clinical manifestations and diagnosis of immune

8/8/2019 Clinical Manifestations and Diagnosis of Immune

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Clinical manifestations and diagnosis of immune (idiopathic) thrombocytopenic purpura in adults Author James N George, MD Section Editor Lawrence LK Leung, MD Deputy Editor Stephen A Landaw, MD, PhD

Last literature review version 18.2: May 2010 | This topic last updated: May 18, 2010 (More)INTRODUCTION Immune thrombocytopenic purpura (also called idiopathicthrombocytopenic purpura, immune thrombocytopenia, ITP) is an acquired disorder. There areonly two criteria required in order to make this diagnosis [1-5]:

Isolated thrombocytopenia is present. The rest of the complete blood count, including anexamination of the peripheral blood smear, is entirely normal, unless other coincidentalabnormalities are present, such as iron deficiency.

Clinically apparent associated conditions (eg, systemic lupus erythematosus, antiphospholipidsyndrome, chronic lymphocytic leukemia) are not present. Patients with these associatedconditions are described as having "secondary immune thrombocytopenia" [6]. Also, drugs,including herbal remedies and quinine-containing beverages that may cause thrombocytopeniaare NOT apparent etiologies.The clinical manifestations, diagnosis, and differential diagnosis of ITP will be reviewed here.The treatment and prognosis of this disorder and the clinical manifestations, diagnosis,treatment, and prognosis of childhood ITP are discussed separately. (See "Treatment andprognosis of immune (idiopathic) thrombocytopenic purpura in adults" and "Clinicalmanifestations and diagnosis of immune (idiopathic) thrombocytopenic purpura in children".)PATHOGENESIS The pathogenesis of ITP is related to a combination of increased plateletdestruction along with inhibition of megakaryocyte platelet production via the production of specific IgG autoantibodies by the patient's B cells, most often directed against plateletmembrane glycoproteins such as GPIIb/IIIa [2,7-9].

Inciting events The etiology of ITP is unclear, but is thought to include genetic as well asacquired factors [6,10,11].

Some cases of ITP are associated with a preceding viral infection. It is possible that resultinganti-viral antibodies cross-react with platelet glycoproteins. Infection with HIV, HCV, CMV [12],and VZV may be associated with such antibodies therefore cause secondary ITP. (See 'Onsetafter infection' below.)

Alterations in the immune response might induce loss of peripheral tolerance and promote thedevelopment of self-reactive antibodies. (See 'B- and T-cell responses in ITP' below.)

Abnormalities in the immune system may predispose to the development of autoimmunethrombocytopenia. Examples include the antiphospholipid syndrome, systemic lupuserythematosus, Evans syndrome, post-hematopoietic cell transplantation ITP, and thesecondary ITP seen in patients with chronic lymphocytic leukemia and other low-gradelymphoproliferative disorders, especially those treated with purine analogs, and the autoimmunelymphoproliferative syndrome [6]. (See appropriate topic reviews).

Although ITP has been reported in association with nonhematologic malignancies, especiallybreast cancer, the association is likely coincidental [13-16].B- and T-cell responses in ITP B cell autoimmune IgG responses in ITP appear to be drivenby CD4+ helper T cells reacting to platelet membrane glycoprotein epitopes [17], possibly


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involving CD40:CD40L co-stimulation processes [18], with splenic macrophages as the major antigen-presenting cells [19,20]. (See "The humoral immune response", section on 'Activationsignals' and "Megakaryocyte biology and the production of platelets", section on 'Immunethrombocytopenic purpura'.)The following pathogenic loop has been suggested to explain this process [19,20]

Membrane GPIIb/IIIa and/or GPIb/IX of phagocytosed platelets are processed, and their digested peptides are presented by macrophages to autoreactive HLA-restricted CD4+ T-cells.

These T-cells become activated when T-cell receptors recognize the HLA-DR antigenicpeptide complex on the antigen-presenting macrophages.

The activated T-cells secrete IL-6 and upregulate CD154 expression, exerting helper activityon autoreactive antibody-producing B-cells. The latter are restricted B-cell clones that undergoproliferation and somatic mutation under antigenic pressure.

The autoantibodies thus produced bind to platelets, and the opsonized platelets arephagocytosed mainly by splenic macrophages, perhaps aided by complement activation [21],thus completing the loop. The autoantibodies can also bind to megakaryocytes, decreasingoverall platelet production.The importance of interactions between B- and T-cells in ITP was illustrated in a study whichevaluated T-cell subset changes in 30 patients with chronic ITP and elevated levels of platelet-associated immunoglobulin, who were treated with the B-cell depleting antibody rituximab [22].Pre-treatment abnormalities in the T-cell compartment of these patients reverted in respondersto rituximab, whereas they remained unchanged in nonresponders. This study suggests thatdepletion of B-cells may reduce co-stimulation of pathogenic T-cell clones in the responders.

