A.P., a 42-year-old woman, presented with rectal bleeding to her primary care physician. Endoscopic examination revealed a mass in the anal canal. Biopsy was positive for squamous cell carcinoma. A.P. underwent local excision and was established as stage II (T2N0M0). After surgery, she received

5-fluorouracil (FU) 1,000 mg/[m.sup.2] by continuous infusion on days 1-4 and on days 29-32, mitomycin-C 10 mg/[m.sup.2] days 1 and 29, and radiation therapy (4c500 cGY). Minimal nausea was the only side effect. A.P. achieved complete remission.

Approximately eight weeks after completing therapy, A.P. presented for an implantable port flush. The nurse noted that A.P. was pale, weak, and short of breath. A complete blood count (CBC) was obtained and revealed a hematocrit of 17.1% (normal range 37%-48%), hemoglobin of 4.9 (normal range 12.3-15.3 g/dl), and platelet count of 50,000 (normal range 150,000-450,000 cells/ml). A physical examination revealed paleness with generalized anasarca. A.P. was afebrile; her blood pressure was 180/100 mm Hg, pulse rate was 72, and respiration was 24. A.P. was admitted to the hospital for further evaluation and possible blood transfusion.

Other laboratory results included a serum creatinine 3.5 mg/dl (normal range 0.7-1.4 mg/dl), lactic dehydrogenase (LDH) 342 units/L (normal range 140-280 units/L), and serum haptoglobin < 38 mg/dl (normal range 60-270 mg/dl). Peripheral blood smear demonstrated prominent schistocytes with overall low blood cells. The coagulation profile was within normal limits. Mitomycin-C--induced hemolytic uremic syndrome (HUS) was diagnosed.

A.P. initially underwent plasmapheresis every other day with daily plasma infusions and IV methylprednisolone. Her blood pressure continued to increase and was treated successfully with a combination of antihypertensive agents, including a calcium channel blocker, an angiotensin-converting enzyme, and a beta blocker. Weekly erythropoietin-stimulating agent (ESA) injections were initiated. Within three weeks, A.P. had significant improvement of hematologic parameters and daily plasma infusion was stopped.

Plasmapheresis continued twice a week. A.P.'s blood pressure had stabilized. Unfortunately, her renal function continued to worsen and she was placed on renal dialysis three times per week with an initial creatinine of 5.6 mg/dl, potassium of 5.6 mEq/l, and LDH of 580 units/L. Symptoms improved with diuretic administration, and A.P.'s creatinine was maintained at 3.2 after one week on dialysis. After eight weeks in the hospital, A.P.'s hematologic parameters stabilized as well as her renal function on dialysis. She was discharged with close monitoring of her counts and continued dialysis three times per week.

What is hemolytic uremic syndrome?

HUS is a rare condition with a clinical triad of acute renal failure, microangiopathic hemolytic anemia, and thrombocytopenia. Thrombotic microangiopathy dominated by renal impairment usually is referred to as HUS. Systemic hypertension and noncardiogenic pulmonary edema commonly occur during the course of the syndrome. Variable signs of organ failure occur because of platelet thrombi in the microcirculation (Pisoni, Ruggenenti, & Remuzzi, 2001).

Little is known about the disease. HUS was first described in 1924 (Wu et al., 1997; Zakarija & Bennett, 2005), but little nursing literature exists concerning risks and management. Because of the complexities identified with this syndrome, a cancer-associated HUS national registry was established in 1984 and ran through 1986 (Lesesne et al., 1989). The registry defined HUS as patients with hematocrit less than 25%, a platelet count less than 100,000, and a serum creatinine greater than 1.6 mg/dl. Clinical characteristics were common among 85 patients identified through the registry, including diagnosis of adenocarcinoma (particularly of the gastrointestinal tract), partial to complete tumor response from treatment, use of mitomycin-C, noncardiogenic pulmonary edema associated with blood product transfusions, and poor response to treatment of HUS with significant mortality.

Agents implicated in the pathogenesis of HUS include mitomycin-C, cyclosporine, quinine, ticlopidine, bleomycin, cisplatin, fluorouracil, gemcitabine, alpha interferon, and fludarabine (Muller et al., 2005; Pisoni et al., 2001; Wu et al., 1997). The most common chemotherapy agent reported to induce HUS is mitomycin-C, with a reported incidence of 2%-10% (Wu et al.).

What is the relationship of mitomycin-C to hemolytic uremic syndrome?

