TTP
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Bone Marrow Transplantation (2000) 25, 679–680 2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt Case report Plasma exchange as successful treatment of thrombotic thrombocytopenic purpura post autologous bone marrow transplant in a child DE Plews 1 , ML Turner 1 and WHB Wallace 2 Departments of 1 Transfusion Medicine, Royal Infirmary of Edinburgh, and 2 Paediatric Oncology, Royal Hospital for Sick Children, Edinburgh, UK Summary: We describe the case of a small child with stage IV neuroblastoma who developed thrombotic thromobocy- topenic purpura (TTP) post autologous bone marrow transplant. Pneumococcal sepsis may have been the cause, a previously unreported association in trans- plant-associated TTP. Despite the child’s size (10 kg) and the severity of the disease early intensive treatment with whole blood exchange and subsequently plasma exchange with cryosupernatant proved to be rapidly effective, in contrast to previous reports on its ineffec- tiveness in this setting. Bone Marrow Transplantation (2000) 25, 679–680. Keywords: thrombotic thrombocytopenic purpura/ haemolytic uraemic syndrome; bone marrow transplan- tation; plasma exchange; cryosupernatant Case report A2.-year-old female presented 13 days post autologous bone marrow transplant with frank haemoglobinuria, epis- taxis and gastrointestinal bleeding. Six months previously she had been diagnosed as having stage IV neuroblastoma and had been randomised to the ENSG 5 trial. She had received seven courses of chemotherapy (vincristine, cyclo- phosphamide, etoposide and alternate carboplatin/cisplatin, ie alternating OPEC/OJEC), followed by definitive tumour excision and autologous bone marrow transplantation. Con- ditioning was with melphalan 200 mg/m 2 following prim- ing with cyclophosphamide 300 mg/m 2 . She received 650 ml of autologous bone marrow with a total CD34 count of 4 × 10 6 /kg. The transplant was uncomplicated until she developed a pneumococcal septicaemia on day + 10 mani- fest by a febrile episode and positive cultures. This resolved rapidly with prompt antibiotic therapy, initially with genta- Correspondence: Dr DE Plews, Department of Transfusion Medicine, Royal Infirmary of Edinburgh, Lauriston Place, Edinburgh, EH3 9YW, UK Received 4 August 1999; accepted 7 November 1999 micin and ceftazidime, changed to benzyl penicillin when culture results were available. On day + 12 she had minor gastrointestinal bleeding asso- ciated with a rising serum bilirubin to 69 mmol/l. Within 24 h, she was drowsy, had frank haemoglobinuria, a bloody nasogastric aspirate, epistaxis and loose, bloody stools and developed repetitive arm movements. Laboratory para- meters demonstrated a falling haemoglobin (104 g/1 to 87 g/1), falling platelet count (56 × 10 9 /1 to 32 × 10 9 /1), ris- ing urea (5.4 mmol/1 to 7.3 mmol/l) and creatinine (47 mmol/1 to 57 mmol/l). There was marked red cell frag- mentation on the blood film. Coagulation was normal. A serum lactate dehydrogenase (LDH) was 3980 U/l. A diag- nosis of thrombotic thrombocytopenic purpura secondary to bone marrow transplantation and pneumococcal sepsis was made. Over the next 12 h she became progressively more hypertensive with a blood pressure of 130/90 mm Hg requiring treatment with hydralazine and subsequently lab- etalol infusion. By day + 14 she was obtunded (GCS 11) and frankly haemorrhagic indicating the need for thera- peutic intervention. In view of the problems associated with the child’s size (10 kg) and venous access initial treatment was with daily manual whole blood volume exchange (800 ml) with leuco- cyte-depleted whole blood. This resulted in a fall in LDH to 3123 U/l, but no clinical improvement. On day + 18 after insertion of a Quentin line we were able to perform a plasma exchange with two volumes of cryosupernatant using a Cobe cell separator with a whole blood prime. This produced immediate improvements in blood pressure con- trol and by 12 h she was alert and speaking appropriately. Daily plasma exchanges with cryosupernatant continued until day + 32 when her serum LDH had normalised and there was no evidence of fragmentation on the blood film. It was stopped at day + 34 (see Figure 1). She continued to haemorrhage significantly throughout this period necessitating alternate day platelet transfusions despite our strong reservations on their use in this con- dition. Although her neurological improvement was sus- tained, she continued to have significant problems with hypertension and fluid overload secondary to left ventricu- lar dysfunction for which she required continuous veno- venous haemofiltration from day + 25 until day + 41. Mar- row engraftment to neutrophils .1 × 10 9 /l was delayed
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Transcript of TTP
