Plasma exchange in thrombotic thrombocytopenic ... - Europe PMC

Plasma exchange in thrombotic thrombocytopenic purpura manifestations d'un PTT au bout de plusieurs jours de plasmapherese pour le syndrome hemolytique-urenique. Dans ce dernier cas le traitement ne reussira pas. On suggere que la forme de debut du PTT peut varier beaucoup et l'hemolyse microangiopathique se manifester tardivement. Le traitement ideal n'a pas encore Three patients were recently treated ete defini. for thrombotic thrombocytopenic purpura (TTP). One presented with Thrombotic thrombocytopenic purtoxic shock syndrome; TTP devel- pura (TTP) is a disease' or synoped but promptly responded to a drome2 characterized by the followregimen of antiplatelet agents, ste- ing pentad: (a) fever (temperature roids and plasma exchange. In an- greater than 38.3°C); (b) microanother the manifestations of TTP de- giopathic hemolytic anemia (hemoveloped after presentation with hy- globin level less than 100 g/L and pertension and abdominal pain. This proportion of reticulocytes greater patient responded to a similar regi- than 5%); (c) purpura or other men but required extended treatment bleeding, generally with thrombefore remission could be maintained bocytopenia (platelet count less than with medications alone. In the third 75.0 X 109/L); (d) transient or perpatient the full TTP syndrome ap- manent neurologic signs; and (e) peared after several days of plasma renal disease, including hematuria, exchange treatment for hemolytic- proteinuria or azotemia (blood urea uremic syndrome. He did not re- nitrogen [BUN] level greater than spond. It is suggested that TTP may 40 mg/dL [urea level 14.3 mmol/L] present in many forms initially, that or serum creatinine level greater microangiopathic hemolysis may be than 3.0 mg/dL [265.2 ,mol/L]).3'4 a late manifestation and that the Tissue samples show typical mioptimal therapy is not known. crovascular occlusions consisting of platelet aggregates with lesser Observation de trois cas recents de amounts of admixed fibrin.5 The purpura thrombocytopenique throm- occlusions, which can be found in all botique (PIT). La premiere malade organs, have an unpredictable distrise presente en etat de choc septique; bution: among subsequently conle PIT qui survient cede rapidement firmed cases they have been detectau traitement 'a base d'antiplaquet- ed through biopsy of the skin in taires, de corticosteroides et de plas- 67%,6 of the gingivae in 39%7 and of mapherese. Dans le second cas le the bone marrow in 30%.' A more PTT, survenu chez une malade qui specific "prethrombotic" subendoetait entree pour hypertension ar- thelial deposition of hyaline has terielle et douleur abdominale, been described,5'9 as have mirepond a un traitement comparable croaneurysms at the arteriolar-capmais qu'il faut poursuivre longtemps illary junction,'0 though the latter avant de pouvoir entretenir la remis- have not been identified in all cases." sion par les seuls medicaments. Le The underlying defects and pathotroisieme malade presente toutes les genetic mechanisms are unknown. Treatment has largely been empirical, and all regimens have had From the divisions of nephrology and hema- only limited success.'2 Corticotology, University of Western Ontario, Lon- steroids have been tried alone,3 but don there have been better responses when they have been administered Reprint requests to: Dr. William F. Clark, in conjunction with other forms of Division of Nephrology, Victoria Hospital Corporation, 375 South St., London, Ont. therapy.'2 Platelet survival in paN6A 4G5 tients with TTP has been found to Edwin B. Toffelmire, MD, CM William F. Clark, MD, FRCP[C] Peter E. Cordy, MD, FRCP[C] Adam L. Linton, MB, FRCP[C] Reinhart C. Lohmann, MD, FRCP[C]

