A 51-year-old woman was in her usual state of good health until she presented to a local emergency department reporting dyspnea of 2 days' duration. Her dyspnea was worse with exertion and with lying flat, but was not associated with chest pain, cough, or fever. Bilateral lower extremity edema had developed over the few weeks preceding her presentation.
Two to three weeks prior to the emergency department visit, she noticed a blister on her left third toe. She was diagnosed with cellulitis and was started on cephalexin. After initiating antibiotic therapy, she developed a diffuse, pruritic, maculopapular rash, and her treatment was switched to doxycycline. The patient stopped taking doxycycline after 2 days because of nausea, and the blister resolved without further therapy.
In the emergency department, the patient was hypertensive and tachycardic, with blood pressure (BP) of 210/110 mm Hg and a heart rate of 105 beats/minute. Her temperature was 98.2°F and her oxygen saturation was 100% on room air. Physical examination revealed bibasilar crackles, pitting edema of both lower extremities, and a dusky area on her left third toe. Her laboratory studies showed a hematocrit of 25.2%, blood urea nitrogen level of 90 mg/dl (normal range 6–20), and serum creatinine level of 9.7 mg/dl (normal range 0.4–1.1).
A chest radiograph showed mild pulmonary vascular congestion with small bilateral pleural effusions. There were no pulmonary infiltrates or nodules. Her hypertension was treated with metoprolol (5 mg intravenously) and her pulmonary edema was treated with furosemide (40 mg via intravenous push). However, she remained hypertensive and was transferred to our institution.
Past medical history
The patient had an unremarkable medical history. She denied any significant previous illnesses and had never undergone surgery. She had had 3 pregnancies and delivered 3 healthy children. The patient denied recent fever, chest pain, jaw pain, diaphoresis, mental status changes, or asymmetric leg swelling. She also denied the use of nonsteroidal antiinflammatory drugs.
The patient was not taking any medications. She noted the cephalosporin skin reaction, but denied any other drug allergies.
Social and family history
The patient worked as a nurse, was married, and had 3 children ages 18, 21, and 24 years. She denied ever using tobacco and had never used illicit drugs. She rarely drank alcoholic beverages. Her father had died of pancreatic cancer at the age of 68 years, and her mother was still alive at age 74 years. Her family history was negative for any cardiac, renal, or hematologic disorders.
The initial examination upon transfer to our institution revealed a comfortable-appearing woman with a temperature of 98.6°F and BP of 189/110 mm Hg. Her heart rate was 94 beats/minute, respiratory rate 14 breaths/minute, and she had an oxygen saturation of 98% on room air. She was again noted to have bilateral pitting edema in her lower extremities, but her bibasilar crackles had resolved. Her neurologic examination was unremarkable.
A complete blood cell count disclosed anemia and thrombocytopenia (Table 1). The peripheral smear revealed >5 schistocytes/hpf; spherocytes were absent (Figure 1). Additional laboratory results showed lactate dehydrogenase of 1,146 IU/liter (normal range 94–250), haptoglobin of <20 mg/dl (normal range 30–200), and a platelet count of 85,000/μl (normal range 150,000–440,000). A direct antiglobulin test was negative and her prothrombin and activated partial thromboplastin times were normal.
Table 1. Initial and subsequent laboratory results
Hospital day 1
Hospital day 2
Hospital day 4
Hospital day 6
White blood cell count, per μl
Differential count, %
Platelet count, per μl
Mean corpuscular volume, fl
Red blood cell distribution width index, %
Prothrombin time, seconds
Partial thromboplastin time, seconds
Urea nitrogen, mg/dl
Total bilirubin, mg/dl
Lactate dehydrogenase, IU/liter
Alkaline phosphatase, IU/liter
Aspartate aminotransferase, IU/liter
Alanine aminotransferase, IU/liter
Creatinine kinase, IU/liter
Troponin T, ng/ml
Red blood cells, per high-power field
White blood cells, per high-power field
Dysmorphic red blood cells
The urine dipstick showed “3+” blood and 500 mg/dl of protein. Microscopic examination of the urine revealed 0–2 white blood cells/hpf, 20–30 red blood cells/hpf, and 1 dysmorphic red blood cell. The protein:creatinine ratio was 4:1. A renal ultrasound showed 11.9 cm kidneys bilaterally without evidence of hydronephrosis. The patient was in frank renal failure with a creatinine level of 9.7 mg/dl.
