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Clinical practice guideline
















Idiopathic thrombocytopaenic Purpura


 

Clinical practice guideline committee of the Ceylon College of physicians Clinical practice guideline series - No. 1


Idiopathic thrombocytopaenic purpura


(These guidelines are based on the American Society of Haematology ITP Practice Guideline - 1997)


Prepared by Dr. Bandula Wijesiriwardena (Consultant Physician, Teaching Hospital, Ragama) and Dr. Arundathi Kurukulasuriya (Senior Lecturer in Pathology, Department of Pathology, Faculty of Medicine, University of Colombo)


Definition.


Isolated thrombocytopaenia (low platelet count with otherwise normal results on complete blood count and peripheral blood smear) in patients with no clinically apparent associated conditions or factors that can cause thrombocytopaenia (HIV infection, SLE, Lymphoproliferative disorders, MDS, drugs, agammaglobulinaemia, alloimmune thrombocytopenia, congenital or hereditary thrombocytopenia).


It is primarily a disorder of increased platelet destruction caused by the autoantibodies to platelet it is membrane antigens (glycoprotein 11b/111a).


It is typically a chronic disorder with an insidious onset.  In about 1/3rd of adults the thrombocytopaenia is persistent and relatively resistant to most forms of treatment.













Classification of immune thrombocytopaenia:



  1. Allo-immune



















Neonatal allo-immune thrombocytopaenia (NAIT)
Post-transfusion purpura (PTP)
Refractoriness to platelet transfusion



  1. Auto-immune (AITP)



















Idiopathic thrombocytopaenia purpura (ITP)
Secondary auto-immune thrombocytopaenia
Acute (post-viral) auto-immune thrombocytopaenia



  1. Drug-induced immune


















Drug-dependent
Drug-independent (auto-immune)



Auto immune thrombocytopaenia (AITP)


There are three distinct clinical syndromes




  1. Idiopathic thrombocytopaenic purpura, a chronic auto-immune thrombocytopaenia of insidious onset without any identifiable antecedent or associated illness, which typically affects young and middle aged adults, predominantly women (3F : 1 M)




  2. Secondary auto-immune thrombocytopaenia, which resembles ITP clinically, but is associated with other auto-immune dise@ses, malignancy or a variety of other disorders.




  3. Acute post - viral auto - immune thrombocytopaenia, an acute, self - limiting thrombocytopaenic purpura, which typically affects young children within 3 weeks of an acute viral infection and occasionally after immunization.





















Conditions associated with secondary auto-immune thrombocytopaenia.
.










































































1.

Other auto-immune disease
  Blood eg; Evan's syndrome
  Generalized eg; SLE, rheumatoid arthritis
  Organ-specific eg; thyroid
.
2. Lymphoproliferative disorders
  Chronic lymphatic leukaemia
  Lymphoma
.
3. Cancer
  Solid tumours
.
4. Immune system imbalance
  HIV infection
  Chemo- / radiotherapy
  Bone marrow transplantation
.
5. Post-viral infection



Health consequences


If platelet counts are low enough, clinically significant and potentially life-threatening bleeding can occur.  Presence or absence of bleeding and severity of bleeding generally correlate well with the degree of thrombocytopaenia.





















> 50,000   Asymptomatic (rarely following trauma)
30,000 - 50,000   bruising on trauma.
10,000 - 30,000   spontaneous bruising, menorrhagia,- prolonged bleeding after trauma.
<10,000 mucosal bleeding (epistaxis, gastrointestinal and genitourinary) and severe bleeding (includes life-threatening bleeding such as CNS bleeding)

Diagnosis.


Requires a history, physical examination, complete blood count and examination of the peripheral blood smear.  In the absence of findings that are atypical or suggest another diagnosis (eg; splenomegaly, lymphadenopathy) further tests are not indicated.  Splenomegaly is not a feature of ITP and if present would suggest an associated disease or another diagnosis.  As AITP can be the first manifestation of SLE, immunological tests for SLE should be carried out.


The characteristic haematological features of AITP are isolated thrombocytopaenia (usually <80,000 x 109/1) and normal or inceased numbers of megakaryocytes in the bone marrow.  Other conditions (DIC, TTP) which can produce similar findings should be excluded.


If anaemia (without obvious bleeding) is also present the possibility of Al HA (Evan's syndrome) should be investigated.


The diagnosis is supported by the demonstration of platelet auto-antibodies.


Bone marrow aspiration is indicated in patient > 60 yrs (to exclude MDS) and before splenectomy to confirm the diagnosis.  The bone marrow shows a normal/increased megakaryopoiesis.


Three other immunological conditions can mimic AITP and should always be considered.




  1. Drug induced immune thrombocytopaenia which occurs within 5-14 days of the first exposure or within a few hours of the're-exposure.




  2. Post-transfusion purpura which occurs suddenly within 2 weeks of a blood transfusion.




  3. Pseudothrombocytopaenia which is due to an EDTA dependent antibody which reacts with platelets in7Vitro.  This is not seen when citrate is used.




Treatment.




  1. Initial therapy




    1. Glucocorticoid therapy




      1. Conventional dose oral glucocorticoids (CDOG)




      2. High dose parenteral glucocorticoid.  Eg; dexamethazone, methyl prednisolone.






    2.  IV IgG.




    3.  Platelet transfusions




    4. Splenectomy






  2. Further therapy for refractory patients (Patients whose thrombocytopaenia persist after primary treatment with CDOG and splenectomy).




Initial therapy.


Depends on the degree of thrombocytopaenia and the severity of bleeding.

























Severity of bleeding: Asymptomatic, minor purpura, mucous membrane bleeding, severe bleeding.
> 50,000 no treatment is generally indicated.  CDOG if there is bleeding.
30,000 - 50,000 asymptomatic - CDOG if there are major risk factors for bleeding.
Symptomatic - CDOG.
< 30,000 CDOG.

