Hematology

Immune thrombocytopenia

Immune thrombocytopenia

What every physician needs to know about immune thrombocytopenia:

Background

Immune thrombocytopenia (ITP) comprises a heterogeneous group of disorders characterized by autoimmune-mediated platelet destruction and impairment of platelet production.

ITP may occur in the absence of an evident predisposing etiology (primary ITP) or as a sequela of an associated condition (secondary ITP).

The major clinical manifestation of ITP is an increased risk of bleeding.

The traditional goal of therapy is to achieve a hemostatic platelet count (greater than or equal to 20-30 x 109/L for most patients) while minimizing treatment-related toxicity

Definitions

"ITP" refers to all forms of immune-mediated thrombocytopenia, whether occurring in the absence of an evident predisposing etiology (primary ITP) or as a sequela of an associated condition (secondary ITP).

A platelet count of less than 100 x 109/L (rather than 150 x 109/L) is recommended as the cut-off for diagnosis. This threshold is based on the observation that fewer than 10% of otherwise healthy individuals with a stable platelet count between 100 and 150 x 109/L develop more severe thrombocytopenia over the ensuing 10 years.

ITP is classified by duration of disease. ITP diagnosed within the last 3 months, 3-12 months ago, and >12 months ago is referred to as newly diagnosed, persistent, and chronic, respectively (See Table I).

Table I.

ITP is categorized by disease duration as shown
  Time since ITP onset
Newly diagnosed less than 3 months
Persistent 3 to 12 months
Chronic greater than 12 months

What features of the presentation will guide me toward possible causes and next treatment steps:

Epidemiology

The incidence of ITP in adults is estimated to be 1.6 to 3.9 per 100,000 persons per year.

Adult-onset ITP was once thought to be largely a disease of young women. It is now appreciated that the incidence distribution of ITP is bimodal, with a smaller peak during young adulthood and a larger peak among the elderly.

Among young adults, ITP is approximately twice as common in females as in males. In contrast, incident ITP in the elderly affects males and females equally.

Primary ITP

ITP that occurs in the absence of a clear predisposing etiology is referred to as primary ITP.

The etiology of primary ITP is unknown. Predisposing polymorphisms in various cytokines and Fc-gamma receptors have been described. Reduction in T-regulatory cell function and polarization towards T-helper cell-related cytokines have been identified during active disease.

Secondary ITP

ITP that occurs as a sequela of an associated condition is referred to as secondary ITP. For causes of secondary ITP, see Table II.

Table II.

Secondary causes of ITP
Category Examples
Broader autoimmune disorders Systemic lupus erythematosusAntiphospholipid syndromeEvans syndrome
Infections Human immunodeficiency virusHepatitis C virusHelicobacter pylori
Lymphoproliferative disorders Chronic lymphocytic leukemia
Congenital immune deficiencies Common variable immune deficiencyAutoimmune lymphoproliferative syndrome
Drugs AlemtuzumabPurine analogues

Clinical manifestations

The major clinical manifestation of ITP is an increased risk of bleeding. However, it is now recognized that non-hemorrhagic manifestations (including fatigue and reduced quality of life) are common and potentially disabling sequelae.

Bleeding

The most important clinical manifestation of ITP is an increased risk of bleeding.

As with other disorders of primary hemostasis, bleeding in ITP is primarily mucocutaneous. Petechiae, purpura, ecchymoses, epistaxis, gingival bleeding, and menorrhagia are common. Major gastrointestinal hemorrhage and hematuria are less frequent.

Intracranial hemorrhage (ICH), the most dreaded complication of ITP, is rare. A Danish case-control study found a relative risk of ICH of 3.2 among adults with chronic primary ITP compared with the general population.

The platelet count is a fairly crude, but widely used predictor of bleeding. In the absence of a hemostatic comorbidity, trauma, or surgery, major bleeding is rare when the platelet count exceeds 20 to 30 x 109/L.

Nevertheless, there is substantial interindividual variation in bleeding phenotype. Some severely thrombocytopenic (less than 10 x 109/L) patients may be asymptomatic, while others with milder thrombocytopenia may suffer from frequent bleeding symptoms.

Advanced age is a risk factor for hemorrhage. In a systematic review and pooled analysis of case series of adults with chronic ITP and platelet counts persistently less than 30 x 109/L, the risk of fatal hemorrhage and major non-fatal hemorrhage was substantially higher in individuals older than 60 than in those less than 40 years of age.

