Immune thrombocytopenic purpura (ITP) and its' therapy- BY LAW JIA JUIN

Immune thrombocytopenic purpura (ITP) is a bleeding disorder in which the blood doesn't clot as it should, this is due to the deficient of blood cell fragments called platelets or thrombocytes. ^[1]There are two types of ITP which are acute ITP and chronic ITP. ^[1]Acute ITP generally lasts temporary or short term (less than 6 months). ^[1]It is the most common type of ITP. ^[1] It occurs mainly in children. ^[1]Males and females have the equal chance of getting it. ^[1]Acute ITP usually occurs after an infection by virus. ^[1]On the other hand, chronic ITP lasts around 6 months or more than 6 months. ^[1] Unlike acute ITP, chronic ITP affects adults more readily than children. ^[1] But there are some exceptions. Chronic ITP also found to affects women more than men (around two to three times more). ^[1]Spleen plays a key role in the development ITP. ^[2]This is because the autoantibodies which attack the platelets are formed in the white pulp, in addition to that there are also many splenic macrophages present in the spleen. ^[2] The autoantibody formed is an abnormal antibody, usually immunoglobulin G (IgG) which specifically bind to the glycoproteins IIb-IIIa and/or Ib-IX 1 of the membrane of circulating platelets. ^[2][3] The coatings of platelets with these IgGs are called opsonisations. ^{[2] [3]}These opsonisations facilitate the phagocytosis of platelets by splenic and systemic macrophages. ^{[2] [3]}These can result in the depletion of blood platelets, if the bone marrow megakaryocytes at the same time fail to compensate the number of platelets been engulfed. ^{[2] [3]}In this case, ITP is said to be developed.  In this portfolio I am going to discuss on the first line therapies or treatments for ITP patient. Treatments for ITP depend on the patient’s condition and severity. If the bleeding is mild and the platelets count is still above the limitation line, then treatment may or may not be needed. The treatments will be started ,only when there are sufficient evidences been shown. A first line treatment is defined as the first treatment recommended for a disease or illness. It is used as a "gold standard treatment" for someone who had been diagnosed with a particular disease or condition. On the other hand, the second line therapies are used as adjuncts to these first line therapies. They are also used when the first line therapies had failed.

Generally, the first line therapies used for ITP patients are:

i. Corticosteroids eg: prednisolone, methyprednisolone (derivative of prednisolone), and betamethasone

ii. Intravenous Immunoglobulin

Second Line Treatments for ITP patients are:

i. Splenectomy

ii. Danazol

iii. Azathioprine

iv. Dapsone

v. Anti-D7

            The first drug I am going to discuss here is prednisolone and its’ derivative (methyprednisolone).^[4] Prednislolone is an immunosuppressant corticosteroid drug. ^[4] It is used to treat inflammation and autoimmune mediated diseases like asthma, arthritis, and immune thrombocytopenic purpura. ^[4] An ITP patient is a patient having an over-expressed inflammation and immune response. ^[4] These over-expressed inflammation and immune response are due to the recognition of self-platelets by the auto-antibodies as foreign. ^[4] These auto-antibodies will then kill the self platelets by the process called auto-immune response. ^[4] So by using corticosteroids like prednisolone and methyprednisolone, the inflammation and immune response can be suppressed. ^[4]Thus, although the platelets can still be recognized by auto-antibodies but the autoimmune response can not be triggered. ^[4]

           Prednisolones have a high affinity toward glucocorticoid receptors (GR) alpha and beta (found in body tissues) . ^[4]They will bind irreversibly to these receptors (AlphaGR and BetaGR) ,upon binding to these receptors, dimerization will happen, forming steroid/receptors complexes . ^[4]The second messengers like cAMP and cAMP-dependent kinase will then relay the signals to cellular DNA in the nucleus, modifying the gene transcription. ^[4] They will promote the transcription and synthesis of some proteins like anti-inflammation agents and inhibit the synthesis of pro-inflammatory agents, for example histamine, COX-2, cytokines, cell adhesion molecules, and inducible NO synthetase. By inhibiting the inflammation process, the auto-immune response mediated by auto-antibodies, B-cells, T-cells ,and macrophages can be suppressed and thus there will be less platelets been destroyed. In addition to that, prednisolone also interfere with the transcription and synthesis of collegenase enzyme. ^[4]By doing so less collagens will be broken down by collegenase enzyme. ^[4]Thus there will be more collagens available for the initiation of platelets aggregations. ^[4] This can indirectly improve the situation of bleeding. Methyprednisolone is also available in the markets, it is a new derivative of prednisolone with higher potency. ^[6]It is derivatized from prednisolone by the process of methylation at position 8 of ring B. ^[6]
The dosage forms available for prednisolones are tablet, intramuscular injection ,and intravenous injection. Methy-prednisolones also have the similar route of administrations. ^[4]

