Case Studies. Scleroderma Renal Crisis or Thrombotic Thrombocytopenic Purpura: Seeing Through the Masquerade. Patient 1

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1 Scleroderma Renal Crisis or Thrombotic Thrombocytopenic Purpura: Seeing Through the Masquerade Emily Keeler, DO, 1* Gloria Fioravanti, DO, FACP, 1 Bensson Samuel, MD, PG Dip, 1 Santo Longo, MD 2 Lab Med Spring 2015;46:e39-e44 DOI: /LM72AM5XFHZYOQCB ABSTRACT Scleroderma renal crisis (SRC), a somewhat rare but serious complication of systemic scleroderma, is one of only a few known rheumatologic emergencies; it presents in as many as 10% of patients with scleroderma. Before the use of angiotensin converting enzyme (ACE) inhibitors to treat SRC, the mortality rate for SRC was extremely high as much as 90% after 1 year. However, the mortality rate has significantly improved with the early and aggressive use of ACE inhibitors. SRC typically includes acute renal failure and accelerated hypertension. Patients may report headache, changes in vision, fever, dyspnea, and encephalopathy. Laboratory study results can show elevated creatinine levels, thrombocytopenia, and microangiopathic hemolytic anemia (MAHA) with schistocytes on blood smear. Given this clinical and laboratory presentation, SRC can easily be mistaken for TTP in clinical practice, as we demonstrate in 2 presentations of similar cases of SRC, the first in a 36-year-old Caucasian woman and the second in a 54-year-old Caucasian woman. In both cases, SRC masqueraded as TTP, and both patients were almost mistakenly treated for TTP until the clinical picture changed and certain laboratory test and kidney biopsy results confirmed otherwise. Keywords: scleroderma, renal failure, ACE inhibitor, thrombotic thrombocytopenic purpura, anemia, thrombolysis Patient 1 Blood pressure (BP): 200/100; heart rate (HR): 77 bpm; respiratory rate (RR): 16 breaths per minute; temperature (T): C; oxygen saturation (SaO 2 ): 96% on room air Abbreviations: BP, blood pressure; HR, heart rate; RR, respiratory rate; T, temperature; SaO 2, oxygen saturation; TTP, thrombotic thrombocytopenic purpura; ICU, intensive care unit; LDH, lactate dehydrogenase; DIC, disseminated intravascular coagulation; SRC, sclerodoma renal crisis; ADAMTS13, von Willebrand factor cleaving protease; ACE, angiotensin converting enzyme; BNP, brain naturetic peptide; Bi-PAP, bilevel positive airway pressure; SSc, systemic scleroderma; dcssc, diffuse cutaneous systemic sclerosis; MAHA, microangiopathic hemolytic anemia; HUS, hemolytic uremic syndrome; LDH, lactate dehydrogenase; PT, prothrombin time; INR, international normalized ratio; appt, activated partial thromboplastin time; BUN, blood urea nitrogen; IgM, immunoglobulin M; ECG, electrocardiograph; GBM, glomurulus basement membrane Departments of 1 Internal Medicine and 2 Pathology, St. Luke s University Hospital and Health Network, Internal Medicine Department, Bethlehem, PA To whom correspondence should be addressed. Emily.Keeler@sluhn.org A 36-year-old Caucasian woman with an unknown autoimmune disorder that had not previously been well established before hospital admission had worsening shortness of breath for 1 week, malignant hypertension with elevated blood pressure, and fever. At our institution, we determined that she had new-onset anemia, with a hemoglobin of 9.7 g/dl; thrombocytopenia, with a platelet count of 92,000/μL; and renal failure, with creatinine level of 4.37 mg/dl. Initial chest x-ray imaging showed pulmonary edema; the patient was subsequently intubated due to her increasingly labored breathing and concomitant metabolic acidosis. Given the constellation of her symptoms and the severity of her illness, there was concern that she had thrombotic thrombocytopenic purpura (TTP), so she was transferred to our hospital for a higher level of care and the possible initiation of Downloaded from Spring 2015 Volume 46, Number 2 Lab Medicine e39

2 Table 1. Results of Laboratory Testing of Patient 1, a 36-Year-Old Caucasian Woman Variable Value Units Reference Range LDH 370 U/L Haptoglobulin 21 mg/dl PT 14.9 sec INR 1.22 ratio appt 38 sec D-dimer 2636 ng/ml Fibrinogen 576 mg/dl BUN 56 mg/dl 5-25 Creatinine 4.37 mg/dl LDH, lactate dehydrogenase; PT, prothrombin time; INR, international normalized ratio; appt, activated partial thromboplastin time; BUN, blood urea nitrogen. plasmapheresis. On transfer to our facility, the patient was successfully extubated on her second day of admission and was sufficiently healthy to be transferred out of the intensive care unit (ICU). Further laboratory work revealed that her anemia was hemolytic, with increased lactate dehydrogenase (LDH) levels, decreased haptoglobin levels (Table 1), and schistocytes and helmet cells on blood smear. We consulted the Department of Hematology at our institution to determine whether the patient had TTP. Those health care professionals noted that the platelet