increase with corticosteroid therapy, possibly owing to a suppression of vascular inflammation.'3 Splenectomy has been used effectively to treat other forms of thrombocytopenia. Patients with TTP have undergone splenectomy as well as other forms of treatment,'4"5 and some have done well, but it is difficult to compare the outcome of these patients with that of patients who may not have been selected for the operation because their disease was more severe. It is also difficult to evaluate the removal of the spleen as a distinct treatment when it is associated with intraoperative prostaglandin release and transfusions of whole blood and plasma.'6 Since 1970'` a large variety of antiplatelet agents have been used in an attempt to minimize platelet aggregation in TTP. Again, the response is limited when they are given alone. Their use in conjunction with other forms of treatment is more promising,'2"8 but this inherently impairs evaluation of their effectiveness. Indeed, the balance of their possible detrimental actions (i.e., gastrointestinal, subarachnoid and nasal hemorrhages)'9 compared with any benefit has not been established.20 The administration of blood products containing plasma, first described by Lederer,' was re-established in 1959.2 Further studies have indicated that in some cases full benefit seems to be achieved by transfusion of the noncryoprecipitable plasma portion (as distinct from albumin alone), possibly because this restores a plasma factor that had been deficient;'6'22'23 in other cases removal of the plasma (by exchange transfusion or plasmapheresis) is required, presumably because it removes a plasma toxin, for full benefit.2425 Finally, immunosuppressive agents have been used. Limited experience with vincristine infusions26'27 suggests that they may be useful in treating an underlying endothelial cell disorder that may have caused the platelet aggregation.5 We recently saw three patients

CAN MED ASSOC J, VOL. 131, DECEMBER 1, 1984

1371

who presented with the classic pentad of TTP. All three were given multitherapy regimens, including plasma exchange.28 During each plasma exchange about 4.0 L of plasma was exchanged for 2.7 L of ABO-matched fresh frozen plasma and 1.3 L of normal saline and acidcitrate-dextrose anticoagulant. While receiving fresh frozen plasma, the patients were given chlorpheniramine maleate, 10 mg intravenously, as prophylaxis. In patient 2 remission could not be achieved with only dipyridamole, and antiplatelet drugs alone were not sufficient to maintain early remission. In patient 3 remission could not be achieved by treatment with adrenocorticosteroids, fresh frozen plasma infusions and plasma exchanges. Case reports

Patient 1 A previously well 31-year-old housewife noted the acute onset of palmar erythema and digital arthropathies, followed by fever (temperature 39°C) and rigors, nausea, watery diarrhea, generalized spreading of the macular rash, and hyperemia of the oropharyngeal and conjunctival mucosa. She was admitted to another hospital within 48 hours of the onset of her illness. Diplopia, blurred vision, hypotension (blood pressure 92/56 mm Hg while she was lying down) and azotemia (BUN level 72 mg/dL [urea level 25.7 mmol/L]) developed; however, her urine output averaged 2400 mL daily. Six days after the onset of her illness she was transferred to our hospital. She complained of myalgia in her legs and of transient frontal headaches. Her last menstrual period had started 2 weeks before the onset of the illness; she denied using tampons but said she had had a copious white, odourless discharge for several days. She looked ill and had a generalized purpuric rash. She was afebrile, but her blood pressure had dropped further, to 90/40 mm Hg while she was lying down; she had a regular heart rate of 110 beats/min. She had mild ptosis on the left, and her left pupil was 4 mm in diameter; her 1372

right pupil was 5 mm in diameter and was sluggishly reactive to light and accommodation. Her conjunctivae and the oropharyngeal and vaginal mucosa were hyperemic, and she had diffuse dandruff-like desquamation. Her palms were swollen and very erythematous. The remainder of the examination yielded unremarkable findings. At the time of transfer to our hospital, urinalysis revealed a moderate amount of blood and a trace of protein. In her peripheral blood the leukocyte count was 20.4 X 109/L (72% neutrophils, 20% band cells and 8% lymphocytes), the platelet count 91.0 X 109/L, the proportion of reticulocytes less than 1% and the zeta sedimentation ratio 40% to 55%; crenated erythrocytes and toxic granules in many of the leukocytes were seen in a smear. The clotting times were normal. The hemoglobin level was 131 g/L, the serum creatine kinase level was elevated, at 474 UIL, the serum lactate dehydrogenase (LDH) level was normal, at 147 U/L, the BUN level was 66 mg/dL (urea level 23.6 mmol/L) and the serum creatinine level was 3.4 mg/dL (300.6 ,umol/L). Culture of vaginal and conjunctival swabs yielded Staphylococcus aureus, but cultures of blood and urine yielded no microorganisms. A working diagnosis of toxic shock syndrome was made,29 and therapy with cloxacillin, 2 g intravenously every 6 hours, was started. The patient remained afebrile and hypotensive over the next 24 hours but became transiently confused, disoriented and agitated. Her hemoglobin level dropped to 82 g/L, and occasional fragmented erythrocytes were seen along with toxic granules in a blood smear. Her leukocyte count dropped to 6.1 X 109/L (79% neutrophils, 4% bands, 4% metamyelocytes and 13% lymphocytes). Her platelet count was 19.0 X 1 09/L. The results of a direct antiglobulin test were negative. Her serum LDH level increased to 296 U/L; the isoenzyme pattern was normal. The clotting times and the levels of plasma fibrinogen, fibrin degradation products and serum complement were normal, as were the results of a protamine sulfate test and protein electrophoresis. Im-


