Predictive factors of response to splenectomy in children with immune thrombocytopenic purpura

Predictive factors  of response to splenectomy in children with immune thrombocytopenic purpura

Tamer Fakhry{l), MD; Hassan  S. Badr(2J, MD (1) Pediatric  Surgery Unit, Menoufiya  University  Hospitals.

(2) Pediatric  Department, Menoufiya University Hospitals.

Background: Immune thrombocytopenic purpura (JTP) is an acquired disorder of unknown cause in which autoantibodies  are directed against antigens on the platelet membrane. These platelets are then cleared at an accelerated rate by tissue macrophages in the spleen and other components  of the reticuloendothelial  system, leading to decreased platelet counts. Medical treatment for ITP includes corticosteroids, intravenous immunoglobulin (JVJG), or intravenous anti-Rho(D) immune globulin (WinRho). Splenectomy is effective in 60% to 90% of children with chronic ITP Up to 30% of children with chronic ITP will continue to have bleeding problems after a splenectomy, and there is the small but present risk of overwhelming  postsplenectomy infection,  even  with the proper immunizations  and  penicillin  prophylaxis. Possible  lack  of response to splenectomy"  and "inability to predict response to splenectomy" highlight the need for more potent predictors of response to splenectomy in children with chronic ITP

Patients and methods:  This study was conducted as a retrospective analysis of all pediatric patients 18 years of age or younger at Menoufia University  Hospital with ITP who received medical treatment and eventually required splenectomy between January 2003 and June 2012. Data from files of 24 patients included initial CBC including platelets count and mean platelet volume and initial response to steroid therapy. Also we studied their sex, age, platelet count, years of thrombocytopenia and associated disease. Time of splenectomy and the response to medical therapy were also analyzed to assess their association with splenectomy response.

Results: We found that 16 cases (67%) (11 male and 5 female) achieved complete remission

while 8 cases (33%)(3  male and 5 female) didn t, but 3 of them achieved partial remission. The  mean  age  at  splenectomy  of  responders  and  non-responders  was  9.906±1.3193  and

11.938±2.4413 respectively, the initial platelets count at diagnosis was 22.4825±11.52027and

22.1813±9.23428 respectively, there were a statistically significant difference when regarding age in years at time of splenectomy (age was higher in non-responders),  and platelets count just before splenectomy (higher in non-responders), while other variables did not significantly differ.

Conclusion: We concluded  that steroid response period is the main predictive  factor for response to splenectomy in the study. Also initial MPV, and age in years can be considered as a predictive factor while other variables are not.

Introduction:

Immune thrombocytopenic  purpura (ITP) is  an  acquired  disorder  of  unknown  cause in which autoantibodies  are directed  against antigens on the platelet membrane. These platelets  are then  cleared  at  an accelerated rate by tissue macrophages  in the spleen and other  components  of the  reticuloendothelial

system, leading to decreased platelet counts.l

ITP usually occurs in children between 2 and

10 years of age with the sudden appearance of  bruising  and/or  bleeding,  and  60%  of patients have a history of a recent previous infection.2   The acute  form  of  this  disorder often  occurs  after  a  viral  infection  and  is caused  by  an  immune  response   in  which

antiplatelet antibodies are produced primarily in the  spleen.3 Most children  with  immune thrombocytopenic  purpura  (ITP)  experience spontaneous            resolution         of   their                        disease without medical intervention.4  About 70% to

80% of children have the acute form  of the

disease, which, by definition, entails a full recovery of platelets >150,000/-tL within 6 months with or without therapy. In contrast,

20% to 30% of children develop chronic ITP

with  continued  platelet counts  <150,000/-tL for >6 months.2 Medical therapy is initiated generally when a patient has a platelet count of <10,000/-tL  with cutaneous bleeding or in the presence of a concomitant  or preexisting condition that increases the risk ofbleeding.5

