Thrombotic thrombocytopenic purpura without schistocytes on the peripheral blood smear.
Key Words: hemolytic uremic syndrome, plasma exchange, renal failure, schistocytes, thrombotic thrombocytopenic purpura
Thrombotic thrombocytopenic purpura (TTP) is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and ischemic manifestations, resulting from platelet aggregation in the arterial microvasculature. (1) Widespread formation of platelet microthrombi results in consumptive thrombocytopenia, tissue ischemia, and intravascular hemolysis caused by fragmentation of red blood cells as they traverse partially occluded arterioles and capillaries. The characteristic occlusive hyaline thrombi have been shown to consist primarily of von Willebrand factor and platelets. (2) Most adults with the idiopathic form of TTP have autoantibodies directed against a von Willebrand factor-cleaving protease in plasma. (3,4) This protease has recently been identified as a new member of the zinc metalloproteases, ADAMTS13 (A Disintegrin And Metalloprotease with ThromboSpondin Type 1 motifs). (5,6)
Before the advent of plasma-based therapy, TTP was associated with a mortality rate greater than 90%. Current outcomes of TTP and hemolytic uremic syndrome (HUS) have improved dramatically with the use of plasma exchange, which should be initiated promptly at diagnosis. The incidence of TTP in the United States has been estimated to be 3.7 cases per million people and appears to be increasing. (7)
The clinical syndrome of TTP has been associated with a classic pentad: thrombocytopenia, microangiopathic hemolytic anemia (MAHA), fever, and renal and neurologic involvement. Though the presence of all the above components is not required to make a diagnosis of TTP, the presence of thrombocytopenia and MAHA--as evidenced by prominent schistocytosis on the peripheral blood smear, decreased haptoglobin, and elevated lactate dehydrogenase levels--are usually used to diagnose the disorder. (8-11)
We present the case of a patient who had an episode of classic TTP followed by a relapse 4 months later. Her presentation at the time of relapse lacked clear-cut evidence of MAHA. However, she responded well to plasma exchange on both occasions.
A 66-year-old female was admitted to the hospital for progressive deterioration of renal function and decreasing platelet counts. The patient reported nausea and two episodes of watery diarrhea 2 hours after dinner 3 days before admission to our facility. She also reported fever and a brief period of confusion, with blurring of vision in both eyes as well as spasmodic pain in her lower back that lasted a few minutes. She had felt tired the whole day and had noticed that her urine was darker than usual and had decreased in volume. All of her symptoms were reminiscent of those resulting in an extended hospitalization about 4 months earlier. She was admitted to a community hospital on the evening of her symptoms and was subsequently transferred to our facility 3 days later.
The patient had a 20-year history of hypertension that was apparently under good control. About 10 years ago, she had an acute coronary syndrome necessitating percutaneous angioplasty; her coronary artery disease has been stable since then. She also had a history of hyperlipidemia and related a history of being diagnosed with porphyria about 30 years ago when she had severe abdominal pain; workup for the same 4 months ago was indeterminate. Her surgical history was significant for cholecystectomy, appendectomy, and hysterectomy. Her home medications included atorvastatin, atenolol, trazodone, verapamil, citalopram, calcium carbonate, and alprazolam. Allergies included sulfa and tetracycline. The patient has a 30 pack-year history of tobacco use but had quit smoking a number of years ago. She consumed alcohol occasionally and reported no use of recreational drugs and alternative medicines.