Bone Marrow Transplantation (2000) 25, 679–680 2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00
www.nature.com/bmt
Case report
Plasma exchange as successful treatment of thromboticthrombocytopenic purpura post autologous bone marrow transplant ina child
DE Plews1, ML Turner1 and WHB Wallace2
Departments of1Transfusion Medicine, Royal Infirmary of Edinburgh, and2Paediatric Oncology, Royal Hospital for Sick Children,Edinburgh, UK
Summary:
We describe the case of a small child with stage IVneuroblastoma who developed thrombotic thromobocy-topenic purpura (TTP) post autologous bone marrowtransplant. Pneumococcal sepsis may have been thecause, a previously unreported association in trans-plant-associated TTP. Despite the child’s size (10 kg)and the severity of the disease early intensive treatmentwith whole blood exchange and subsequently plasmaexchange with cryosupernatant proved to be rapidlyeffective, in contrast to previous reports on its ineffec-tiveness in this setting. Bone Marrow Transplantation(2000)25, 679–680.Keywords: thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome; bone marrow transplan-tation; plasma exchange; cryosupernatant
Case report
A 2.-year-old female presented 13 days post autologousbone marrow transplant with frank haemoglobinuria, epis-taxis and gastrointestinal bleeding. Six months previouslyshe had been diagnosed as having stage IV neuroblastomaand had been randomised to the ENSG 5 trial. She hadreceived seven courses of chemotherapy (vincristine, cyclo-phosphamide, etoposide and alternate carboplatin/cisplatin,ie alternating OPEC/OJEC), followed by definitive tumourexcision and autologous bone marrow transplantation. Con-ditioning was with melphalan 200 mg/m2 following prim-ing with cyclophosphamide 300 mg/m2. She received650 ml of autologous bone marrow with a total CD34 countof 4 × 106/kg. The transplant was uncomplicated until shedeveloped a pneumococcal septicaemia on day+10 mani-fest by a febrile episode and positive cultures. This resolvedrapidly with prompt antibiotic therapy, initially with genta-
Correspondence: Dr DE Plews, Department of Transfusion Medicine,Royal Infirmary of Edinburgh, Lauriston Place, Edinburgh, EH3 9YW,UKReceived 4 August 1999; accepted 7 November 1999
micin and ceftazidime, changed to benzyl penicillin whenculture results were available.
On day+12 she had minor gastrointestinal bleeding asso-ciated with a rising serum bilirubin to 69mmol/l. Within24 h, she was drowsy, had frank haemoglobinuria, a bloodynasogastric aspirate, epistaxis and loose, bloody stools anddeveloped repetitive arm movements. Laboratory para-meters demonstrated a falling haemoglobin (104 g/1 to87 g/1), falling platelet count (56× 109/1 to 32× 109/1), ris-ing urea (5.4 mmol/1 to 7.3 mmol/l) and creatinine(47 mmol/1 to 57mmol/l). There was marked red cell frag-mentation on the blood film. Coagulation was normal. Aserum lactate dehydrogenase (LDH) was 3980 U/l. A diag-nosis of thrombotic thrombocytopenic purpura secondaryto bone marrow transplantation and pneumococcal sepsiswas made. Over the next 12 h she became progressivelymore hypertensive with a blood pressure of 130/90 mm Hgrequiring treatment with hydralazine and subsequently lab-etalol infusion. By day+14 she was obtunded (GCS 11)and frankly haemorrhagic indicating the need for thera-peutic intervention.
In view of the problems associated with the child’s size(10 kg) and venous access initial treatment was with dailymanual whole blood volume exchange (800 ml) with leuco-cyte-depleted whole blood. This resulted in a fall in LDHto 3123 U/l, but no clinical improvement. On day+18 afterinsertion of a Quentin line we were able to perform aplasma exchange with two volumes of cryosupernatantusing a Cobe cell separator with a whole blood prime. Thisproduced immediate improvements in blood pressure con-trol and by 12 h she was alert and speaking appropriately.Daily plasma exchanges with cryosupernatant continueduntil day +32 when her serum LDH had normalised andthere was no evidence of fragmentation on the blood film.It was stopped at day+34 (see Figure 1).
She continued to haemorrhage significantly throughoutthis period necessitating alternate day platelet transfusionsdespite our strong reservations on their use in this con-dition. Although her neurological improvement was sus-tained, she continued to have significant problems withhypertension and fluid overload secondary to left ventricu-lar dysfunction for which she required continuous veno-venous haemofiltration from day+25 until day+41. Mar-row engraftment to neutrophils.1 × 109/l was delayed
TTP post autologous BMTDE Plews et al
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Figure 1 Daily lactate dehydrogenase values with plasma exchange.
until day +40 despite the use of GCSF to day+35 andsubsequently GMCSF in accordance with EBMT guide-lines.
