Pediatr Nephrol (2002) 17:867–870 DOI 10.1007/s00467-002-0944-9

B R I E F R E P O RT

Georges Deschênes · Agnès Veyradier Sylvie Cloarec · Stéphane Benoit · Isabelle Desbois Yves Gruel · Hubert Nivet

Plasma therapy in von Willebrand factor protease deficiency Received: 7 January 2002 / Revised: 10 June 2002 / Accepted: 10 June 2002 / Published online: 16 August 2002 © IPNA 2002

Abstract We report a patient with relapsing hereditary hemolytic uremic syndrome (HUS) that began in the neonatal period with life-threatening jaundice and hemolytic anemia. He progressed to end-stage renal failure at 14 years of age and had a cerebrovascular accident while on dialysis. The cause of HUS was a constitutional deficiency in the von Willebrand factor cleaving protease. Hematological features of HUS significantly improved following bilateral nephrectomy. After renal transplantation, he had an early recurrence of HUS associated with two episodes of retinal and cerebral ischemia. Long-term treatment with freshfrozen plasma exchanges prevented recurrence of HUS, cerebrovascular attacks, and early loss of the graft. Keywords Hemolytic uremic syndrome · Thrombotic thrombocytopathic purpura · Fresh-frozen plasma · Von Willebrand factor cleaving protease · Recurrence of hemolytic uremic syndrome · Renal transplant

clinical expressions with similar endothelial damage including microthrombi that are also called thrombotic microangiopathy [3]. TTP-HUS can be classified according to the cause of the disease. Acquired forms are the most frequent in childhood and are mainly due to verotoxigenic Escherichia coli and Shigella gastrointestinal infections. Several hereditary diseases, including factor H deficiency [4, 5], methylmalonic acidemia secondary to deficiency in cobalamin derivatives [6], and deficiency of von Willebrand factor cleaving protease (vWF-protease) [7], have been identified as causes of atypical or chronic HUS in some patients. This report concerns a patient with HUS caused by vWf-protease deficiency who developed end stage renal failure (ESRF) and recurrence of the disease. He was treated with repeated fresh-frozen plasma exchange following renal transplantation [8, 9].

Case report Introduction Thrombotic thrombocytopathic purpura, TTP [1], and hemolytic uremic syndrome, HUS [2], are closely related G. Deschênes (✉) · S. Cloarec · S. Benoit · H. Nivet Unité de Néphrologie Pédiatrique, Hôpital Gatien de Clocheville, 49 Boulevard Béranger, 37044 Tours, France e-mail: [email protected] Tel.: +33-1-44736662, Fax: +33-1-44736663 A. Veyradier Service d’Hématologie Biologique, Hôpital Antoine Béclère, 157 rue de la Porte de Trivaux, 92141 Clamart, France I. Desbois Centre de Transfusion Sanguine, Hôpital Bretonneau, 2bis Boulevard Tonnelé, 37044 Tours, France Y. Gruel Laboratoire d’Hématologie, Hôpital Trousseau, 37044 Tours, France G. Deschênes Service de Néphrologie Pédiatrique, Hôpital Trousseau, 26 Avenue du Dr Arnold Netter, 75571 Paris Cedex 12, France

The patient was the third child of consanguineous parents. The mother’s first pregnancy resulted in a stillborn male who had jaundice. The second child, born at 40 weeks’ gestation, was a female who died at 24 h of life with severe jaundice and anemia. These children’s files were no longer available and autopsies were not performed. At the time of the second pregnancy, the mother was 32 years of age and suffered a reversible cerebrovascular attack during the 5th month of pregnancy. The third child was a boy who was born at 40 weeks’ gestation with a unilateral lobster claw. He was treated during the 1st week of life with four blood exchange transfusions because of severe jaundice and hemolytic anemia. Coombs’ test was negative. He also had microhematuria and transient mild renal failure. From the age of 4 to 10 years, he had splenomegaly, chronic hemolytic anemia (mean hemoglobin 7 g/dl) with schistocytosis (mean 4%), and a decreased platelet count (mean 43,000/mm3). He developed proteinuria at the age of 8 years, mild hypertension at 9 years, and chronic renal failure at 10 years. Renal biopsy showed glomerular and arteriolar lesions of thrombotic microangiopathy associated with diffuse and severe interstitial fibrosis. A global sclerosis was observed in 50% of the glomeruli. Immunohistochemistry revealed fibrin deposits in glomerular afferent vessels. Hemodialysis was started at the age of 14 years and this phase was marked by uncontrolled hypertension despite multiple antihypertensive therapy, severe thrombocytopenia, and hemolytic anemia that required several blood transfusions. Following bilateral nephrectomy, there was a dramatic normalization of blood pres-

