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posted Jul 10, 2013, 4:23 AM by Eliany Mejia   [ updated Jul 10, 2013, 6:56 AM by Purnema Madahar ]

Yesterday we discussed about a young adult patient presenting with thrombocytopenia, consistent with the diagnosis of ITP, our today’s topic. So let’s talk about:

·         What’s the epidemiology of ITP? What causes it?

·         What’s the pathophysiology behind ITP?

·         How does ITP present? How is it diagnosed?

·         What’s the deal with MPV? Is it useful?

·         What are the treatment options, and what’s the overall prognosis?

What’s the epidemiology of ITP? What causes it?
Immune Thrombocytopenia Purpura (and not idiopathic, as Dr. Lief pointed out) is primarily a disease of increased platelet destruction, typically caused by antibodies directed against the plt glycoprotein IIb/IIIa complex. It is defined as an isolated low plt count with nl bone marrow function and the absent of other causes of thrombocytopenia.

The first description of the purpura of ITP was done by the German physician and poet Paul Gottlieb Welhof who in 1735 wrote the most complete initial report of the disease (platelets were unknown at the time, fascinating!), and named the condition ‘‘morbus haemorrhagicus maculosus”, later adopting the name of  "Werlhof's disease" until the current descriptive name became more popular.

Recognition of ITP is increasing because of the increasing frequency of routine blood counts that reveal unexpected thrombocytopenia. The incidence of ITP is estimated at 50–100 new cases/ million/ year, children account for half of that amount. ITP is usually chronic in adults and the probability of durable remission is 20-40%.  In the USA, the adult chronic population is approximately 60,000 with a female to male ratio of 2:1, which has resulted in ITP being designated an orphan disease (in other words, a rare disease that affects a small percentage of the population).

ITP also seems to have a seasonal variation with a peak incidence in the winter and early springtime, thought to be secondary to viral infections, usually URIs. In less than 8% of cases may also be preceded by vaccinations.

What’s the pathophysiology behind ITP?
The Harrington-Hollingsworth experiment, established the immune pathogenesis of ITP, when in the 1950s first demonstrated that a plasma factor found in most patients who had ITP resulted in thrombocytopenia in normal individuals. Subsequently, antiplatelet antibodies directed against platelet surface glycoproteins, such as IIB/IIIA, have been detected in around 50% to 70% of patients. In addition, Direct T-cell mediated cytotoxicity against megakaryocytes and platelets may be the primary mechanism of thrombocytopenia in a proportion of pts without detectable autoantibodies (30%- 40% of pts).

Recent studies also suggest that suppression of plt production may play a role. In the past, it was assumed that platelet production would be enhanced in ITP to compensate for the accelerated plt destruction. There is now much evidence, however, indicating that platelet production is in fact often decreased. Postulated mechanisms are:  direct damage to megakaryocytes, decreasing its function and maturation, and normal or low levels of thrombopoietin has also been documented.

 ITP is associated with multiple viral and bacterial infections, like due to viral/bacterial specific antibodies that cross-react with platelets. Recently, the role of Helicobacter pylori infection in ITP has been examined and its eradication has lead to apparent increases in platelet counts in several studies. (For more information please see the article from Heme Onc Clin, courtesy of Dr. Lief)

How does ITP present? How is it diagnosed?
Signs include petechiae, ecchymoses, menorrhagia and purpura. Hepatosplenomegaly and lymphadenopathy suggest an alternative diagnosis. A very low count, <10,000 per μl may result in the spontaneous formation of hematomas. And fatal complications due to extremely low counts <5,000 per μl include SAH or intracranial hemorrhage, lower GI bleeding or other internal type of bleeding.

The diagnosis of ITP is established only by ruling out other causes of thrombocytopenia. The patient’s history, the findings on physical examination, blood counts, and the findings on the blood smear are usually sufficient.

Examination of the blood smear is essential to r/o in vitro platelet clumping that can cause a falsely low platelet count and to ensure that there are no abnormalities of the WBCs or RBCs. A bone marrow biopsy may be appropriate in older patients to r/o occult myelodysplasia; tests for antiplatelet antibodies are not helpful. Most important is a thorough history taking to rule out drug-induced thrombocytopenia.

Immature platelet fraction (IPF) has also been used as a diagnostic tool to differentiate aplastic and consumptive thrombocytopenic states. IPF is analogous to the platelet reticulocyte count.

What’s the deal with MPV? Is it useful?
“Mean platelet volume is a clue to the age of the plts” paraphrasing Dr. Lief.  All platelet indices ( MPV and PDW) are significantly higher in ITP. Previous studies suggest that these indices provide clinical information about the underlying conditions of thrombocytopenia and have sufficient sensitivity and specificity in the diagnosis of ITP. A MPV > 11 has a 87% sensitivity and 80% specificity. (Please see the article attached from BJM, also courtesy of Dr. Lief).

What are the treatment options, and what’s the overall prognosis?

Once immune thrombocytopenic purpura has been diagnosed, the essential decision is whether any treatment, beyond counseling and observation, is necessary. The goal is not to achieve a normal platelet count, but rather to prevent bleeding. Treatment is routinely initiated if the thrombocytopenia is severe, even if the bleeding is negligible. A reasonable estimate of a safe platelet count, and therefore a reasonable basis for observation without specific treatment, is a platelet count > 30,000. This value is far below normal, but it seems to be sufficient to prevent serious bleeding.

First-line treatments to achieve a rapid platelet response include high dose parenteral corticosteroids, IVIg, and intravenous anti-D. Treatment should be tailored to the individual patient, however, and is often dictated by availability and local experience.

The off-label use of Rituximab, a monoclonal antibody against CD20, has been shown in preliminary studies to be an effective alternative to splenectomy in some patients. (Please see article attached for more detailed info).

There is increasing use of immunosuppresants (mycophenolate mofetil and azathioprine) because of their effectiveness.  In chronic refractory cases, where immune pathogenesis has been confirmed, the off-label use of vincristine, may be attempted.

Surgical treatment with splenectomy is recommended when:

-       No response to steroids, IVIG and Rituximab

-       Unable to taper off steroids

-       Frequent relapses

 Durable remission following splenectomy is achieved in 60-65% of ITP cases.

Thrombopoietin receptor agonists (Romiplostim and Eltrombopag) are approved by the FDA for use in ITP in adults "with insufficient response to corticosteroids, immunoglobulins, or splenectomy", and have been advocated for second-line treatment of ITP in a 2010 review. (See article attached) 
What’s the overall prognosis?

Most adults presenting with plt counts > 30,000 to 50,000 have a stable and benign course without treatment. Data from case series suggest that ≤15% of such pts develop more severe thrombocytopenia and require treatment during 3-7 years of follow-up.

Our patients did well after treatment with IVIG + steroids with significant improvement of his plts count from 3,000 on admission to 30,000 at the time of discharge. He will have a closer follow up with hematology, given high risk of relapse. I have attached multiple review articles, including a study evaluating the sensitivity and specificity of MPV in the diagnosis of ITP, as we discussed above. Thanks Dr. Lief for the references!



Purnema Madahar,
Jul 10, 2013, 4:23 AM
Purnema Madahar,
Jul 10, 2013, 6:47 AM
Purnema Madahar,
Jul 10, 2013, 6:47 AM
Purnema Madahar,
Jul 10, 2013, 6:48 AM
Purnema Madahar,
Jul 10, 2013, 4:34 AM
Purnema Madahar,
Jul 10, 2013, 6:48 AM