A 44-Year-Old Woman With Worsening Fatigue and Shortness of Breath With Exertion

Correct answer: C. Obtain a transesophageal echocardiogram

Discussion. The presented patient manifests a set of important findings in her history, examinations, and laboratory tests, which enable a rather quick and efficient focusing into a tight differential diagnosis. There is a background history of rheumatic fever with resultant valvular disease. Of note, a systolic murmur is heard on examination and new symptoms, relatively acute and consistent with congestive heart failure (CHF) are present, as well as the reasons why she seeks medical care. Thus, one question we need to answer: is there some event causing this new murmur and CHF, such as endocarditis or valvular dysfunction?

The other very salient finding is a recent significant anemia, which is normocytic and accompanied by findings (increased reticulocytes and elevated LDH and bilirubin) strongly suggestive of hemolysis. Can we use these three diagnoses (new onset CHF, patient history, and findings of valvular heart disease) and the presence of a new, apparently hemolytic anemia with fragmented RBC forms on smear to seek a unifying single diagnosis that includes all three?

The answer is yes, and that entity is cardiac valvular disease-related hemolysis, which is the diagnosis for this patient. Cardiac valvular hemolysis was more frequently seen in the earlier days of valve replacement surgeries, when the coarse prosthetics used included the plastic ball-in-cage aortic and metal mechanical tilting disc mitral valves. These devices caused significant turbulence in flow and were prone over time to accrue fibrous deposits, creating abnormal jets, secondary stenoses, and regurgitant flows with resultant significant cardiac dysfunction and mechanical RBC destruction with hemolytic anemia. A badly enough damaged native valve with calcification and fibrosis as seen with rheumatic fever-related valvular disease can do the same.

Due to improved engineering, technology, and surgical techniques, there has been a significant decrease in incidence of these complications (the rate of a clinically significant hemolysis was 15% in the 1970s, but is down to less than 1% currently).¹ Interestingly, however, with the current advent of the transvalvular techniques for both aortic and mitral valve diseases, there has been a rebound in the incidence of valvular leak, cardiac valvular hemolytic anemia, and leak-related CHF, with current estimates of subclinical hemolysis of about 15% and more severe hemolysis of 3% being reported.¹

Generally, there are two presentations for valvular hemolysis, which may also be coincident in the same patient. A patient with valvular heart disease may experience new or increased CHF symptoms from their steady state due to the valve leak and dysfunction, compromising their cardiac function as the prominent presenting symptom complex. As the evaluation proceeds, the presence of a hemolytic anemia of varying severity is found, which leads to valvular leaks causing very abnormal flow characteristics.

The converse presentation will be the symptoms of anemia (weakness and easy fatigue) and findings of a significant hemolytic anemia that when evaluated reveals the classical findings of enhanced RBC destruction (absent or depressed haptoglobin, elevated LDH, elevated bilirubin, and reticulocytosis).² Appropriate workup to exclude auto-immune causes and smear examination demonstrating fragmented RBC, the actual result of the turbulence causation of the destruction, then leads to more detailed diagnostic investigation of the heart and confirms the diagnosis.

Remember that both processes are occurring in the substrate of a patient with known prior cardiac valvular disease. Examined from the other direction, patients with history of significant valvular heart disease, especially with surgical valve replacement/repair presenting with new or increased CHF and/or new anemia are serious candidates for valvular leak and should be quickly evaluated for its presence.

The keystone in diagnosis and evaluation in valvular hemolysis cases is TEE, which offers the best reverberation or shadowing-free view of the mitral valve. Current technology allows both two-dimensional and three-dimensional views, which confirm (1) whether there is a presence of paravalvular leaks; (2) the magnitude of any such leaks; and (3) whether there are any calcifications and its extent in the mitral valve annulus and valvular apparatus.³

Detailed hematologic evaluation of hemolysis and its extent includes hemoglobin and reticulocyte counts, haptoglobin, LDH and bilirubin which confirm hemolysis and smear where fragmented RBC clarify the cause.² Such was the case in our patient.

Returning to imaging, current TEE techniques can render detailed dynamic views of the valve region such as number, location, and size of valve jets, which are important as regards intervention or no and specifics of the intervention.³

Therapy and management strategies have two basic initiatives. There are medical maneuvers to try to ameliorate, or at least keep up with, the hemolysis occurring in the diseased valve area. This involves stimulating marrow production of RBC and keeping the marrow "fed" with supplemental hematinic. The former involves the use of erythropoietin, while the latter is supplementation of iron and folic acid. Attempts to decrease shear force destruction, likely damaging the RBC, involves the use of beta blockers, which lessens shear forces and pentoxyphylline, ultimately improving RBC deformability.1 In my experience, I have used these management strategies successfully to treat patients with mild symptoms. However, experience and literature have demonstrated that medical managements are not adequate in most cases. Indeed, interventional management is often required. The indications to proceed with a procedural intervention are (1) symptomatic, severe hemolytic anemia; (2) onset or worsening of CHF, and (3) demonstration of severe hemodynamic pathology such as paravalvular regurgitations, which will eventually tax the heart beyond its capability to sustain with eventual heart failure. Often, components of all three of these pathophysiologies will be present in the same patient.^1,3,4

