Case 8-2023: A 71-Year-Old Woman with Refractory Hemolytic Anemia

PRESENTATION OF CASE

Dr. Florence H. Porterfield (Medicine): A 71-year-old woman was admitted to this hospital because of refractory hemolytic anemia.

The patient, who had recurrent breast cancer and diffuse cutaneous systemic sclerosis, had been in her usual state of health until 7 months before the current admission, when fatigue and dyspnea on exertion developed. She was reportedly evaluated by a cardiologist and a pulmonologist, but no cause for her symptoms was identified.

Two months before the current admission, dyspnea on exertion worsened, palpitations and dizziness developed, and the patient presented to another hospital for evaluation. Laboratory studies revealed anemia, a low blood level of haptoglobin, and an elevated blood level of lactate dehydrogenase. The blood levels of electrolytes were normal, as were the results of kidney-function tests; other laboratory test results are shown in Table 1. A peripheral-blood smear showed schistocytes. A direct antiglobulin test was negative, complement levels were reportedly low, and a low titer of cold agglutinins was present. Testing for antibodies against β₂-glycoprotein I and cardiolipin was negative, as was a screening test for lupus anticoagulant. Nucleic acid amplification testing for SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) and other common respiratory viruses was negative. Flow cytometry of the peripheral blood revealed no aberrant clonal population of cells and no evidence of paroxysmal nocturnal hemoglobinuria.

Table 1.

Laboratory Data.^*

Variable	Reference Range, Adults, Other Hospital	7 Wk before Admission, Other Hospital	Reference Range, Adults, This Hospital†	On Admission, This Hospital
Hematocrit (%)	33.0–44.0	20.8	36.0–46.0	14.8
Hemoglobin (g/dl)	12.0–16.0	7.0	12.0–16.0	5.3
White-cell count (per μl)	4100–9300	11,200	4500–11,000	13,340
Differential count (%)
Neutrophils	38–50	52	40.0–70.0	82.1
Lymphocytes	28–42	12	22.0–44.0	13.4
Monocytes	4.0–8.5	5.0	4–11	1.8
Eosinophils	0–5	0	0–8	0.9
Platelet count (per μl)	130,000–350,000	230,000	150,000–400,000	43,000
Mean corpuscular volume (fl)	82.3–93.2	106.7	80.0–100.0	101.4
Mean corpuscular hemoglobin (pg)	22.2–33.2	35.5	26.0–34.0	36.3
Mean corpuscular hemoglobin concentration (g/dl)	32.5–35.1	33.7	31.0–37.0	35.8
Red-cell distribution width (%)	12.0–15.0	22.0	11.5–14.5	34.8
Reticulocyte count (%)	0.4–2.0	13.4	0.7–2.5	15.8
Prothrombin time (sec)	9.4–12.3	11.9	11.5–14.5	16.8
Prothrombin-time international normalized ratio	0.9–1.1	1.0	0.9–1.1	1.4
Activated partial-thromboplastin time (sec)	23.6–32.9	24.6	22.0–36.0	25.2
Fibrinogen (mg/dl)	172–400	330	150–400	374
d-dimer (ng/ml)	<500	5021	<500	9321
Haptoglobin (mg/dl)	25–234	<15	30–200	<10
Lactate dehydrogenase (U/liter)	80–225	675	110–210	5896
Ferritin (μg/liter)	—	—	10–200	18,050
Total bilirubin (mg/dl)	0.1–1.2	2.8	0.0–1.0	4.1
Direct bilirubin (mg/dl)	0.0–0.3	0.5	0.0–0.4	0.4
Albumin (g/dl)	3.5–5.2	4.4	3.3–5.0	3.8
Alanine aminotransferase (U/liter)	6–60	36	7–33	58
Aspartate aminotransferase (U/liter)	5–45	68	9–32	135
Alkaline phosphatase (U/liter)	30–115	39	30–100	77

^*To convert the values for bilirubin to micromoles per liter, multiply by 17.1.

^†Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions that could affect the results. They may therefore not be appropriate for all patients.