Other factors that underlie the interindividual variation in bleeding tendency remain to be elucidated.

Non-bleeding manifestations

A substantial proportion of patients with ITP suffer from disabling fatigue, apprehension of bleeding, withdrawal from important professional and recreational activities, and poor quality of life (QOL). In a systematic QOL assessment using a standardized scale for measuring functional health, adults with chronic ITP endorsed health-related QOL that was significantly worse than the general population and intermediate between patients with cancer and heart failure.

In addition, epidemiologic evidence suggests that adults with chronic ITP may have a mildly increased risk of thromboembolism, hematologic malignancy, and other autoimmune disorders such as systemic lupus erythematosus. Further studies are needed to confirm these associations and their relationship to management.

Life expectancy is normal except in patients with severe refractory thrombocytopenia.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

There is no gold standard laboratory test for ITP. The single most compelling evidence of its presence is response to ITP-specific therapy.

As such, initial evaluation of a patient with suspected primary ITP involves:

  • Exclusion of non-autoimmune causes of thrombocytopenia

  • Exclusion of secondary ITP

Exclusion of non-autoimmune causes of thrombocytopenia: differential diagnosis and evaluation

The initial diagnostic evaluation of a patient with suspected ITP must, at a minimum, include:

  • A careful history

  • Physical examination

  • Complete blood count

  • Evaluation of the peripheral blood smear

The archetypal presentation of primary ITP is a generally healthy individual with isolated thrombocytopenia, an otherwise unremarkable peripheral blood smear, and a physical examination notable only for evidence of bleeding commensurate with the platelet count. Any deviation from this paradigm should prompt a focused investigation for other causes of thrombocytopenia (see Table III).

Table III.

Non-autoimmune causes of thrombocytopenia
Causes
Pseudothrombocytopenia
Disorders of decreased platelet production: Hereditory thrombocytopeniasMyelosuppressive therapy (for example, chemotherapy, radiation)Ethanol toxicityFolate or vitamin B12 deficiencyPrimary bone marrow disorders (for example, MDS, myelofibrosis, leukemias, lymphomas)Infiltrative diseases of the bone marrowCertain viral infections
Disorders of decreased platelet survival: Certain drugs (for example, heparin, quinine)Alloimmune thrombocytopenias (for example, post-transfusion purpura)Disseminated intravascular coagulationThrombotic thrombocytopenic purpura/hemolytic uremic syndromeCardiopulmonary bypassSevere infection/sepsis
Splenic sequestration: Portal hypertensionInfiltrative diseases of the spleen
Dilutional thrombocytopenia

Hereditary thrombocytopenias, in particular, must be borne in mind in the evaluation of isolated thrombocytopenia. Documentation of a previous normal platelet count, a focused family history and, when necessary, platelet counts of family members, should be pursued to exclude this group of disorders.

A careful history of recent exposure to prescription, over-the-counter, and recreational drugs as well as herbal supplements should be performed to rule out drug-induced thrombocytopenia.

What conditions can underlie immune thrombocytopenia:

Exclusion of secondary ITP (differential diagnosis and evaluation)

After non-autoimmune causes of thrombocytopenia have been excluded, a thorough history and physical examination should be conducted to assess the likelihood of a predisposing infection, malignancy, autoimmune disorder, or immune deficiency (see Table II). Distinguishing primary ITP from secondary causes may have critical implications with respect to treatment and prognosis.

For instance, many clinicians request HIV and hepatitis C testing in all patients with ITP because of the frequency of these conditions in the general adult population, the high incidence of ITP remission with anti-viral therapy, and concerns regarding the effects of corticosteroids in hepatitis C.

In some parts of the world where H. pylori infection is common, such as Japan and Italy, microbial eradicationproduces platelet responses in more than half of infected individuals with ITP. In these regions, it may be advisable to test routinely for the organism or even to offer empiric eradication therapy to all patients with newly diagnosed ITP. In contrast, H. pylori infection is less common in the US and antimicrobial therapy seldom induces sustained platelet responses. Therefore, it is our practice to test only individuals with gastrointestinal symptoms suggestive of H. pylori, as well as those from parts of the world where H. pylori infection is endemic. Some experts in the United States advocate such testing in all ITP patients.