mune complexes were not detected. The results of testing for antinuclear antibody (ANA), lupus erythematosus cells and hepatitis B surface antigen (HBsAg) were all negative. Cultures of two blood samples yielded no microorganisms. The results of viral serologic testing suggested a recent infection with mumps and adenovirus, and a skin biopsy specimen showed traces of IgM and fibrinogen in the dermal vessels. The development of microangiopathic hemolytic anemia and a transient neurologic deficit in a person who had already had fever, renal abnormalities and a purpuric rash with thrombocytopenia could not be explained on the basis of toxic shock syndrome alone, so TTP was diagnosed. Treatment with continuous plasma infusion, prednisone, 14-

Hemoglobin dL 10 6- 6-(3)

3.1052X105 -

_

Platelets MpL X1405

BUN

080-

mg/dL

40_ 40-

_

O-

plasma exchange

plasma infjsion chlorpromazine ASA dipyridamole prednisone

0

2

4

6

8 10 12 14 16 18 20 Day

Fig. 1-Patient I received plasma exchange on days 2, 3, 4 and 5 after transfer to our hospital. Fresh frozen plasma was infused at a rate of 100 mL/h for the first 2 days. Three units of packed red cells were given on day 2. Chlorpromazine, 100 mg, was given intramuscularly for behavioural control. Therapy with acetylsalicylic acid (ASA), 325 mg given orally twice daily, was begun at the time of admission. Therapy with dipyridamole, 50 mg three times daily, was begun at the same time; the dosage was increased to 100 mg three times daily on day 3 and 150 mg three times daily on day 5. Therapy with prednisone, 60 mg daily, was also begun at the time of admission; after improvement was maintained the dosage was tapered over 40 days, and then the drug was discontinued. BUN = blood urea nitrogen.

