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their habits of critical inquiry and balanced judgement, and to contribute to better patient care. Disclosures: Donald M. Arnold, MD, MSc, current

author of this module, was a consultant for Amgen; received speaking honoraria from Amgen, GlaxoSmithKline, Hoffman-LaRoche and Talecris; was a

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Primary Immune Thrombocytopenia View online at http://pier.acponline.org/physicians/diseases/d340/d340.html

Module Updated: 2013-10-08

CME Expiration: 2016-10-08

Author

Donald M. Arnold, MD, MSc

Table of Contents

1. Diagnosis ..........................................................................................................................2

2. Consultation ......................................................................................................................7

3. Hospitalization ...................................................................................................................9

4. Therapy ............................................................................................................................10

5. Patient Counseling ..............................................................................................................17

6. Follow-up ..........................................................................................................................18

References ............................................................................................................................20

Glossary................................................................................................................................23

Tables ...................................................................................................................................25

Figures .................................................................................................................................32

http://pier.acponline.org/physicians/diseases/d340/d340.html

Primary Immune Thrombocytopenia


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1. Diagnosis Top

Consider the diagnosis of primary immune thrombocytopenia in patients with isolated thrombocytopenia without a known precipitating cause.

1.1 Use patient history to make the diagnosis largely by excluding other

causes.

Recommendations

• Use the history to explore other immune or nonimmune causes of thrombocytopenia, including:

Medication use (such as heparin, quinidine/quinine, and sulfonamides), including over-the-counter vitamin preparations or health supplements

Alcohol use

Viral illness (such as varicella, infectious mononucleosis, hepatitis C, and HIV), especially in children

Hepatitis may cause secondary ITP and other liver diseases (cirrhosis and portal hypertension are associated with nonimmune thrombocytopenia)

HIV risk factors, including injection drug use, sexual contact, transfusions

H. pylori infection, especially for mild to moderate thrombocytopenia

Exclude illnesses that can cause thrombocytopenia or are associated with secondary ITP (such as systemic lupus erythematosus)

Exposure to toxins such as benzene and its derivatives, nitrogen mustard, insecticides, organic hair dyes,

and ionizing radiation

Acquired hematologic disorders, such as myelodysplastic syndrome, acute leukemia, chronic lymphocytic leukemia, or lymphoproliferative disorders

Inherited hematologic disorders, such as thrombocytopenia with absent radius, Bernard-Soulier syndrome, Gray platelet syndrome, Wiskott-Aldrich syndrome, May-Hegglin anomaly and other autosomal dominant thrombocytopenic disorders, Fanconi syndrome, and X-linked thrombocytopenia

Pregnancy is associated with the onset of ITP, or more commonly, gestational (physiologic) thrombocytopenia when mild, transient, and occurring towards the end of pregnancy

Transfusions within the last 5 to 14 days to exclude post-transfusion purpura

• Ask about systemic symptoms such as weight loss, fevers, headache, arthralgias, and rash, as well

as symptoms of hyper- or hypothyroidism, all of which can be associated with other related

systemic or autoimmune diseases.

• Use the history to explore the severity of bleeding symptoms, including:

The anatomic sites of bleeding, especially skin, mucous membranes, gastrointestinal, and vaginal

Bleeding following surgical challenges

Evidence

• The American Society of Hematology revised practice guidelines for ITP in 2011. This guideline is

based on review of scientific evidence (where available) which was assessed using GRADE criteria

(1).

• A study to determine the strength of clinical evidence for individual drugs as a cause of

thrombocytopenia showed 515 patient case reports on patients with drug-induced

thrombocytopenia (excluding heparin). In 247 case reports (48%), the drug appeared to be the

cause. The reports included 98 drugs, most frequently quinidine, trimethoprim-sulfamethoxazole,

and gold. However, many of the reports did not provide sufficient evidence to confirm drug-related

thrombocytopenia (2).

http://bloodjournal.hematologylibrary.org/content/117/16/4190.long



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• Databases of published case reports of drug-induced thrombocytopenia ranking drugs according to

the strength of clinical evidence for a causal relation to thrombocytopenia are available at this

website or in a published compilation (2).

• A retrospective study based on clinical symptoms and laboratory parameters, which included

platelet kinetics and mean platelet volume, describes an autosomal dominant

macrothrombocytopenic disorder in which patients tend not to bleed and platelet counts do not

respond to immune-modulating therapy (3).

• A narrative review describes a classification for hereditary thrombocytopenic disorders (4).

• A consensus statement addresses the investigation and management of adults and children with

ITP (5).

Rationale

• Primary ITP is a diagnosis of exclusion. Thrombocytopenia may be immune (drug-induced,

infection-associated) or nonimmune (congenital, alcohol- or toxin-induced, myelodysplasia). The

presence of infection or other concomitant illnesses may also point to a cause.

Comments

• Immune thrombocytopenia was previously known as idiopathic or immune thrombocytopenic

purpura.

1.2 Use physical examination to help exclude other causes.

Recommendations

• On physical exam look for:

Splenomegaly suggesting sequestration of platelets rather than ITP

Lymphadenopathy suggesting possible infection, lymphoproliferative disease, or cancer

Hepatomegaly that may indicate liver disease

Synovitis or arthritis suggesting an underlying rheumatologic disease

Fevers and/or neurologic changes suggesting TTP

Skeletal malformations suggesting a rare congenital thrombocytopenia

Evidence

• The presence of splenomegaly makes the diagnosis of ITP unlikely (6).

• The American Society of Hematology revised practice guidelines for ITP in 2011. This guideline is

based on review of scientific evidence (where available) which was assessed using GRADE criteria

(1).

• Impaired mental status is associated with TTP, as detailed in a recent review (7).

Rationale

• Thrombocytopenia is associated with hepatitis, cirrhosis, and portal hypertension, due to

splenomegaly, and splenic sequestration of platelets, which are more common than ITP.

• The presence of synovitis or arthritis may indicate secondary ITP in the context of systemic lupus

erythematosus or another rheumatologic disorder.

• Fever and neurologic impairment are found in TTP, which is characterized by thrombocytopenia,

microangiopathic hemolytic anemia, and renal failure.

1.3 Specifically assess patients for signs of bleeding.

Recommendations

• On physical examination, look for:

Ecchymoses and petechiae on the skin

http://moon.ouhsc.edu/jgeorge/DITP.html

http://moon.ouhsc.edu/jgeorge/DITP.html




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Mucous membrane, petechiae, or purpura in the mouth

Hemorrhagic bullae of the oral mucous membranes or tongue

Blood in the nose

Neurologic findings suggesting intracranial hemorrhage

Retinal hemorrhages

• Recognize that patients may be diagnosed with ITP during a ‘routine’ medical examination.

• See figure Petechia due to Thrombocytopenia.

Evidence

• Based on accepted clinical practices and the 2011 consensus statement of the American Society of

Hematology (1).

• A prospective study explored demographic and comorbid clinical factors in 205 patients with ITP. Of

the 186 adults in the study, 87 (47%) had been diagnosed with ITP incidentally during a routine

medical examination, while 96 (52%) presented with bleeding symptoms (8).