At 3 months post transplant our patient was well withno disease sequelae evident. She remained thrombocyto-penic, but had no neurological problems and was dialysisindependent. Her improvement was sustained and by 6months she had achieved appropriate developmental mile-stones for age. Unfortunately she died 1 year post transplantfrom relapsed neuroblastoma. There was no evidence ofrelapse of TTP during this period.
Discussion
Thrombotic thrombocytopenic purpura (TTP) is often a dif-ficult diagnosis in the setting of bone marrow transplan-tation. Many patients experience renal impairment or alt-ered sensorium and most are thrombocytopenic or febrilesecondary to other causes. Microangiopathic changes arefrequently found post transplant in the absence of TTP orother established causes of red cell fragmentation.1 TTP isincreasingly reported after allogeneic, and more recentlyautologous, bone marrow transplant.1–3 The most likelypathogenesis is widespread endothelial damage resultingfrom high-dose chemotherapy and /or radiotherapy, cyclo-sporin administration, graft-versus-host-disease (GVHD),cytomegalovirus infection and veno-occlusive disease(VOD).1 Bacterial infection has not been reported as acause of post-transplant TTP, although classical TTP/HUSis commonly associated with ST verotoxin produced by shi-gella andE. coli species and has been reported in pneumo-coccal septicemia.4
Endothelial damage probably allows the release ofunusually high molecular weight von Willebrand factor(vWF) multimers which have an increased affinity for plat-elet receptors at high shear stress levels leading to wide-spread microvascular thrombosis. These large multimersare proteolysed in normal conditions, but in TTP thereappears to be an absence of vWF cleaving protease or aprotease inhibitor which prevents this.5,6 Cyclosporin is themost important cause of post-tranplant TTP;1 it causesdirect endothelial damage and produces a concentrationdependent increase in vWF release. Radiation can causeendothelial damage and is implicated in 95% of cases ofpost-transplant TTP.1 However, the association with GVHD
and VOD has led to suggestions that a cytokine releasecascade after endothelial damage may in part be responsibleand that these represent different reactions to a commonendothelial insult. There is no direct evidence implicatingcyclophosphamide in endothelial cell damage.3
Despite the similarities in the clinical and laboratorypresentation of classical TTP and post-transplant TTP, thereis no evidence for a deficiency of a plasma factor in trans-plant-associated TTP and plasma exchange with freshfrozen plasma (FFP) has classically proved disappointingin this setting with mortality rates of 84%.1 Transplant-associated TTP is classically treated late because of the dif-ficulties in making the diagnosis and this may in part beresponsible for the traditionally high mortality. The use ofcryosupernatant as the exchange fluid is more promising.Byrnes et al7 reported treatment successes in a series ofseven patients with classical TTP who had failed to respondto standard treatment with FFP and further work by TheCanadian Apheresis Group8 confirmed these findings witha 95% 1 month survival. Several reports have looked at thistherapy in transplant-associated TTP – in 23 patients withhigh risk disease treated with plasma exchange with cryosu-pernatant with or without immunoadsorbtion the mortalityrate appears to be much lower at 52%.1
We believe that early, intensive, two volume plasmaexchange with cryosupernatant in this child with high riskTTP proved to be an effective, life saving treatment. Theuse of whole blood exchange in the initial managementprobably served as a useful temporising measure.
References
1 Schriber JR, Herzig GP. Transplantation-associated throm-botic thrombocytopenic purpura and hemolytic uremic syn-drome.Semin Haematol1997;34: 126–133.
2 Lugassy G, Ducach A, Blumenthal R. Fatal chronic relapsingthrombotic thrombocytopenic purpura following autologousbone marrow transplantation for chronic myeloid leukaemia.Bone Marrow Transplant1998;21: 859–860.
3 Sarode R, McFarland JG, Flomberg Net al. Therapeuticplasma exchange does not appear to be effective in the man-agement of thrombotic thrombocytopenic purpura/hemolyticuremic syndrome following bone marrow transplantation.Bone Marrow Transplant1995;16: 271–275.
4 McTaggart SJ, Burke JR. Streptococcus pneumoniae inducedhaemolytic uraemic syndrome.J Paediat Child Health1998;34: 192–195.
5 Tsai HM, Lian ECY. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic pur-pura.New Engl J Med1998;339: 1585–1594.
6 Furlan M, Robles R, Galbusera Met al. Von Willebrand fac-tor-cleaving protease in thrombotic thrombocytopenic purpuraand the hemolytic-uremic syndrome.New Engl J Med1998;339: 1578–1584.
7 Byrnes JJ, Moake JL, Klug Pet al. Effectiveness of the cryo-supernatant fraction of plasma in the treatment of refractorythrombotic thrombocytopenic purpura.Am J Haematol1990;34: 169–174.
8 Rock G, Shumak KH, Sutton EMet al. Cryosupernatant asreplacement fluid for plasma exchange in thrombotic throm-bocytopenic purpura.Br J Haematol1996;94: 383–386.