counts of the patient were improving without any specific intervention and that her anemia was stable; this evidence decreased the likelihood of true TTP. After review of newly available laboratory results, plasmapheresis was not initiated by the Department of Hematology because the lab results were consistent with a diagnosis of disseminated intravascular coagulation (DIC; Table 1) secondary to possible sclerodoma renal crisis (SRC). The von Willebrand factor cleaving protease results for the patient, as measured through activity-based assay, were normal (92%). These data provided further confirmation that the disease process of the patient was likely not TTP, in which case we would expect the ADAMTS13 level to be extremely low. Microscopic images from specimens from this patient are shown in Image 1, Image 2, and Image 3. Several days later, further laboratory results indicated that the patient had strong positive results for RNA polymerase III antibodies, at U/mL. This type of antibody is more prevalent in patients with diffuse cutaneous scleroderma and has been highly associated with increased risk of acute scleroderma renal crisis. 2-4 The renal function of the Image 1 In patient 1, a 36-year-old Caucasian woman, vascular damage consistent with scleroderma is evidenced by an intraluminal fibrin thrombus associated with endothelial degeneration, medial hyalinosis, and loss of myocytes; original magnification 40x. patient continued to worsen and so we initiated inpatient hemodialysis. Renal biopsy was obtained; at that point, we started the patient on an angiotensin converting enzyme (ACE) inhibitor, presuming that she had SRC. Biopsy results were consistent with scleroderma-associated renal disease showing acute and subacute arterial and arteriolar thrombotic microangiopathys, arterial onionskin mucointimal edema and arteriolar fibrin thrombosis, tubular atrophy and interstitial fibrosis, and acute diffuse tubular injury. The patient required treatment for renal failure with hemodialysis through the course of her hospitalization and is still undergoing hemodialysis on an outpatient basis. Patient 2 BP: 162/108; HR: 85 bpm, RR: 16 breaths per minute, T: C, SaO 2 : 94% in room air A 54-year-old Caucasian woman with elevated blood pressure and reported worsening exertional dyspnea, intermittent chest pain during the previous week, and increasing edema of the lower extremities. Laboratory Downloaded from e40 Lab Medicine Spring 2015 Volume 46, Number 2

3 Image 2 In patient 1, a 36-year-old Caucasian woman, marked onionskin mucointimal edema has caused stretching of the media and occlusion of the vessel lumen; original magnification 100x. The absence of inflammatory cells rules out arteritis. Image 3 In patient 1, a 36-year-old Caucasian woman, a dominant arterial positivity for fibrin/fibrinogen, within the intima, is visible in this medium-sized arteriole; original magnification 40x. Weak positivity for immunoglobulin M (IgM), C3, and C1 in this same area supports the microscopic impression of a predominating vascular thrombotic microagniopathy. results showed an elevated troponin level of 1.21 ng/ ml and an initially elevated creatinine level of 1.6 mg/dl, which rapidly peaked at 4.8 mg/dl during the course of 5 days. The patient also experienced new onset of anemia and thrombocytopenia, with a hemoglobin count of 9.4 g/dl and platelet count of 97,000/ μl, respectively. Her brain naturetic peptide (BNP) level was 3350 pg/ml. Also, an echocardiogram showed an ejection fraction of 25% with diffuse hypokinesis, which was a significant change from an echocardiogram performed 3 months earlier that had shown an ejection fraction of 60% and no other abnormalities. Given these findings, we consulted the Division of Cardiology at our institution. The health care professionals in that department believed that the patient was having a non ST-segment elevation myocardial infarction (Figure 1) and so they planned to perform a cardiac catheterization on the patient the following day. However, that evening, the patient experienced acute respiratory failure secondary to flash pulmonary edema, requiring treatment with bilevel positive airway pressure (Bi-PAP) and transferred to the ICU. She never required intubation; her health was stabilized, and she was eventually transferred back to the medical floor. During these critical events, the patient received an ongoing work-up to determine the cause of her new renal failure, anemia, and thrombocytopenia. Similar to the first case, concern was present for TTP, given the laboratory findings (Table 2) and the constellation of symptoms, so we consulted the Department of Hematology. Plasmapheresis was planned for this patient; however, after subsequently analyzing more laboratory data, the Department of Hematology noted that the platelet count was improving on its own, and the patient had a significantly elevated D-dimer level, which was more consistent with the diagnosis of DIC. Also, the ADAMTS13 activity level of the patient, measured through activity-based assay, was mildly decreased (53%). Also, similar to patient 1, concern for TTP had decreased given current lab findings, and so plasmapheresis was not initiated. We did not test RNA polymerase III levels in this patient. Microscopic images from specimens from this patient are shown in Image 4 and Image 5. Because the renal function of this patient continued to worsen, we initiated hemodialysis. An outpatient rheumatologist began to perform a work-up on the patient to screen for an autoimmune disease; however, Downloaded from Spring 2015 Volume 46, Number 2 Lab Medicine e41