• Using a mathematical model applied to patients with ITP identified by a systematic literature

search, age-adjusted rates of fatal hemorrhage were 0.004, 0.012, and 0.31 cases per patient-year

for age groups younger than 40, 40 to 60, and older than 60, respectively (9).

Rationale

• Patients may be asymptomatic or have minimal symptoms at presentation.

• It is important to assess the level of bleeding to determine the severity of the disease and the

intensity of treatment.

1.4 Recognize that there is no single diagnostic test for ITP but that CBC is

essential in supporting the diagnosis.

Recommendations

• Obtain CBC and examine a peripheral blood film to confirm thrombocytopenia and determine that

the leukocyte count and red cell morphology are normal.

• See table Laboratory Tests to Support the Diagnosis of Primary Immune Thrombocytopenia.

Evidence

• A prospective study examined the likelihood of developing ITP among 217 individuals with mild

thrombocytopenia (platelet counts between 100 × 109 cells/L and 150 × 109 cells/L). The 10-year

probability of developing a persistent platelet count <100 × 109 cells/L was 6.9% (CI, 4.0% to

12.0%) (10).

• A consensus statement established the cutoff platelet count for ITP as <100 × 109 cells/L (11).

• See the 2011 American Society of Hematology consensus statement (1).

Rationale

• Thrombocytopenia (platelet count <100 × 109 cells/L) is an essential feature of ITP.

• The leukocyte count is normal in ITP. However, the presence of anemia does not exclude ITP if it

can be explained by iron deficiency or bleeding, or if there is a known hemoglobinopathy such as

sickle cell disease.

• Autoimmune hemolytic anemia may be present concomitantly with ITP, known as Evan's

syndrome.

• Fragmented red cells with thrombocytopenia suggest microangiopathic hemolytic anemia rather

than ITP.



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1.5 Examine the peripheral blood smear to confirm the diagnosis.

Recommendations

• Examine the blood smear to:

Confirm thrombocytopenia and exclude clumping, which is indicative of a laboratory-only phenomenon called pseudothrombocytopenia

Confirm the presence of normal erythrocyte and leukocyte number and morphology; in particular, exclude:

o Microangiopathic changes in erythrocytes

o The presence of nucleated erythrocytes and early or abnormal myeloid forms

o Leukocyte inclusion bodies

• See table Laboratory Tests to Support the Diagnosis of Idiopathic Thrombocytopenic Purpura.

• See figure Pseudothrombocytopenia.

• See figure Normal Platelets on Peripheral Blood Smear.

• See figure Giant Platelet on Peripheral Blood Smear.

Evidence

• Consensus (1; 5).

Rationale

• In ITP, the erythroid and myeloid morphology is normal.

• The presence of schistocytes is associated with microangiopathic hemolytic anemia, such as TTP

and hemolytic uremic syndrome, rather than ITP.

• The presence of nucleated erythrocytes and early myeloid forms suggests a myelophthisic process

as seen in neoplastic and metastatic disease, lymphoma, granulomatous disease, and infections of

the bone marrow.

• The presence of pseudo-Pelger-Huet anomaly and hypogranulation of myeloid cells suggests

myelodysplastic syndrome.

• Leukocyte inclusion bodies called Döhle bodies are suggestive of a hereditary thrombocytopenia

syndrome (such as May-Hegglin anomaly).

1.6 Consider a bone marrow aspiration and biopsy in patients with atypical

findings to identify an alternate diagnosis. Bone marrow aspiration and biopsy is not necessary to establish the diagnosis in patients presenting with typical

ITP.

Recommendations

• Consider a bone marrow aspiration and biopsy to identify an alternative diagnosis if atypical

findings are present in history, physical exam, or lab studies, including abnormalities on the

peripheral blood smear.

• See table Laboratory Tests to Support the Diagnosis of Idiopathic Thrombocytopenic Purpura.

Evidence

• These recommendations are drawn from the 2011 American Society of Hematology guidelines (1).

• A bone marrow examination is not required to establish the diagnosis in patients with history,

physical, lab, and peripheral smear findings consistent with ITP (1).

• Over a 1-year period in 2003, health care providers prospectively collected data on adverse events

associated with bone marrow aspiration and biopsy procedures. Of 19,259 procedures, there were




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16 adverse events, 1 of which occurred in a patient with ITP and a platelet count of 6 × 109 cells/L

(12).

Rationale

• Bone marrow biopsy is not essential for the diagnosis but can help exclude underlying diagnoses if

atypical features are present.

• Bleeding complications following bone barrow biopsy in patients with ITP are very rare and

generally easily controlled.

Comments

• On bone marrow examination in patients with ITP, typical findings are normal or increased

numbers of megakaryocytes, normal morphology and relative percentages of the myeloid and

erythroid precursors, and absence of extrinsic nonhematopoietic cells.

1.7 Consider testing for H. pylori infection in certain geographic locations.

Recommendations

• In some patients with ITP who do not respond to initial therapy or who relapse, consider a 13C urea

breath test to test for infection with H. pylori.

Evidence

• In a systematic review of 696 patients with ITP, 42.7% (CI, 31.8% to 53.9%) achieved a platelet

count response following H. pylori eradication; the response rate was lower in patients with severe

thrombocytopenia (defined in this review as <30 × 109 cells/L) (13).

Rationale

• Diagnosis of H. pylori infection and its treatment may be an alternative therapy for ITP and may

allow some patients to avoid immunosuppressive therapy.

• Proposed mechanisms of H. pylori-induced ITP are antibody cross-reactivity with platelet

autoantigens, activation of autoreactive B-cells, and enhancement of monocyte phagocytic activity.

Comments

• There seems to be geographic variability in the prevalence of H. pylori and in the serotype of the H.

pylori bacteria, such that in certain countries, including Japan, rates of platelet count responses

following H. pylori eradication in patients with ITP have been significant. In other countries,

response rates are much lower.

1.8 Exclude other causes of thrombocytopenia.

Recommendations

• History, physical, and lab studies should exclude other diseases or conditions associated with

thrombocytopenia, such as medications or liver disease, which are more common than ITP.

• See information on patient history and physical exam.

• See table Differential Diagnosis of Primary Immune Thrombocytopenia.

Evidence

• Consensus (1; 5).

Rationale

• The diagnosis of primary ITP is made when other causes of thrombocytopenia have been excluded.



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2. Consultation Top

Consult a hematologist or oncologist for patients with severe thrombocytopenia (<50 × 109 cells/L) when there is diagnostic uncertainty. Obtain consultation with an appropriate specialist if there is no response to initial therapy or other hematologic disorders develop.

2.1 Consider consultation by a hematologist or oncologist for severe thrombocytopenia or if there are abnormalities in the number or morphology

of other cell lines.

Recommendations

• Consult a hematologist or oncologist if there is:

Thrombocytopenia with platelet counts <50 × 109 cells/L

Leukopenia

Leukocytosis

Anemia not due to blood loss or iron deficiency

Morphologic abnormalities of the erythroid or myeloid series

Presence of nucleated erythrocytes or myeloid precursors on the peripheral blood smear

Evidence

• Myelodysplastic syndrome can present with isolated thrombocytopenia (15).