An international working group also recommends measuring quantitative immunoglobulins in all patients with ITP to screen for immune deficiencies. We generally do not perform such screening unless there is a history of frequent infection or other manifestations to suggest an underlying immune deficiency state.

When do you need to get more aggressive tests?

Bone marrow aspiration and biopsy is often unnecessary in individuals presenting in typical fashion, but should be performed in patients that do not respond to standard first-line ITP therapy. Bone marrow examination may also be considered in individuals over the age of 60, when the incidence of myelodysplastic syndrome (MDS) becomes significant.

Assays for platelet-antigen specific antibodies lack sufficient sensitivity to exclude ITP and are hampered by limited interlaboratory reproducibility. Conversely, though the presence of such antibodies is suggestive of ITP, antibodies are also detected in 10-20% of individuals with non-immune causes of thrombocytopenia, such as MDS and chronic liver disease. (Table III)

What imaging studies (if any) will be helpful?

Physicians may occasionally order imaging of the chest, abdomen, and pelvis to search for an occult lymphoma in patients presenting with ITP. We do not request imaging unless there are findings in the history, physical examination, or peripheral blood smear concerning for an underlying lymphoproliferative disorder.

What therapies should you initiate immediately and under what circumstances - even if root cause is unidentified?

Management

The traditional goal of therapy is to provide a hemostatic platelet count (20-30 x 109/L or greater for most patients) while minimizing treatment related morbidity. As such, treatment is rarely indicated for patients with platelet counts above this threshold. Nevertheless, treatment should be tailored to the individual patient and clinical setting.

Patients with extensive bleeding symptoms, comorbidities, or lifestyles that predispose to bleeding and those that require an invasive procedure may benefit from a higher target platelet count. We generally strive for a platelet count of 50 x 109/L or higher in patients who require antithrombotic therapy.

First-line therapy

Corticosteroids, supplemented with either intravenous immunoglobulin (IVIG) or immunoglobulin anti-D (anti-Rh[D]) as needed, are used as upfront therapy to stop bleeding and raise the platelet count acutely in patients with newly diagnosed or newly relapsed disease. Dosing, time to response, and selected toxicities of these agents are shown in Table IV.

Table IV.

First line therapy - toxicities, dosing and time to response
Agent Dosing Time to response Selected toxicities
Prednis(ol)one 0.5 to 2mg/kg/day x 2 to 4 weeks, followed by slow taper Several days to several weeks Mood swings, insomnia, anxiety, psychosis, weight gain, Cushingoid facies, hyperglycemia, decreased bone density, hypertension, skin changes, gastrointestinal distress and ulceration, avascular necrosis, increased susceptibility to infections, cataracts, adrenal insufficiency
Methylprednisolone 30mg/kg/day x 7 days 2 to 7 days
Dexamethasone 40mg/day for 4 days, every 2-4 weeks for 1-4 cycles Several days to several weeks
IVIG 0.4g/kg/day x 5 days or1g/kg/day x 1 to 2 days 1 to 4 days Headache, aseptic meningitis, renal insufficiency, fever, chills, nausea, thromboembolism, anaphylactoid reactions in patients with IgA-deficiency
Anti-Rh(D) 50 to 75mcg/kg 4 to 5 days Hemolytic anemia, fever, chills. Rarely, intravascular hemolysis, disseminated intravascular coagulation (DIC), and renal failure

Most patients respond to first-line therapy. Indeed, non-response should prompt reconsideration of the diagnosis and an investigation for alternative causes of thrombocytopenia.

Anti-Rh(D) therapy is rarely associated with life-threatening intravascular hemolysis, disseminated intravascular coagulation (DIC), and acute renal failure. Its use should therefore be avoided in patients with pre-existing hemolysis or a positive direct antiglobulin test not due to prior therapy.

Intensification of therapy at presentation is under investigation as a potential means of curing or mollifying the long-term course of ITP.

Two randomized controlled trials suggest that high-dose dexamethasone increases initial response rates and hastens the time to response, but does not prolong remission compared with standard-dose prednis(ol)one. Rituximab added to high-dose dexamethasone improves response rates at 6 and 12 months compared with high-dose dexamethasone alone, but at the expense of greater toxicity. Further studies with longer follow-up are needed to determine whether intensive upfront therapy can ameliorate the natural history of or even cure ITP.