Medical treatment for ITP includes corticosteroids, intravenous immunoglobulin (IVIG),     or     intravenous     anti-Rho     (D) immune  globulin  (WinRho).  Other  drug therapy  options  for  children  who  have proven  refractory  to  standard  treatment include rituximab, cyclosporine, vincristine, vinblastine,   danazol   and   others.   Patients with persistent bleeding symptoms requiring repeated  or continuous medical therapy, and those who develop chronic ITP may benefit from splenectomy.  Splenectomy  is effective in 60% to 90% of children with chronic ITP. Up to 30% of children with chronic ITP will continue to have bleeding problems after a splenectomy, and there is the small but present risk of overwhelming postsplenectomy infection, even with the proper immunizations and penicillin prophylaxis.6 In very young children, especially children under 2 years of age, it is wise to attempt to defer splenectomy because of the greater risk of overwhelming postsplenectomy infection.7

Possible lack of response to splenectomy" and "inability to predict response to splenectomy" highlight  the  need for more potent predictors of response to splenectomy in children with chronic ITP.8

We    have,     therefore     in     this      study,

undertaken    a    review    of    splenectomies for ITP at our institution in an attempt to identify preoperative factors that could guide pediatricians   and  surgeons  in  determining

which  children  are  most  likely  to  have  a

favorable response to splenectomy.

Patients and methods:

This study was conducted as a retrospective analysis of all pediatric patients 18 years of age or younger at Menoufia University Hospital with ITP who received medical treatment and eventually required splenectomy between January 2003 and June 2012. Inpatient and outpatient records were reviewed for the patients selected, and all data were compiled in a spread sheet. Twenty four consecutive patients with chronic primary ITP refractory to ordinary treatment; prednisone, IV anti-D immunoglobulin and IV immunoglobulin (did not achieve complete remission after one year oftreatment), who had been splenectomized, were included in the study.

All  patients   in  this  study  had  chronic

ITP, defined as thrombocytopenia  (platelet count <100,000/mm3) that persisted for a minimum of 6 months without other clinical or laboratory findings that could support another   etiology   of  the  thrombocytopenia and  presence  of  abundant  megakaryocytes in bone marrow aspiration according to ASH panei.9 Exclusion criteria included positive markers for HBV, HCV and HIV; antinuclear antibodies and Coomb's test and patients that did not need treatment. Each patient in our study received at least 1 course of steroid therapy  during the course of the disease and some patients were treated  with intravenous IG,  anti-D  immunoglobulin.  All  of the patients eventually went on to receive open splenectomy. A retrospective study was done from their files to see initial CBC including platelets count and mean platelet volume and initial response to steroid therapy. Also we studied their sex, age, platelet count, years of thrombocytopenia, associated  disease,  time of splenectomy and the response to medical therapy were also analyzed to assess their association with splenectomy response.

Response to splenectomy  was considered as complete (CR) if platelet count rose to >100 x 109/1.  Remission was defined as complete response persisting after all treatments  were discontinued  for  one year, platelet count  of

50,000/-tL or more but less than 100,000/ -tL

m-     ams      ur;g_      4;    _:        -- _

constituted  a partial response  (PR), and platelet count less than 50,000/)lL was defined as no response (NR).4

Responses to medical therapy were categorized  according  to  the  peak  platelet count with treatment. Splenectomy responses were defined by the platelet count on postoperative  day  1, at initial follow-up  (at least 2 weeks after splenectomy), and at the latest follow-up time-point available in the medical record.

Results:

Table (1)    shows    that    there    were    a statistically significant difference when comparing  the  cases  responding  to splenectomy with other cases who did not respond  to  splenectomy  during  the  follow up period regarding  age in years at time of splenectomy and platelets count just before splenectomy  x103, while other variables  did not significantly differ.

In Table (2) when the variable has a beta

coefficient  >0.5  as  steroid  response  period

(Beta  coefficient=O.736:  that  means  every

1  day  increase  in  steroid  response  period there is chance about 73.6% to respond to splenectomy) (P <0.05). So, it is the main predictor of the study. Also initial MPV and age in years can be considered as a predictive factors while other variables are not.