Alternative mechanisms involving T-cells, including T-cell-mediated cytotoxicity and defects inthe number and/or function of regulatory T-cells (Tregs) have also been postulated [23-31]. Thelatter mechanism is supported by a study showing a reduced number and defective suppressivecapacity of Tregs in ITP patients compared with controls, and restored Treg numbers and

regulatory function, especially in responders, following treatment with rituximab [30] Antibodies are not demonstrable in all patients with ITP and assays for antiplatelet antibodieshave not yet proven to be important for management decisions [2,3,32,33]. (See"Megakaryocyte biology and the production of platelets", section on 'Immune thrombocytopenicpurpura'.)INCIDENCE ITP is a common acquired bleeding disorder. The incidence of ITP in children isgreater than the incidence among adults (figure 1). In children, the incidence of ITP in boys andgirls is similar [34]. (See "Clinical manifestations and diagnosis of immune (idiopathic)thrombocytopenic purpura in children".)

A Denmark survey from 1973 to 1995 estimated the annual incidence of ITP among adults to be22 per million per year, using a platelet count cut-off of 50,000/microL [35]. The incidence raterose during the study period, due primarily to increased recognition of asymptomatic patients[35].However, this incidence estimate primarily includes symptomatic patients. This is animportant issue since, in two large case series, 18 percent [36] and 29 percent [37] of adultswere discovered to have ITP when they had no bleeding symptoms. Therefore, the totalincidence of ITP among adults is likely to be greater than 22 per million per year. This wasshown in a UK population-based study of patients all diagnosed with ITP from 1990 through2005. The crude ITP incidence for this period was 39 and 44 per million per year for men and


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women, respectively [38].Because ITP in adults is typically a chronic disease, the prevalenceexceeds the incidence. In one estimate of the prevalence of ITP in the US, the estimate wasapproximately 100 per million per year, with age cohorts ranging from 41 to 160 per million per year, with the highest values seen in the oldest age cohort [39].Many reports have suggestedthat, among adults with ITP, approximately 70 percent are women and 72 percent of these

women are less than 40 years of age. However, the Denmark survey reported a sex differencein the incidence of ITP only for those 75 years of age [38]. The incidence of ITP was greater in females in the agerange from 18 to 64 years, while it was greater in males for those 65 years of age.All published reports on the incidence of ITP have been critically reviewed, comparing thestrengths and weakness of their methodology [40].CLINICAL MANIFESTATIONS AND ASSOCIATIONS There is marked interpatient variabilityin the clinical presentation of ITP. Although the onset of ITP may be acute and abrupt, it is moreoften insidious. Similarly, bleeding in symptomatic patients can range from petechiae and easybruising to a severe bleeding diathesis. In addition, the clinical laboratory routine of reporting aplatelet count with all requests for blood counts, which began with the introduction of automatedcell counters, has resulted in the discovery of asymptomatic, mild thrombocytopenia, therebyenlarging the clinical spectrum of ITP.The clinical manifestations of ITP are limited to those

related to excessive bleeding caused by thrombocytopenia. The bleeding manifestations of thrombocytopenia are described as mucocutaneous, to distinguish them from the delayed,slowly evolving visceral hematomas characteristic of coagulation disorders such as hemophilia(see below). Thus, in patients with thrombocytopenia due to ITP:

Petechiae, purpura, and easy bruising are expected. Epistaxis, gingival bleeding, and menorrhagia are common. Overt gastrointestinal bleeding and gross hematuria are rare. Intracranial hemorrhage, a potentially fatal bleeding complication, is so uncommon that there

is no reliable estimate of its frequency.The clinical manifestations of thrombocytopenia also vary with age. Older patients may havemore severe bleeding manifestations, such as gastrointestinal bleeding and possibly intracranialhemorrhage because of comorbidities such as hypertension [41,42].Onset after infection Children with ITP typically present with an acute, sudden clinical onset,usually associated with a history of infection in the several weeks preceding the illness [43-46].In one series, for example, infection in the three weeks prior to the onset of ITP was seen in 84percent of cases [43,44].How infection, viral or bacterial, might promote the development or worsening of ITP is uncertain, although a number of mechanisms have been postulated:


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Virus-specific antibodies may crossreact with normal platelet antigens, and contribute toincreased platelet clearance [45].

Helicobacter pylori infection has been associated with ITP in some reports. Experimentalobservations, including the induction of platelet aggregation by certain strains of H. pylori, andcross-reactivity between platelet-associated IgG and H. pylori cytotoxin-associated gene A

(CagA) protein may explain this association. (See "Chronic refractory immune (idiopathic)thrombocytopenic purpura in adults", section on 'Helicobacter pylori infection'.)