60 mg daily, dipyridamole, in- evident, but funduscopy revealed bicreased from 50 to 150 mg three lateral nerve-fibre-layer hemortimes daily over 5 days, acetylsali- rhages, engorged vessels and nmacucylic acid (ASA), 325 mg twice lar edema. A choroidal effusion was daily, daily plasma exchange and evident superiorly, and bullous retichlorpromazine, 100 mg as required nal detachments were noted inferiorto control behaviour, was begun ly. There was no arteriovenous nicking or other vascular abnormality. (Fig. 1). After the first day she was much The chest was clear, and the cardiac more alert and oriented, and her sounds were normal. Abdominal explatelet count began to increase. On amination revealed marked right the fourth day of this treatment her upper quadrant tenderness but no platelet count was 250.0 X 109/L, signs of peritoneal involvement. Neiand no fragmented erythrocytes ther the liver nor the spleen was were seen in peripheral blood palpable. A stool sample tested for smears. Plasma exchange was occult blood yielded negative results. stopped, and her improvement con- The results of a complete neurologic tinued. The reticulocyte count had examination were normal. The inirisen to 153.2 X 109/L by day 11. tial electrocardiogram was unreOn day 12 full-thickness palmar markable, but nonspecific repolaridesquamation was complete. Over zation changes suggestive of toxic the following 40 days prednisone myocarditis developed. was discontinued. A confluent macUrinalysis showed a moderate ular rash developed over her face amount of protein, 10 to 50 erythroand trunk, but it resolved on discon- cytes per high power field and 3 to 6 tinuance of dipyridamole. She has red-cell casts per slide. In the perbeen in good health for over a year, ipheral blood the leukocyte count taking only ASA, 325 mg twice was 16.6 X 109/L, the platelet count 5.0 X 1 09/L and the proportion of daily. reticulocytes 2%; occasional fragPatient 2 mented erythrocytes, toxic granules and numerous immature cells were A 39-year-old, obese woman was seen in a smear. The clotting times admitted to another hospital com- were normal, with the concentration plaining of intermittent pain in the of fibrinogen being 4.8 g/L and that right upper quadrant of the abdo- of fibrin degradation products 10 to men and bilateral visual blurring of 40 ,ug/mL. The serum haptoglobin sudden onset, both of which had level was low, the hemoglobin level 134 g/L, the LDH level 1500 U/L begun the previous day. Her past history included only (with isoenzymes 4 and 5 predomimiscarriages related to Rh incom- nating), the serum glutamic oxaloapatibility and tubal ligation 10 years cetic transaminase concentration 76 earlier. She had been otherwise well U/L and the total bilirubin level 3.1 until 8 months before admission, mg/dL (53 ,tmol/L). The BUN and when she began to experience creatinine levels were both high normonthly week-long episodes of the mal, and the creatinine clearance rate same type of abdominal pain, which was 44 mL/min. A direct antiwas not associated with gastrointes- globulin test gave negative results, tinal symptoms. It was exacerbation and platelet antibodies were not deof this pain that had led to admis- tected. The levels of the third and sion. She denied fever, chills, prior fourth components of complement infection and previous renal, neuro- and of total hemolytic complement logic or psychiatric disorders. She were normal; immune complexes was noted to be thrombocytopenic. were absent. ANA and HBsAg were A major generalized seizure oc- not detected. A bone marrow aspicurred, and the day after admission rate was hypercellular. Seven blood she was transferred to our hospital. samples, taken throughout the womThe woman was obviously dis- an's illness, were sterile; Haemophtressed by her abdominal pain. She ilus parainfluenzae and Candida was afebrile, had a blood pressure of were isolated from a throat swab, 220/120 mm Hg while lying down and Escherichia coli was cultured and had a regular pulse of 90 beats/ from the urine. min. No petechiae or purpura was In hospital the hypertension was

treated with diazoxide and nitroprusside and eventually controlled with hydrochlorothiazide, triamterene and metoprolol. The patient received prophylactic antibiotic therapy until the initial culture reports were received and, because of the low levels of platelets and hemoglobin, was given packed red cells and plasma. By day 7 (Fig. 2) she had become febrile, the BUN level had risen to 37 mg/dL (urea level to 13.2 mmol/L) and the creatinine level to 2.4 mg/dL (212.2,umol/L), and the hemoglobin level had dropped to 71 g/L, with characteristics of microangiopathic hemolysis being found. Diffuse petechiae and purpura developed while thrombocytopenia continued. Left-sided paresthesia with transient weakness developed; although an electroencephalogram was diffusely abnormal, computed tomography (CT) images of the head were normal. Therapy with dipyridamole, 50 mg three times daily, was begun, but when no response was seen after 5 days plasma exchange was initiated. An immediate response was evident by a platelet count of 361.0 X 109/L, a reticulocyte count of 720.0 X 109/L and an LDH concentration of less than 400 U/L. It was obvious that a hematologic remission had been achieved. However, rapid deterioration accompanied the discontinuance of her treatment. Reinstitution of the same therapy with the addition of ASA did not produce as prompt an effect, but the LDH concentration and the platelet and reticulocyte counts did respond. On two such occasions (days 29 and 35), with a good reticulocyte response and platelet counts above 75.0 X 109/L, discontinuation of the plasma exchange alone resulted in prompt deterioration despite infusions of fresh frozen plasma. High-dose corticosteroid therapy was added: initially it did not alter the erythrocyte or platelet counts; however, when another remission became evident on day 46, it was maintained in the absence of plasma exchange. The patient was eventually discharged from hospital while receiving tapering doses of prednisone and continued taking an antihypertensive agent, ASA and dipyridamole.


