Idiopathic Thrombocytopenic Purpura (ITP)Jayatheeswaran. VijayakumarЖаятесваран вижаякумарGroup: 88

Background

ITP is also know as: Primary Immune Thrombocytopenic Purpura Autoimmune Thrombocytopenic Purpura

It is defined as an isolated thrombocytopenia with normal bone marrow in the absence of other causes of thrombocytopenia.

ITP has 2 distinct clinical syndromes, manifesting as an acute condition in children and a chronic condition in adults.

Background

Acute ITP often follows an acute infection and has a spontaneous resolution within 2 months. Chronic ITP however, persist longer than 6 months without a specific cause.

It is important to note that ITP is a diagnosis of exclusion.

Pathophysiology

ITP is a disease of increased peripheral platelet destruction, with most patients having autoantibodies against platelet membrane glycoproteins IIb-IIIa and Ib-IX.

In approximately 60% of cases autoantibodies against platelets can be detected. They are typically of the IgG type.

IgG autoantibodies are also thought to damage megakaryocytes. As such, relative marrow failure may contribute to this condition, since most patients have either a normal or diminished platelet production.

Pathophysiology

Abnormal T-cell activity is thought to be the stimulus for autoantibody production in ITP.

Impaired production of the glycoprotein hormone thrombopoietin which is a stimulant for platelet production may be a contributing factor to the reduction in circulating platelets.

Epidemiology

In the United States: The Incidence of ITP in adults is approximately 66 cases per 1,000,000 per year. An average estimate of incidence in children is 50 cases per 1,000,000 per year. New cases of chronic refractory ITP comprise approximately 10 cases per 1,000,000 per

year.

Hemorrhage represents the most serious complication; intracranial hemorrhage is the most significant. The mortality rate from hemorrhage is approximately 1% in children and 5% in adults.

Spontaneous remission occurs in more than 80% of cases in children. However, it is uncommon in adults.

Epidemiology

In the United States: Peak prevalence occurs in adults aged 20-50 years. Peak prevalence occurs in children aged 2-4 years. Approximately 40% of all patients are younger than 10 years.

In Chronic ITP (adults), the F:M ratio is 2.6:1. More than 72% of patients older than 10 years are female.

In Acute ITP (children), distribution is approximately equal between males (52%) and females (48%).

Bleeding

occurs if the platelet count is below 20,000 per μl.

Presentation Purpura

Hemorrhagic Bullae (on mucous membranes)

Intracranial Hemorrhage (with possible neurological symptoms)

Non-Palpable Petechiae (mostly occur in dependent regions)

Presentation Epistaxis

Gingival Bleeding

Signs of GI bleeding

Retinal Hemorrhage

Menometrorrhagia/ Menorrhagia

Spontaneous Bleeding (when platelet count is less than 20,000/mm 3.)

Presentation

Non-Palpable Spleen The prevalence of palpable spleen in patients with ITP is approximately the

same as that in the non-ITP population (i.e. 3% in adults, 12% in children.) Despite the destruction of platelets by splenic macrophages, the spleen is

normally not enlarged. In fact, an enlarged spleen should lead to a search for other possible causes for the thrombocytopenia.

Diagnosis

As ITP is a diagnosis of exclusion it is important that a complete and through patient history be taken.

It is important to focus on the symptoms of bleeding (e.g. type, duration & severity) and on symptoms that may exclude other causes of thrombocytopenia such as liver disease, thrombosis, autoimmune disease (e.g. nephritis, cutaneous vasculitis & arthritis), and infection (particularly HIV.)

It is also important to elicit risk factors of HIV, and systemic symptoms linked to other illnesses or to medications (e.g. heparin, alcohol, quinidine/quinine or sulfonamides) that may cause thrombocytopenia. Medications can be a common etiology for inducing thrombocytopenia, and patients should have their medications carefully reviewed. In children specifically, recent live virus immunization should also be considered (MMR, Flu & Chickenpox vaccines.)

Diagnosis

Bone marrow examination may be performed on patients over the age of 60 and those who do not respond to treatment, or when the diagnosis is in doubt. On examination of the marrow, an increase in the production of megakaryocytes may be observed and may help in establishing a diagnosis of ITP.

An analysis for anti-platelet antibodies is a matter of clinician's preference, as there is disagreement on whether the 80% specificity (true positive rate) of this test is sufficient to be clinically useful.

In order to make an accurate diagnosis, the clinician should be able to differentiate between the many hematological diseases that share a similar clinical picture to ITP but have very different modes of therapy.