A serologic evaluation was sent. This included testing for antinuclear antibodies, antibodies to double-stranded DNA and extractable nuclear antigens (Ro, La, Sm, and RNP), tests for hepatitis B and hepatitis C, serum complement and cryoglobulin levels, antineutrophil cytoplasmic antibodies, antistreptolysin O titers, anti–glomerular basement membrane antibodies, serum and urine electrophoresis, and measurement of ADAMTS-13 levels.
INTERIM CASE SUMMARY AND FORMULATION
An otherwise healthy woman developed cellulitis several weeks prior to evaluation in the emergency department for shortness of breath and lower extremity edema. Her presentation was remarkable for marked hypertension and volume overload. She was in acute renal failure (creatinine 9.7 mg/dl) and her peripheral blood smear showed schistocytes and thrombocytopenia.
Therefore, our patient presented with microangiopathic hemolytic anemia (MAHA) and several other issues, including thrombocytopenia, severe hypertension, and severe renal failure. None of these is a diagnosis in itself; each needs to be evaluated within its clinical context.
Microangiopathic hemolytic anemia
MAHA is a form of hemolysis characterized by the intravascular deposition of fibrin. The syndrome results in schistocyte (red cell fragment) formation, along with the laboratory findings typical of hemolysis (e.g., elevated concentrations of indirect bilirubin and lactate dehydrogenase and a low haptoglobin concentration). Although up to 50% of normal subjects have an occasional schistocyte on the peripheral blood smear, the presence of ≥2 schistocytes/hpf suggests the existence of a microangiopathic process (1). The polyspecific direct antiglobulin test is negative in MAHA because the process of red cell destruction in MAHA is not associated with deposition of an autoantibody or complement on the surface of the red blood cell.
Careful examination of the urine sediment is critical in the setting of renal dysfunction. Active urinary sediment is characterized by the presence of white blood cell casts, red blood cell casts, and/or dysmorphic red blood cells. These features generally indicate glomerular disease. Red blood cell casts were not present in the urine of our patient, pointing away from a glomerular process, although in rare cases red blood cell casts can be seen in acute interstitial nephritis.
The finding of renal failure in this patient is consistent with a working diagnosis of thrombotic microangiopathy (TM), which can be operationally defined as a combination of MAHA, thrombocytopenia, and microvascular thrombosis, here involving the kidney. The underlying causes of TM are multiple and a partial list is shown in Table 2.
Table 2. Differential diagnosis of thrombotic microangiopathy
Disseminated intravascular coagulation secondary to infection or malignancy
Idiopathic thrombotic thrombocytopenic purpura
Hemolytic uremic syndrome secondary to Shiga toxin–producing E coli
Severe pregnancy complications (preeclampsia/eclampsia/hemolysis, elevated liver enzymes, and low platelets syndrome)
Distinguishing among the causes of TM is often challenging because of overlap in the disorder's presenting symptoms. However, correct identification of the underlying diagnosis is essential, because the treatment of TM varies substantially according to its cause. For example, high-dose glucocorticoids and cyclophosphamide may be required to treat systemic vasculitis, whereas high-dose glucocorticoids are suspected of contributing to some cases of scleroderma renal crisis (SRC) and are contraindicated in that disorder (2). The mainstay of treatment for antiphospholipid syndrome (APS) is anticoagulation, not immunosuppression (3). As discussed below, of all of the causes of TM, only idiopathic thrombotic thrombocytopenic purpura (TTP) responds to plasma exchange.
One etiology of TM in a patient with renal dysfunction is malignant hypertension. It is postulated that severe hypertension fosters an inflammatory milieu in the vasculature that disrupts the endothelium, leading to activation of the coagulation cascade and the development of fibrinoid necrosis, edema, and local platelet aggregation. Red cells are damaged or fragmented as they try to pass through the fibrin deposits within narrowed, edematous arterioles (4). Most cases of malignant hypertension are preceded by lengthy periods of moderate hypertension that require medical therapy. Our patient had no history of hypertension prior to her presentation, but malignant hypertension remained a possibility as the inciting event.