1373

Her serum LDH levels and hematologic indices remained normal for 91/2 months after she had been admitted, at which time she arbitrarily discontinued the ASA and dipyridamole. Ten days later she presented to hospital, again with colicky epigastric pain, a blood pressure of 184/114 mm Hg and a platelet count of 45.0 X 109/L. Further investigations confirmed a relapse of TTP. Therapy with ASA and dipyridamole was restarted, but the full regimen of ASA, dipyridamole, prednisone, plasma infusions and plasma exchange was again necessary to achieve remission. A further relapse 5 months later was treated successfully in the same manner. Patient 3

A 35-year-old man was admitted to a neighbouring hospital with the sudden onset of painless gross hematuria. His past history included a myocardial infarction at the age of 29 years, followed by resection of a ventricular aneurysm a year later. He had been otherwise free of complications and in good health until 1 week before admission, when he had presented to his family physician with a right-sided sore throat and earache of sudden onset. A throat swab had produced only normal flora when cultured, so the patient was given no specific treatment, and the complaint gradually subsided. He denied having had fever, chills or any history of renal, neurologic or psychiatric symptoms. His only medications were digoxin and isosorbide dinitrate. The patient was afebrile but mildly icteric and had occasional petechiae. Mild pharyngeal erythema was seen, and a soft, nontender right jugulodigastric lymph node was palpable. The chest was clear, and the cardiac sounds were normal. The abdomen was nontender, the spleen was not palpable, and no occult blood was detected in a stool sample. The results of a complete neurologic examination were normal. Urinalysis confirmed the hematuria, and granular casts were seen. In the peripheral blood the leukocyte count was 12.1 X 109/L, the proportion of reticulocytes 1.3% and the platelet count 6.0 X 109/L; fragmented erythrocytes and sphero1374

cytes were seen in a smear. The clotting times were normal, with the concentration of fibrinogen being 2.8 g/L and that of fibrin degradation products less than 10 ,g/mL. The hemoglobin level was 134 g/L, there was methemalbumin in the serum, the serum haptoglobin level was low, and the results of a direct antiglobulin test were negative. The LDH and total bilirubin concentrations were grossly elevated, the BUN level was 47 mg/dL (urea level 16.8 mmol/L) and the creatinine concentration was 2.4 mg/dL (212.2 ,umol/L). Antiviral antibody titres suggested recent influenza A and adenovirus infections, and the antistreptolysin 0 test yielded negative results. Cultures of blood samples, repeated once, and of urine yielded no microorganisms.

A working diagnosis of hemolytic-uremic syndrome was made on the basis of the microangiopathic hemolytic anemia, the abnormal urine sediment and the azotemia. Treatment was started in hospital (Fig. 3), the patient receiving a 4-L plasma exchange on days 1, 3, 6 and 8 and daily infusions of fresh frozen plasma totalling 5.0 L during this period. Daily blood counts showed the rapid development of anemia, which was confirmed on a smear as being of the microangiopathic hemolytic type. The reticulocyte count rose to 400.0 X 109/L, with 110 nucleated erythrocytes/,uL in the peripheral blood. The platelet count remained below 10.0 X 109/L. On day 8 an acute organic brain syndrome characterized by agitation, confusion, delusions and aphasia de-

16-

Hemoglobin 14 g/dL 12108t

6X105 - 1) 5x105

t

(2) (2)

t

t

(2)

(2)

+

(2)

t

(2)

-

4x105 Platelets /ML

3105 2X105-

1x105 0BUN mg/dL

604020-

plasma exchange plasma infusion ASA dipyridamole prednisone

99

9

99999

9

999

99t 9

99999 t

*1m.. U11

0

r-

0

10

20

30

40

Day

50

60

1-l

70 3

1

1l

5 7 Month

Fig. 2-Patient 2 began plasma exchange on day 12 after transfer. On some days between 1 and 7 units of fresh frozen plasma were infused. Two to three units of packed red cells were infused to maintain the hemoglobin level above 70 g/L. Therapy with ASA, 75 mg daily given orally, was started on day 21. Therapy with dipyridamole, 50 mg three times daily, was started on day 7; the dosage was increased to 100 mg three times daily on day 51 and 150 mg three times daily on day 69. Therapy with prednisone, 60 mg daily, was started on day 44; the dosage was eventually tapered to 10 mg daily, and finally the drug was discontinued.