• Retrospective studies have shown that platelet count correlates with clinical bleeding, that clinically

significant bleeding occurs in less than 5% of patients with platelet counts of >10 × 109 cells/L,

and rarely in patients with platelet counts <50 × 109 cells/L (16).

• In a cohort of 117 patients with chronic ITP, 49 with platelet counts <30 × 109 cells/L were seen

without treatment, and none of these had hemorrhagic complications over a mean follow-up of 30

months (17).

• Guidelines suggest that treatment is indicated for patients with ITP and a platelet count <30 x 109

cells/L. Threshold platelet counts may be higher for patients with bleeding (1).

Rationale

• There is no established cutoff in platelet count that correlates precisely with bleeding risk.

• Consultation will aid in the diagnosis and management of hematologic malignancies or

microangiopathic disorders associated with thrombocytopenia and with the treatment of severe

ITP.

2.2 Obtain hematologic consultation if there is no response to initial therapy.

Recommendations

• Obtain hematologic consultation if there is no increase in platelet count after 1 to 2 weeks of

prednisone or after initial dose of IVIG.

Evidence

• Consensus.

Rationale



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• The patient may have refractory ITP or another hematologic disorder.

2.3 Obtain surgical consultation for splenectomy if medical therapy is ineffective.

Recommendations

• Note that splenectomy is recommended for patients with persistent platelet counts <10 × 109

cells/L for 4 to 6 weeks and for patients who have had ITP for 3 months with persistent severe

thrombocytopenia (platelet count <30 × 109 cells/L) despite treatment.

Evidence

• Splenectomy has been shown to be effective in leading to the resolution of ITP in observational

studies (6; 21; 45; 56; 60; 61; 62; 63; 64); however, there are not enough data to make

evidence-based recommendations on the timing of splenectomy in ITP.

• Recommendations are based on the American Society of Hematology Consensus statement (1) and

the international consensus statement (5).

• A systematic review of 135 case series of splenectomy showed that complete remission was

reported in 66% (1731 of 2623) of patients. Younger age was an independent predictor of a

platelet count response in a multivariate analysis. Other preoperative characteristics, including

response to corticosteroids, were not predictive of response to splenectomy (46).

• A retrospective cohort study of 30 consecutive patients with ITP reported that a good or excellent

response to IVIG, defined as the achievement of a platelet count >50 × 109 cells/L or >150 × 109

cells/L, respectively, predicted a good or excellent response to splenectomy at 1 year (65).

Rationale

• Splenectomy results in a sustained platelet count response in approximately 60% of patients.

Comments

• Laparoscopic splenectomy is a valid alternative to conventional splenectomy in the treatment of ITP

(48).

• With the development and introduction of new drugs for ITP, such as anti-CD20 monoclonal

antibody and thrombopoietin mimetics, splenectomy may be delayed or avoided (50).



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3. Hospitalization Top

Hospitalize patients with severe bleeding or severe thrombocytopenia with mucous membrane bleeding.

3.1 Hospitalize patients with severe life-threatening bleeding, regardless of platelet count.

Recommendations

• Hospitalize patients with mucous membrane bleeding and new-onset severe thrombocytopenia

(typically, platelet counts <20 × 109 cells/L).

• Hospitalize patients with bleeding (e.g., vaginal, epistaxis) requiring clinical intervention, even if

platelet count is >20 × 109 cells/L.

• Begin therapy (see section on Therapy) to halt bleeding and prevent complications of bleeding.

• Note that hospitalization is not required for patients with platelet counts >20 × 109 cells/L who are

asymptomatic or have only minor bleeding, such as epistaxis that resolves in less than 15 minutes,

gingival bleeding with toothbrushing, or petechiae or ecchymoses on the skin.

Evidence

• There is no direct evidence that hospitalization is associated with improved survival or outcome in

patients with ITP. Recommendations are based on consensus (1).

Rationale

• Severe bleeding complications are less likely in patients with platelet counts >20 × 109 cells/L who

are asymptomatic or have only minor bleeding.



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4. Therapy Top

Consider careful observation for some patients, advise patients on the avoidance of activities associated with a high risk for bleeding, consider drug therapy to improve the platelet count and decrease the risk for bleeding, and consider splenectomy for patients in whom steroid therapy is unsuccessful.

4.1 Consider careful observation for patients at low risk for bleeding.

Recommendations

• Recognize that mild ITP is often associated with a good prognosis.

• For patients with platelet counts >50 × 109 cells/L who have no history of bleeding, consider

careful observation with regular visits and platelet count determinations.

Evidence

• In a cohort study of 152 patients previously treated with a defined algorithm for ITP and followed

for a median of 10.5 years, only those patients with refractory disease (n=12) had excess mortality

risk compared with the general population (RR, 4.2 [CI, 1.7 to 10.0]). Patients with refractory or

persistent ITP (n=20) had excess hospitalizations (18).

Rationale

• Treatment of ITP is associated with side effects that can be safely avoided for many patients with

mild ITP.

4.2 Counsel patients to abstain from alcohol and avoid certain medications, contact sports, and other activities that increase risk for bleeding.

Recommendations

• Advise patients to:

Abstain from drinking alcohol

Avoid contact sports and other recreational activities associated with increased risk for trauma

Avoid aspirin, NSAIDs, and anticoagulants unless otherwise advised by a physician

• In some patients, increase the target platelet count for treatment when necessary to accommodate

lifestyle activities and the need for anticoagulation or antiplatelet agents.

Evidence

• Consensus.

Rationale

• Alcohol may impair platelet function and cause or exacerbate thrombocytopenia; heavy alcohol use

also can lead to accidents and traumatic hemorrhage.

• Avoiding certain sports decreases risk for traumatic hemorrhage.

• Aspirin, NSAIDs, and anticoagulants increase risk for bleeding.

4.3 Recognize that corticosteroids are the initial therapy of choice.

Recommendations

• Begin initial therapy with prednisone, 1 to 2 mg/kg·d, in adults with platelet counts <20 to 30 ×

109 cells/L and/or purpura or other bleeding.



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• If there is a response with a normalization of the platelet count over 1 to 2 weeks, taper by 5 to 10

mg/week.

• Consider high-dose dexamethasone, 40 mg/d for 4 days, as a reasonable alternative to prednisone.

• See table Drug Treatment for Primary Immune Thrombocytopenia.

Evidence

• There are no randomized trials showing a benefit of corticosteroids on overall morbidity or

mortality.

• A randomized trial of prednisone 0.5 mg/kg·d vs. 1.5 mg/kg·d showed no significant difference in

platelet counts between the low- or high-dose arms in adults (30% vs. 34% complete response,

respectively) (19).

• A randomized trial of low (0.25 mg/kg·d) vs. high (1 mg/kg·d) prednisone for 3 weeks, with taper

and discontinuation by the end of 4 weeks, showed a complete response (platelet count >100 ×

109 cells/L for at least 6 months) in 74% of adults, with no difference between the low- and high-

dose groups (20).

