THROMBOTIC THROMBOCYTOPENIC PURPURA IN A CASE OF SCLERODERMA RENAL CRISIS TREATED WITH TWICE-DAILY THERAPEUTIC PLASMA EXCHANGE

Abstract

We report the rare complication of thrombotic thrombocytopenic purpura (TTP) in an elderly patient with the uncommon scleroderma renal crisis (SRC) at the advanced age of 85 years. Initially, she was treated by standard daily one and a half plasma volume therapeutic plasma exchange (TPE), in combination with steroid therapy. Due to an unsatisfactory clinical response, she was consequently, treated by an intensive twice-daily one and a half plasma volume TPE regimen. Although there was an increase in the platelet count, a 7-day course of the intensive regimen did not elicit further propitious laboratory test results or a clinical improvement and the patient expired secondary to the pulmonary and cardiac conditions related to SRC. Intensive TPE administration has been advocated in few specific patients who are refractory to standard daily treatment. The unfavorable outcome in this case may be attributed to the multiple complications associated with her primary disorder. In conclusion, we observed intensive twice-daily TPE to increase temporarily the platelet count, but not to be of benefit in a patient with SRC and multiple organ failure. The two TPE regimens and outcomes are compared and the pathogenesis of TTP and scleroderma are discussed.

• Scleroderma renal crisis
• Systemic sclerosis
• Thrombotic thrombocytopenic purpura
• Therapeutic plasma exchange
• Twice-daily
• Intensive regimen

INTRODUCTION

Thrombotic thrombocytopenic purpura (TTP), first described in 1925 [[1]], is a clinical pentad of 1) thrombocytopenia (platelet count often < 30 × 10⁹/L), 2) hemolytic anemia with schistocytes, 3) neurologic symptoms ranging from transitory mental status changes to seizures and coma, 4) renal impairment and, 5) fever. The types of TTP are the acute, relapsing, and chronic relapsing; it can be idiopathic or associated with a diversity of disorders [[2]]. TTP has been reported as an uncommon complication of systemic sclerosis [[3]].

Systemic sclerosis (scleroderma) is a rare disease that was first described in 1753 [[4]]. It is a generalized connective tissue disorder characterized by deposition of excessive collagen and other extracellular matrix proteins in the skin and visceral organs. This leads to fibrosis of the integument and organ failure particularly the heart, lungs, kidneys and gastrointestinal tract [[5]]. Although the etiology is not known, the pathogenesis has been associated with an immune-based injury to the endothelium. Thus, the disease process involves an immunologic mechanism, vascular damage, and activation of fibroblasts [[6]].

We describe a patient with scleroderma renal crisis (SRC) who developed the rare complication of TTP. She was refractory to daily therapeutic plasma exchange (TPE), and, consequently, intensive TPE was administered by exchanging one and a half plasma volumes twice daily. The two regimens are compared.

CASE REPORT

An 85-year-old white female previously healthy was admitted to the American University of Beirut Medical Center because of progressive dyspnea of one-week duration. Four months prior to admission she started developing progressive skin thickening associated with itching over the distal extremities and face. On interview she had no history of cardiac, pulmonary nor renal disorders. She was not known to have hypertension, diabetes, fever, cough, nor chest pain. On physical examination, the patient, moderately overweight, was in respiratory distress. She was afebrile with a normal blood pressure and heart rate. A soft heart murmur but no friction rub was noted. Pulmonary auscultation revealed bilateral basal crackles. The integument was thick and tight over the distal extremities reaching the knees and elbows. The face had a similar integument and erythematous plaques. The fingertips had cuticular hypertrophy and acrosclerosis.

Initial laboratory studies were as follows: hematocrit (Hct), 40%; hemoglobin, 12.8 g/dL; leukocyte count, 7.6 × 10⁹/L with a differential count within normal range; platelet count, 295 × 10⁹/L; blood urea nitrogen (BUN) 13 mg/dL; creatinine, 0.8 mg/dL; serology was positive for anti-nuclear antibodies with a homogeneous pattern; and negative for anti-topoisomerase I (Scl-70), anti-SS-A(Ro), and anti-SS-B(La) antibodies. Roentgenogram of the lungs revealed diffuse pulmonary interstitial changes with small bilateral pleural effusions. The echocardiogram was normal. Skin biopsies from the forearm and leg were consistent with dermal sclerosis.

The diagnosis of systemic sclerosis (limited cutaneous subset of scleroderma) with pulmonary fibrosis was made according to the American College of Rheumatology criteria [[7]]. Treatment was initiated with inhaled B₂ stimulants and steroids with favorable response. On the fourth day of admission, her pulmonary functions deteriorated rapidly with recorded arterial blood gases: PaO₂, 27 mmHg; PaCO₂, 77 mmHg; pH, 7.19; and she required assisted respiration. Pulmonary embolism was ruled out by roentgenogram of the lungs that showed no diagnostic changes; moreover, the venous duplex scan showed no evidence of venous thrombosis in major veins of both lower extremities. Blood pressure rose to 180/100 mmHg with a rapid pulse rate. The electrocardiogram (ECG) revealed low voltage with ventricular premature systoles and coronary insufficiency involving the anterolateral myocardial wall. Laboratory studies were as follows: normal complete blood count and platelet count; BUN, 67 mg/dL, and creatinine, 1.3 mg/dL, these increased progressively to 136 mg/dL and 2.8 mg/dL on day 18, respectively. She was diagnosed to have SRC, with both cardiac and pulmonary involvement. Hemodialysis (HD) was started and a total of 8 sessions were administered over a 15-day period. Angiotensin converting enzyme inhibitors and intravenous cyclophosphamide pulse therapy were initiated.