Mitomycin-C was approved in 1974 to treat a wide variety of malignancies, including gastric, pancreatic, renal, and anal carcinoma. Mitomycin-C is classified as an alkylating agent and is isolated from the broth of streptomyces and caespitosus. The first cases of mitomycin-C--induced HUS were described in 1985 by Cantrell, Phillips, and Schein. Several syndromes have been recognized describing mitomycin-C--induced issues, such as microangiopathic hemolytic anemia, cancer-related thrombotic thrombocytopenic purpura, mitomycin-C--induced nephrotoxicity, and chronic glomerular microangiopathy (Cantrell et al.).

What is the pathophysiology of hemolytic uremic syndrome?

Pathogenesis of mitomycin-C--induced HUS is not well understood. Tissues from renal biopsy and at autopsy show a thrombotic microangiopathic process. Pathology features include endothelial cell injury and development of platelet aggregatory immune complexes (Zakarija & Bennett, 2005). Mitomycin-C can cause direct damage to the kidney vascular endothelial cells and inhibit prostacyclin production, which results in promotion of platelet aggregation and microthrombi formation, predominately in the kidney vasculature, resulting in severe renal failure (Wu et al., 1997). Significant immune complex levels dissociated into antigen and antibody components have been found to be elevated in the serum of patients diagnosed with HUS (Lesesne et al., 1989).

What is the course of this syndrome?

Clinically, HUS can consist of variable combinations of microangiopathic hemolytic anemia, thrombocytopenia, renal failure, pulmonary edema, systemic arterial hypertension, and neurologic abnormalities (Wu et al., 1997). However, blood transfusions often will exacerbate any or all of these clinical abnormalities. Other clinical features include rash, fever, interstitial pneumonitis, hematuria, and proteinuria.

HUS typically occurs four to eight weeks after completion of mitomycin-C therapy; however, reports of HUS occurring immediately following or up to nine months after treatment do exist (Wu et al., 1997). Incidences of mitomycin-C--induced HUS appear to be dose-related. A total cumulative dose of mitomycin-C greater than 40-60 mg increases the risk for HUS (Lesesne et al., 1989). Renal insufficiency usually is progressive and dialysis is required in almost a third of patients (Pisoni et al., 2001). The majority of patients will die from renal failure, with a median time-to-death of four weeks from the initial HUS presentation.

What are the presenting signs and symptoms?

The most common symptoms of HUS include anorexia, weight gain, weakness, fatigue, jaundice secondary to hemolysis, dyspnea, and neurologic issues (headache, confusion, hemiplegia, hemiparesis, or coma). Patients may experience anxiety or feelings of impending doom. A dry cough may be present in patients with pulmonary edema.

A review of systems and physical examination findings are vague; neither is definitively diagnostic of the syndrome. Patients may have generalized anasarca (soft tissue swelling or edema), pallor, and hypertension. Jaundice may be present in the dermis or sclera. Abnormal breath sounds with scattered wheezing will be present with pulmonary edema.

How is hemolytic uremic syndrome diagnosed?

HUS is primarily diagnosed from laboratory findings (see Table 1), with the presence of schistocytes helpful in confirming the diagnosis (Gordon & Kwaan, 1999). The absence of coagulopathy with normal prothrombin time and normal partial thromboplastin time differentiates HUS from a diagnosis of disseminated intravascular coagulation. Rapidly declining renal function is noted with proteinuria and hematuria. A chest x-ray may be useful in detecting pulmonary edema or interstitial pneumonitis.

Table 1. Laboratory Findings

Parameter        Laboratory        Description
                 Results

Bone marrow    Usually normal    No effect on bone
                                 marrow function

Coagulation    Normal            No effect on
parameters                       coagulation
                                 factors

Direct         Increased         Refects red blood
bilirubin                        cell hemolysis

Direct Coombs  Negative          Lack of red cell
                                 auto-antibodies

Hematocrit     Decreased,        Direct effect of
               usually less      hemolysis
               than 25% in
               40% of cases

Hemoglobin     Decreased,        Direct effect of
               usually less      hemolysis
               than 6.5
               mg/dl, in 40% of
               cases

Lactate        Increased         Refects
dehydrogenase                    intravascular
                                 hemolysis

Peripheral     Schistocytes,     Result of fbrin
smear          fragmented red    and platelet deposits
               blood             that sheer
               cells, helmet     red blood cells
               cells             in
                                 microvasculature

Platelets      Decreased,        Direct effect of
               usually less      hemolysis
               than 50,000
               cells/ml

Renal biopsy   Thrombotic        Renal damage
               microangiopathy

Reticulocyte   Increased         Compensates for
                                 low red blood
                                 cells

Serum          Increased,        Declining renal
creatinine     usually greater   function
               than 2.5
               upper limit of
               normal

Serum          Decreased         Hemolysis
haptoglobin                      process

Urinalysis     Hematuria and     Declining renal
               protein           function


Note. Based on information from Gordon & Kwaan, 1999; Pisoni et al.,
2001; Wu et al., 1997.