The combination of otherwise unexplained renal dysfunction, MAHA, and thrombocytopenia should trigger the immediate working diagnosis of TTP. The renal dysfunction in idiopathic TTP is usually characterized by proteinuria, hematuria, and/or active urinary sediment, although frank renal failure as seen in this patient is distinctly uncommon. Early suspicion of this condition is essential because the mortality of untreated TTP is high and plasma exchange can be life-saving (5).
The classic pentad of idiopathic TTP includes MAHA, thrombocytopenia, renal abnormalities, fluctuating neurologic abnormalities, and fever. The full pentad of features, which was classically seen in the era before plasma exchange, is not required for the diagnosis of TTP. Therefore, it is critical to consider this diagnosis and to initiate plasma exchange in the presence of only otherwise unexplained MAHA and thrombocytopenia. Glucocorticoids may be added to plasma exchange if the initial response to treatment is poor, although there are no randomized controlled studies that demonstrate an improvement in patient outcomes with this strategy (1).
The finding of extremely low levels (i.e., <5% of normal activity) of the von Willebrand factor–cleaving protease (ADAMTS-13) and the demonstration of inhibitors to ADAMTS-13 are both highly specific tests for idiopathic TTP. However, the results of such testing are not usually available for several days, during which time the patient may die if plasma exchange is not initiated. Moreover, in a study of 48 patients with idiopathic TTP/hemolytic uremic syndrome (HUS), clinical responses to plasma exchange appeared to occur across a broad range of ADAMTS-13 levels, including some patients whose levels were >25% of normal (6). The clinical value of ADAMTS-13 appears to be in identifying patients who will likely relapse; namely those with an activity level <5% in the presence of an inhibitor.
Hemolytic uremic syndrome
When adult patients present with MAHA, thrombocytopenia, and prominent renal failure, with or without a prodromal diarrheal illness, they are often diagnosed as having adult HUS. In contrast, those patients with the same hematologic presentation, less renal involvement, and prominent neurologic abnormalities are more likely to be diagnosed as having TTP. Because there is great heterogeneity of presentations, some clinicians prefer to group these patients under the umbrella term of TTP/HUS. However, in general, patients with more classic HUS, such as those seen after a diarrheal illness associated with Shiga toxin–producing E coli, do not have low levels of ADAMTS-13 and do not respond to treatment with plasma exchange.
Severe glomerulonephritis (GN) can sometimes lead to MAHA-like changes on the peripheral blood smear. For example, in a review of patients with anti–glomerular basement membrane disease, 50% had peripheral blood smear changes consistent with MAHA, accompanied by the laboratory findings of hemolysis (7). Other potential etiologies of such renal dysfunction include membranous GN and pauci-immune rapidly progressive GN, although MAHA-like changes are less common in those conditions.
Systemic vasculitis can also be associated with MAHA and TM. Such patients typically have severe GN (8). Polyarteritis nodosa, a vasculitis of medium-sized muscular arterioles, can also cause severe malignant hypertension and lead to the abnormal urinalysis changes similar to those seen in our patient.
Systemic lupus erythematosus
TTP occurs in a subset of patients with systemic lupus erythematosus (SLE) (9). The 2 disorders have been estimated to occur together in ∼0.5% of SLE patients. In ∼75% of such cases, TTP presents in a patient with an established diagnosis of SLE (10). The finding of immune complex–mediated GN on renal biopsy is helpful in distinguishing SLE-associated TTP from idiopathic TTP. However, the features of TM on light microscopy alone do not differentiate lupus nephritis from either TTP or the APS that can be associated with SLE. Immunofluorescence and electron microscopy studies are essential for the demonstration of IgG, IgM, C3, and other immunoreactant depositions that characterize lupus nephritis.
APS is associated with thrombosis and/or pregnancy-related morbidity occurring in the setting of antiphospholipid antibodies. TM, thrombocytopenia, and renal disease caused by intraglomerular thrombi can all occur in the spectrum of APS. Catastrophic APS is a rare variant associated with high mortality due to widespread thrombosis (11). Due to the many clinical variations of APS, patients with antiphospholipid antibodies and TM are frequently misdiagnosed as having TTP/HUS, catastrophic APS, acute renal failure, and/or malignant hypertension (12).
Scleroderma renal crisis
SRC is a complication of systemic sclerosis (SSc) associated with malignant hypertension, rapidly progressive renal insufficiency, and MAHA (13). Although it is more common in patients with diffuse SSc, it can also be seen in those with limited SSc as well. Before the availability of angiotensin-converting enzyme (ACE) inhibitors, SRC was the most common cause of death among patients with SSc.