Molecular mimicry between HIV proteins and platelet GPIIb/IIIa may be important in thepathogenesis of primary HIV-associated thrombocytopenia. (See "Hematologic manifestationsof HIV infection: Thrombocytopenia and coagulation abnormalities", section on 'Reducedplatelet survival'.)

A number of autoimmune phenomena have been noted following infection with the hepatitis Cvirus, including immune thrombocytopenia and autoimmune hemolytic anemia [47]. Molecular mimicry between HCV core envelope protein 1 and platelet GP IIb/IIIa has been implicated inthe genesis of HCV-associated thrombocytopenia [48]. (See "Extrahepatic manifestations of hepatitis C virus infection", section on 'Autoimmune disorders'.)

Bacterial products, such as lipopolysaccharides, when attached to the surface of platelets inthe presence of antiplatelet antibodies, can significantly increase platelet phagocytosis [49].Drug-associated immune thrombocytopenia A number of drugs have been associated withthe development of autoimmune disorders, such as pure red cell aplasia, autoimmune hemolyticanemia, and immune thrombocytopenic purpura. Two of these are discussed below.

Alemtuzumab Use of the monoclonal anti-CD52 antibody alemtuzumab in several treatmentsettings (eg, chronic lymphocytic leukemia, organ transplantation, multiple sclerosis) has beenassociated with the development of autoimmune disorders (eg, autoimmune hemolytic anemia,pure red cell aplasia), including ITP [50-53]. The mechanism involved may be related to theability of this agent to cause severe immune dysregulation. (See "Treatment of relapsed or

refractory chronic lymphocytic leukemia", section on 'Alemtuzumab' and "Treatment of relapsing-remitting multiple sclerosis in adults", section on 'Alemtuzumab'.)Purine analogs Use of purine analogs in patients with low-grade lymphoma has beenassociated with an increased incidence of autoimmune hemolytic anemia and immunethrombocytopenic purpura. This subject is discussed separately. (See "Autoimmunecomplications following purine analog therapy", section on 'Autoimmune thrombocytopenia'.)Comparison with vasculitic purpura The defining characteristics of petechiae and purpura inthrombocytopenic patients are that they are asymptomatic and not palpable. This is animportant clinical distinction from patients with vasculitis, such as Henoch-Schnlein purpura or drug hypersensitivity. In vasculitic purpura, the patient experiences a prodrome of stinging or burning. On examination, vasculitic purpura has a palpable, papular character. (See "Clinicalmanifestations and diagnosis of Henoch-Schnlein purpura".)Thrombocytopenic purpura andvasculitic purpura also have a different pattern of distribution. Thrombocytopenic purpura isconsistently localized to dependent portions of the body. As a result, petechiae are most denseon the feet and ankles, fewer are present on the legs, and only scattered petechiae occur elsewhere on the body. Areas with firm subcutaneous tissue, such as the soles of the feet, areprotected from petechiae, while areas with minimal subcutaneous support, such as the oralmucosa and conjunctivae, may have large bullous appearing hemorrhages (picture 1). In


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contrast, vasculitic purpura may occur in symmetrical patches without regard for a dependentdistribution (picture 2).Comparison with coagulation disorders The clinical manifestations of ITP are distinct from thebleeding abnormalities that occur with a coagulation disorder. Patients with hemophilia, for example, do not have petechiae or purpura because their platelet function is normal. The most

common manifestation of hemophilia is the delayed formation of a hematoma following trauma,as in a muscle or joint space. In comparison, muscle hematomas and hemarthroses rarely occur in patients with ITP (table 1). (See "Approach to the adult patient with a bleeding diathesis",section on 'Clinical manifestations'.)Correlation between bleeding and the platelet count There are few data that describe the riskof clinically important bleeding at different levels of thrombocytopenia. Furthermore, thecorrelation between bleeding symptoms and the platelet count may be in part related to theetiology of the thrombocytopenia.Because the pathogenesis of ITP involves accelerated plateletdestruction by autoantibodies, with a compensatory increase in platelet production in somepatients, circulating platelets in patients with ITP are younger and have greater hemostaticeffectiveness [54]. As a result, bleeding manifestations in patients with ITP are less severe atequivalent platelet counts than in patients with thrombocytopenia due to marrow aplasia or chemotherapy-induced marrow suppression.There are more direct observations on patients withchemotherapy-induced marrow suppression to determine the appropriate platelet countthreshold that requires platelet transfusion support. These data indicate that clinically importantbleeding rarely occurs with platelet counts above 10,000/microL, unless the patient is febrile or has a serious systemic illness [55].There is suggestive evidence that a similar threshold existsin ITP. Clinically important bleeding does not appear to occur in these patients unless theplatelet count is less than 10,000/microL; even at this level, most patients do not have seriousbleeding episodes (figure 2) [56]. These observations suggest that treatment of ITP may beunnecessary unless the platelet count is less than 10,000/microL. However the standard of