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Fig. 1 Time course of platelet count before and after bilateral nephrectomy. Day 0 corresponds to the day of bilateral nephrectomy. Mean platelet counts were 34,500±13,844/mm3 and 175,000± 60,987 between days –75 and –10 and days +1 and +68, respectively, and thereafter remained unchanged until renal graft. Hemoglobin progressively increased from 7.0±0.9 g/dl (1 blood transfusion between –75 and day 0) to 12.2 g/dl 8 weeks following kid-

ney removal (0 blood transfusion between day +1 and +68) and thereafter plateaued at around 12.0 g/dl. Schistocyosis decreased from 3.0±0.0 to 0%, respectively. Interestingly, the administration of 1 unit of platelets with 200 ml of fresh plasma on day –10 was followed by a transient increase up to 88,000 and 115,000/mm3 on days –6 and –4, respectively. On day –1, the platelet count began to decrease to 76.000/mm3 (PI plasma infusion)

Fig. 2 Time course of platelet count before and after renal graft. Day 0 corresponds to the day of renal transplantation. Platelet count began to decrease as early as day +1. On day +5, severe thrombocytopenia (21,000/mm3) was associated with anemia (hemoglobin 6.3 g/dl) and 2% schistocytes. The first two plasma exchanges dramatically reversed the course of the platelet count for 12 days. A trial of plasma infusion with a volume of 400 ml each on day +22 and +23 gave a partial and short effect. Therefore, plasma exchange was performed with a periodicity of 1 exchange every second 2 weeks (PE plasma exchange)

sure that resulted in the withdrawal of antihypertensive therapy, an increase in the hemoglobin level and platelet count, and disappearance of schistocytes (Fig. 1). He received a cadaveric renal transplantation after 9 months on hemodialysis. There was early diuresis and a reduction in serum creatinine concentration while on triple immunosuppression therapy with antithymoglobulins (5 doses), azathioprine, and prednisone. Anemia, thrombocytopenia, and schistocytosis recurred on day 5 post transplantation (Fig. 2). The serum creatinine concentration decreased from 550 to 200 µmol/l in 2 days and stabilized at 200–210 µmol/l on days 4–5. Two plasma exchanges with fresh-frozen plasma (total volume 6,930 ml) were performed on days 7 and 8 post transplantation and dramatically improved the platelet counts (Fig. 2). Hemoglobin increased to 9 g/dl following blood transfusions and then stabilized at 11 g/dl. The schistocytosis disappeared on day 20 and serum creatinine concentration decreased to 160 µmol/l by day 16. On day 22, a decrease in the platelet count from 300,000/mm3 to 35,000/mm3 signaled another relapse of HUS (Fig. 2). Freshfrozen plasma (total volume 800 ml) was infused on days 24 and 25, leading to a moderate and transient increase in platelet

count to 90,000/mm3 which remained stable for 5 days (Fig. 2). The serum creatinine concentration progressively improved to 100 µmol/l. On day 34, the platelet count was 30,000/mm3, the hemoglobin decreased from 11.4 g/dl to 9.5 g/dl, and the serum creatinine concentration increased from 110 to 160 µmol/l. Renal biopsy showed vascular thrombotic microangiopathy. A 400-ml volume of virus-inactivated fresh-frozen plasma was given as an infusion and a second volume of 3,400 ml was given during a plasma exchange. These led to an increase in the platelet count to 195,000/mm3 and the hemoglobin to 12.3 g/dl, and a decrease in serum creatinine concentration to 80 µmol/l on day 42 (Fig. 2). Thereafter, continuous treatment with plasma exchanges was undertaken twice monthly until the present time. A volume of 3,500 ml of fresh-frozen plasma (60 ml/kg) was infused at each exchange, representing a cumulative volume of 820 l for 9 years. This stabilized platelet counts and hemoglobin concentrations (Table 1). Chronic immunosuppression included prednisone, azathioprine, and cyclosporin (6.3 mg/kg per day). Three episodes of rejection, proven by kidney histology, were successfully treated with methylprednisolone pulses during the first 2 years after trans-

869 Table 1 Long-term follow-up of renal graft. Values are mean and SD of 4 samples (HD hemodialysis)

Serum creatinine (µmol/l) Blood hemoglobin (g/dl) Platelet count (×103/mm3)