Fourteen days after admission the patient became febrile (38.6°C) and was agitated with a transient change in her mental status requiring sedation. Laboratory studies revealed: Hct, 28%; hemoglobin, 8.8 g/dL; platelet count, 21.8 × 10⁹/L; lactate dehydrogenase (LDH), 2845 U/L; peripheral blood smear revealed schistocytes; BUN, 85 mg/dL; and creatinine, 1.7 mg/dL. TTP was diagnosed and daily TPE was administered. A continuous flow cell separator was used (Spectra, Cobe BCT, Lakewood, CO, U.S.A.). During each daily procedure, one and a half plasma volumes were exchanged, 60 mL/kg/day (4500 mL/day), and replaced with cryosupernatant (cryo-poor) plasma at a 1:1 ratio. Due to the modest improvement following 8 daily standard TPE sessions concomitant with steroid administration and HD, the TPE sessions were increased to twice a day and the same volume was exchanged during each session. Cryosupernatant plasma was maintained as the replacement fluid at a 1:1 ratio. This intensive treatment represented a plasma exchange of 120 mL/kg/day (9,000 mL/day). All other variables were maintained as during the standard daily TPE sessions. After 7 days of intensive twice-daily TPE, no distinct improvement was observed neither clinically nor in the laboratory blood test results of the patient. Clinically, her neurologic status continued to deteriorate. Regarding the laboratory studies, the LDH had dropped from 1902 U/L to 897 U/L during the daily sessions; this decrease continued during the first 3 days of intensive therapy to 461 U/L. Thereafter, there was a consistent increase reaching 669 U/L on the last day of the 7-day intensive TPE, and the LDH levels continued to escalate as the daily sessions of TPE were resumed reaching a level of 1123 U/L. Meanwhile, the Hct decreased from 27% to 23% after 4 days of intensive treatment initiation, necessitating the patient to be transfused twice, as demonstrated in Figure 1. During the first 6 days of intensive treatment the platelet count increased from 9 × 10⁹/L to 31 × 10⁹/L; however, it dropped again on day 7 of twice-daily TPE. Once the daily sessions were resumed the platelet count varied but remained below 35 × 10⁹/L. The peripheral blood smears continued to show schistocytes during both regimens of treatment. Due to the lack of appreciable improvement during intensive twice-daily TPE, other than a transient increase in the platelet count, daily sessions of TPE were resumed. However, these were discontinued after 8 days on account of no substantial progress in the patient's condition. In total, the patient underwent 23 sessions of TPE. The laboratory results in relation to the administration of TPE are demonstrated in Figure 1.

Figure 1. Serial changes of the LDH, Platelet count, and Hct over a 23 day treatment course.

Ultimately, the patient's cardiac and renal status deteriorated and she became comatose. The family consented to discontinue medications, TPE and HD; only mechanical ventilation was maintained. The patient expired 41 days after admission secondary to the pulmonary and cardiac conditions related to SRC.

DISCUSSION

To the best of our knowledge, intensive TPE in the treatment of TTP complicating SRC has not been previously reported. The patient we report is a case of TTP complicating rapidly progressive SRC with the known related interstitial lung and cardiac disorders [[5]]. Scleroderma has an incidence range of 2 to 9 cases per million population per year [[8]]. Furthermore, TTP is a rare complication of scleroderma [[3]]. Intensive TPE of single plasma volume twice daily has been recommended in TTP patients with fulminant disease or rapidly deteriorating neurologic status and in ABO-incompatible organ transplantation [[2]]. Because our patient was refractory to daily TPE administration, she was put on an intensive regimen of twice-daily TPE with one and half plasma volumes exchanged for 7 consecutive days. Despite administration of an intensive regimen, the patient remained refractory to TPE as demonstrated by her continuously deteriorating clinical status and laboratory blood test results that did not improve relative to the single daily TPE administration. Thus, this intensive TPE treatment failed to alter the course of the disease and the patient expired following rapidly progressive multi-system organ failure.

Although a transient increase in the platelet count was seen, the overall response to intensive TPE was not advantageous over the regular daily sessions. The unfavorable response may be attributed to the multiple comorbid complications associated with the patient's disorder. The rapidly progressing scleroderma of the limited cutaneous variety over few months is a unique course of her disease, which may imply an aggressive form. Scleroderma has its onset more commonly between the ages of 40 and 50 years; it is rare both in childhood and above the age of 80 years [[8]]. Moreover, recent studies have shown that patients with TTP often have in their plasma either the presence of unusually large von Willebrand factor (vWf) or, an increase the largest vWf due to a decrease or absence of the proteolytic enzyme, vWf metalloproteinase, which degrades the multimer [[9]]. Interestingly, in scleroderma there have been reports of an increased level of the vWf [[10]]. The endothelial injury in this patient may have been more fulminant because of the presence of two disease processes that lead to endothelial damage and eventually to end organ failure.

Conceivably, the aggressive form of the disease and the older age group made the response to this intensive regimen of TPE not more favorable than the standard daily administration. Further information needs to be assessed if more elderly patients are seen as the population at large gets older. In conclusion, we observed intensive twice-daily TPE to increase temporarily the platelet count, but not to be of benefit in a patient with SRC and multiple organ failure.