Autoimmune Thrombocytopenia

Autoimmune Thrombocytopenia

Immune thrombocytopenic purpura (ITP) is characterised by antibodies to glycoproteins IIb/IIIa complex on platelets. The mechanism by which these antibodies originate is not known. Platelets with antibodies on their surface are trapped and removed by the spleen. 
Platelets are released into bloodstream by megakaryocytes. Development of megakaryocytes is dependent on thrombopoetin (TPO) and certain cytokines( Interleukin 3, 6 and 11)

Two forms of ITP are known:

1) An Acute Form - sudden onset

- this is a self-limiting illness and occurs almost exclusively in children (5 cases per 100,000 persons)

-occurs in both male and female children with equal frequency.

-bleeding which occurs is usually mild 

- petechiae and ecchymoses are observed following mild trauma when  platelet counts fall in between 20,000/µL -50,000/µL

-generalized petechiae, ecchymoses, and mucosal bleeding occur when platelet counts fall to less than 10,000/µL.

-widespread ecchymoses, hemorrhagic b)
llae, and retinal hemorrhage occur when platelet counts fall below 2000/µL.

Diagnosis is based on findings on physical exsm and periphrral smear. On examinition petechiae,purpura and ecchymoses are noticed. On peripheral smear, a decreased number of platelets are moticed. Often, the smear shows giant platelets, which is a reflection of increased thrombopoietin-induced stimulation of the bone marrow. Bond marrow examinition shows increased megakaryocytes.

Any child with isolated thrombocytopenia ( and normal WBC or RBC count) mostly is diagnos
 With ITP.

2) A Chronic Form - insidious onset
- this form is occurs mostly in adults (3-5 cases per 100,000 persons) and rarely in children.
-more common in females
Bleeding manifestations are similar to those seen in acute form of ITP.
Diagnosis is made by excluding other causes such as thrombotic thrombocytopenic purpura, drug induced thrombocytopenia, hypertensive disorders of pregnancy, hemolytic uraemic syndrome, post transfusional thrombocytopenia etc.

TREATMENT OF ITP IN CHILDREN
-acute ITP is self limiting therefore is generally not treated.
-Treatment is generally when platelet levels fall bellow 20,000/microlitre.
-intravenous gamma globulins these result in a prompt rise in the platelet count.
-The adverse effects of IVIG include fever, nausea, vomiting, and, occasionally, renal failure. IVIG is also very expensive compared with prednisone and is not available in all countries.
- Corticosteroids

Oral prednisone (4 mg/kg, with tapering and discontinuation by day 21) or IV methylprednisolone (30 mg/kg for 3 d) is also effective, although recovery is not as quick as with IVIG. The mode of action of prednisone is probably multifold, decreasing antibody production, increasing platelet formation, decreasing macrophage-mediated clearance of platelets in the spleen, and immunomodulating the immune response.

-The combination of steroids and IVIG is synergistic and can be used in patients with imminent hemorrhage.

-Inducing a mild hemolytic state by administering anti-D D  immunoglobulin (25-50 μg/kg for 2 d) is also effective in individuals who are Rh positive. This therapy is less expensive than IVIG. The limitations include a dose-dependent mild anemia, inapplicability in individuals who are Rh negative, and a limited response in patients who have undergone splenectomy.

With these modalities, the platelet counts in most children can be maintained at more than 30,000/µL until spontaneous remission occurs.

TREATMENT OF CHRONIC ITP

1. Steroids

• Generally treatment is started when platelets fall below less than 50,000/microlitre or bleeding manifestations are present.
• Steroids: a course of prednisone(1mg/kg) is generally tried initially and continued until the platelet count reaches 50,000/microlitre and then gradually tapered.

2. Splenectomy

Incase steroids fail splenectomy is considered as spleen is effective is the major site of destruction and the major source of antiplatelet antibody synthesis. Before splenectomy, patients should receive a pneumococcal vaccine.

3. Intravenous gamma globulins

• IVIG (1 g/kg/d for 1-2 d) induces a short-term increase in the platelet count, starting within several days and lasting approximately 2-3 weeks, both in patients who have undergone splenectomy and in those who have not. No clear evidence indicates that repeated infusions induce a lasting remission. Significant adverse effects include hypotension and renal failure.
• Anti-D immunoglobulin (WinRho, 50-75 μg/kg IV) is also as effective as IV immunoglobulin in Rh-positive adults with an intact spleen. Rarely, massive intravascular hemolysis with DIC and occasional death has occurred with the use of anti-D immunoglobulin.
• Both IVIG and anti-D immunoglobulin are relatively expensive therapy for adults compared with steroids, and these agents are primarily used on an interim basis during a crisis (eg, before splenectomy or major surgery).
• Approximately 10-20% of patients who undergo splenectomy remain thrombocytopenic and continue to have a bleeding risk that requires continued treatment. Both steroid therapy and splenectomy are considered to have failed in these patients, and the patients are challenging to treat. An accessory spleen should be excluded as the cause of treatment failure after splenectomy.

4. Thrombopoietin Receptor Agonist

Stimulation of megakaryopoiesis by  thrombopoietin receptor agonists improves the platelet count. Two thrombopoietin receptor agonists for the treatment of chronic refractory ITP are

 1) Eltrombopag is an oral nonpeptide thrombopoietin receptor agonist that interacts with the transmembrane domain of the thrombopoietin receptor and induces megakaryocyte proliferation and differentiation. 

Eltrombopag is given in doses of 25-75 mg orally daily. The adverse effects include hepatotoxicity, worsening of cataracts, and increased bone marrow reticulin fibers.

2) Romiplostim (AMG-531) is another thrombopoietin receptor agonist, consisting of human immunoglobulin Fc region covalently linked to a peptide sequence that binds to and activates the thrombopoietin receptor. 

Weekly subcutaneous doses of 1-7 μg/kg, romiplostim can increase the platelet count in chronic ITP. The adverse effects include bone marrow reticulin formation.

The responses to thrombopoietin receptor agonists take 10-15 days, and, hence, they are unlikely to replace steroids or intravenous immunoglobulins as initial therapy. Currently, these agents are recommended for ITP patients whose conditions are refractory to previous treatments, including splenectomy.