• In retrospective studies in adults, corticosteroids have been associated with a complete response

rate of 30% to 38%, an overall response rate (platelet counts >50 × 109 cells/L) of 65% to 80%,

and prolonged remission rates of 15% to 20% (21; 22; 23; 24; 25).

• Corticosteroids have been recommended in the 2011 American Society of Hematology guidelines

(1).

• A randomized study of IVIG (0.7 g/kg·d for 3 days) vs. high-dose methylprednisolone (15 mg/kg·d

for 3 days) followed by a second randomization to prednisone (1 mg/kg·d) vs. placebo showed that

response to IVIG was more rapid: more patients achieved a platelet count >50 × 109 cells/L within

the first 5 days, and the number of days with a platelet count >20 × 109 cells/L between days 1

and 21 was higher in the group receiving IVIG. Patients receiving subsequent prednisone therapy

were more likely to have a platelet count >50 × 109 cells/L on day 21 than patients treated with

placebo. There was no difference in long-term outcome (26).

• The results of two noncontrolled, prospective cohort studies (one single center [n=37] and one

multicenter [n=95]) examining repeated cycles of high-dose dexamethasone were published as a

single report. In the single-center study, previously untreated patients with newly diagnosed ITP

were given dexamethasone, 40 mg/d iv for 4 consecutive days, repeated every 28 days for six

cycles. Of the 37 patients, 23 (62.2%) achieved a complete response, defined as a platelet count

>150 × 109 cells/L, and, of those, 20 had a prolonged complete response lasting for a median of

26 months. In the multicenter study, previously untreated patients with ITP were given oral or

intravenous dexamethasone as a single daily dose of 40 mg for 4 consecutive days every 14 days

for four courses. Of the 95 patients, 58 (64.5%) achieved a complete response, and, of those, 53

had a prolonged response lasting for a median of 8 months. In both studies, patients were

supplemented with additional corticosteroids if needed (27).

Rationale

• Proposed mechanism is inhibition of autoimmune destruction of platelets.

Comments

• The prolonged use of corticosteroids is associated with significant side effects, including

osteoporosis, hypertension, diabetes, and glaucoma.

4.4 Consider using intravenous immune globulin in selected patients.

Recommendations




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• Use IVIG, 1 to 2 g/kg (administered in divided doses given over 2 to 5 days), in patients who are

refractory to treatment with corticosteroids, before surgical procedures, or as initial treatment for

patients with severe bleeding.


Evidence

• Most IVIG studies have been done in children (28; 29).

• Studies in adults show that most patients achieve increases in platelet counts (30; 31; 32).

• A randomized study showed that treatment with IVIG at 1g/kg or 2g/kg yielded similar platelet

count responses (33).

• A randomized study of IVIG (0.7 g/kg·d for 3 days) vs. high-dose methylprednisolone (15 mg/kg·d

for 3 days) followed by a second randomization to prednisone (1 mg/kg·d) vs. placebo showed that

response to IVIG was more rapid: more patients achieved a platelet count >50 × 109 cells/L within

the first 5 days, and the number of days with a platelet count >20 × 109 cells/L between days 1

and 21 was higher in the group receiving IVIG. Patients receiving subsequent prednisone therapy

were more likely to have a platelet count >50 × 109 cells/L on day 21 than patients treated with

placebo. There was no difference in long-term outcome (26).

• A systematic review and meta-analysis of randomized, controlled trials comparing the efficacy of

corticosteroids with the efficacy of IVIG for the initial treatment of children with acute ITP (n=401)

reported that the achievement of a platelet count >20 × 109 cells/L at 48 hours was 26% less

likely among children treated with corticosteroids compared with children treated with IVIG (34).

Rationale

• IVIG rapidly increases the platelet count in most patients.

4.5 Consider RhIG for patients with blood group Rh(+) who have not had a splenectomy.

Recommendations

• Consider RhIG, 50 to 75 µg/kg, for some patients with ITP:

Patients who are Rh(+) and have not had a splenectomy

Patients in whom splenectomy is not feasible

Patients for whom corticosteroids have failed or other options are unavailable, in lieu of IVIG

• Be aware that complications related to hemolysis are a concern with RhIG.


Evidence

• A randomized clinical trial compared routine care (prednisone) with RhIG in 70 newly diagnosed

patients with ITP with platelet counts <30 × 109 cells/L. Rates of splenectomy were similar (38%

vs. 42%), but time to splenectomy was 36 days in the routine care group and 112 days in patients

who had been treated with RhIG (35).

• A randomized trial of 105 children who had newly diagnosed ITP and were Rh(+) found that RhIG,

75 µg/kg, was as effective as IVIG, 0.8 g/kg, and more effective than RhIG, 50 µg/kg, at achieving

a platelet count >20 × 109 by 24 hours (36).

Rationale

• RhIG therapy leads to sustained increases in platelet counts in some patients who have not had a

splenectomy.

• RhIG may allow for deferral of splenectomy.



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• RhIG can be administered much faster (10 to 15 minutes) than IVIG (approximately 4 hours).

Comments

• Hemolysis and varying degrees of anemia are expected side effects of RhIG. Rare cases of

disseminated intravascular coagulation and death have been reported (37). This has led to a boxed

warning for this drug and removal from several European markets.

4.6 Administer appropriate vaccinations before splenectomy.

Recommendations

• Vaccinate patients against S. pneumoniae, N. meningitidis, and H. influenzae type b at least 2

weeks prior to splenectomy.

• Note that revaccination with pneumococcal vaccine should be done every 5 years.


Evidence

• Case series of patients undergoing splenectomy for hereditary spherocytosis showed 1 death per

5000 patient-years (38).

• A literature review showed a 1.8% risk for fulminant sepsis and retrospective study showed 1.5%

or 0.17 cases of sepsis per 100 patient-years (39).

• There are no randomized trials studying the need for revaccination; however, case series have

shown that antibody levels to specific pneumococcal and H. influenzae antigens decline over time.

In one series of 149 vaccinated splenectomized patients, 50% had anti-pneumococcal and 60%

had anti-H. influenzae antibody levels in the range thought to be protective from infection (40, 41).

• The Center for Disease Control and Prevention's Advisory Committee on Immunization Practices

provides recommendations for the use of vaccines and immune globulins for immunocompromised

persons (42).

• Asplenic patients are at increased risk for infection. In a pooled analysis of 19,680 splenectomized

patients from 78 studies, the incidence of post-splenectomy septicemia and/or meningitis was

3.2% after a median follow-up of 6.9 years (43).

• In a population cohort study of 3812 splenectomized patients, the adjusted odds ratio for the risk

for any infection requiring hospitalization among those with ITP compared with non-splenectomized

ITP patients was 2.6 (CI, 1.3 to 5.1) in the first 90 days; the hazard ratio was 1.0 (CI, 0.5 to 2.0)

from 91 days to 1 year and 1.4 (CI, 1.0 to 2.0) beyond 1 year (44).

Rationale

• Splenectomy is associated with a risk for infection with bacterial organisms.

4.7 Consider splenectomy for patients who do not respond to, or who relapse following, first-line corticosteroid-based treatments.

Recommendations

• Note that splenectomy is recommended for patients with ITP in whom corticosteroid-based therapy

has failed. Splenectomy is often considered for patients who have had ITP for 12 months or more,

after which time spontaneous remissions are unlikely.