Computed tomography (CT) of the chest, abdomen, and pelvis, performed after the administration of intravenous contrast material, showed bilateral mediastinal and hilar lymphadenopathy that was unchanged from that observed on imaging performed 2 years earlier. Packed red cells were transfused, and the patient was admitted to the other hospital. Treatment with glucocorticoids was initiated for a working diagnosis of Coombs’-negative autoimmune hemolytic anemia.

On the third hospital day, anemia persisted, and additional units of packed red cells were transfused. The blood pressure had increased from 118/62 mm Hg on admission to 150/60 mm Hg. Treatment with glucocorticoids was stopped, and treatment with captopril was initiated for a working diagnosis of scleroderma renal crisis. Blood testing for the level of ADAMTS13 activity was performed, and on the sixth hospital day, treatment with plasmapheresis was started for the possible diagnosis of thrombotic thrombocytopenic purpura (TTP). The patient underwent a total of six sessions of plasmapheresis during the first 2 weeks of the hospitalization.

During the second week of the hospitalization, treatment with eculizumab was initiated. The patient received packed red-cell transfusions every 2 or 3 days for ongoing hemolytic anemia. The results of the blood test for activity of ADAMTS13 returned; the activity level was 65% (reference value, >67%), and treatment with plasmapheresis was stopped.

During the third week of the hospitalization, treatment with eculizumab was continued, and treatment with rituximab was initiated; however, the patient still received packed red-cell transfusions every 2 or 3 days. During the fourth week of the hospitalization, weekly treatment with both eculizumab and rituximab was continued, and a 3-day course of intravenous immune globulin was administered. Despite this treatment, there was no reduction in hemolysis.

During the fifth week of the hospitalization, the patient continued to receive packed red-cell transfusions every 2 or 3 days, and thrombocytopenia developed. Treatment with glucocorticoids was resumed, and treatment with twice-weekly injections of epoetin alfa was initiated. A biopsy specimen of the bone marrow reportedly showed hypercellular marrow with maturing trilineage hematopoiesis and erythroid predominance.

During the sixth week of the hospitalization, the need for red-cell transfusion persisted, treatment with cyclophosphamide was initiated, and the dose of captopril was increased. During the seventh week of the hospitalization, acute kidney injury (AKI) developed, and treatment with captopril and glucocorticoids was stopped. On the 50th hospital day, the patient was transferred to this hospital for further evaluation.

On evaluation at this hospital, the patient reported nausea, poor appetite, and weight loss of 9 kg during the past 2 months. She also reported that her urine had appeared pink or cola-colored after each transfusion of packed red cells.

Twenty-one years earlier, localized clinical stage T1cpN1aM0 (according to the tumor–node–metastasis classification system), estrogen receptor (ER)–positive, human epidermal growth factor receptor 2–negative invasive lobular breast cancer of the left breast was diagnosed. She had been treated initially with lumpectomy, radiation, and adjuvant chemotherapy, as well as with tamoxifen for 5 years and letrozole for 2 years. Three years before the current admission, there was a locoregional recurrence of ER-positive breast cancer in her left axilla; a lymph-node biopsy was negative. Staging studies reportedly revealed mildly prominent mediastinal and hilar lymph nodes and several indeterminate hepatic and renal lesions. Biopsy of the mediastinal and hilar lymph nodes was reportedly negative. The patient declined recommended chemotherapeutic treatment options for recurrent breast cancer and instead opted for surveillance imaging. Findings on magnetic resonance imaging, ultrasonography, and mammography of the breasts, which had been performed 6 months before the current admission, were reportedly unchanged from previous imaging. She had not palpated any new breast lumps on self-examination.

