aggregation, and infection-associated thrombocytopenia.

Investigations

The platelet count on blood test on admission was 14,000/μL. His other blood test results on admission are shown in Table 1. The electrocardiogram showed atrial fibrillation and incomplete right bundle branch block, whereas chest radiograph showed a cardiothoracic ratio of 50% with no signs of pulmonary congestion or pleural effusion. Computed tomography did not reveal a clear source of fever; however, mild hepatomegaly and marked splenomegaly were observed.

Table 1.

Blood Examination Results

Test	Result	Units
Complete blood count
White blood cells	5300	/μL
Red blood cells	300	104/μL
Hemoglobin	9.3	g/dL
Hematocrit	27.3	%
Platelets	14,000	/μL
Biochemistry
Total protein	6.9	g/dL
Albumin	2.9	g/dL
Total bilirubin	1.5	mg/dL
Aspartate aminotransferase	93	U/L
Alanine aminotransferase	72	U/L
Lactate dehydrogenase	597	U/L
Alkaline phosphatase	755	U/L
γ-glutamyl transpeptidase	294	U/L
Blood urea nitrogen	20	mg/dL
Creatinine	0.93	mg/dL
Creatine phosphokinase	24	U/L
Sodium	131	mmol/L
Potassium	4.2	mmol/L
Chloride	98	mmol/L
C-reactive protein	5.27	mg/dL
Interleukin-2 receptor∗	3380	U/mL
Coagulation
Activated partial thromboplastin time	74	Seconds
Prothrombin time	42.4	Seconds
Prothrombin time-INR†	3.82
Fibrinogen	353	mg/dL
Fibrinogen/fibrin degradation products‡	4.8	μg/mL
D-dimer	2.60	μg/mL

INR = international normalized ratio.

^∗Reference range: 122,496.

^†Under oral administration of warfarin at a dose of 4.25 mg/d.

^‡Reference range: <5.0.

Management

On admission, for thrombocytopenia, the patient initially received a platelet transfusion. Based on blood test and computed tomography findings, hematologic disorders such as idiopathic thrombocytopenic purpura (ITP) or intravascular lymphoma were suspected. Consequently, oral prednisolone (60 mg/d) was initiated after a bone marrow biopsy performed on day 2. Additionally, considering the possibility of a biliary tract infection, antibiotic treatment with sulbactam/cefoperazone (1 g every 12 hours) was started.

On the third day of hospitalization, Candida parapsilosis was identified in the blood cultures obtained on admission. Additional blood tests revealed β-D glucan levels >600 pg/mL. Consequently, treatment for candidemia was initiated with micafungin (300 mg every 24 hours). On the fourth day, transthoracic echocardiography revealed a large (15 × 13 mm) mobile vegetation on the aortic bioprosthetic valve (Figure 2A), leading to a diagnosis of infective endocarditis (IE) of the aortic bioprosthetic valve caused by C parapsilosis. Given the patient's extremely low platelet count and history of 3 prior open-heart surgeries, surgical treatment for IE was deemed too high risk, with a EuroSCORE II score of 10.85%, and was avoided in favor of medication therapy.

Figure 2.

Transthoracic Echocardiogram From an Apical 5-Chamber View

The images show vegetation (red circle) on the aortic bioprosthetic valve on day 4 (A) and day 44 (B). The vegetation increased in size from 15 × 13 mm to 27 × 17 mm despite the administration of appropriate antimicrobial therapy. Ao = aorta; LA = left atrium; LV = left ventricle; RV = right ventricle.

Bone marrow examination revealed no evidence of lymphoproliferative disorders, such as blast proliferation or atypical lymphocytes, effectively ruling out lymphoma. Furthermore, there were no findings suggestive of ITP, such as increased megakaryocytes and abnormal morphology. Combined with the lack of improvement in platelet count after the initiation of prednisolone therapy, ITP was also excluded. Considering the risk of infection exacerbation, the prednisolone dosage was tapered off.

On the tenth day, based on antifungal susceptibility results, antifungal treatment was switched to fosfluconazole (400 mg every 24 hours). Because of the persistence of positive blood cultures, liposomal amphotericin B was added to the treatment regimen on the 29th day. However, despite these adjustments, multiple blood cultures remained positive (Figure 1), and the vegetation on the aortic bioprosthetic valve continued to enlarge (Figures 1 and 2B). Furthermore, there was still a minimal improvement in the platelet count (Figure 1). Surgical intervention was deemed essential for infection control. Thus, on the 46th day, the patient underwent aortic valve replacement, ascending aorta replacement, and removal of the pacemaker leads. A large vegetation measuring up to 30 mm in diameter was observed on the aortic bioprosthetic valve (Figure 3).

Figure 3.

Intraoperative Image

When the artificial blood vessel (black arrows) was incised, the aortic bioprosthetic valve was found to be almost completely covered by very large vegetation (white arrow).