• Vaccinate patients undergoing splenectomy against S. pneumoniae, N. meningitidis, and H.

influenzae type b at least 2 weeks prior to surgery (see previous section regarding vaccination

before splenectomy).

Evidence



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• Splenectomy has been shown to be effective in up to 80% of patients with a sustained response for

up to 5 years achieved in 66% of patients (45; 46; 47).

• Recommendations are based on the American Society of Hematology 2011 Guidelines (1). A

consensus statement on terminology of ITP defined chronic ITP as lasting longer than 12 months

(11).

• A systematic review of 135 case series of splenectomy showed that complete remission was

reported in 66% (1731 of 2623) of patients. Younger age was an independent predictor of a

platelet count response in a multivariate analysis. Other preoperative characteristics, including

response to corticosteroids or IVIG, were not predictive of response to splenectomy (46).

• Asplenic patients are at increased risk for infection. In a pooled analysis of 19,680 splenectomized

patients from 78 studies, the incidence of post-splenectomy septicemia and/or meningitis was

3.2% after a median follow-up of 6.9 years (43).

• In a population cohort study of 3812 splenectomized patients, the adjusted odds ratio for the risk

for any infection requiring hospitalization among those with ITP compared with non-splenectomized

ITP patients was 2.6 (CI, 1.3 to 5.1) in the first 90 days; the hazard ratio was 1.0 (CI, 0.5 to 2.0)

from 91 days to 1 year and 1.4 (CI, 1.0 to 2.0) beyond 1 year (44).

Rationale

• Splenectomy results in a sustained platelet count response in approximately 66% of patients.

Comments

• Laparoscopic splenectomy is a valid alternative to conventional splenectomy in the treatment of ITP

(48) and is associated with less postoperative pain, shorter hospital stays, and decreased wound

complication rates (49).

• With the development and introduction of new drugs for ITP, such as anti-CD20 monoclonal

antibody (rituximab) and thrombopoietin mimetics, splenectomy may be delayed or avoided (1;

50).

• Immediate perioperative complications following splenectomy include pneumonia, subphrenic

abscess, or pleural effusion (4% of patients); major bleeding (1.5%); and thromboembolism (1%).

Perioperative mortality is approximately 1% with laparotomy and 0.2% with laparoscopic

splenectomy (46).

4.8 Recognize that patients with refractory ITP for whom corticosteroids and splenectomy are unsuccessful or in whom splenectomy is contraindicated may

require therapy with other agents.

Recommendations

• Recognize that there is no single established algorithm for treating refractory ITP and that drug

treatment should be based on individual needs and the side effect profiles of the medications.

• Consider treatment with thrombopoietin receptor agonists, such as romiplostim and eltrombopag,

administered as maintenance therapy.

• Consider treatment with rituximab, 375 mg/m2 once weekly, for 4 weeks.

• Treat patients who relapse after splenectomy with prednisone at the lowest doses possible to

maintain a safe platelet count.

• Understand that some patients will not respond to corticosteroids or will need doses higher than 10

to 15 mg/d, which may lead to unacceptable side effects and necessitate treatment with other

agents.





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• Recognize that some patients who do not respond to other drug therapy continue to respond to

high dose IVIG, although responses are generally transient, lasting a few weeks, and therapy is

expensive.

• Give platelet transfusion to patients who are severely thrombocytopenic and experiencing serious

or life-threatening bleeding.

• Consider these other options for drug treatment of patients with ITP that is refractory to

corticosteroids and splenectomy:

Danazol, 200 mg qid

Immunosuppressive agents, such as azathioprine, 150 mg/d; mycophenolate mofetil, 1.5 to 2 g/d; or cyclosporine, 2 to 3 mg/kg·d

Cytoreductive agents, such as vincristine, 1 to 2 mg/week, iv; vinblastine, 5 to 10 mg/week; oral

cyclophosphamide, 2 mg/kg·d; or high-dose intravenous cyclophosphamide, 1 to 1.5 mg/m2 every 4 weeks


Evidence

• The 2011 American Society of Hematology guidelines provide recommendations for the treatment

of patients who require additional treatment following splenectomy (1).

• Two randomized trials showed that in splenectomized and non-splenectomized patients with ITP

and a platelet count <30 × 109 cells/L, 16 of 42 splenectomized patients and 24 of 41 non-

splenectomized patients given romiplostim achieved a durable platelet count response (platelet

count ≥50 × 109 cells/L during 6 of the last 8 weeks of treatment) compared with 0 of 21

splenectomized patients and 1 of 21 non-splenectomized patients given placebo (51).

• In a randomized trial of romiplostim (n=157) or standard of care (n=77) for non-splenectomized

adults with ITP, patients receiving romiplostim had a significantly lower incidence of treatment

failure (18 of 157 patients [11%]) than those receiving the standard of care (23 of 77 patients

[30%]; P<0.001) (OR with romiplostim, 0.31 [95% CI, 0.15 to 0.61]). Fewer splenectomies were

performed in the romiplostim group, which had a lower rate of bleeding events, fewer blood

transfusions, and greater improvements in the quality of life (52).

• A randomized, placebo-controlled trial of eltrombopag (n=197) in patients with ITP for at least 6

months' duration and a platelet count <30 ×109 cells/L showed that 106 (79%) patients in the

eltrombopag group responded to treatment at least once during the study, compared with 17

(28%) patients in the placebo group. The odds of responding were greater in patients in the

eltrombopag group compared with those in the placebo group throughout the 6-month treatment

period (OR, 8.2 [99% CI, 3.59 to 18.73]; P<0.0001) (53).

• Concerns have been raised over the increased bone reticulin found in 10 of over 271 patients

included in the romiplostim trials and in 7 of 117 patients in the eltrombopag trials. Liver function

test abnormalities were seen in 13% of patients treated with eltrombopag (5).

• A 2004 systematic review of the literature, including 90 articles with 656 patients treated with 22

therapies, showed that evidence supporting effectiveness and safety of any treatment in patients

with chronic ITP is minimal (54).

• A 2007 systematic review of studies examining the effect of rituximab in ITP concluded that

rituximab was associated with the achievement of an overall response (platelet count >50 × 109

cells/L) in 62.5% of patients and a complete response (platelet count >150 × 109 cells/L) in 43.6%

of patients (55). This review was limited by the lack of controlled studies.

• In a retrospective analysis, the rate of fatal hemorrhage patients with a platelet count <30 × 109

cells/L was 0.019 cases per patient-year. Patients who did not respond to therapy at 2 years had a

4-fold increase in mortality compared to the general population (56).




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• In a study of 105 patients with refractory ITP after splenectomy (platelets <30 × 109 cells/L), 75%

eventually achieved remission. In 51 (49%) patients, remission continued after therapy was

stopped, and in 24 (23%) patients, continued therapy with low-dose corticosteroids or danazol was

needed to maintain remission (57).

Rationale

• Pharmacologic agents may be necessary to increase platelet counts to a level that is safe in

individual patients with chronic ITP for whom corticosteroids and splenectomy have failed.