The usual prednisolone dose for anti-inflammation action in adult is^[4] :
1. Oral tablets                                 :5 to 60 mg per day in divided doses 1 to 4 times/day.
2. Intravenous or Intramuscular :4 to 60 mg/day

The usual prednisolone dose for immunosuppressant effect in pediatric is^[4]:

1. Oral tablets                                 :0.1 to 2 mg/kg/day in divided doses 1 to 4 times a day.

2. Intravenous or Intramuscular :0.1 to 2 mg/kg/day in divided doses 1 to 4 times a day.

The usual methyprednisolone dose for immunosuppressant effect in adult is^[7]:

1. Oral tablets:   4 to 48 mg orally per day.

2.IV/IM:             2 to 2.5 mg/kg per day IV or IM, tapered slowly over 2 to 3 weeks or 250 to 1,000 mg IV once daily or on alternate days for 3 to 5 doses.

The usual methyprednisolone dose for immunosuppression effect in pediatric is ^[7]:

1.Oral tablets:   4 to 48 mg orally per day.
2.IV/IM:            2 to 2.5 mg/kg per day IV or IM, tapered slowly over 2 to 3 weeks or 250 to 1,000 mg IV once daily or on alternate days for 3 to 5 doses.

The side effect of prednisolone and methy-prednisolone include^[4] :

·         sleep problems (insomnia), mood changes;

·         acne, dry skin, thinning skin, bruising or discoloration;

·         slow wound healing;

·         increased sweating;

·         headache, dizziness, spinning sensation;

·         nausea, stomach pain, bloating; or

·         changes in the shape or location of body fat (especially in your arms, legs, face, neck, breasts, and waist).

            Prednisolone and methyprednisolone should not be given when the patient is currently taking other drugs like furosemide and tacrolimus.^[6][9] This is because prednisolone ore methyprednisolne will cause electrolyte disturbance via mineralcorticoid effect, leading to hypokalaemia which is also one of the side effect of loop diuretic like furosemide. ^[6][9]  Excessive lost of potassium ions may lead to arrhythmias and other problems. ^[6][9]  So in this case, if the prednisolone or methyprednisolone still have to be given with the same dose, then ACE inhibitor can be used to replace the furosemide. ^[10] ACE inhibitor works by reducing the angiotensin 2 level in blood and thus reducing the release of aldosterone level. ^[10] Less aldosterone level means there will be less re-absorption of NaCl in exchange to potassium ion secretion. ^[10]  So the hyperkalaemia effect of this ACE inhibitor may be used to compensate the hypokalaemia effect of prednisolone and loop diuretic like furosemide. ^[10]  But serum potassium level monitoring must be done overtime before the most appropriate doses can be found. ^[10]  On the other hand, prednisolone or methyprednisolone can also induce the enzyme CYP450 responsible for the metabolism of tacrolimus (acts on T-cells, usually used before and after organ-transplantation ,more effective as prophylaxis for organ rejection) ,leading to therapeutic failure of tacrolimus. ^[6][9] Prednisolone and methyprednisolone also play a role in the blockage of Vit D3-mediated induction of osteocalcin gene in osteoblasts, so if the patient is currently taking vitamin D supplement for bone enhancement, then the pharmacist can advise him/her to stop the vitamin D supplement temporary, as this supplement will not increase its’ bone strength when taking together with prednisolone or methy prednisolone. ^[6][9]

            Other immunosuppressant and anti-inflammation corticosteroid drug like betamethasone can also be used to treat ITP by suppressing the production of autoantibodies.^[11] According to MIMS betamethasone works by glucocorticoid activity. ^[11]It prevents and controls inflammation by controlling the rate of pro-inflammation protein synthesis (same to other corticosteroid like prednisolone and methyprednisolone), depressing the migration of polymorphonuclear leukocytes and fibroblasts, and reversing capillary permeability and improve lysosomal stabilisation. ^[11]It is available in oral, IV and IM route. ^[11]

The usual betamethasone dose for immunosuppressant effect in adult is^[11]:

Oral tablets:    0.5-5mg/day

IV/IM:  As sodium phosphate: 4-20 mg up to 4 times/24 hr

The usual betamethasone dose for immunosuppressant effect in pediatric is^[11]:

Oral tablets:       0.5-5mg/day

IV/IM:   6-12 yr: 4 mg;          1-5 yr: 2 mg;           ≤1 yr: 1 mg. (3-4 times daily depending on the condition to be treated.)