About 4 months before this admission, the patient had similar symptoms with more pronounced confusion and headache, renal failure, thrombocytopenia, and concomitant MAHA; the patient underwent daily plasmapheresis for 15 days, with concomitant hemodialysis for 10 days, for the diagnosis of TTP. In addition to the above-mentioned medications, the patient was also taking bupropion at that time. She had clear-cut evidence of microangiopathic hemolysis with abundant schistocytes on peripheral blood smear, elevated serum bilirubin, elevated lactic dehydrogenase, moderate reticulocytosis, and undetectable serum haptoglobin levels. Stool studies for leukocytes, Salmonella, Shigella, and Escherichia coli O157:H7 at that admission were negative. She was admitted with a creatinine level of 6.0 mg/dL, hemoglobin of 8.1 g/dL, and a platelet count of 69,000/[mm.sup.3]. Her laboratory values 1 week after discharge were 1.8 mg/dL, 11 g/dL, and 330,000/[mm.sup.3], respectively.
In the 4-month period until the current hospitalization, the patient had been generally well, with no recurrence of her symptoms. Her platelet count had normalized and her renal function was stable at follow-up with the hematology service 1 week after discharge from the hospital.
At admission to the community hospital, the patient complained of epigastric pain. Her diarrhea apparently resolved after the two episodes she had at home; her temperature was 102.9[degrees]F, blood pressure was 112/60 mm Hg, heart rate was 98 beats per minute and regular, and respiratory rate was 24 per minute. The physical examination was within normal limits except for mild epigastric tenderness. Neurologic examination was normal, with normal visual fields and funduscopy. Laboratory findings and other workup at the community hospitals are reported in the Table. Serum creatinine level had increased to 3.6 mg/dL on the morning of day 3, prompting transfer to our facility.
On transfer to our hospital, the patient was asymptomatic except for feeling exhausted. Medications on discharge from the other hospital included atorvastatin, trazodone, levofloxacin, famotidine, atenolol, verapamil, and citalopram. Upon admission, pantoprazole was substituted for famotidine. After obtaining blood, urine, and stool cultures, the patient was empirically started on piperacillin-tazobactam while discontinuing the levofloxacin. The patient reported no chest pain, dyspnea, abdominal pain, diarrhea, skin rash, arthralgias, hematuria, upper respiratory tract symptoms, or headaches. Her temperature was 36.7[degrees]C, with a pulse rate of 59 beats per minute, blood pressure of 160/84 mm Hg, and respiratory rate of 18 per minute.
On physical examination, the patient appeared weak and had a petechial rash over her anterior abdominal wall and soft palate. Her physical examination was unremarkable except for trace peripheral edema. Neurologic examination including the fundus and visual fields were normal.
Laboratory studies and other investigations on the day of admission to our facility (day 3 of illness) are reported in the Table. A chest roentgenogram and electrocardiogram were unremarkable, as was a renal ultrasound. Stool studies at both the hospitals, which included smear for leukocytes, routine cultures, and an assay for Clostridium difficile toxin, were negative. Antibiotic was subsequently discontinued after 2 days. With a presumptive diagnosis of recurrent TTP despite the absence of convincing evidence for MAHA, we proceeded with plasmapheresis on the day of admission. The patient underwent a total of 8 days of plasmapheresis over her 11-day stay in the hospital, with progressive improvement in her renal function and platelet counts (Fig. 1). To test the hypothesis that the clinical improvement was not related to the institution of plasmapheresis but possibly to the natural history of an unknown disease process, plasmapheresis was held for 48 hours. This resulted in a fall in the platelet counts, and she was subsequently restarted on plasmapheresis. She did not need hemodialysis during this hospitalization. The sequential response to plasmapheresis is shown in the accompanying figure. She was observed off plasmapheresis for 24 hours before being discharged home with a platelet count of 203,000/[mm.sup.3], serum creatinine of 2.6 mg/dL, and serum lactic dehydrogenase of 233 U/L.
The patient had fever, transient neurologic symptoms, progressive deterioration in renal function, thrombocytopenia, and a previous episode of TTP that had responded to plasma exchange; however, she had normal serum haptoglobin levels and only an occasional schistocyte on the peripheral blood smear.
