Quality Ratings: The preponderance of data supporting guidance statements are derived from:
level 1 studies, which meet all of the evidence criteria for that study type;
level 2 studies, which meet at least one of the evidence criteria for that study type; or
level 3 studies, which meet none of the evidence criteria for that study type or are derived from expert opinion, commentary, or consensus.
Study types and criteria are defined at http://smartmedicine.acponline.org/criteria.html
Disclaimer: The information included herein should never be used as a substitute for clinical judgement and does not represent an official position of
the American College of Physicians. Because all PIER modules are updated regularly, printed web pages or PDFs may rapidly become obsolete. Therefore, PIER users should compare the module updated date on the offical web site with any printout to ensure that the information is the most
current available.
CME Statement: The American College of Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide
continuing education for physicians. The American College of Physicians designates this enduring material for a maximum of 1 AMA PRA Category 1
CreditTM. Physicians should claim only credit commensurate with the extent of their participation in the activity. Purpose: This activity has been
developed for internists to facilitate the highest quality professional work in clinical applications, teaching, consultation, or research. Upon completion
of the CME activity, participants should be able to demonstrate an increase in the skills and knowledge required to maintain competence, strengthen
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
member of advisory boards for Amgen and GSK; received research funding from Hoffmann-LaRoche, Amgen and GSK. Deborah Korenstein, MD, FACP, Co-Editor, PIER, has no financial relationships with pharmaceutical companies, biomedical device manufacturers, or health-care related
organizations. Richard B. Lynn, MD, FACP, Co-Editor, PIER, has no financial relationships with pharmaceutical companies, biomedical device
manufacturers, or health-care related organizations.
PIER is copyrighted ©2013 by the American College of Physicians. 190 N. Independence Mall West, Philadelphia, PA 19106, USA.
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
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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).
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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
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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.
• See table Drug Treatment for Primary Immune Thrombocytopenia.
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.
• See table Drug Treatment for Primary Immune Thrombocytopenia.
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.
• See table Drug Treatment for Primary Immune Thrombocytopenia.
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
• See table Drug Treatment for Primary Immune Thrombocytopenia.
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.
• See table Drug Treatment for Primary Immune Thrombocytopenia.
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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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.