Major risk factors for bleeding.


Hypertension, peptic ulcer disease, a vigorous lifestyle.


CDOG


Prednisolone 1-2 mg/kg/day until the platelet count normalizes and then continued for 2 weeks. Then reduced by 10mg/wk until the does is halved and then by 5mg/wk.  Minimum dose that is required to keep the count above 50,000 is used as the maintenance dose.


Severe bleeding (life threatening).


High dose parenteral glucocorticoid therapy, IV IgG, platelet transfusions.


High dose parenteral glucocorticoids.


Methylprednisolone 1g IV daily for 3 days or

Dexamethazone 40mg/day for 3 days.


IV IgG


400 mg/kg for 3 days is followed by an increase in platelet count within a week of starting treatment and lasting up to 3 weeks.  This is very expensive and should be used selectively.


Indications.




  1. Severe and life-threatening bleeding.  




  2. To prepare the patient for an invasive procedure.  




  3. Before splenectomy.  




  4. To improve response to CDOG after a failed trial.  




  5. To reduce destruction of platelets following platelet transfusions.  A smaller dose (1 mg/kg) is adequate in this situation and given before the transfusion.




Splenectomy.


Indications:




  1. Platelet counts are still < 30,000 after 2-3 months of CDOG therapy.




  2. Platelet count goes above 30,000 but decreases when the CDOG therapy is tapered.




  3. Glucocorticoid dose required to maintain a platelet count > 30,000 is unacceptably high.




In older patients a trial of other drugs (eg; danazol, azathioprine) should be tried before making a final decision on splenectomy as the response is not as good as in younger people.


TSH/free T4 are indicated pro-operatively to exclude occult hypo / hyperthyroidism


Pre-operative therapy for elective splenectomy.




  1. IVIgG or CDOG




  2. Platelet transfusions if the count is < 10,000

    Vaccination against H. influenza, pneumococcus and menigococcus at least 2 weeks before surgery.




Bleedingcomplicationsfromsplenectomyappeartobeminimalwhenthecountisabove 10,000.


Post-operatively penicillin should be given indefinitely because of the risk of overwhelming pneumococcal sepsis.


Patients who relapse after splenectomy should be evaluated for possible accessory spleens which should be removed if found.  In the absence of accessory spleens a second trial of CDOG should be considered.


Therapy for refractory patients.


About 20% of patients are refractory to the above therapeutic approaches.  They are relatively refractory to other forms of treatment as well.


Treatment is indicated for patients with counts < 30,000 who have active bleeding.


Opinions of experts are too diverse to allow for consensus.


Should be referred to a clinical haematologist or an oncologist.


Agents that are used include  




  1. Azathioprine  




  2. Cyclophosphamide  




  3. Vincristine  




  4. Danazol  




  5. Cyclosporin  




  6. Pulsed high dose dexamethazone (40 mg/day for 4 days, repeated every 28 days)  




  7. Combination chemotheraphy (eg; CHOP)




ITP in pregnant women.


Thrombocytopenia in pregnancy;


75% have gestational thrombocytopaenia (mild, late in pregnancy, resolves spontaneously after delivery).


Most of the others have PET


Only a few have ITP.


Neonatal thrombocytopaenia.


10-13% risk of developing counts of < 50,0000.


1% risk of intracranial haemorrhage.


Drops to lowest levels around 1-2 days after delivery.


Diagnosis in pregnant women


It is more difficult to diagnose when thrombocytopaenia is not severe (can be indistinguishable from gestational thrombocytopaenia).


PET should be excluded,


Liver function testing is indicated.


Treatment in pregnant women






























>50,000 - no routine treatment is required.
30,000-50,000 - no treatment in the 1st and 2nd trimester. 3rd trimester - CDOG
10,000-30,000 - 2nd and 3rd trimester - No bleeding - CDOG Bleeding - IV IgG.
< 1 0,000 - No bleeding - CDOG Bleeding or 3rd trimester - IV IgG
Spienectomy -

< 1 0,000 - who are bleeding and in whom CDOG and IV IgG have failed. Appropriate in the 2nd trimester


At labour and delivery

























>10,000 - platelet transfusions
10,000-30,000 - ? platelet transfusions
30,000 - 50,000 - CDOG
> 50,000 - safe, no treatment is indicated

After delivery,


Infants platelet count should be monitored during the first week after delivery.


For severe thrombocytopaenia or mucosal bleeding.  IV IgG is the treatment of choice.


Platelet transfusions can be added.


Acute post-viral AITP


This condition generally affects young children (>90% of cases) but occasionally young adults can get affected.  It is essential to exclude acute leukaemia by examination of the blood film and bone marrow.


The majority of the patients recover spontaneously within 3 months but a few may relapse.


The major concern is the risk of ICH which occurs in about 1% of children when the count is <20,000.  A single dose of IVIG 0.8mg/kg offers the fastest recovery for the least treatment; additional treatment with IVIG or CDOG is reserved for about one-third of children who continue to have counts of <20,000.


Drug induced immune thrombocytopaenia.


This is a rare adverse reaction to drugs.  The majority of the proven cases are due to a few compounds: quinine, quinidine, trimethoprim, gold and heparin.  A careful drug history and serial haematological charting are essential for the diagnosis.  The onset is within 5-14 days of the first exposure and within a few hours of the re-exposure.


The most effective treatment is the immediate withdrawal of the implicated drug.  The platelet count usually recovers within a few days.  In cases of life-threatening bleeding, plasma exchange and platelet transfusions may be effective.  If the thrombocytopaenia persists for more than 1-2 weeks high dose IVIG or a short course of CDOG may help to accelerate recovery.








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