ITP vs. TTP vs. DICParameters ITP TTP DIC

Pathogenesis Antiplatelet Antibodies Endothelial Defect Thrombin Excess

Clinical Condition Not Sick Sick Sick

Red Cells N Schistocytes Schistocytes +/-

PT/INR N N/Slightly Increased Increased

PTT N N/Slightly Increased Increased

Fibrinogen N N DecreasedFibrin Monomers N Slightly Increased Increased

Fibrin Degradation N Slightly Increased Increased

D-dimer N Slightly Increased Increased

Therapy Steroids, IVIg & Splenectomy

Plasma Exchange & Vincristine (mitosis inhibitor)

Plasma/Platelet Transfusion & ATIII?

Workup

Complete Blood Count (CBC): Isolated thrombocytopenia (key laboratory finding). The white blood cell (WBC) count should be normal. Hemoglobin level should be normal, unless severe hemorrhage has occurred.

Peripheral Smear: If truly giant platelets are found this is indicative of congenital thrombocytopenia.

Coagulation Studies: Results typically appear normal and a normal bleeding time does not exclude a

platelet disorder. (e.g. vWD type 2)

Workup

Imaging Studies: A CT scan of the head is warranted if concern exists regarding intracranial

hemorrhage.

Treatment Treatment of children is

usually supportive because most children spontaneously recover.

Even after months or years of thrombocytopenia, most children have spontaneous remissions.

If mucosal bleeding occurs, corticosteroids or IVIG may be given.

Treatment

Corticosteroids & IVIg: Prednisone (Deltasone, Orasone, Sterapred) Methylprednisolone (Solu-Medrol, Depo-Medrol) Intravenous immune globulin (IVIg)

Treatment is based on the patient's clinical condition, the absolute platelet count, and the degree of symptoms.

In children with ITP who have no bleeding or mild bleeding (e.g. cutaneous manifestations such as bruising and petechiae), the American College of Hematology (ACH) recommends management with observation alone, regardless of the platelet count.

Treatment

TPO Receptor Agonist:

Eltrombopag (25 to 75 mg po once/day) Romiplostim (1 to 10 mcg/kg sc once/week)

Available to patients with Chronic ITP who have failed other therapies. TPO Receptor Agonists have response rates of > 85%. However, thrombopoietin

receptor agonists need to be administered continuously to maintain the platelet count >50,000/μL.

While they show promise for raising platelet counts, there are potential safety concerns such as thrombocytosis and rebound thrombocytopenia.

Treatment

Splenectomy: Splenectomy can achieve a complete remission in about two thirds of patients who relapse

after initial corticosteroid therapy, but it is usually reserved for patients with severe thrombocytopenia, bleeding, or both.

Splenectomy may not be appropriate for patients with mild disease. If thrombocytopenia can be controlled with medical therapies, splenectomy is often deferred for 6 to 12 months to allow for the chance of spontaneous remission. Splenectomy is rarely done in children. However, if thrombocytopenia is severe and symptomatic for > 6 mo, then splenectomy is a consideration.

Splenectomy results in an increased risk of thrombosis and infection (particularly with encapsulated bacteria such as pneumococcus); patients require vaccination against Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis (ideally > 2 weeks before the procedure).

Treatment

Rituximab (Mabthera, Rituxan) Rituximab has a response rate of 57%, but only 21% of adult patients remain

in remission after 5 yr. Newer studies on rituximab suggest that this agent is an effective treatment

option in splenectomized refractory or relapsed ITP patients

More intensive immunosuppression may be required with drugs such as cyclophosphamide and azathioprine in patients unresponsive to other drugs who have severe, symptomatic thrombocytopenia.

Platelet transfusion is given only for life-threatening bleeding.

Key Points

The immune system destroys platelets in the circulation and at the same time attacks bone marrow megakaryocytes, thereby reducing platelet production.

Other causes of isolated thrombocytopenia (e.g. drugs, alcohol, lymphoproliferative disorders, autoimmune diseases & viral infections) need to be excluded.

Children usually have spontaneous remission; in adults, spontaneous remission may occur during the first year but is uncommon thereafter.

Key Points

Corticosteroids (and sometimes IVIg or IV anti-D immune globulin) are first-line treatments for bleeding or severe thrombocytopenia.

Splenectomy is often effective but is reserved for patients in whom medical therapy is ineffective or those whose disease persists after 12 months.

Platelet transfusion is given only for life-threatening bleeding.

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