veloped. On day 9 his temperature rose to 38.5°C. With the development of the classic pentad of TTP he was transferred to our hospital. Treatment with daily plasma exchange and methylprednisolone, 25 mg intravenously twice a day, was begun. The patient remained febrile, but blood cultures (repeated twice) yielded no microorganisms. Oral medication was refused, so haloperidol was administered intramuscularly for behavioural control. During the next 2 days there was no change in his status other than transient neurologic abnormalities. On day 11 he became more restless, disoriented and uncooperative; his responses were inappropriate. A total of 35 mg of haloperidol was ineffective, and chlorpromazine, 100 mg given intramuscularly three times, was used to gain control. Over the next 2 days the rate at which the erythrocyte count declined decreased, and the platelet count seemed to increase. However, the serum LDH and total bilirubin levels increased, and his neurologic status deteriorated further. Infusion of fresh frozen plasma was added to the daily regimen of plasma exchange. His neurologic status continued to fluctuate, but CT scans and the cerebrospinal fluid remained normal. On day 20 his family refused consent to the continued daily plasma exchange. Apneic episodes developed, and respiratory 14 Hemoglobin 12 8g/dL 6

(2X

12X

(2)

(3)

X2}

14X103-8 Platelets -x3 l,L

X

1ox103

I'

6x103 /

V

80BUN 60-, mg,/dL 40 20-

plasma exchange plasma infusion chlorpromazine methylprednisolone

t t

t

t t t t t tt t t

0

2

4

6

8 10 12 14 16 18

Day

Fig. 3-Patient 3 received intermittent plasma exchange and infusion of 2 to 10 units of fresh frozen plasma before transfer to our hospital on day 9. Therapy with methylprednisolone, 25 mg given intravenously twice daily, was started after transfer, and chlorpromazine, 300 mg, was given intramuscularly on two occasions to control behaviour.

arrest occurred. A postmortem examination was refused.

Discussion

These three patients demonstrate a wide variation in the presentation of TTP and in the response to treatment. Each patient had complained of symptoms for several days before the full syndrome became manifest; each became critically ill and received several kinds of therapy. Patient 1 clearly presented in a manner typical of toxic shock syndrome,30 which proceeded with the development of body and palmar desquamation. However, the transient ptosis, visual blurring, pupillary inequality and quite marked fluctuations in personality were not consistent with this syndrome alone. The late, precipitous development of microangiopathic hemolysis in the absence of intravascular fibrinogen consumption or fibrinolysis completed the pentad of TTP. The temporal relation of anemia in this presentation suggests that hemolysis may be a late consequence of the disorder. The relation of TTP to recent mumps or adenovirus infection,3 or even more remarkably to toxic shock syndrome, in this previously healthy woman supports the hypothesis that TTP may sometimes be secondary to a primary insult and that this primary insult may be an infection.4 The course of her illness changed dramatically with the initiation of immunosuppressive and antiplatelet therapy. Which components of treatment were critical in this patient is not known, but since dipyridamole was discontinued without consequence shortly after remission had been achieved (because of an apparent adverse drug reaction), it seems that this medication was not essential at that time. In contrast, patient 2 presented three times with hypertension and colicky abdominal pain, like Weinstein's pre-eclampic patients who were labelled with the "HELLP" syndrome (Hemolysis, Elevated Liver enzyme levels and a Low Platelet count).3' These features preceded the development of the TTP pentad. Dipyridamole had been given early in the course of her disease, but it was not until plasma exchange was performed that her

hematologic indices were affected. Her initial inability to maintain hematologic remission in the absence of plasma exchange may have indicated a continuing process. Immune complexes were not detectable on three occasions in this patient.25 It is possible that during relapses there is a plasma factor present that inactivates either prostacyclin or another plasma factor that would normally stabilize prostacyclin32 or stimulate its production.33 The mechanism by which remissions are maintained in the presence of ASA and dipyridamole and in the absence of continued support by plasma exchange is not known but has been observed by others.34 Although it may simply be part of the natural course of the disease, it is of interest that relapse occurred shortly after the antiplatelet agents were discontinued. Patient 3 intially presented with the features of the rare adult form of hemolytic-uremic syndrome. No response to aggressive management was evident; in fact, the pentad of TTP was demonstrated with time. While hemolytic-uremic syndrome often differs from TTP when several characteristics are compared,4 the course of the illness in this patient suggests a relation between the two disorders. Although there was evidence of an initial infection, which indicates that his disease may have been secondary TTP, the course supports the suggestion that some forms of hemolytic-uremic syndrome and TTP are actually portions of the spectrum of one disorder,2'35'36 regardless of the stimulus causing that defect to be unveiled. This patient's disease also represents a subgroup of TTP that is resistant to both infusions of fresh frozen plasma (51 in this case) and

plasma exchange (over

11

L).12,24,28

Furthermore, no obvious benefit was observed when treatment with infusions of fresh frozen plasma or plasma exchange became more intense (totalling 56 L) or when high-dose corticosteroid therapy was added to the regimen. The patient refused oral antiplatelet therapy when an acute organic brain syndrome developed. Wensley and Cuthbert37 recently reported the remission of TTP in a patient given chlorpromazine for treatment of his confusional state after a trial of ASA and dipy-