Second-line therapy

Although upwards of 80-90% of patients respond to first-line therapy, most ultimately relapse after treatment is tapered and require a second-line approach to maintain a hemostatic platelet count. Standard second-line options include splenectomy, rituximab, and the thrombopoietin receptor agonists (TRAs), romiplostim and eltrombopag. (Table V)

Table V.

Standard second-line therapy options
Strategy Dose Response rate Selected toxicities
Splenectomy NA Two-thirds of patients achieve a long-term response with no additional therapy Adverse effects of surgery, increased risk of infection, thrombosis
Rituximab 375mg/m2 weekly x 4 weeks (lower doses may be effective) 40% at one year, 20% at 5 years Infusion reactions, reactivation of hepatitis B infection, serum sickness, hypogammaglobulinemia, rare cases of progressive multifocal leukoencephalopathy
RomiplostimEltrombopag - 1 to 10mcg/kg SC weekly- 25 to 75mg PO daily 80%. Most responses are sustained with continual administration of drug Increased bone marrow reticulin, thrombosis, worsening thrombocytopenia after discontinuation of drug. Eltrombopag also associated with liver function test abnormalities

Splenectomy offers the best chance for prolonged remission. Two-thirds of patients attain a durable long-term remission and others attain a partial response that may allow for a reduction in concomitant ITP medications.

Because spontaneous remission is most likely in the first year, it is recommended that splenectomy be deferred, if possible, until ITP has been present for at least 12 months.

The incidence of post-splenectomy sepsis is reduced but not eliminated by adhering to recommended vaccination protocols and initiating antibiotics at the first signs of a febrile illness. Patients with newly diagnosed ITP should be vaccinated in anticipation of possible splenectomy in the future.

Other early complications of splenectomy include complications referable to surgery and anesthesia, bleeding, and deep vein and intra-abdominal thrombosis.

Recent concerns raised about late complications of splenectomy including atherosclerosis, pulmonary hypertension, and thrombosis require further study.

Standard-dose rituximab induces complete remissions in approximately 40% of patients at one year. Only 20% of these individuals enjoy sustained responses lasting 5 or more years. In a randomized, placebo-controlled trial, the response rate was not significantly different at 1.5 years in the rituximab and placebo arms.

Patients that achieve a complete remission with rituximab and subsequently relapse often respond to retreatment. Partial responders, in contrast, often relapse within one year and generally do not achieve sustained responses with retreatment.

Rituximab is contraindicated in patients with active hepatitis B infection due to the risk of fulminant hepatitis.

Over 50 cases of progressive multifocal leukoencephalopathy (PML) have been reported in HIV-negative patients treated with rituximab, one of whom had ITP. The contribution of rituximab to the acquisition of PML in these heavily pre-treated patients is unclear.

The most common toxicity associated with rituximab is infusion reaction, which can be managed in most cases with pre-medications and decreasing the rate of infusion. Other toxicities associated with rituximab include hypogammaglobulinemia, serum sickness, and neutropenia.

The TRAs, romiplostim and eltrombopag, are approved by The US Food and Drug Administration for use in patients with primary ITP, who require treatment after an initial course of corticosteroids. In some parts of the world, approval is restricted to patients who are refractory to or ineligible for splenectomy.

Romiplostim is given as a weekly subcutaneous injection that must be administered in the physician's office. Eltrombopag is formulated for daily oral administration. It must be taken several hours removed from meals and medications or products containing polyvalent cations and an initial 50% dose reduction is necessary in individuals of East Asian origin. Both agents have demonstrated high response rates, even among splenectomized and refractory patients, in randomized clinical trials. Romiplostim and eltrombopag are generally well-tolerated.

Increased bone marrow reticulin has been observed in a small number of patients within 1 year of initiating therapy. The prevalence increases with longer duration of treatment. However, loss of response associated with evidence of a myelophthisic picture is rare and deposition of reticulin appears to be reversible with discontinuation of the drug in most reported cases. The need to monitor for reticulin fibrosis in patients on TRAs requires additional study.

Some experts recommend a baseline bone marrow biopsy prior to TRA initiation and annual surveillance bone marrow biopsies in patients on long-term TRA therapy. A biopsy should be performed if there is loss of response to treatment or new abnormalities appear in the peripheral blood cell counts or smear.