Three years before the current admission, systemic sclerosis associated with antibodies against RNA polymerase III was diagnosed. Sclerosis was limited to the skin, and the patient had not received any specific treatment. Other medical history included Sjögren’s syndrome, gastroesophageal reflux disease, latent tuberculosis that had been diagnosed 30 years earlier and treated with isoniazid for 9 months, dyslipidemia, and osteoporosis. Medications included exemestane, goserelin, calcium, cholecalciferol, pantoprazole, and rosuvastatin. The patient took no over-the-counter remedies or supplements. She was allergic to trimethoprim–sulfamethoxazole, which had caused fever and hives. She drank alcohol rarely and did not use any other substances. She had smoked tobacco for 3 years but had quit 50 years before the current admission. The patient was married and lived with her husband in New England. She was retired from work in health care. Three of her sisters had had breast cancer in their seventh decades of life; there was no family history of hemolysis.

On examination, the temperature was 36.3°C, the blood pressure 162/98 mm Hg, the pulse 105 beats per minute, the respiratory rate 22 breaths per minute, and the oxygen saturation 99% while the patient was breathing ambient air. The body-mass index (the weight in kilograms divided by the square of the height in meters) was 17. The patient was alert and oriented. There was jaundice and scleral icterus. She had a well-healed lumpectomy scar on the upper outer quadrant of the left breast. There was no cervical, supraclavicular, or axillary lymphadenopathy. Mild skin thickening was present on the hands and feet, with subtly reduced skin mobility of the forearms and legs. The remainder of the examination was normal.

The blood level of creatinine was 2.87 mg per deciliter (254 μmol per liter; reference range, 0.60 to 1.50 mg per deciliter [53 to 133 μmol per liter]), and the blood urea nitrogen level was 62 mg per deciliter (22 mmol per liter; reference range, 8 to 25 mg per deciliter [3 to 9 mmol per liter]). Other laboratory test results are shown in Table 1. Urinalysis revealed 3+ blood and 2+ protein, without bilirubin, urobilinogen, glucose, ketones, leukocyte esterase, or nitrates; the specific gravity and pH were normal. Microscopic examination of the urinary sediment revealed 10 to 20 red cells per high-power field (reference range, 0 to 2) and 3 to 5 white cells per high-power field (reference value, <10), and there were muddy-brown casts without dysmorphic red cells. The total protein:creatinine ratio in a spot urine sample was 6.41 (reference value, <0.15). A peripheral-blood smear was obtained.

Dr. Robert Ta: The peripheral-blood smear (Fig. 1) showed anisopoikilocytosis, 10 to 15 schistocytes per high-power field, teardrop cells, nucleated red cells, reticulocytes, and mature and left-shifted myeloid cells.

Figure 1. Peripheral-Blood Specimens on Admission to This Hospital.

Wright–Giemsa staining shows anisopoikilocytosis and schistocytes (Panel A, arrows); in other areas, teardrop cells are present (Panel B, arrows). Immature myeloid precursors (Panel C, arrow) and nucleated red cells (Panel C, arrowheads) can also be seen.

Dr. Porterfield: Additional imaging studies were obtained, and a diagnostic test was performed.

DIFFERENTIAL DIAGNOSIS

Dr. Alfred I. Lee: This 71-year-old woman with breast cancer and systemic sclerosis had several months of progressive fatigue and dyspnea and was found to have microangiopathic hemolytic anemia (MAHA). MAHA is a subtype of intravascular hemolysis that is characterized by red-cell fragmentation due to direct trauma; the identification of two or more schistocytes on multiple blood-smear fields at high magnification suggests a diagnosis of MAHA.

Thrombotic microangiopathy (TMA) is characterized by MAHA and thrombocytopenia, whereby endothelial activation and thrombosis lead to microvascular occlusion, shearing of red cells, and platelet consumption, although a small percentage of patients with TMA may have a normal platelet count on initial presentation.¹ This patient initially had hemolytic anemia, and schistocytes were observed on a peripheral-blood smear; then, during the fifth week of hospitalization at the other hospital, thrombocytopenia developed. Taken together, these features are consistent with a diagnosis of TMA. Numerous conditions can give rise to TMA through one of three principal mechanisms: primary or secondary hemostatic derangements or endothelial injury. Determining the underlying cause of TMA is critical so that appropriate treatment can be initiated.