1375

ridamole had failed. As a membrane stabilizer38 and antihemolytic agent39 chlorpromazine may exert a therapeutic effect in TTP. Indeed, it is possible that an initial response was occurring in our patient on days 11 to 13, coincident with the parenteral chlorpromazine administration. Unfortunately the effects of chlorpromazine given to patient 3 as an antipsychotic agent cannot be separated from the effects of the other treatments administered at the same time. Although the optimal therapy for TTP-associated acute brain syndrome is not known, chlorpromazine has theoretical advantages over other antipsychotic agents. Patient 1 responded when several treatments were begun together; patient 2 responded in a dramatic fashion only when corticosteroid therapy was added to plasma exchange and administration of antiplatelet agents; and no obvious response was observed in patient 3 despite high doses of steroids, daily plasma exchange and plasma infusions. Patient 3 was difficult to treat when the acute organic brain syndrome developed. One could suggest that the absence of antiplatelet agents played a role in his lack of hematologic or clinical response. However, in patient 2 the antiplatelet therapy exhibited no "remissioninducing" property by itself and was unable to sustain remissions associated with plasma exchange until high-dose corticosteroid therapy wag added. Thus, intensive plasma exchange and plasma infusion coupled with either steroid or antiplatelet therapy is not capable of inducing hematologic remission in all cases of TTP. References 1. Moschcowitz E: An acute febrile pleio-

chromic anemia with hyaline thrombosis of the terminal arterioles and capillaries. Arch Intern Med 1925; 36: 89-93 2. Umlas J, Kaiser J: Thrombohemolytic thrombocytopenic purpura (TTP): a disease or a syndrome? Am J Med 1970; 49: 723-728 3. Amorosi EL, Ultmann JE: Thrombotic thrombocytopenic purpura: report of 16 cases and review of the literature. Medicine (Baltimore) 1966; 45: 139-159 4. Bukowski RM: Thrombotic thrombocytopenic purpura: a review. Prog Hemost Thromb 1982; 6: 287-337 1376

5. Feldman JD, Mardiney MR, Unanue ER et al: The vascular pathology of thrombotic thrombocytopenic purpura: an immunohistochemical and ultrastructural study. Lab Invest 1966; 15: 927-946 6. Kwaan HC: The pathogenesis of thrombotic thrombocytopenic purpura. Semin Thromb Hemostas 1979; 5: 184-198 7. Goodman A, Ramos R, Hirsch SA et al: Gingival biopsy in thrombotic thrombocytopenic purpura. Ann Intern Med 1978; 89: 501-504 8. Berkowitz LR, Dalldorf FG, Blatt PM: Thrombotic thrombocytopenic purpura; a pathology review. JAMA 1979; 241: 1709-1710 9. Gore I: Disseminated arteriolar and capillary platelet thrombosis; a morphologic study of its histogenesis. Am J Pathol 1950; 26: 155-167 10. Orbison JL: Morphology of thrombotic thrombocytopenic purpura with demonstration of aneurysms. Am J Pathol 1952; 28: 129-143 11. Harkness DR, Byrnes JJ, Lian EC-Y et al: Hazard of platelet transfusion in thrombotic thrombocytopenic purpura. JAMA 1981; 246: 1931-1933 12. Bukowski RM, Hewlett JS, Reimer RR et al: Therapy of thrombotic thrombocytopenic purpura: an overview. Semin Thromb Hemostas 1981; 7: 1-8 13. Harker LA, Slichter SJ: Platelet and fibrinogen consumption in man. N Engl J Med 1972; 287: 999-1005 14. Cuttner J: Thrombotic thrombocytopenic purpura: a ten-year experience. Blood 1980; 56: 302-306 15. Salky BA, Kreel 1, Gelernt IM et al: Splenectomy for thrombotic thrombocytopenic purpura. Mt Sinai J Med (NY) 1983; 50: 56-59 16. Nalbandian RM, Henry RL: A proposed comprehensive pathophysiology of thrombotic thrombocytopenic purpura with implicit novel tests and therapies. Semin Thromb Hemostas 1980; 6: 356390 17. Jobin F, Delage JM: Aspirin and prednisone in microangiopathic hemolytic anemia. Lancet 1970; 2: 208-210 18. Amorosi EL, Karpatkin S: Antiplatelet treatment of thrombotic thrombocytopenic purpura. Ann Intern Med 1977; 86: 102-108 19. Rosove MH, Ho WG, Goldfinger D: Ineffectiveness of aspirin and dipyridamole in the treatment of thrombotic thrombocytopenic purpura. Ann Intern Med 1982; 96: 27-33 20. Zacharski LR: Aspirin, dipyridamole, and thrombotic thrombocytopenic purpura [C]. Ibid: 679 21. Rubenstein MA, Kegan EM, MacGillviray MH et al: Unusual remission in a case of thrombotic thrombocytopenic purpura syndrome following fresh blood exchange transfusion. Ann Intern Med 1959; 51: 1409-1419 22. Byrnes JJ, Khurana M: Treatment of