4 Figure 1 The electrocardiograph (ECG) readings from our patient, a 54-year-old Caucasian woman, showing T-wave inversions in the anterior leads and non-specific T-wave changes in the lateral leads. the results of this work-up were not available or accessible to the in-house medical team. A renal biopsy was performed; the final pathology report demonstrated findings consistent with scleroderma-associated renal disease. Those findings included thrombotic microangiopathy with prominent involvement of blood vessels and severe secondary ischemic glomerular changes (acute and subacute); tubular degenerative changes and tubular atrophy with interstitial fibrosis were also present. The patient had also recently undergone a skin biopsy before the most recent hospital admission; the specimen material had been sent to another facility for analysis, and the results were consistent with scleroderma. At the time of this writing, this patient, like patient 1, continues to receive hemodialysis on an outpatient basis. Discussion Systemic scleroderma (SSc) is an autoimmune disease that causes thickening and fibrosis of the skin, and in some cases, progressive visceral fibrosis, which leads to eventual organ dysfunction. The pathogenesis of SSc is a complex process that involves 3 hallmark features: vasculopathy (cellular and humoral autoimmunity), progressive multiorgan visceral and vascular fibrosis. 1 In particular, the form of systemic sclerosis known as diffuse cutaneous systemic sclerosis (dcssc) generally involves multiple organs, including the skin, lungs, gastrointestinal tract, kidneys, and heart. 1 Patients with this form of the disease have been found to have the highest risk of acute renal crisis. 4 Downloaded from e42 Lab Medicine Spring 2015 Volume 46, Number 2

5 Image 4 In patient 2, a 54-year-old Caucasian woman, small shrunken glomeruli exhibit prominent ischemic changes, including wrinkling, retraction, and focal narrow duplication of the glomular basement membrane (GBM) and mesangilollysis; original magnification 100x. Image 5 In patient 2, a 54-year-old Caucasian woman, severe thrombotic occlusion of an intrarenal artery exhibits intimal edema, endothelial swelling, focal intimal sclerosis, and prominent extravasation of the red blood cells through the arterial wall; original magnification 40x. Vascular endothelial injury results in activation of inflammatory and immune responses, causing progressive small and medium-sized arterial lumen occlusions, tissue ischemia, and fibrosis, all of which perpetuate an ongoing cycle of vascular damage and subsequent organ damage. In renal disease, the renal arcuate and interlobular arteries are obliterated, and a reduction in renal blood flow occurs along with hyperplasia of renal juxtaglomerular cells. 1 This sequence of events leads to increased renin and angiotensin and, therefore, worsening renal vasoconstriction that eventually causes (frequently malignant) hypertension. Thrombocytopenia can occur as a result of continuous platelet activation and deposition at damaged endothelial sites. Microangiopathic hemolytic anemia (MAHA) results from fragmentation of red blood cells as they pass through vessels occluded by fibrin or platelet thrombi. 1 TTP is a rare disorder of the blood characterized by thrombocytopenia, thrombosis of the microvasculature, and MAHA. In its fulminant form, the classic findings are thrombocytopenia, MAHA, renal failure, neurologic abnormalities, and fever; however, with earlier diagnosis, this constellation of symptoms is less frequently observed now. Histology findings in TTP generally reveal thrombi Table 2. Results of Laboratory Testing of Patient 1, a 36-Year-Old Caucasian Woman Variable Measurement Units Reference Range LDH 645 U/L Haptoglobulin <10 mg/dl PT 15.0 secs INR 1.25 ratio APPT 51.0 sec D-dimer 1172 ng/ml Fibrinogen 272 mg/dl BUN 38 mg/dl 5-25 Creatinine 1.6 mg/dl LDH, lactate dehydrogenase; PT, prothrombin time; INR, international normalized ratio; appt, activated partial thromboplastin time; BUN, blood urea nitrogen. in the microcirculation that are relatively platelet rich and fibrin poor (white clot) and are most prominent in the kidneys and the central nervous system. These thrombi are composed of platelets and fibrin and are found in the arterioles of many organs throughout the body; thrombi in the kidneys are of eosinophilic granular composition and are found predominantly in the terminal part of the interlobular arteries and glomerular capillaries. 5 Before treatment with plasma exchange, the mortality rate for TTP was greater than 95%; because of early, aggressive treatment with this therapy, the mortality rate has decreased to 10% to 20%. 6 Downloaded from Spring 2015 Volume 46, Number 2 Lab Medicine e43