THROMBOTIC THROMBOCYTOPENIC PURPURA

TTP is a life-threatening disease arising from primary hemostatic abnormalities. Under physiologic conditions, von Willebrand factor (VWF) mediates platelet binding to subendothelial collagen at sites of vascular injury; during this process, activated endothelial cells release VWF in multimerized forms that are then cleaved by the ADAMTS13 metalloproteinase. In patients with TTP, a deficiency or functional impairment in ADAMTS13 leads to the accumulation of ultra-large VWF multimers, which results in the formation of microvascular platelet–VWF plugs that cause shearing of red cells. Under normal conditions, ADAMTS13 activity levels are usually above 50%; ADAMTS13 activity levels below 10% are diagnostic of TTP, whereas levels exceeding 20% indicate that this diagnosis is unlikely.²

At many hospitals, the wait time for the results of testing for ADAMTS13 activity levels can be days or weeks. The PLASMIC score is a useful gauge of pretest probability of TTP that incorporates seven readily available clinical and laboratory variables (platelet count, levels of hemolytic markers, active cancer, previous solid-organ or stem-cell transplantation, mean corpuscular volume, international normalized ratio, and creatinine level).³ Because of the high morbidity and mortality associated with delays in the treatment of TTP, patients with TMA and a high PLASMIC score are often treated empirically for TTP until the results of ADAMTS13 testing become available,² as was the case with this patient. The mainstay of therapy for TTP is plasmapheresis, which replenishes ADAMTS13 and removes possible autoantibodies against ADAMTS13, with adjunctive use of glucocorticoid therapy, rituximab (an anti-CD20 monoclonal antibody), and caplacizumab (an anti-VWF bivalent nanobody).⁴ In this patient, the ADAMTS13 activity level of more than 20% and the lack of response to plasmapheresis and rituximab make the diagnosis of TTP unlikely.

HEMOLYTIC–UREMIC SYNDROME

Hemolytic–uremic syndrome (HUS) is a heterogeneous group of TMAs that arise from endothelial injury and predominantly affect the renal glomeruli.⁵ Classic HUS is characterized by bloody diarrhea that occurs after consumption of undercooked meats contaminated with Shiga toxin–producing bacteria, which cause direct endothelial injury.

Atypical HUS is a complement-mediated disorder, in which germline mutations in — or autoantibodies against — alternative-pathway complement-regulating factors lead to uncontrolled formation of the membrane-attack complex and consequent renal glomerular damage. In patients with atypical HUS, the presentation varies and often resembles TTP. Although a peripheral-blood smear will show abundant schistocytes in both conditions, renal impairment is a predominant clinical feature of atypical HUS, whereas neurologic impairment is more common with TTP. With atypical HUS, germline complement mutations or autoantibodies to alternative-pathway complement-regulating factors are found in 50 to 70% of cases, and a low C3 level with a normal C4 level occurs in half of cases — factors that together indicate activation of the alternative complement cascade. Complement inhibition with the use of eculizumab or ravulizumab is an effective therapy for atypical HUS. In this patient, the lack of response to eculizumab makes a diagnosis of atypical HUS unlikely.

DISSEMINATED INTRAVASCULAR COAGULATION

Disseminated intravascular coagulation (DIC) is a form of MAHA that arises from abnormal activation of the coagulation cascade, which leads to microvascular thrombosis, with the consumption of endogenous anticoagulants, excessive generation of fibrin, and the development of fibrinolytic derangements.⁶ A scoring system established by the International Society on Thrombosis and Haemostasis incorporates four laboratory test results (d-dimer level, fibrinogen level, prothrombin time, and platelet count) to determine the pretest probability of overt DIC.⁷ The most common causes of DIC are infection, cancer, trauma, or complications from pregnancy. The evaluation for DIC must therefore include a search for the underlying trigger in order to treat DIC effectively. In this patient, the marked elevation in the d-dimer level, the presence of thrombocytopenia, and the prolonged prothrombin time are all consistent with a diagnosis of DIC, although an underlying trigger was not readily apparent.