6 months

1 year

2 years

3 years

4 years

6 years

8 years

230±17 10.5±0.2 312±13

207±3 9.2±0.2 302±26

220±2 8.8±0.1 275±11

265±7 8.7±0.2 233±3

257±12 10.6±0.6 319±47

529±89 10.0±1.7 207±34

HD 10.2±1.8 212±42

plantation. Plasma creatinine concentration remained stable for 4 years and then increased progressively (Table 1). The patient returned to hemodialysis 8 years after transplantation and is continuously being exchanged twice monthly to prevent hematological features of HUS. Hepatitis C virus, HIV 1 and 2, HTLV 1 and 2 serology remained negative at the last follow-up evaluation. This patient also complained of transient diplopia at the age of 11 years and had a thrombosis of the middle cerebral artery while on hemodialysis. He had retinal ischemia with amaurosis 5 days after renal transplantation, and suffered from a second cerebrovascular attack with coma and seizures on day 35 after transplantation. The episode of amaurosis dramatically improved after the first two plasma exchanges. He recovered from both cerebrovascular attacks with normal brain function, although cerebral computerized scan showed five hypodense lesions in the frontal and parietal areas. Preventing cerebrovascular attacks was a major reason for continuing the plasma therapy despite the loss of the graft. There were no mutations of factor II or factor V. There was a heterozygous mutation (C677T) of methyltetrahydrofolate reductase (MTHFR) associated with an increased plasma level of homocysteine (39 µmol/l, normal values 4–18; the sample was obtained while the patient was dialyzed). Plasma levels of protein C, protein S, and antithrombin III were normal. Complement fractions, CH50, and factor H were in the normal range. As a result of recent reports of the involvement of wWF-protease in the pathogenesis of HUS, we assayed this enzyme. We demonstrated complete deficiency of wWFprotease in the absence of any detectable inhibitor (the sample was obtained before a plasma exchange session). The plasma wWF-protease activity increased to 44% the activity of normal pooled plasma at the end of plasma exchange and decreased to 15% after 72 h.

Discussion Unusually large vWF multimers have been reported in patients with relapsing TTP [10]. Subsequently, a deficient activity of vWF-protease was found in some patients with chronic relapsing forms of TTP-HUS, including children with early onset of the disease [8, 9, 11]. This vWF-protease deficiency is the result of mutations of a member of the family of zinc metalloproteinase genes (ADAMTS 13) [12]. Patients with vWF-protease deficiency have a predominantly hematological phenotype, with severe thrombocytopenia and dramatic acute hemolytic crises that are successfully prevented with repeated infusions of freshfrozen plasma [9] or cryoprecipitate fractions [8]. In contrast to our patient, renal manifestations were usually limited to hematuria and proteinuria without hypertension, and renal function was preserved for several years even in the absence of repeated plasma therapy [8]. Bilateral nephrectomy in our patient was performed because of intractable hypertension, as previously described in a similar case of HUS but with C3 consumption [13]. After removal of the kidneys, there was significant improvement of thrombocytopenia, disappearance of schistocytosis, and no further need for blood transfusion. The immediate recurrence of hematological signs of TTP-HUS after renal

transplantation might indicate a special reactivity of the renal microcirculation to the protease deficiency. TTP-HUS after renal transplantation may recur in recessive and dominantly inherited cases. Over 20 children experiencing recurrence of HUS after renal transplant have been reported in the literature [14, 15, 16, 17, 18, 19, 20, 21, 22, 23], most within the 1st month following transplantation. One had a complement factor H deficiency that was treated successfully with fresh-frozen plasma [22]. We show that vWF-protease deficiency is another cause of recurrence of TTP-HUS after renal transplantation. Exchange transfusions [24], fresh-frozen plasma infusions [25], plasma exchanges [26], and infusions of cryosupernatant [27] are beneficial in the treatment of TTP and atypical HUS [28, 29, 30]. All these treatments provide vWF-protease and can restore cleavage of large multimers [8, 27]. In our patient, plasma therapy prevented hematological evidence of TTP-HUS. In addition, the prevention of early graft loss was likely because of early plasma therapy. This additional beneficial effect of plasma exchange and infusion is likely accounted for by the large amounts of fresh-frozen plasma, and thereby the amount of vWF-protease, that were given. Our data suggest that plasma infusions limited to 400 ml produce a transient and partial effect, whereas plasma exchanges up to 3,500 ml produce a complete and protracted effect. The volume and periodicity of plasma exchanges we used are in the same range as those given by Furlan et al. [31] to three patients, assuming a 100% protease activity in fresh-frozen plasma, a mean halflife of 3.3 days, and the patient’s estimated plasma volume. Moreover, the plasma kinetics of protease activity was similar in our patient and in two of three of the patients treated by Furlan et al. [31]. In contrast, the plasma dosage (50 ml/kg) and the periodicity of exchanges (every 2nd week) we used were significantly higher than those used by Barbot et al. [9] to treat their patient (10 ml/kg every 3 weeks). Our patient also had more severe renal disease that lead to early ESRF compared with other reports [8, 9]. Thrombotic microangiopathy of the central nervous system and large-vessel thrombosis of the anterior and middle cerebral arteries are life-threatening features of TTP and atypical HUS [23, 32]. Our patient had both types of lesions (middle artery thrombosis and thrombotic microangiopathy of retina and parietal areas of the brain) at the time of dialysis and after transplantation. Heterozygous C677T mutation of MTHFR may have increased the frequency of these attacks, as it was associated with a high plasma level of homocysteine. Plasma exchanges, both by supplying vWF-protease and by removing homocysteine excess, dramatically improved the retinal ischemia and prevented further cerebrovascular attacks.

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In conclusion, vWF-protease deficiency is a cause of recurrent TTP-HUS with a neonatal onset that can lead to renal failure and recurrence following renal transplantation. vWF-protease deficiency may be associated with extrarenal ischemia in the retina and the central nervous system. Both renal and extrarenal involvement as well as hematological signs can be prevented using repeated therapy with fresh-frozen plasma.

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