This case, which we believe is one of relapsing TTP, is interesting for two reasons. First, the classic teaching and clinical experience since the first description of TTP by Moschcowitz (12) eight decades ago has been that schistocytes on the peripheral blood smear are a prerequisite for the diagnosis of TTP and HUS, and their apparent absence in the present case did hinder our ability to make a confident diagnosis before committing the patient to plasmapheresis. Reports of cases of HUS without evidence of microangiopathic hemolysis on the peripheral blood smear have been made previously. (13-15) Brilliant et al (13) and Scully et al (14) each reported a case of HUS without evidence of microangiopathic hemolysis. Morel-Maroger et al (15) reported the presence of fragmented red cells in only 9 of 14 patients with HUS. Fava and Galizia (16) reported a TTP-like syndrome in the absence of schistocytes; however, their case did not have any evidence of renal failure, but the patient did respond to plasmapheresis and steroids. Our case was interesting in that there was evidence of microangiopathic hemolysis during the first episode but it lacked such evidence at the time of its recurrence 4 months later; however, both the episodes responded promptly to plasma exchange.
Although careful attention should be paid to the microscopic examination of a blood smear in any patient presenting with acute renal failure and thrombocytopenia, the present case and those reported previously emphasize the need to consider TTP and HUS strongly in the differential diagnosis, in view of the overwhelming improvement in morbidity and mortality with plasma exchange therapy, even in the absence of some of the classic signs of microangiopathic hemolysis.
Some editors are failed writers, but so are most writers. --T.S. Eliot Table 1. Laboratory data during recurrent episode of thrombotic thrombocytopenic purpura (a) Laboratory Parameter Day 1 Day 2 Day 3 (b) Hemoglobin (g/dL) 12.7 11.5 11.7 Hematocrit (%) 38.2 35.3 34.5 WBC (per [mm.sup.3]) 9,200 27,000 15,700 Neutrophils (% of 95 84 85 WBC) Platelets (per [mm.sup.3]) 126,000 66,000 29,000 Peripheral blood Vacuolated Normocytic, slightly smear neutrophils hypochromic Serum creatinine 1.2 2.8 5.1 (mg/dL) BUN (mg/dL) 28 53 64 Urinalysis 2+ protein, No proteinuria, < 5 white hematuria, or cells, < 2 casts red cells per HPF Reticulocyte count 0.9 (% of RBC) Coomb test (direct Negative and indirect) LDH (normal range, 5,313 691 60-230 U/L) Total bilirubin (mg/ 2 1 dL) Unconjugated 1.5 0.8 bilirubin (mg/dL) D-dimer (normal, >20.00 0-0.50 [micro]g/mL) Haptoglobin (normal 83 range, 15-230 mg/dL) C3 (normal range, 82 70-200 mg/dL) C4 (normal range, 20 15-50 mg/dL) Serum ALT (U/L) 35 Serum AST (U/L) 43 Alkaline phosphatase 89 (U/L) PTT (seconds) 32.1 International 0.9 normalized ratio Blood cultures Negative Urine cultures Negative (a) WBC, white blood cells; BUN, blood urea nitrogen; RBC, red blood cells; LDH, lactic dehydrogenase; AST, aspartate transaminase; ALT, alanine transaminase; PTT, partial thromboplastin time. (b) Day of admission to our hospital. Laboratory values are from our hospital.
Accepted March 11, 2004.
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RELATED ARTICLE: Key Points
* Renal involvement is a hallmark of thrombotic thrombocytopenic purpura (TTP).
* Absence of schistocytes on the peripheral blood smear does not rule out TTP.
* Prompt institution of plasma exchange therapy is critical in management of TTP.
Sumanth R. Daram, MD, Marie Philipneri, MD, Nidhi Puri, BS, and Bahar Bastani, MD
From the Division of Nephrology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO.
Reprint requests to Dr. Bahar Bastani, Saint Louis University School of Medicine, 3635 Vista Ave, FDT-9N, Saint Louis, MO 63110. Email: email@example.com