What is the treatment?

Interventions generally fail to control the syndrome and patients usually die from HUS rather than cancer. Administration of red blood cells (RBCs) and platelets usually produces a transient reversal of the anemia and thrombocytopenia; however, blood product transfusions often will cause an exacerbation of HUS as a result of rapid worsening of hemolysis and induce noncardiogenic pulmonary edema within a few hours after the initial transfusion (Lesesne et al., 1989). Subsequently, blood product transfusions are reserved for patients with life-threatening bleeding or markedly symptomatic anemia. Weekly ESA injections can enhance RBC production without causing HUS exacerbation (Catalano, Gianesini, & Fabbian, 2002). No reports have been documented regarding efficacy of oprelvekin in reversing thrombocytopenia.

Because elevated levels of circulating immune complexes may play a role in HUS, plasma therapy has been used to remove these complexes (Pisoni et al., 2001). Treatment is given every day to every other day according to the patient's hematologic parameters. The procedure usually normalizes the blood count but rarely reverses renal insufficiency. Plasma exchange usually is considered over high-volume plasma infusion because renal insufficiency and heart failure limit the amount of volume that can be infused. Renal dialysis eventually will be necessary to rid the body of waste products and reduce serum creatinine (Coppo et al., 2003).

Immunoperfusion to alter or deplete circulating immune complexes has been a promising treatment based on a hypothesis that HUS is related to the presence of the complexes that are believed to suppress the body's immune response. Immunoperfusion involves plasmapheresis with the reinfusion of plasma over a column of staphylococcal protein-A (SPA). SPA is a component of the cell wall of pathogenic Staphylococci that nonspecifically binds the Fc portion of the immunoglobulin G (IgG) molecule and is capable of binding to the complex forms of IgG molecules found in patients with HUS (Korec et al., 1986; Pisoni et al., 2001). After the patient undergoes immunoabsorption, plasma is then reinfused. As with plasma exchange, hematologic abnormalities usually normalize, yet rarely does the renal failure reverse.

Splenectomy may be considered in patients with disabling disease requiring frequent plasma therapy. Bilateral nephrectomy has been an option for patients with severe renal impairment in imminent danger of death from thrombocytopenia associated with refractory hypertension and hypertensive encephalopathy (Pisoni et al., 2001). Kidney transplantation may be an option for patients on chronic dialysis with normalized hematologic parameters.

What are the nursing implications with regard to hemolytic uremic syndrome?

Preventing HUS is extremely difficult because mitomycin-C often is the best or only chemotherapy option in certain cancers. During mitomycin-C administration, strict monitoring of the patient's renal function and the CBC for anemia and thrombocytopenia is important. Urinalysis is useful in detecting hematuria and proteinuria. Markers for microangiopathic process include monitoring LDH levels, reticulocyte count, and peripheral smears for the presence of schistocytes. When abnormalities are detected, mitomycin-C administration should immediately be discontinued. Patients should be monitored for several months following completion of therapy because HUS may occur at any time.

Monitoring and documenting the cumulative dose of mitomycin-C are important and consideration should be given to hold further mitomycin-C when the cumulative dose of 40 mg is reached. Nurses should cautiously administer blood products and monitor for complications. During plasmapheresis, nurses should monitor patients for fever, chills, nausea, or vomiting, and provide supportive care as needed. Although rare, hypotension and bronchospasm can occur during plasmapheresis. Thrombocytopenic precautions should be instituted when platelets are less than 50,000 cells/ml to minimize the occurrence of bleeding (see Figure 1). Patient and family education should include interventions that may be beneficial with anemia (see Figure 2). Early recognition is vital to prompt treatment and hope for a full recovery.

Figure 1. Thrombocytopenia Precautions

Nursing Education Key Points

* Avoid using or over-inflating a blood pressure cuff.

* Avoid using a tourniquet.

* Avoid invasive procedures, such as bladder catheterization, venipunctures, and rectal temperatures.

* Apply pressure to venipuncture or implantable port sites for approximately five minutes.