MALIGNANT HYPERTENSION

Malignant hypertension is characterized by severe hypertension with end-organ damage, which can lead to microvascular thrombosis and TMA as a result of severe sclerosis and fibrinoid necrosis of the renal vasculature.⁸ The mainstay of treatment is antihypertensive therapy. In this patient, hypertension developed only after the onset of MAHA, a pattern that is not consistent with a diagnosis of malignant hypertension.

DRUG-INDUCED TMA

Several drugs, including immunosuppressive therapy, antineoplastic medications, and cocaine, have been reported to cause TMA.⁹ Drug-induced TMA may be immunologically mediated by antibodies with specificity against endothelial or other inflammatory cells, or it may arise as a result of a toxic effect of a drug on endothelial cells. The primary treatment is cessation of the offending agent. This patient was not taking any medications that are associated with TMA, which makes drug-induced TMA unlikely.

CATASTROPHIC ANTIPHOSPHOLIPID SYNDROME

Antiphospholipid syndrome (APS) is an autoimmune disease in which autoantibodies to β₂-glycoprotein I lead to thrombotic or obstetrical complications. Catastrophic APS (CAPS) is a severe phenotype of APS that is characterized by the occurrence of multiple thrombotic events, with multiorgan damage, microvascular thrombosis, and, in many cases, TMA. Complement derangements arising from germline complement mutations are believed to underlie the progression from APS to CAPS.¹⁰ Treatment of CAPS consists of anticoagulation, glucocorticoids, plasmapheresis, and, in some cases, complement inhibition.¹¹ In this patient, tests for antiphospholipid antibodies (i.e., lupus anticoagulant and antibodies against cardiolipin and β₂-glycoprotein I) were negative, findings that rule out APS.

SCLERODERMA RENAL CRISIS

Systemic sclerosis, also known as scleroderma, is an autoimmune disease characterized by progressive fibrosis of the skin and other organs. In patients with diffuse cutaneous systemic sclerosis, the fibrosis may affect the renal vasculature, which can lead to scleroderma renal crisis with AKI, rapid-onset hypertension, and TMA.¹² Digital nailfold capillaroscopy, which evaluates for microvascular damage, may identify patients who are at risk for scleroderma renal crisis and other systemic microvascular involvement. Scleroderma renal crisis is associated with glucocorticoid use and RNA polymerase III antibodies. Glomerulonephritis is not a characteristic feature, and the urinary sediment is often bland. Antihypertensive treatment is the mainstay of therapy. This patient had cutaneous systemic sclerosis associated with RNA polymerase III antibodies, as well as hypertension and renal impairment, findings that suggest scleroderma renal crisis. However, hypertension developed only after her initial presentation with TMA, and muddy-brown casts were present in the urinary sediment, a finding that is suggestive of acute tubular necrosis; these characteristics are not consistent with the diagnosis of scleroderma renal crisis.

CANCER-ASSOCIATED TMA

Cancer-associated TMA is a devastating condition, in which intravascular fibrin deposition and microvascular occlusion arise from tumor cells in the microcirculation and lead to MAHA.^13,14 Classically, cancer-associated TMA occurs in patients with adenocarcinomas, particularly of gastric, pulmonary, breast, or prostatic origin; bone marrow infiltration and pulmonary tumor microembolism are common, and most affected patients have laboratory evidence of DIC. In addition to showing schistocytes, the peripheral-blood smear often shows evidence of leukoerythroblastosis with left-shifted myeloid cells, nucleated red cells, and teardrop cells, findings indicative of myelophthisis of the bone marrow by metastatic cancer. Antineoplastic therapy is the only appropriate treatment for cancer-associated TMA. The mortality associated with this condition is high, approaching 50% within a month after presentation with TMA.¹

This patient had laboratory test results that were suggestive of DIC, and her history of breast cancer suggests the possibility of cancer-associated TMA. A bone marrow biopsy performed at the other hospital was negative for cancer; however, the sensitivity of bone marrow biopsy for the detection of metastatic disease is only approximately 50%. The patient’s peripheral-blood smear showed left-shifted myeloid cells, nucleated red cells, and teardrop cells, in addition to abundant schistocytes, findings that are suggestive of myelophthisis of the marrow. Given the constellation of TMA, DIC, leukoerythroblastic findings on a peripheral-blood smear, and a history of breast cancer, I suspect that she had cancer-associated TMA from breast cancer. A repeat bone marrow biopsy would probably confirm the diagnosis of metastatic disease.