• Patients with platelet counts <20 × 109 cells/L are at an increased risk for hemorrhage.

• Treatment modalities are targeted to various mechanisms of disease, and are aimed at reducing

autoantibodies to platelets, preventing destruction of platelets by macrophages, removing

autoreactive B-cells, improving T-cell abnormalities, and increasing platelet production.

4.9 Recognize that eradication of H. pylori has been shown to induce platelet recovery in some patients with ITP.

Recommendations

• Consider testing for H. pylori infection in regions where infection is endemic, and, if results are

positive, treating with one of triple drug regimens shown to be effective.


Evidence

• In a 2009 systematic review of 696 patients with ITP, 42.7% (CI, 31.8% to 53.9%) achieved a

platelet count response following H. pylori eradication; the response rate was lower in patients with

severe thrombocytopenia (defined in this review as <30 × 109 cells/L) (13).

• In a 2007 systematic review of 788 patients with ITP from 17 studies (16 prospective cohorts and

1 randomized trial), H. pylori eradication was associated with an increase in platelet count of 41 ×

109 cells/L (CI, 21 to 61 × 109 cells/L) compared with untreated patients, 52 × 109 cells/L (CI, 34

to 70 × 109 cells/L) compared with patients who failed to respond to eradication, and 46 × 109

cells/L (CI, 28 to 65 × 109 cells/L) compared with H. pylori-negative patients (58).

Rationale

• Eradication of H. pylori may decrease antigenic stimulus for autoantibody formation and

autoimmune destruction of platelets.

Comments

• These recommendations are based only on small case series.

• There seems to be geographic variability in the prevalence of H. pylori and in the serotype of the H.

pylori bacteria, such that in certain countries, including Japan, rates of platelet count responses

following H. pylori eradication in patients with ITP have been significant. In other countries,

response rates are much lower.



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5. Patient Counseling Top

Educate patients about the mechanism, complications, and treatment of their disease.

5.1 Teach patients to recognize symptoms of bleeding that may indicate a decreased platelet count.

Recommendations

• Teach patients how to recognize petechiae, oral mucosal purpura (oral blood blisters), ecchymoses,

epistaxis, gingival bleeding, rectal bleeding, and excess vaginal bleeding.

Evidence

• Consensus.

Rationale

• Patients who recognize that hemorrhagic symptoms may indicate decreasing platelet counts will

seek medical attention.

5.2 Teach patients to recognize the immunosuppressive effects of therapy.

Recommendations

• Teach patients to recognize that steroid use leads to immunosuppressive effects, with increased

susceptibility to infections and poor wound healing.

• Inform splenectomized patients that they are more susceptible to infection, especially with

encapsulated organisms such as pneumococcus.

• Consider suggesting that splenectomized patients wear a medical information bracelet or the

equivalent.

• Educate patients and their families to recognize the signs of serious infection:

Fever

Cough

Shortness of breath

Altered mental status

Headache

Stiff neck

Photophobia

• Urge patients to avoid contact with children or adults with meningitis, pneumococcal pneumonia,

and other bacterial illnesses.

Evidence

• Consensus.

• Guidelines from experienced practitioners (59).

Rationale

• Patients on steroids or after splenectomy are immunocompromised.



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6. Follow-up Top

Monitor all patients for recurrent thrombocytopenia after therapy.

6.1 Schedule, monitor, and taper medication appropriately for all patients initially started on corticosteroids.

Recommendations

• After an initial response to corticosteroids with normalization of platelets, and 1 to 2 weeks of

therapy at 1 to 2 mg/kg·d of prednisone, taper prednisone by 5 to 10 mg/week for 4 weeks and 5

mg/week thereafter, provided the platelet count remains stable.

• Monitor for signs and symptoms of bleeding and check CBC weekly or biweekly during steroid

taper.

• Recognize that the tapering schedule may need adjustment depending upon the individual clinical

situation.

Evidence

• Consensus.

Rationale

• Careful tapering of steroids is necessary to decrease the possibility of relapse.

6.2 Monitor symptoms, signs and CBC in patients with disease remission or chronic ITP who do not require treatment.

Recommendations

• Monitor patients who have achieved normal platelet counts after therapy for signs or symptoms of

bleeding.

• Ask about petechiae, purpura (including oral blood blisters), epistaxis, gingival bleeding, and

menstruation.

• Look for ecchymoses, purpura, and petechiae.

• If patient has achieved a complete response after steroids or splenectomy, perform a follow-up

CBC every month for 6 months, every 2 months for 6 months, every 3 months for 6 months, then

every 6 months for 1 year.

• Patients with chronic ITP who do not require treatment may be followed every 3 months. Patients

with bleeding or lower platelet counts (<50 x 109 cells/L) may need to be followed biweekly or

monthly.

Evidence

• A prospective study of 245 patients with ITP was performed in a population-based cohort in

England, with a median follow-up of 60 months. The study showed that 135 patients (55%)

responded to first-line therapy, 30 (12%) underwent splenectomy, 4 (1.6%) died from bleeding

complications, and 17 (7%) had minimal or no response to therapy. Platelet count at diagnosis did

not predict outcome (66).

• Based on case series, 10% to 40% of patients will relapse after splenectomy, with half of these

relapses occurring within the first 6 months (64).

• Platelet response of >150 × 109 cells/L on the third day after splenectomy (64) or >500 × 109

cells/L on the tenth day after splenectomy (67) correlate with long-term improvement in platelet

counts.



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• In a retrospective study, 75% of patients who were splenectomized had a partial or complete

response at 2 years, and the long-term remission rate was 66% (56).

• In a study of 105 patients with refractory ITP after splenectomy (platelets <30 × 109 cells/L), 75%

eventually achieved remission. Median time to remission was 46 months. Seventeen (16%) of

these patients died of bleeding complications associated with thrombocytopenia or therapy-related

complications (57).

Rationale

• Despite achieving remission, some patients will relapse and present with signs and symptoms of

bleeding.



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67. Fenaux P, Caulier MT, Hirschauer MC, Beuscart R, Goudemand J, Bauters F. Reevaluation of the prognostic factors for

splenectomy in chronic idiopathic thrombocytopenic purpura (ITP): a report on 181 cases. Eur J Haematol. 1989;42:259-64. (PMID: 2924888)


























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Glossary Top

ANA antinuclear antibody

bid twice daily

CBC complete blood count

CI confidence interval

CT

computed tomography

DNA

deoxyribonucleic acid

EBV Epstein-Barr virus

EDTA ethylene diamine tetra-acetic acid

ESR

erythrocyte sedimentation rate

G-CSF granulocyte colony-stimulating factor

HELLP hemolysis, elevated liver enzymes, and low platelet (count)