Patient Education Key Points

* Reduce risk of trauma by maintaining clear hallways, using hand rails going up and down stairs, and avoiding physical activity that may lead to trauma.

* Wear shoes or thick-soled slippers during ambulation.

* Avoid sharp objects such as cutting with a knife or using a straight-edge razor.

* Avoid constipation and implement a bowel regimen.

* Call a healthcare professional for bleeding episodes or go directly to the emergency room.

Figure 2. Patient Education Key Points for Anemia

* Avoid sudden changes in position such as sitting to standing.

* Ask for assistance with walking and self-care activities.

* Conserve energy and allow for frequent rest periods as needed.

* Eat a nutritionally balanced diet and use vitamins or mineral supplements as directed.

Call a healthcare professional for symptoms related to anemia complications, such as shortness of breath, confusion, chest palpitations, or headaches.

Author Contact: Dawn Camp-Sorrell, MSN, FNP, AOCN[R], can be reached at onpdawn@bellsouth.net, with copy to editor at ONF Editor@ons.org.

References

Cantrell, J.E., Phillips, T.M., & Schein, P.S. (1985). Carcinoma-associated hemolytic-uremic syndrome: A complication of mitomycin C chemotherapy. Journal of Clinical Oncology, 3(5), 723-734.

Catalano, C., Gianesini, C., & Fabbian, F. (2002). Erythropoietin is beneficial in mitomycin-induced hemolytic-uremic syndrome. Nephron, 91(2), 324-326.

Coppo, P., Bussel, A., Charrier, S., Adrie, C., Galicier, L., Boulanger, E., et al. (2003). High-dose plasma infusion versus plasma exchange as early treatment of thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome. Medicine, 82(1), 27-38.

Gordon, L.I., & Kwaan, H.c. (1999). Thrombotic microangiopathy manifesting as thrombotic thrombocytopenic purpura/hemolytic uremic syndrome in the cancer patient. Seminars in Thrombosis and Hemostasis, 25(2), 217-221.

Korec, S., Schein, P.S., Smith, F.P., Neefe, J.R., Woolley, P.V., Goldberg, R.M., et al. (1986). Treatment of cancer-associated hemolytic uremic syndrome with staphylococcal protein An immunoperfusion. Journal of Clinical Oncology, 4(2), 210-215.

Lesesne, J.B., Rothschild, N., Erickson, B., Korec, S., Sisk, R., Keller, J., et al. (1989). Cancer-associated hemolytic-uremic syndrome: Analysis of 85 cases from a national registry. Journal of Clinical Oncology, 7(6), 781-789.

Muller, S., Schutt, P., Bojko, P., Nowrousian, M.R., Hense, J., Seeber, S., et al. (2005). Hemolytic uremic syndrome following prolonged gemcitabine therapy: A report of four cases from a single institution. Annals of Hematology, 84(9), 621-622.

Pisoni, R., Ruggenenti, P., & Remuzzi, G. (2001). Drug-induced thrombotic microangiopathy. Drug Safety, 24(7), 491-501.

Wu, D.c., Liu, J.M., Chen, Y.M., Yang, S., Liu, S.M., Chen, L.T., et al. (1997). Mitomycin-C-induced hemolytic uremic syndrome: A case report and literature review. Japanese Journal of Clinical Oncology, 27(2), 115-118.

Zakarija, A., & Bennett, C. (2005). Drug-induced thrombotic microangiopathy. Seminars in Thrombosis and Hemostasis, 31(5), 681-690.

RELATED ARTICLE: Do You Have an Interesting Clinical Experience to Share?

Clinical Challenges provides readers with a forum to discuss creative clinical solutions to challenging patient care issues. Case studies or descriptions may be submitted with or without discussion or solutions. References, tables, figures, and illustrations can be included. Materials or inquiries should be directed to Oncology Nursing Forum Associate Editor Susan Moore, RN, MSN, ANP, AOCN[R], at smoore46@yahoo.com.

Dawn Camp-Sorrell, MSN, FNP, AOCN[R]

Susan Moore, RN, MSN, ANP, AOCN[R]

Associate Editor

Dawn Camp-Sorrell, MSN, FNP, AOCN[R], is an oncology nurse practitioner at Hematology Oncology Associates of Alabama in Sylacauga. No financial relationships to disclose. Mention of specific products and opinions related to those products do not indicate or imply endorsement by the Oncology Nursing Forum or the Oncology Nursing Society.

Digital Object Identifier: 10.1188/08.ONF.593-596