Two other features of this patient’s case that are unrelated to TMA merit discussion. One is the markedly elevated blood level of ferritin, which I suspect was caused by metastatic cancer.¹⁵ The other feature is proteinuria, which probably resulted from nephrosis due to breast cancer.¹⁶

DR. ALFRED I. LEE’S DIAGNOSIS

Cancer-associated thrombotic microangiopathy due to metastatic breast cancer in the bone marrow.

IMAGING STUDIES

Dr. Pedram Heidari: Whole-body positron-emission tomography–CT (Fig. 2), performed after the administration of ¹⁸F-fluorodeoxyglucose (FDG) tracer, revealed diffuse heterogeneous FDG uptake in the bone marrow. Contemporaneously performed whole-body CT revealed no suspicious lytic or blastic bone lesions that correlated with the pattern of FDG uptake. There were no sites of suspicious extraskeletal abnormal uptake.

Figure 2. Imaging Studies.

An anteroposterior maximum intensity projection image from ¹⁸F-fluorodeoxyglucose (FDG) positron-emission tomography–CT shows diffuse, heterogeneous, abnormally increased FDG uptake in the axial and appendicular skeleton (Panel A, arrows). Sagittal images of the skeleton show multiple focal sites of abnormal uptake in the spine (Panel B, arrows), with no correlative lytic or blastic bone lesions on CT (Panel C). Axial images of the pelvis show multiple focal sites of abnormal uptake in the iliac bones and sacrum (Panel D, arrows), with no correlative lytic or blastic bone lesions on CT (Panel E). Overall, this pattern of FDG uptake is seen in patients with osseous metastases or with lymphoproliferative or myeloproliferative processes.

A diffuse increase of FDG uptake in the bone marrow could be due to bone marrow reconversion or cancer. A homogeneous and uniform uptake pattern would suggest reactive bone marrow due to inflammation associated with cancer, administration of granulocyte colony-stimulating factor, or long-standing severe anemia. This patient had a diffuse heterogeneous pattern of uptake, which was suggestive of osseous metastasis of malignant tumor or lymphoproliferative or myeloproliferative diseases such as lymphoma or leukemia. Given her history of breast cancer, there was a high suspicion for recurrent metastatic breast cancer, and tissue sampling of the bone marrow was recommended.

PATHOLOGICAL DISCUSSION

Dr. Ta: Examination of a core-biopsy specimen of bone marrow (Fig. 3) revealed a cellularity of 80 to 90%, with most marrow elements replaced by nonhematopoietic cells. These cells had enlarged irregular nuclei, prominent nucleoli, and ample pale cytoplasm and were arranged in sheets, small nests, and cords. They occupied 80% of the marrow space and were consistent with metastatic carcinoma. Reticulin staining showed increased reticulin fibers within the nonhematopoietic cells and no increase in fibers within the hematopoietic areas. On immunohistochemical staining, the large, atypical cells were positive for MNF116 (cytokeratin), ER, and GATA3 and were negative for CD45, E-cadherin, and CDX2; these findings were consistent with metastatic carcinoma of primary breast origin.

Figure 3. Core-Biopsy Specimens of Bone Marrow.

Hematoxylin and eosin staining shows infiltration of atypical nonhematopoietic cells (Panel A, outlined by dashed lines). Immunohistochemical staining shows membranous staining for MNF116 (cytokeratin) (Panel B, in brown) and nuclear staining for estrogen receptor (Panel C, in brown) in the atypical cells, findings that indicate a carcinoma of primary breast origin.