Generally, the surgical intervention includes: (1) closure by patch and/or vascular plug often performed intravascularly; (2) valvular repairs either open or transvascularly, and (3) removal and replacement of the diseased valve and valve apparatus.4 Such interventions are associated with increased survival,5 with success rates for closure between 73-84%.^3,5

Patient follow-up. A complete hematologic evaluation confirmed the presence of significant hemolytic anemia. Direct anti-globulin tests were negative, and RBC fragments were continually seen on smear, essentially confirming an acquired microangiopathic causation. Simultaneous cardiac evaluation using TEE followed by cardiac catheterization demonstrated minimal coronary artery disease, normal systolic left ventricle function with ejection fraction of 60%, severely dilated left atrium, mild mitral stenosis, and severe pulmonary hypertension with pulmonary artery pressures above 60. There was moderate calcification of the posterior leaflet of the mitral valve, with severely restricted motion of the posterior leaflet and severe regurgitation transvalvular with an eccentrically directed jet lesion. There was co-existing mild to moderate mitral stenosis as well.

Considering the several indications including (1) new and increased CHF, (2) the abnormal hemodynamics with severe mitral regurgitation and co-existing mitral stenosis with associated pulmonary hypertension, (3) the presence of a significant paravalvular leak, and (4) new and symptomatic cardiac hemolysis secondary to paravalvular leak, the patient underwent open mitral valve replacement with a tissue valve.

The patient tolerated the procedure well, with intra-operative and post-operative TEE confirming absence of mitral valve regurgitation and paravalvular leak. She is home with no symptoms of CHF, complete blood count within normal range, and hemolysis parameters at 8 weeks post-operation.

What’s the take home? Paravalvular leak is a complication encountered in patients with severely damaged native valves or those who have experienced procedures to address valvular heart disease including open surgeries for aortic/mitral valve replacements and repairs. Increased usage of these techniques is making this syndrome more common. These para-valvular leaks result in abnormal cardiac hemodynamics, usually involving regurgitation of the valves, which stresses cardiac function eventually causing pulmonary hypertension and CHF. An additional resultant is the formation of jet lesions causing intense shear stresses on the erythrocytes caught flowing in them with fragmentation hemolysis of these RBC. Thus, the two major pathophysiologies seen are CHF and hemolytic anemia.

Reviewing the case study and the options offered, Answer A suggests a recurrence of rheumatic fever, but there is no evidence for this such as pharyngitis, fever, or other systemic inflammatory findings. Answer B is therapy for another form of acquired hemolytic anemia, namely auto-immune hemolytic anemia. The anti-globulin test (DAT) is negative, and smear shows fragmented RBC rather than the round spherocytes typical of auto-immune disease. Steroids are not effective in fragmentation forms of hemolysis. Answer D, aggressive CHF therapy for 3 months, is the treatment of choice for secondary mitral regurgitation associated with left ventricular failure usually caused by ischemia/coronary artery disease. The presented patient has history of rheumatic fever, which damages and scars the mitral valve such that early evaluation of that area with trans-esophageal echocardiogram (TEE) is optimal here.

A patient presenting with a background history of serious valve disease or repair/replacement, new/worsening CHF, and/or new hemolytic anemia, valvular leak becomes a primary diagnostic consideration. The key diagnostic is TEE, which offers the best views of the valves without interfering echoes that can obfuscate findings on transthoracic echocardiography.

Once diagnosed, the key decision is whether to pursue surgical intervention. There exist temporizing medical supportive regimens, but most patients will require some type of procedural intervention such as transdermal patch repairs, valvular repair, and de-novo valve replacement depending upon anatomic, pathologic, and hemodynamic findings. Importantly, the prognosis for resolution and long-term survivorship is good following these procedures.

AUTHOR
Ronald N. Rubin MD^1,2

AFFILIATIONS
¹Lewis Katz School of Medicine at Temple University, Philadelphia, PA
²Department of Medicine, Temple University Hospital, Philadelphia, PA

CITATION
Rubin RN. A 44-Year-Old Woman With Worsening Fatigue and Shortness of Breath With Exertion. Consultant. 2024;65(1):doi: 10.25270/con.2025.01.000001

DISCLOSURES
The author reports no relevant financial relationships.

CORRESPONDENCE:
Ronald N. Rubin, MD, Temple University Hospital, 3401 N. Broad Street, Philadelphia, PA 19140 (blooddocrnr@yahoo.com)

References

1. Alkhouki M, Farooq A, Gio RS, Balla S. Cardiac prostheses related hemolytic anemia. Clin Cardiol. 2019;42:693-700.
2. Phillips J, Henderson AC. Hemolytic anemias: evaluation and differential diagnosis. Am Fam Physician. 201;98:354-361
3. Malhotra R, Namasivayam M, Ghoshhajra BB, Passeri JJ, Hoenig PA, Stone JR. Case 36-2020: A 72-Year-Old Woman with Dark Urine and Weakness. N Engl J Med. 2020;383(21):2066-2076. doi:10.1056/NEJMcpc2027077
4. Elaid M. Interventional management of paravalvular leak. Heart. 2018;104:1797-1802
5. Millán X, Skaf S, Joseph L, et al. Transcatheter reduction of paravalvular leaks: a systematic review and meta-analysis. Can J Cardiol. 2015;31(3):260-269. doi:10.1016/j.cjca.2014.12.012