6 Hemolytic uremic syndrome (HUS) manifests in forms similar to TTP but includes the more prominent component of renal failure. HUS is primarily observed in children; moreover, it is highly associated with preceding hemorrhagic diarrhea typically caused by Escherichia coli O157:H7. 1 As a result, this entity was not high on our differential diagnosis list, given the demographics of our 2 patients and their lack of diarrheal illness. Given the similarities between the typical manifestations of SRC and TTP with thrombocytopenia, MAHA, microvascular thrombosis, and renal failure, those conditions can easily be mistaken for each another clinically and, therefore, potentially treated inappropriately. The common finding of moderate to severe hypertension in our 2 patients, in addition to their vague history of autoimmune disease, helped to support the correct diagnosis of SRC for both. Awareness of the ability of SRC to mimic TTP is required to make the correct diagnosis; higher initial suspicion for SRC in the appropriate clinical setting is recommended. Before the advent of ACE-inhibitors, the mortality rate of SRC was 90% at 1 year from onset. Now, with early and aggressive blood-pressure control with ACE inhibitors, that rate has decreased to less than 15% at 1 year after onset. 1 One set of study results states that approximately 25% of patients with SRC require immediate dialysis at initial arrival at the hospital 2 ; however, this number can be as high as 66%. 2 Nevertheless, with the introduction of ACE inhibitors, as many as 60% of these patients undergoing dialysis do not require permanent dialysis, and with concurrent use of an ACE inhibitor and dialysis, as many as 30% can experience functional renal recovery. 7 ACE inhibitors have been shown 6 to be more effective for renal recovery when there is less initial renal damage in individuals with a creatinine level of less than 4 at time of drug introduction. In both of our patients, creatinine levels were less than 4 at the time of initiation of captopril. Average renal recovery time is approximately 12 months; at 24 months, recovery is less likely. At 36 months, recovery is highly uncommon; the patients who have not experienced recovery by that time tend to require permanent dialysis. 2,7 of therapy in SRC has been shown to be beneficial for patients and can improve renal function. 7 Early identification and initiation of treatment for patients with SRC can impact their long-term renal recovery and need for permanent dialysis. The cases of our 2 patients demonstrate the importance of increased awareness of the ways that SRC can masquerade as TTP, sometimes causing delay in diagnosis and treatment of SRC. Also, plasmapheresis in patients receiving ACE inhibitor therapy can cause dangerous refractory hypotension. 8 Therefore, incorrectly initiating ACE-inhibitor therapy in a patient with TTP could delay initial plasmapheresis or make that procedure more acutely dangerous. References 1. Longo DL, Fauci A, Kasper D, et al. Harrison s Prinicples of Internal Medicine. 18 th edn. New York: McGraw-Hill Companies Inc. 2012: , Denton CP, Lapadula G, Mouthon L, Müller-Ladner U. Renal complications and scleroderma renal crisis. Rheumatology (Oxford). 2009;48(suppl 3):iii32-iii Okano Y, Steen VD, Medsger TA Jr. Autoantibody reactive with RNA polymerase III in systemic sclerosis. Ann Intern Med. 1993;119(10): Penn H, Howie AJ, Kingdon EJ, et al. Scleroderma renal crisis: patient characteristics and long-term outcomes. QJM. 2007;100(8): Kumar V, Abbas AK, Fausto N.. Robbins and Cotran Pathologic Basis of Disease. Philadelphia: Elsevier Saunders; Papadakis MA, McPhee SJ. Current Medical Diagnosis and Treatment. New York: McGraw-Hill Companies Inc; 2013: Shanmugam VK, Steen VD. Renal disease in scleroderma: an update on evaluation, risk stratification, pathogenesis and management. Curr Opin Rheumatol. 2012;24(6): Abudiab M, Krause ML, Fidler ME, Nath KA, Norby SM. Differentiating scleroderma renal crisis from other causes of thrombotic microangiopathy in a postpartum patient. Clin Nephrol. 2013;80(4): Prophylactic use of ACE inhibitors in patients with SSc has not been shown to prevent SRC and, in some cases, the use of those inhibitors has been shown to contribute to decline in kidney function. Despite this, early introduction Downloaded from e44 Lab Medicine Spring 2015 Volume 46, Number 2