Outcomes and Follow-Up

Shortly after the surgery, a rapid improvement in platelet count was observed, and blood cultures became negative (Figure 1). Subsequently, the patient underwent removal of the pacemaker generator and underwent a pericardial pacemaker implantation. After cardiac rehabilitation, he was discharged home on the 88th day, able to ambulate independently.

Discussion

Despite improvements in diagnosis and treatments, IE is still a highly fatal infectious disease, with its incidence and mortality rates increasing over the past few decades.¹ Thus, IE presents a clinical challenge that needs to be addressed now more than ever. Fungal IE is often refractory, and the decision for early surgery is in line with current guidelines.² However, in some cases of fungal IE, severe thrombocytopenia may be observed, which can be a reason for hesitation in surgical management.

A previous case report of IE caused by C parapsilosis with severe thrombocytopenia demonstrated that medical therapy improved platelet count, leading to a diagnosis of the thrombocytopenia attributed to ITP.³ However, unlike the previous report, medical therapy in our case did not result in an improvement in the platelet count. Furthermore, the bone marrow examination revealed no specific findings. Although blood disorders including ITP or lymphoma were initially suspected because of the rapid decrease in platelet count, such diseases were ultimately ruled out. Consequently, we considered that severe thrombocytopenia in this case was likely caused by the fungal infection itself and the subsequent increase in vegetation formation. It has been established that platelets play a role in endocardial vegetation formation through platelet-bacterial interactions via ligand-receptor pairs.⁴ Although much research in this field has focused on Staphylococcus species, it is possible that the causative agent in this case, C parapsilosis, may also contribute to thrombocytopenia associated with vegetation formation. The improvement in platelet counts shortly after surgery supports the theory that severe thrombocytopenia was caused by the fungal infection itself and the increase in vegetation formation.

Biofilm-forming Candida species are more resistant to antimicrobial agents, and C parapsilosis produced a higher volume of biofilms than the other Candida species.⁵ This increased biofilm production may be a possible reason for the failure to control the infection with medical treatment, leading to persistent positive blood cultures, severe thrombocytopenia, and increased vegetation.

A study found that among 533 patients diagnosed with IE, 175 (33%) had concurrent thrombocytopenia,⁶ suggesting that thrombocytopenia is frequently observed in patients with IE. Furthermore, thrombocytopenia has the potential to serve as a prognostic marker in patients with IE.⁷ These findings underscore the importance of recognizing thrombocytopenia in the diagnosis and management of IE. However, thrombocytopenia is not included in the Duke criterion, which may be considered a limitation of the current diagnostic framework. The absence of thrombocytopenia in the criteria could lead to a risk of overlooking cases of IE. Some case reports including our case of bleeding and thrombocytopenia because of IE may support the risk of diagnostic oversight.^3,8

Several features in patients with IE, such as vegetation >10 mm, progressive vegetation enlargement, embolic events during antibiotic therapy, severe valve insufficiency, and decompensated heart failure, are associated with a high risk of a complicated clinical course. IE patients exhibiting these features therefore may require surgical intervention.² This case demonstrated characteristics related to the size and its progressive enlargement. Furthermore, current guidelines strongly recommend early surgical intervention after diagnosis for fungal IE, particularly in cases of prosthetic valve endocarditis.^2,9 In this case, considering EuroSCORE II, the fact that it was a fourth redo procedure, and the presence of severe thrombocytopenia, surgical intervention itself was deemed extremely high risk, leading to the decision to proceed with antibiotic therapy. However, antibiotic treatment did not result in improvement. Fortunately, no severe adverse events occurred during medical therapy, but the possibility remains that the patient could have experienced a critical event such as intracranial hemorrhage, potentially leading to a fatal outcome. Therefore, in cases of prosthetic fungal IE, particularly when infection control cannot be achieved through medical therapy, early surgical intervention may be warranted despite the high operative risk.

This case highlights the necessity of surgical intervention in the treatment of fungal IE on a prosthetic valve with severe thrombocytopenia that does not respond to medical treatment alone. Although surgical treatment can be challenging in cases with severe thrombocytopenia, the improvement in infection control and the dramatic increase in platelet count observed immediately after surgery in our case provide strong support for the rationale for early surgical treatment in such situations.

Conclusions

In cases of medically refractory fungal IE on a prosthetic valve accompanied by severe thrombocytopenia, surgical treatment can contribute not only to effective infection control but also to a substantial improvement in platelet count. Early surgical intervention may be essential for patients with fungal IE, particularly those with prosthetic valve endocarditis, even in high-risk patients with conditions such as severe thrombocytopenia or a history of multiple open-heart surgeries.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Take-Home Messages

• •IE can cause severe thrombocytopenia, which may become a factor preventing surgical intervention for IE itself.
• •Surgical treatment for medially refractory IE with severe thrombocytopenia can aid in infection control and lead to a significant improvement in platelet count.