23. 24.

25.

26.

thrombotic thrombocytopenic purpura with plasma. N Engl J Med 1977; 297: 1386-1389 Byrnes JJ: Thrombotic thrombocytopenic purpura. Adv Intern Med 1980; 26: 131157 Ansell J, Beaser RS, Pechet L: Thrombotic thrombocytopenic purpura fails to respond to fresh frozen plasma infusion. Ann Intern Med 1978; 89: 647-648 Sacher RA, Phillips TM, Shashaty GG et al: Demonstration of immune complexes in thrombotic thrombocytopenic purpura and effect of exchange transfusion. Scand J Haematol 1980; 24: 373-380 Gutterman LA, Stevenson TD: Treatment of thrombotic thrombocytopenic purpura with vincristine. JAMA 1982;

247: 1433-1436 27. Schreeder MT, Prchal JF: Successful treatment of thrombotic thrombocytopenia purpura by vincristine. Am J Hematol 1983; 14: 75-78 28. Bukowski RM, King JW, Hewlett JS: Plasmapheresis in the treatment of thrombotic thrombocytopenia purpura. Blood 1977; 50: 413-417 29. Centers for Disease Control: Follow-up on toxic shock syndrome. MMWR 1980; 29: 441-445 30. Wager GP: Toxic shock syndrome: a review. Am J Obstet Gynecol 1983; 146: 93-102 31. Weinstein L: Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy. Am J Obstet Gynecol 1982; 142: 159-167 32. Remuzzi G, Imberti L, de Gaetano G: Prostacyclin deficiency in thrombotic microangiopathy. Lancet 1981; 2: 14221423 33. Remuzzi G, Misiani R, Mecca G et al: Thrombotic thrombocytopenic purpura - a deficiency of plasma factors regulating platelet-vessel wall interaction? [C]. N Engl J Med 1978; 299: 311 34. Myers TJ, Wakem CJ, Ball ED et al: Thrombotic thrombocytopenic purpura: combined treatment with plasmapheresis and antiplatelet agents. Ann Intern Med 1980; 92: 149-155 35. Kaplan BS, Drummond KN: The hemolytic-uremic syndrome is a syndrome [EJ. N Engl J Med 1978; 298: 964-966 36. Ridolfi RL, Bell WR: Thrombotic thrombocytopenic purpura. Report of 25 cases and review of the literature. Medicine (Baltimore) 1981; 60: 413-428 37. Wensley RT, Cuthbert AC: Response of thrombotic thrombocytopenic purpura to chlorpromazine. Br Med J 1982; 284: 1446 38. Seeman P: The membrane actions of anaesthetics and tranquilizers. Pharmacol Rev 1972; 24: 583-655 39. Born GVR, Wehmeir A: Inhibition of platelet thrombus formation by chiorpromazine acting to diminish haemolysis. Nature 1979; 282: 212-213 For prescribing information see page 1407-