Thrombosis is another potential complication of the TRAS, though the incidence of thromboembolism in clinical trials of romiplostim and eltrombopag in ITP has been similar in TRA and placebo-treated subjects. Among patients treated with TRAs, both venous and arterial events have been observed, most occurring at normal or below normal platelet counts. Many patients who developed thrombosis in the clinical studies of romiplostim and eltrombopag had pre-existing risk factors for thrombosis. Therefore, treatment with TRAs, as with other therapies, should take into consideration predisposing risk factors for thrombosis.

Hepatobiliary laboratory abnormalities were detected in 13% of eltrombopag treated patients in clinical studies, prompting a black box warning that calls for regular monitoring of liver function tests.

What other therapies are helpful for reducing complications?

Hospitalization and emergency therapy

Patients with ITP should be hospitalized for major bleeding. Admission should also be considered in patients with platelet counts less than 10 to 20 x 109/L, particularly if there is a history of significant bleeding, non-compliance, or if responsiveness to therapy has not been established.

Hospitalized patients are generally treated with standard first-line therapy and discharged when bleeding has ceased and the platelet count rises above 20 to 30 x 109/L. We use a combination of IVIG, methylprednisolone, vinca alkaloid, a TRA, and/or anti-Rh(D) in patients with severe thrombocytopenia who fail first-line therapy.

Platelet transfusions, delivered in combination with medical therapy, may be useful in the setting of life or organ threatening hemorrhage.

Recombinant factor VIIa is reserved for the very rare patient unresponsive to other modalities in whom an immediate hemostatic response is necessary.

Aminocaproic acid or tranexamic acid may be useful adjuncts to manage mucosal bleeding.

What should you tell the patient and family about prognosis?

Primary ITP in adults is typically a chronic disease. Approximately 80-90% of patients respond to standard first-line treatments, but the large majority subsequently relapse and require additional therapy. Long-term survival with proper treatment and follow-up is excellent for most patients.

The likelihood of achieving a sustained remission lessens as the duration of disease increases. Nevertheless, rare individuals show spontaneous improvement after years of severe disease requiring intensive therapy.

It is estimated that 5 to 10% of patients presenting with primary ITP will eventually develop systemic lupus erythematosus or another autoimmune disorder in addition to ITP.

"What if" scenarios.

Special populations and clinical settings

Patients with refractory ITP - those requiring hospitalization, emergency therapy, or an invasive procedure - and pregnant women may require specific treatment considerations.

Refractory ITP

Most patients respond to first and second line therapy. A small minority, perhaps 10%, have symptomatic refractory disease that requires third line agents, alone or in combination. Hematopoietic stem cell transplantation is reserved for extreme circumstances. (Table VI)

Table VI.

Third line agents
Agent Dose Selected toxicities
Azathioprine 1 to 2mg/kg/day (maximum 150mg/day) Liver function abnormalities, neutropenia, anemia, infection
Cyclosporin A 5mg/kg/day x 6 days, then 2.5 to 3mg/kg/day (titrated to blood levels of 100 to 200ng/ml) Renal failure, hypertension, tremor, infection
Cyclophosphamide 1 to 2mg/kg PO daily or 0.3 to 1g/m2 intravenously (IV) every 2 to 4 weeks x 1 to 3 doses Myelosuppression, infection, secondary malignancy
Danazol 10-15 mg/kg/day divided into 2-3 daily doses Acne, hirsutism, dyslipidemia, amenorrhea, liver function abnormalities
Dapsone 75 to 100mg daily Hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, rash, methemoglobinemia
Mycophenolate mofetil 1,000mg twice daily Headache, back pain, infection
Vincristine 1 to 2mg IV weekly (total dose 6mg) Neuropathy, constipation, cytopenias, thrombophlebitis at infusion site

ITP in pregnancy

Pregnancy has a variable effect on ITP. Thrombocytopenia may worsen, remain stable, or improve during gestation.

During the first two trimesters, the goals of therapy are similar to the non-pregnant state, that is, maintenance of a platelet count of 20 to 30 x 109/L and prevention of bleeding.

As delivery approaches during the third trimester, the target platelet count increases to 50 x 109/L in preparation for the possible need for urgent cesarean section. Neuraxial anesthesia may require a platelet count of 75 x 109/L or higher, depending on the preference of the anaesthesiologist.