Other disorders associated with TM include disseminated intravascular coagulation secondary to sepsis or malignancy, various drugs, certain pregnancy complications, and posttransplant status. None of these conditions is the likely cause of TM in our patient.
On hospital day 1, the patient began hemodialysis with plasma exchange for a presumptive diagnosis of idiopathic TTP. Renal biopsy was debated seriously by the Renal Consultative team, but was not performed. Immunosuppressive and cytotoxic agents were not administered.
Over hospital days 2 through 6, the patient underwent daily plasma exchange and hemodialysis. Her BP improved slightly and there was some decrease in her peripheral edema. However, her anemia, thrombocytopenia, and renal failure persisted, with only a slight decrease in her lactate dehydrogenase (Table 1).
After discussion with the Hematology, Renal, and Transfusion Medicine teams, a decision was made to discontinue plasma exchange due to the lack of significant initial clinical improvement with therapy, and more importantly, due to additional data that pointed to an alternative diagnosis to explain the MAHA, thrombocytopenia, and renal failure.
Further history was obtained. The patient reported 6 months of joint pain and stiffness in the metacarpophalangeal joints of both hands, inability to make a fist, and symptoms consistent with Raynaud's phenomenon. A more detailed skin examination revealed thickening of the skin of her hands bilaterally, erythema in her periungual regions, and dilatation of the nailbed capillaries (Figure 2).
The results of her immunologic evaluation are shown in Table 3. The antinuclear antibodies were positive at a titer of 1:1,280 (speckled pattern). The ADAMTS-13 activity was low (41%), but well above the range characteristic of idiopathic TTP (i.e., <5% of the normal value) (14). An inhibitor screen was not indicated for this level of activity. The ADAMTS-13 result was returned the day after plasmapheresis was discontinued. This result supported the clinical suspicion that the patient did not have idiopathic TTP and that an alternative diagnosis was likely.
Table 3. Immunologic evaluation
IgM, MPL units
IgG, GPL units
Antineutrophil cytoplasmic antibody
Antinuclear antibody titer
Anti–glomerular basement membrane antibody, U/ml
≤1 index value
Serum protein electrophoresis
Urine protein electrophoresis
Human immunodeficiency virus antibody
ADAMTS-13 activity, %
A procedure was performed.
The procedure consisted of a skin biopsy of the dorsum of her left hand (Figure 3). The biopsy sample revealed sclerosis of the cutaneous tissues in the mid to deep dermis. There was a slight increase in dense collagen within this region, but no inflammation and no basement membrane abnormalities. These findings were consistent with either scleroderma or morphea.
The patient began treatment with captopril. The dosage was titrated quickly to the maximum amount (25 mg 3 times daily), with some improvement in her BP. However, management of the patient's BP remained challenging, requiring the addition of an angiotensin receptor blocker and a calcium-channel blocker to the ACE inhibitor. Over the next few days, her hematocrit value and platelet count began to improve, but she remained dialysis dependent.
Pulmonary function testing demonstrated a mild restrictive process, and a computed tomography scan of the chest revealed possible mild early interstitial lung disease. An echocardiogram showed a normal left ventricular ejection fraction of >55% and no evidence of pulmonary artery hypertension.
After discharge, the patient opted to switch to peritoneal dialysis. Eight months after her admission for shortness of breath, she underwent the successful implantation of a living-related renal allograft.
The assessment of this patient with MAHA, thrombocytopenia, severe hypertension, and severe renal dysfunction posed a clinical challenge that traversed multiple medical subspecialties. In the evaluation of such patients, it is essential to think beyond subspecialty boundaries and to complete a broad initial evaluation quickly because of the potentially dire consequences to the patient with this constellation of findings who does not receive appropriate therapy.
A number of findings in our patient eventually pointed away from the initial working diagnosis of idiopathic TTP. At the time of her admission, the patient had severe hypertension and severe renal failure, which are unusual features for TTP (15). In addition, there were subtle historic features and physical findings not appreciated by the physicians who initially evaluated her; specifically, the 6-month history of Raynaud's phenomenon and musculoskeletal reports, the mild sclerodactyly, and the dilatation of the nailbed capillaries. Later in her hospital course, information from the testing of her ADAMTS-13 status, the only slightly diminished ADAMTS-13 level without evidence of an ADAMTS-13 inhibitor, did not support the diagnosis of idiopathic TTP.