Flow cytometry of the bone marrow–biopsy specimens showed that less than 1% of the myeloid blasts were positive for CD34, with no abnormal B-cell or T-cell populations. Cytogenetic analysis of the bone marrow revealed a normal female karyotype.

In summary, the patient’s bone marrow was hypercellular, given her age, with involvement of a myelophthisic process. The overall morphologic and immunophenotypic findings are consistent with metastatic breast carcinoma with extensive bone marrow involvement.

PATHOLOGICAL DIAGNOSIS

Metastatic breast carcinoma with extensive bone marrow involvement.

NEPHROLOGY DISCUSSION

Dr. Andrew Z. Fenves: The nephrology consult service was asked to determine whether the patient had normotensive scleroderma renal crisis and whether a kidney biopsy should be performed. At the other hospital, the patient’s TMA was attributed to scleroderma renal crisis. Her risk factors for scleroderma renal crisis included diffuse cutaneous systemic sclerosis, exposure to glucocorticoids, and RNA polymerase III antibody positivity. However, her systemic sclerosis had been stable for more than 3 years without treatment, and she had received glucocorticoid therapy for only 3 days. In addition, the patient initially did not have AKI, an essential feature of scleroderma renal crisis. The blood pressure never increased to above 150/60 mm Hg during the 50 days she spent at the other hospital. Although the blood pressure was elevated on admission to this hospital, it was ultimately easily controlled with one antihypertensive medication within 2 days. Normotensive scleroderma renal crisis is unusual; it occurs in less than 10% of cases of scleroderma renal crisis and is accompanied by AKI. Finally, this patient had nephrotic-range proteinuria, which is not a feature of scleroderma renal crisis.

AKI developed during the seventh week of this patient’s first hospitalization. The history of persistent hemolytic anemia, with presumed hemodynamic instability on several occasions, and the presence of muddy-brown casts together pointed to the likelihood of ischemic acute tubular necrosis. We could not rule out a possible contribution of pigment nephropathy (from free urinary hemoglobin) or, even less likely, renal injury due to MAHA.

A kidney biopsy is often not indicated in patients with scleroderma renal crisis because there are no specific diagnostic findings. Even if a biopsy had been performed in this patient, it probably would not have changed the overall management of her illness. The risk of a biopsy-induced bleeding episode was substantial because of her severe anemia, acute tubular necrosis, thrombocytopenia, and active hemolysis, thus outweighing any potential benefit.

The patient did not have the full nephrotic syndrome, given that her blood albumin level was normal and she did not have anasarca. Without performing a kidney biopsy, we could only speculate about the cause of nephrotic-range proteinuria. However, in patients with a large burden of metastatic adenocarcinoma, nephrotic-range proteinuria may be caused by paraneoplastic membranous nephropathy.¹⁷

DISCUSSION OF MANAGEMENT

Dr. Aditya Bardia: Endocrine therapy with a cyclin-dependent kinase 4 and 6 inhibitor is the recommended first-line treatment for patients with hormone receptor–positive metastatic breast cancer. However, if such a patient has clinically significant “visceral dysfunction,” such as TMA, chemotherapy is generally the preferred treatment.¹⁸

Traditional methods of managing MAHA such as plasmapheresis or immunosuppression are generally not effective in the context of cancer, and treating the underlying cancer is the mainstay of management.^19,20 Paclitaxel is excreted primarily through oxidative metabolism and biliary excretion and thus can be administered without modification to patients who are undergoing hemodialysis.^21,22

Accordingly, this patient started chemotherapy with paclitaxel. During the next few days, she continued to have myelosuppression, along with fatigue and drowsiness. After discussion with the inpatient team, she opted for no further treatment and chose to instead focus on quality of life. She was discharged home with hospice services and died a month later, surrounded by her family.

Despite major strides in the field of cancer therapeutics, the outcome of this case was similar to that of a case reported nearly 40 years ago in the Case Records of the Massachusetts General Hospital.²³ The management of cancer-associated TMA remains a major problem.

FINAL DIAGNOSIS

Breast cancer–associated thrombotic microangiopathy.