Discussion:

Splenectomy is a treatment option for children   with   ITP   refractory   to   medical therapy or for those who require continuous drug therapy  in order to maintain acceptable platelet levels. The first reported splenectomy for ITP was performed  in Germany  in 1916 and splenectomy continues to be an important treatment  for  patients  with  uncontrolled chronic ITP or with life-threatening hemorrhage complicating acute ITP.lO

This  study  included  twenty  four consecutive patients (14 male and 10 female) with  chronic primary  ITP refractory  to ordinary treatment (medical treatment did not achieve complete remission after one year of treatment), who had been splenectomized.

We found  that  16 cases  (67%)  (11 male

and 5 female) achieved complete remission while 8 cases (33%) (3 male and 5 female) didn't,  but  3 of  them  achieved  partial remission. The mean age at splenectomy of responders   and  non-responders   was  9.906

±1.3193  and  11.938  ±2.4413  respectively,

the  initial  platelets  count  at  diagnosis  was

22.4825 ±11.52027 and 22.1813 ±9.23428 respectively.

When  we  compared  between  the  cases

responding to splenectomy with other cases who did not respond to splenectomy  during the follow up period regarding all the parameters  included  in the study  we found that there were a statistically significant difference  when  regarding  age  in  years  at time of splenectomy  (age was higher in non­ responders), and platelets count just before splenectomy  (higher  in  non-responders), while other variables did not significantly differ.

When we studied the correlation between

response to splenectomy and the variables included  to find out their  role in predicting the response  we found that steroid response period  is  the  main  predictor  of  the  study. Also initial  MPV, and  age in years  can  be considered as predictive factors while other variables are not.

Previous   studies   have   reported   a   60-

90% immediate  remission  rate. It has been difficult  to  identify  predictors  of  response to  splenectomy,  and  studies  have  reported conflicting       findings.                      Ramenghi                 et al.ll found  that  an  excellent  response  to  either steroids        or            IVIG                 with             platelet                counts

>150,000/)lL was predictive of a positive response to splenectomy. Coonl2 showed that any response to steroid therapy  >50,000/ )lL was suggestive of a success with splenectomy (72% success vs. 24% failure). Both groups found that a poor response to steroids was not predictive of a poor response to splenectomy and  these  findings  agree  with  the  finding of  our  study.  In  contrast,  Wood  et  al 13. found that a poor response to steroids with platelets   <50,000/)lL  was   indicative   of  a CR to splenectomy  with platelets >150,000/

)lL and that a good response to steroids was not  predictive  of  a  favorable   response  to

Table (1): Comparison between responders  and non responders  to splenectomy.

Table (2): Correlation between different factors and response to splenectomy.

splenectomy. Holt etal 14. reviewed 24 patients treated  with  prednisone  for  ITP and found no significant  association  between response to prednisone and response to splenectomy. However, neither the steroid regimen nor the method of categorizing steroid responses is explicitly  described  in the  study.  Hemmila et aF. also found no correlation of steroid response to splenectomy response in 17 patients.  However,  94%  of  patients  in this series  had  either a "good" or "excellent" response to corticosteroids.

Some recent studies on children with ITP have reported  that a good response to IVIG predicted a good response to splenectomy, but a poor response to IVIG was not predictive of a poor response to splenectomy. Few children in  our  study  received  IVIG  and  anti-D  Ig, but the number of patients did not support meaningful statistical analysis.

Limitations of this study include the small

patient  number  (n = 24),  limited  follow-up for some patients included  in the study, and the  inability  to  examine  steroid  dose  and

exact duration oftherapy. Validation of these

findings would require a prospective study.

Conclusion:

It is  important  to  identify  preoperative factors that could guide pediatricians and surgeons in determining which children are most likely to have a favorable  response to splenectomy. When we studied the correlation between response to splenectomy and the variables included to find out their role in predicting the response we found that steroid response period is the main predictor  of the study. Also initial MPV, and age in years can be  considered   as  predictive  factors  while other variables are not.

References:

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