First-line treatment options for ITP during pregnancy include corticosteroids and IVIG at standard dosing. Splenectomy is reserved for refractory cases and is most safely performed in the second trimester. Anti-Rh[D], rituximab, romiplostim, and eltrombopag are all pregnancy risk category C, and should generally be avoided during pregnancy, though successful use of these agents during late gestation has been reported.

Because maternal anti-platelet antibodies can cross the placenta, approximately 5-10% of neonates born to mothers with ITP will develop severe thrombocytopenia (less than 20 x 109/L) during the first few days of life. Neonatal thrombocytopenia may worsen within several days after birth, perhaps owing to improved splenic function.

Fortunately, the rate of intracranial hemorrhage and mortality in neonates born to mothers with ITP is considerably less than 1%. There is no evidence that this risk is reduced by cesarean delivery. Therefore, the decision to pursue a cesarean section should be based on maternal indications alone.

Fetal procedures associated with hemorrhagic risk such as cordocentesis, fetal scalp blood sampling or electrode placement, and forceps or vacuum-assisted delivery should be avoided.

Neonatal platelet count monitoring should be initiated shortly after birth under the care of a pediatrician.

Some pediatricians advocate transcranial ultrasonography in all neonates with severe thrombocytopenia to exclude silent intracranial hemorrhage.

Invasive procedures

There is little evidence regarding management of ITP in the perioperative setting.

An expert panel recommends the following target platelet counts in patients with ITP. (See Table VII)

Table VII.

Target platelet counts in patients with ITP who are undergoing invasive procedures
Procedure Recommended platelet count (x 109/L)
Dental cleaning greater than or equal to 20 to 30
Simple dental extraction greater than or equal to 30
Complex dental extraction greater than or equal to 50
Regional dental block greater than or equal to 30
Minor surgery greater than or equal to 50
Major surgery greater than or equal to 80
Neurosurgery greater than or equal to 100

Standard first-line therapy is generally used to increase the platelet count for surgery. In addition, antifibrinolytic agents may be a useful adjunct for the prevention of bleeding with dental procedures.

Pathophysiology

The normal platelet life span is 7 to 10 days.

It has long been recognized that platelet life span is reduced in ITP as a consequence of antibody-mediated clearance of platelets by tissue macrophages.

Newer evidence suggests that platelet production may also be impaired in ITP by antibody, and possibly cell-mediated suppression of megakaryopoiesis.

What other clinical manifestations may help me to diagnose immune thrombocytopenia?

N/A

What other additional laboratory studies may be ordered?

N/A

What's the evidence?

Rodeghiero, F, Stasi, R, Gernsheimer, T. "Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group". Blood. vol. 113. 2009. pp. 2386-2393.

(These guidelines comprise up-to-date, evidence-based, consensus recommendations on terminology, diagnosis, and management of ITP by international experts.)

Provan, D, Stasi, R, Newland, AC. "International consensus report on the investigation and management of primary immune thrombocytopenia". Blood. vol. 115. 2010. pp. 168-186.

(These guidelines comprise up-to-date, evidence-based, consensus recommendations on terminology, diagnosis, and management of ITP by international experts.)

Neunert, C, Lim, W, Crowther, M, Cohen, A, Solberg, L, Crowther, MA. "The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia". Blood. vol. 117. 2011. pp. 4190-4207.

(These guidelines comprise up-to-date, evidence-based, consensus recommendations on terminology, diagnosis, and management of ITP by international experts.)

Cines, DB, Bussel, JB, Liebman, HA, Luning Prak, ET. "The ITP syndrome: pathogenic and clinical diversity". Blood.. vol. 113. 2009. pp. 6511-6521.

(A review of secondary causes of ITP and their associated pathophysiology.)

Lacey, JV, Penner, JA. "Management of idiopathic thrombocytopenic purpura in the adult". Semin Thromb Hemost.. vol. 3. 1977. pp. 160-174.

(A classic article illustrating the relationship between platelet count and bleeding risk in ITP.)

Cines, DB, Bussel, JB. "How I treat idiopathic thrombocytopenic purpura (ITP)". Blood.. vol. 106. 2005. pp. 2244-2251.

(Expert recommendations on the evaluation and treatment of ITP. See also second and third references above.)