HIV human immunodeficiency virus

HUS hemolytic-uremic syndrome

IgA immunoglobulin A

IgE immunoglobulin E

IgG

immunoglobulin G

ITP immune thrombocytopenia, also called immune thrombocytopenic purpura or idiopathic thrombocytopenic purpura

iv intravenous

IVIG

intravenous immunoglobulin

NSAID nonsteroidal anti-inflammatory drug

PT plasma thromboplastin

PTT partial thromboplastin time



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qd

once daily

qid four times daily

RhIG rhesus immune globulin

RR

relative risk

tid three times daily

TSH

thyroid-stimulating hormone

TTP thrombotic thrombocytopenic purpura



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Tables Top

Laboratory Tests to Support the Diagnosis of Primary Immune Thrombocytopenia

Test Notes

CBC Low platelet count with normal hemoglobin/hematocrit and leukocyte count is evidence for the

diagnosis of ITP. Anemia due to a nonimmune condition such as hemoglobinopathy or iron deficiency

does not exclude ITP (1)

Peripheral blood smear Exclude platelet clumping (pseudothrombocytopenia). Myeloid and erythroid morphology should be normal. Platelets should appear normal or may be large in size. Abnormal or immature leukocytes

should be absent. The presence of schistocytes is associated with TTP and is evidence against ITP. The

presence of polychromatophilia, poikilocytosis, and spherocytes suggests hemolytic anemia. Nucleated

erythrocytes should be absent

Bone marrow aspiration Bone marrow aspiration and biopsy should be done to exclude other causes of thrombocytopenia, not

to confirm the diagnosis of ITP. Typically, bone marrow examinations in patients with ITP show normal

or increased numbers of megakaryocytes, normal myeloid and erythroid morphology, and no extrinsic

cells

HIV antibodies Indicated to identify patients with HIV-associated ITP

HCV antibodies Indicated to identify patients with HCV-associated ITP

PT/PTT Coagulation testing is not recommended for routine diagnosis (1). However, an abnormal PT or PTT is

evidence against ITP. The presence of thrombocytopenia and coagulopathy is associated with

disseminated intravascular coagulation, or may be seen in the antiphospholipid antibody syndrome

Thyroid function test Hypo- or hyperthyroidism can be associated with ITP and should be excluded in patients for whom

splenectomy is being considered

ANA and other serologic tests Consider ANA, ESR, and other serologic tests such as rheumatoid factor, complement levels, and anti-

DNA, in patients with rash, synovitis, arthralgias, or other signs of rheumatologic disease, which may

be secondary causes of ITP

13C urea breath test or fecal antigen test to test for infection with H. pylori H. pylori eradication with antibiotics and a proton-pump inhibitor in patients with a positive 13C urea

breath test or fecal antigen test has been shown to induce platelet recovery in some patients with ITP

(13). The effect is mostly limited to certain countries, including Japan

ANA = antinuclear antibody; CBC = complete blood count; DNA = deoxyribonucleic acid; ESR = erythrocyte sedimentation rate; HCV = hepatitis C virus; HIV = human immunodeficiency virus; ITP = immune thrombocytopenia; PT = plasma thromboplastin; PTT = partial thromboplastin time.



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Differential Diagnosis of Primary Immune Thrombocytopenia

Disease Characteristics

Primary ITP Primary ITP is a diagnosis of exclusion. Use history, physical exam and laboratory testing to rule out

secondary causes of thrombocytopenia

The American Society of Hematology 2011 evidence-based practice guidelines are an excellent

resource (1)

Pseudothrombocytopenia In vitro clumping of platelets caused by EDTA-dependent agglutinins leads to falsely decreased platelet

counts

Excluded by examination of peripheral blood smear and may require obtaining a platelet count in

citrate (14)

Drug-induced thrombocytopenia Many drugs have been implicated in thrombocytopenia, including heparin, beta lactams, sulfonamides,

quinidine, quinine, abciximab, and Aggrenox (a fixed dose combination of aspirin and dipyridamole); alcohol also may lead to thrombocytopenia

Heparin-induced thrombocytopenia may be associated with thrombosis

Chronic liver disease Portal hypertension can lead to splenic sequestration of platelets with resultant thrombocytopenia

Thrombotic thrombocytopenic purpura/HUS TTP is characterized by thrombocytopenia, fever, microangiopathic hemolytic anemia, neurologic symptoms, and renal disease. HUS is characterized by thrombocytopenia, microangiopathic hemolytic

anemia, and renal disease

Characterized by thrombocytopenia and the presence of schistocytes on peripheral blood smear

Disseminated intravascular coagulation Coagulopathy characterized by an elevated prothrombin time and activated partial thromboplastin

time, low fibrinogen, and thrombocytopenia

HELLP syndrome Thrombocytopenia associated with elevated liver enzymes and hypertension in late pregnancy

Chronic lymphocytic leukemia ITP may be a secondary complication of chronic lymphocytic leukemia; alternatively, thrombocytopenia

in the setting of chronic lymphocytic leukemia may be nonimmune due to disease progression

Myelophthisis Thrombocytopenia may be a manifestation of myelophthisis due to lymphoma, metastatic cancer, or

granulomatous disease of the bone marrow

Infection Thrombocytopenia is seen in HIV, hepatitis B and C, EBV, rubella, and other infections

Congenital thrombocytopenias While rare, these conditions should be considered in younger patients with persistent thrombocytopenia

and affected family members. May be accompanied by skeletal abnormalities

Includes Fanconi syndrome, Wiskott-Aldrich syndrome, thrombocytopenia with absent radius, and

autosomal dominant macrothrombocytopenic disorders associated with MYH-9 mutations

EBV = Epstein-Barr virus; EDTA = ethylene diamine tetra-acetic acid; HELLP = hemolysis, elevated liver enzymes, and low platelet (count); HIV = human immunodeficiency virus; HUS = hemolytic-uremic

syndrome; ITP = immune thrombocytopenia; TTP = thrombotic thrombocytopenic purpura.






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Drug Treatment for Primary Immune Thrombocytopenia

Drug or Drug Class Dosing Side Effects Precautions Clinical Use

Corticosteroids Long-term use can result in: HPA

suppression, immuno-suppression,

hypertension, adverse neurologic

effects, glucose intolerance, weight

gain, myopathy, glaucoma,

osteoporosis

Prednisone 1-2 mg/kg qd. If platelet count

normalizes over 1-2 weeks, taper by 5-

10 mg/week

Use if platelets are <20-30 x 109

and/or there is purpura or other

bleeding

Dexamethasone PO: 40 mg daily for 4 days Alternative to prednisone

Immune globulin GI symptoms, flushing, diaphoresis,

chills, wheezing, hypotension, hypersensitivity, injection site

reactions. Rare: transfusion-related

acute lung injury

Remote risk of transmission of viral

infection. Caution with elderly

Can temporarily raise platelet count in

patients who do not respond to corticosteroids

Intravenous immune globulin, IVIG

(Gammar-P I.V., Carimune NF,

Gammagard S/D)

1-2 g/kg IV (administered in divided

doses given over 2-5 days)

Thrombotic events, coagulation

adverse events, hemolytic anemia,

aseptic meningitis syndrome

Risk of nephrotoxicity and death.