The side effects and drugs interaction of betamethasone are similar to other corticosteroid drugs like prednisolone and methyprednisolone. ^[11]

            The third drug I am discussing here is Intravenous Immunoglobulin, IV.lG is a mixture of blood proteins called antibodies which are extracted from donor blood and are used to treat a number of medical conditions. ^[12][13]It is usually administered to patients via intravenous infusion. ^[12][13] The precise mechanism of action of IV.lGs in the treatment of ITP remained unclear. ^[12][13] But some journals said that IV.lGs work by 3 main actions. ^[12][13] Firstly, it is believed that these IV.lGs will bind to the Fc-receptors on the surface of macrophages, these bindings prevent the recognition of pre-tagged(tagged by auto-antibodies) platelets by macrophages. ^[12][13] Thus the among of platelets been engulfed and destroyed by phargocytosis can be reduced. ^[12][13] Secondly, it is believe that these IVlGs will bind to the auto-antibodies, activating the host complement system. ^[12][13]Been activated, this complement system will start to destroy the auto-antibodies, reducing the number of auto-antibodies attacking our systemic platelets. ^[12][13]Thirdly, it is been believed that IV.lG will bind to the receptors on T-cells and suppressing the release of tumour-necrosis-factors alpha as well as interleukin-10. ^[12][13]Thus the auto-immune response towards the self-platelets can be suppressed. ^[12][13] It is available only in intravenous infusion route. ^[12][13] For autoimmune diseases the dose will be 2 grams per kilogram of body weight is implemented for three to six months over a five days course once a month. ^[12][13]Then maintenance therapy of 100 to 400 mg/kg of body weight every 3 to 4 weeks follows. The side effects of IV.lG include headache, allergies, dermatitis and infection due to contaminated blood product. ^[12][13]

            Now let us discuss on the clinical guidelines for the treatments of acute and chronic ITP in different groups of patients.

            If the ITP suffered by an adult (male or female) is an acute one or it is the first attack in his/her lifetime , then we should check whether there is any evidence of acute hemorrhage. ^[14]If there is no hemorrhage then we should check the platelets count of the patient. ^[14] An acute ITP usually last for less than 6 months. ^[14]If there is an evidence for acute hemorrhage then we should give methylprednisolone(1g/day for 3 days), IVIG (1g/kg/day for 2 –3 days) and platelet transfusion. ^[14] If there is no acute hemorrhage but the platelets count is still less than 30 x 10⁹/L, then prednisolone (1 mg / kg /day) is given. ^[14]But if the platelets count is within 30 - 50 x10⁹/L or > 50 x 10⁹/L, then there will be no treatment needed, unless bleeding happen, in this case prednisolone (1 mg / kg /day) can be given. ^[14]All the doses suggested can be adjusted based on patient situation and medical history. ^[14]

            If the adult is suffering from chronic ITP with platelets count less than 30 x10⁹/L, then we should check for any evidence of active bleeding, if there is no active bleeding medical therapy which involve IV.lG, prednisolone ,azathioprine, diapsone, and IV.anti-D can be started. ^[14]The dose needed for each medication can be adjusted according to patient situation and should concise with the recommendation from BNF and guideline. ^[14] If the platelets count increases back to ≥ 30 x 10⁹/L, then the treatment can be discontinued. ^[14]But if the platelets count remains < 30 x 10⁹/L, then we should consider splenectomy or using other immunosuppressant drugs. ^[14]If there is an evidence of active bleeding in chronic patient with platelets count less than 30 x 10⁹/L, then we should immediately give the patient IVIG, and methylprednisolone with or without splenectomy. ^[14]There will be no treatment needed for chronic patient with platelets count within 30 - 50 x 10⁹/L, but if bleeding happens then we should give prednisolone as directed. ^[14]

            For adult which is suffering from refractory immune thrombocytopenic purpura, platelets count is also important. For those with platelets count ≥ 30 x 10^9/L, treatment is not needed. ^[14]But if the patient is having a platelets count less than 30 x 10⁹/L and is currently suffering from active bleeding, medical regimens like Inhibitors of platelet clearance (eg: prednisolone, IV immunoglobulin, vinca alkaloid and danazol), Immunosuppressive drugs(eg: Azathioprine, Cyclophosphamide, Cyclosporin, Mycophenolate mofetil), experimental agents(eg: BMT and Campath), and even drugs(like rituximab and H.pylori antibiotics can be given. ^[14]