Kojouri, K, Vesely, SK, Terrell, DR, George, JN. "Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet responses, prediction of response, and surgical complications". Blood.. vol. 104. 2004. pp. 2623-2634.

(This systematic review of 135 case series shows that splenectomy is associated with a complete response rate of 66% and a low incidence of surgical mortality.)

Arnold, DM, Dentali, F, Crowther, MA. "Systematic review: efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura". Ann Int Med. vol. 146. 2007. pp. 25-33.

(This systematic review demonstrates the response rates and toxicity of rituximab for the treatment of ITP.)

Kuter, DJ, Bussel, JB, Lyons, RM. "Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial". Lancet. vol. 371. 2008. pp. 395-403.

(This reference details a pivotal phase 3 trial demonstrating the efficacy and safety of romiplostim, which led to its approval for the management of primary ITP.)

Cheng, G, Saleh, MN, Marcher, C. "Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study". Lancet. vol. 377. 2011. pp. 393-402.

(This reference details a pivotal phase 3 trial demonstrating the efficacy and safety of eltrombopag, which led to its approval for the management of primary ITP.)

Ghanima, W, Godeau, B, Cines, DB, Bussel, JB. "How I treat immune thrombocytopenia: the choice between splenectomy or a medical therapy as a second-line treatment". Blood.. vol. 120. 2012. pp. 960-969.

(This reference summarizes expert opinion and evidence on the choice of second-line therapy in adults with primary ITP.)

Gernsheimer, T, James, AH, Stasi, R. "How I treat thrombocytopenia in pregnancy". Blood.. vol. 121. 2013. pp. 38-47.

(This reference summarizes expert opinion and evidence on the evaluation and management of ITP and other causes of thrombocytopenia in pregnancy.)

Cuker, A, Neunert, C. "How I treat refractory immune thrombocytopenia". Blood. 2016.

(This article provides an expert-based approach to management of patients with ITP who do not respond to or are unable to undergo splenectomy.)

Cuker, A, Prak, ET, Cines, DB. "Can immune thrombocytopenia be cured with medical therapy?". Semin Thromb Hemost. vol. 41. 2015. pp. 395-404.

(This review summarizes data on long-term response rates and the potential for cure after treatment with medical therapy for ITP. A biological rationale for medical therapy that targets the innate and adaptive immune responses administered early in the disease course is proposed.)

Wei, Y, Xue-bin, J, Wang, Y. "High-dose dexamethasone vs prednisone for treatment of adult immune thrombocytopenia: a prospective multicenter randomized trial". Blood. vol. 127. 2016. pp. 296-302.

(This is the largest randomized controlled trial comparing high-dose dexamethasone with standard-dose prednisone in adults with newly diagnosed ITP.)

Chugh, S, Darvish-Kazem, S, Lim, W. "Rituximab plus standard of care for treatment of primary immune thrombocytopenia: a systematic review and meta-analysis". Lancet Haematol. vol. 2. 2015. pp. e75-e81.

(This meta-analysis included five randomized controlled trials of rituximab for ITP in adults. Rituximab was associated with a greater rate of complete response than standard of care, but not with a reduction in bleeding.)

Ghanima, W, Khelif, A, Waage, A. "Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): a multicentre, randomised, double-blind, placebo-controlled trial". Lancet. vol. 385. 2015. pp. 1653-1661.

(In this randomized, double-blind, trial, 112 adults with ITP were assigned to standard-dose rituximab or placebo. There was no difference in response rates between the two groups at 1.5 years.)

Cines, DB, Gernsheimer, T, Wasser, J. "Integrated analysis of long-term safety in patients with chronic immune thrombocytopaenia (ITP) treated with the thrombopoietin (TPO) receptor agonist romiplostim". Int J Hematol. vol. 102. 2015. pp. 259-270.

(This safety analysis of 14 romiplostim trials demonstrated comparable rates of thrombosis and malignancy between patients treated with romiplostim and those treated with placebo/standard of care.)

Brynes, RK, Orazi, A, Theodore, D. "Evaluation of bone marrow reticulin in patients with chronic immune thrombocytopenia treated with eltrombopag: Data from the EXTEND study". Am J Hematol. vol. 90. 2015. pp. 598-601.

(Bone marrow biopsies were collected from 117 patients treated with eltrombopag for up to 5.5 years. Moderate to marked reticulin fibrosis was noted in 2 patients.)

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