Reduce dose, concentration, and/or

rate in patients at risk for renal failure

For patients: refractory to

corticosteroids or with severe bleeding

or for use prior to surgery

Rho(D) Immune Globulin, RhIG

(WinRho SDF)

50-75 μg/kg IV as a single dose Intravascular hemolysis leading to

death; severe anemia, nephrotoxicity,

DIC

For Rh(+) patients who have not had

splenectomy

Agents for refractory ITP For patients with severe or

symptomatic thrombocytopenia

unresponsive to corticosteroids

Thrombopoietin receptor agonists Thrombotic complications, myalgia,

paresthesias

Monitor CBC with differential weekly

during dose adjustment, then monthly

Can improve platelet count but do not

induce true remission

Eltrombopag (Promacta) 50 mg PO qd. Maximum total daily

dose 75 mg. Take 1 hour before or 2

hours after a meal. Do not take within 4 hours of: antacids, dairy, mineral

supplements

Vomiting, diarrhea, infection, rash Hepatotoxicity. Measure LFTs at

baseline, every 2 weeks during dose

adjustment, then monthly. Decrease initial dose with: hepatic disease, East

Asian ancestry

Romiplostim (Nplate) 1 μg/kg SC once weekly. Maximum

weekly dose 10 μg/kg

Arthralgia, dizziness, insomnia,

extremity pain, abdominal pain,

dyspepsia

Anti-CD20 monoclonal antibody

Rituximab (Rituxan) 375 mg/m2 IV weekly for 4 doses Hematologic toxicity, risk of: infection,

bleeding, malignancy. Hypotension,

nephrotoxicity, vomiting, abdominal

pain, GI perforation, peripheral

neuropathy

Fatal infusion reactions, severe

mucocutaneous reactions, PML, HBV

reactivation. Avoid with pregnancy

Can induce remission or delay

splenectomy

Androgen



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Danazol 200 mg qid Androgenic and hypoestrogenic effects,

GI side effects, hypercholesterolemia, allergic reactions, CNS side effects,

hematologic toxicity, interstitial

pneumonitis

Avoid with pregnancy. Thrombotic

events, benign intracranial hypertension. Peliosis hepatitis and

benign hepatic adenoma with long

term use. Avoid with: severe hepatic or

cardiac disease, CrCl<30, acute

intermittent porphyria. Caution with

elderly. Inhibits CYP3A4

Immunosuppressants Hematologic toxicity; risk of

malignancy, infection. Vomiting

Avoid with pregnancy For patients refractory to multiple other

therapies

Azathioprine (Imuran, Azasan) 150 mg qd Hepatotoxicity Increased risk of malignancy.

Caution with: CKD, thiopurine

methyltransferase deficiency

Cyclosporine (Gengraf, Sandimmune,

Neoral)

1-1.5 mg/kg bid Nephrotoxicity, hyperkalemia,

hyperuricemia, hypertension,

hepatotoxicity, hypercholesterolemia, seizures, hirsutism, hypertrichosis,

gingival hyperplasia, gynecomastia

For use by experienced physicians.

Immuno-suppression and risk of

infection. Formulations are not interchange-able. Monitor blood levels.

Avoid excess sunlight. Caution with

hepatic disease. Substrate of CYP3A,

substrate and inhibitor of P-gp

Mycophenolate mofetil (CellCept) 1.5-2 g qd GI side effects, nephrotoxicity,

respiratory adverse events, ophthalmic

adverse events, asthenia, insomnia,

paresthesias

Administer by experienced

personnel in an equipped facility.

Immuno-suppression and risk of

infection. Risk of pregnancy loss and

teratogenicity. Caution with: hepatic

disease, CrCl<25

Cytoreductive agents Hematologic toxicity, infection, risk of

malignancy

Avoid with pregnancy

Cyclophosphamide PO: 2 mg/kg qd. High-dose IV: 1-1.5

g/m2 every 4 weeks

Hemorrhagic cystitis, infertility, SIADH,

cardiotoxicity, interstitial pneumonitis, anaphylaxis, alopecia, vomiting

Consider dose reduction if CrCl<55

Vinca alkaloids SIADH IV use only, must not be given intrathecally. Severe granulocytopenia,

avoid extravasation. Decrease dose if

total bilirubin is elevated. Substrates of

CYP3A4 and P-gp

For patients refractory to multiple other therapies

Vinblastine IV: 5-10 mg weekly Myelosuppression is dose-limiting.

Neurotoxicity less common than with

vincristine. Mild alopecia, peripheral

vasoconstriction

Vincristine IV: 1-2 mg weekly Neurotoxicity is dose-limiting. Severe

constipation, alopecia, rash,

hypotension, urinary retention

Other

Colchicine (Colcrys) 0.6 mg tid GI side effects, myelosuppression,

myopathy, peripheral neuropathy,

Avoid if taking a moderate-strong

CYP3A4 inhibitor or P-gp inhibitor with



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rhabdomyolysis, nephrotoxicity,

elevated hepatic enzymes

hepatic disease or CKD. Decrease dose

if taking a moderate-strong CYP3A4 inhibitor or P-gp inhibitor. Decrease

dose with CKD. Caution with hepatic

disease. Avoid alcohol

Dapsone 75 mg qd Hemolytic anemia,

methemoglobinemia, toxic hepatitis,

jaundice, nephrotoxicity, vomiting

Monitor hepatic function. Caution with:

G6PD deficiency, sulfonamide allergy.

Substrate of CYP3A4

= first-line agent; = black box warning; bid = twice daily; CBC = complete blood count; CKD = chronic kidney disease; CNS = central nervous system; CrCl = creatinine clearance; CV = cardiovascular;

CYP = cytochrome P450 isoenzyme; DIC = disseminated intravascular coagulation; ECG = electrocardiogram; G6PD = glucose-6-phosphate dehydrogenase; GI = gastrointestinal; HPA = hypothalamic-

pituitary-adrenal; IM = intramuscular; IV = intravenous; LFT = liver function test; P-gp = P-glycoprotein; PML = progressive multifocal leukoencephalopathy; PO = oral; prn = as needed; q12hr = every 12

hours; qd = once daily; qid = four times daily; SC = subcutaneous; SCr = serum creatinine; SIADH = syndrome of inappropriate antidiuretic hormone secretion; tid = three times daily.

PIER provides key prescribing information for practitioners but is not intended to be a source of comprehensive drug information.



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Figures Top

Pseudothrombocytopenia

The peripheral blood smear shows platelet clumping, which suggests pseudothrombocytopenia. Pseudothrombocytopenia is a laboratory artifact in which platelets drawn into an EDTA-anticoagulated test tube clump and fails to be counted accurately by the automated counter, resulting in a spuriously low platelet count.



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Petechia due to Thrombocytopenia

A petechia is a round, discrete, hemorrhagic area typically less than 2 mm in diameter that is caused by thrombocytopenia. As the lesion ages and the hemoglobin is metabolized, the color changes from bright red to green to yellow and then fades. Petechiae do not blanch with pressure and are flat and nontender.



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Normal Platelets on Peripheral Blood Smear

Platelets are small purple anuclear cells. Seven platelets per 100-power field is normal and less than seven suggests thrombocytopenia.



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Giant Platelet on Peripheral Blood Smear

Giant platelets suggest an increased marrow response secondary to a destructive process as might be seen with immune thrombocytopenic purpura. If associated with fragmented erythrocytes, giant platelets might suggest the presence of thrombotic, thrombocytopenic purpura.

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