            After looking into the treatment regimens for different group of adults (acute, chronic, and relapse), I am now going to discuss on the treatment guidelines for ITP children (both acute and chronic). The first thing we have to do in the treatment of small kid with acute ITP is to check whether there is any bleeding . ^[14]If there is a bleeding and the bleeding is serious life threatening haemorrhage then Platelet transfusion(2-3 fold of normal dose) plus i.v methylprednisolone or combined with IVIG should be given. ^[14] Besides that, emergency splenectomy can also be done if the situation is too severe. ^[14] On the other hand if the bleeding is mild and only happen at the mucosal layer of mouth then Prednisolone 2mg/kg/day for 2weeks OR prednisolone 4mg/kg x4 days or IVIG 0.8 gm/kg can be given. ^[14] If there is no bleeding but the platelets count is < 10x 10⁹/L ,then the treatments needed wil be the same as those with mucosal bleeding. ^[14] But if there is no bleeding and the platelets count is > 10x 10⁹/L, then no active treatment is needed. ^[14]For chronic ITP children, bleeding should also be checked. If there is an acute bleeding the we should treat it as acute ITP. ^[14] If the bleeding is not acute but is a recurrent which affects the quality of life of this patient, then a second line therapies plus dexamethasone and methylprednisolone should be started. If there is no bleeding, then there can either be no treatment, or a short term coverage as per acute ITP for children can be started. ^[14]

***For the treatment of ITP pregnant women, I had provided a flow chart as a guideline of treatments. So please refer to the flow chart on the next page. ^[14] thanks!

            As a conclusion, ITP can be treated when a correct diagnosis ,effective treatment regimens(involving both first line and second line treatments) as well as strict monitoring are given to the patient. The patient should be councelled on the side effect of some immunosuppressant drugs and the way to prevent serious infections. Those undergoing splenectomy should be advised with the possible problems faced in the future as well as the prognosis of this treatment as they have the right to know these and make their own decisions and arrangements.

References

1.        National Heart Lungs and Blood institution.What Is Immune Thrombocytopenia?.[internet].2012[updated on 2012 February 24.Cited on 2012 March 14].Available from: http://www.nhlbi.nih.gov/health/health-topics/topics/itp/

2.        Stasi R, Evangelista ML, Stipa E, et al. Idiopathic thrombocytopenic purpura: current concepts in pathophysiology and management. Thromb Haemost. Jan 2008;99(1):4-13.

3.        McMillan R. The pathogenesis of chronic immune thrombocytopenic purpura. Semin Hematol. Oct 2007;44(4 suppl 5):S3-S11.

4.        Wikipedia..Prednisolone.[internet].2012[updated on 2012 February 27.Cited on 2012 March 14].Available from: http://en.wikipedia.org/wiki/Prednisolone

5.        Drug info..Prednisolone.[internet].2012[updated on 2012 February 27.Cited on 2012 March 14].Available from: http://www.drugs.com/mtm/prednisolone.html

6.        Drug info..Prednisolone drug interactions.[internet].2012[updated on 2012 February 27.Cited on 2012 March 14].Available from: http://www.drugs.com/druinteractions/prednisolone.html

7.        Wikipedia..Methyprednisolone.[internet].2012[updated on 2012 February 27.Cited on 2012 March 14].Available from: http://en.wikipedia.org/wiki/Methylprednisolone

8.        Drug info..Methyprednisolone.[internet].2012[updated on 2012 February 27.Cited on 2012 March 14].Available from: http://www.drugs.com/dosage/methylprednisolone.html

9.        Drug info..Methyprednisolone drug interactions.[internet].2012[updated on 2012 February 27.Cited on 2012 March 14].Available from:

http://www.drugs.com/drug-interactions/methylprednisolone.html

10.     Medical-Library:ACE inhibitors.[internet].2012[updated on 2012 February 11.Cited on 2012 March 14].Available from: http://www.medical-library.net/content/view/555/41/

11.     MIMS..Betamethasone.[internet].2012[updated on 2012 February 17.Cited on 2012 March 14].Available from: http://www.mims.com/USA/drug/info/betamethasone/?q=betamethasone&type=full

12.     Intravenous Infusion of Immunoglobulins.[internet].2012[updated on 2012 February 17.Cited on 2012 March 14].Available from: http://www.ivig.nhs.uk/documents/ivig_patient_guide.pdf

13.     Wikipedia..Intravenous Immunoglobulins.[internet].2012[updated on 2012 February 29.Cited on 2012 March 14].Available from: http://en.wikipedia.org/wiki/Intravenous_immunoglobulin#Mechanism_of_action

14.     Dr. Jameela Sathar. Dr.Soo Thian Lian .Dr. Sinari Salleh.et.al. CLINICAL PRACTICE GUIDELINES: MANAGEMENT OF IMMUNE THROMBOCYTOPENIC.[Guide lines].2006[cited on on2012 March 14 ] (2006) page30-32.