In the endothelium, von Willebrand factor (vWF) is present as ultra-large multimers of >20,000 kd. However, vWF circulates in plasma as a series of multimers, generally on the order of 500–20,000 kd. ADAMTS-13 (an acronym for a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) is the enzyme responsible for cleaving vWF after vWF is formed and secreted into the circulation by the endothelium and megakaryocytes/platelets (16).
A lack of ADAMTS-13 activity can result from either an inherited gene mutation or autoantibody formation. This leads to an increase in the plasma concentration of ultra-large vWF multimers, and it is postulated that an additional insult may then take place, resulting in the pathologic process seen in congenital or idiopathic TTP.
Since the discovery of ADAMTS-13 and its role in patients with TTP (17), assays for ADAMTS-13 activity and detection of inhibitors and autoantibodies have been developed. Results of these assays are not usually available for ≥2 days. Accordingly, the diagnosis and treatment of TTP must be initiated based on the presence of otherwise unexplained MAHA and thrombocytopenia alone without an alternative diagnosis. Because delayed treatment of TTP can be life-threatening, plasma exchange is recommended as the initial management strategy.
Plasma exchange has a dual effect in this condition: it functions to remove antibodies to ADAMTS-13 if present and to increase circulating levels of this protease by infusing plasma that contains normal levels. Given that plasma exchange in idiopathic TTP has been demonstrated to be more effective than plasma infusion alone, it has been surmised that both effects are required for clinical improvement (18).
SRC is estimated to occur in 4–6% of patients with SSc (scleroderma) (19). SRC is a catastrophic illness usually associated with the diffuse form of scleroderma. It usually presents within 3 years of the first scleroderma manifestation. SRC classically presents with malignant hypertension, MAHA, and diffuse skin thickening. Although in this case a skin biopsy was obtained, a careful physical examination of the skin and joints is often sufficient to make the diagnosis of scleroderma. Bland urine sediment with mild proteinuria and dysmorphic red blood cells, precisely the manner in which our patient presented, is characteristic of SRC.
Scleroderma kidney involvement was initially described in the mid-1800s, but the term SRC was not coined until 1952 (20). The underlying etiology of this condition is not well understood, but renal vascular intimal proliferation, vascular hyperreactivity, decreased cortical blood flow, and activation of the renin–angiotensin–aldosterone axis have all been implicated (21). The systemic manifestations of SRC are propagated through renin-aldosterone–mediated malignant hypertension. Therefore, primary treatment for SRC is aggressive ACE inhibition, even in the presence of renal failure. The role of angiotensin receptor blockers in the management of renal crisis is less clear (22).
Glucocorticoid use in patients with scleroderma has been postulated to trigger the onset of SRC, although this point is contentious. A case–control study showed that the use of high-dose steroids (≥15 mg/day) was associated with SRC when used in the 6 months prior to diagnosis (23). Although there is still considerable morbidity associated with SRC, mostly related to the effects of malignant hypertension, the introduction of ACE inhibitor therapy reduced the 1-year mortality in this disorder from 76% to <15% (24). Some patients who require dialysis are able to discontinue this intervention if ACE inhibition is maintained (13).
The diagnosis of SRC can be challenging for several reasons. SRC may be part of the initial clinical presentation of SSc, as was the case in our patient. Among patients who have established scleroderma, the differential diagnosis of renal failure must include hypovolemia and renal artery stenosis, as well as the adverse effects of medications. SRC can also have atypical presentations. For example, although hypertension is a hallmark of SRC, normal BPs have been described in some patients (21). It is essential for all patients with SSc to have routine BP monitoring to watch for the development of renal crisis.
After the patient was discharged from the hospital, assays for anti–RNA polymerase I/III antibodies were obtained and returned positive on 2 occasions at 312 and 254 units (normal value <20 units). In a Canadian cohort of patients with SSc, these antibodies were positive by enzyme-linked immunosorbent assay in 19.4% of patients and were associated with diffuse disease and the development of kidney and joint/tendon involvement (25). Therefore, anti–RNA polymerase antibodies may serve as an adjunctive diagnostic tool in patients with SSc and may be a more informative prognostic tool in portending SRC.