practice for adults with ITP is that treatment is generally initiated when the platelet count is lessthan 30,000 to 50,000/microL because the course of the disease and risks for bleeding cannotbe predicted at the time of the initial diagnosis. (See "Treatment and prognosis of immune(idiopathic) thrombocytopenic purpura in adults".)Acquired platelet function abnormality When bleeding in ITP appears to be more severe than would be suggested by the platelet

count alone, the patient may (rarely) have an autoantibody that inhibits the function of plateletglycoprotein (GP) IIb/IIIa, resulting in abnormal platelet aggregation (ie, acquired Glanzmannthrombasthenia) in addition to the underlying thrombocytopenia [57]. (See "Congenital andacquired disorders of platelet function", section on 'Acquired Glanzmann thrombasthenia'.)DIAGNOSIS There is no "gold standard" test that can establish the diagnosis of ITP. Thediagnosis is, in part, one of exclusion, requiring that other causes of thrombocytopenia be ruledout (table 2). Few diagnostic studies other than the history, physical examination, completeblood count, and examination of the blood smear are necessary.Overall approaches to thepatient with thrombocytopenia are presented separately. (See "Evaluation and management of thrombocytopenia by primary care physicians" and "Approach to the adult patient withthrombocytopenia".)Peripheral smear Examination of the blood smear may provide evidence for other causes of thrombocytopenia, such as the presence of schistocytes in patients with thrombotic


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thrombocytopenic purpura-hemolytic uremic syndrome (picture 3). (See "Approach to the adultpatient with thrombocytopenia", section on 'CBC and peripheral smear' and "Diagnosis of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults".)Examination of theperipheral blood smear is essential to exclude "pseudothrombocytopenia" due to the artifact of platelet agglutination induced by the standard blood count anticoagulant, EDTA (picture 4).

EDTA-dependent agglutinins are present in approximately 0.1 percent of people in the generalpopulation [58-61]. This phenomenon is thought to result from a "naturally occurring" plateletautoantibody directed against a normally concealed epitope on the platelet membraneglycoprotein (GP) IIb/IIIa, which becomes exposed by EDTA-induced dissociation of GP IIb/IIIa[62]. This subject is discussed separately. (See "Approach to the adult patient withthrombocytopenia", section on 'Pseudothrombocytopenia'.)It is important for each clinicallaboratory to have an established procedure for responding to artifactually low platelet countscaused by these agglutinins. An appropriate procedure is to report that an artifact due to plateletclumping is present, rather than the actual platelet count, which could be misinterpreted as truethrombocytopenia.Three other artifacts can affect platelet counting:

Cold-dependent platelet agglutinins and autoantibodies may induce "rosetting" of plateletsaround neutrophils and/or monocytes, resulting in pseudothrombocytopenia.

Giant platelets that can occur in certain congenital thrombocytopenic disorders (picture 5) maynot be recognized as platelets by some automated instruments used for blood counts, resultingin pseudothrombocytopenia. (See "Automated hematology instrumentation", section on 'Plateletcounting' and "Automated hematology instrumentation", section on 'The optical platelet count'.)

Cryoglobulin particles may be counted as platelets, artifactually elevating the platelet count inpatients who have cryoglobulinemia [63]. (See "Approach to the patient with thrombocytosis",section on 'Spurious thrombocytosis'.)Making a presumptive diagnosis A presumptive diagnosis of ITP is made when the history(eg, lack of ingestion of a drug, beverage, food, or herbal remedy that can cause

thrombocytopenia, such as quinine, including quinine in beverages such as tonic water, asulfonamide such as sulfamethoxazole, or heparin [64]), physical examination, complete bloodcount, and examination of the peripheral blood smear do not suggest other etiologies for thepatient's isolated thrombocytopenia. (See "Drug-induced thrombocytopenia", section on 'Initialapproach'.)The only recommended further tests in such patients are [1,65]:

Testing for HIV and HCV in patients with appropriate risk factors Thyroid function testing to exclude the infrequent presence of occult hyperthyroidism or

hypothyroidism before elective splenectomy is performed Bone marrow aspiration/biopsy in patients over 60 years of age to rule out myelodysplastic

syndrome [66,67]. Bone marrow studies should also be performed in patients responding poorlyto therapy and/or prior to splenectomy in order to reevaluate/reconfirm the initial diagnosis of ITP.For patients with presumed ITP, severe thrombocytopenia, and/or clinical bleeding, urgenthematologic consultation is most appropriate. For asymptomatic patients with modest degreesof thrombocytopenia, consultation is less urgent, but should be pursued in order to establish abaseline, should treatment be required in the future.

Antiplatelet antibody testing The American Society of Hematology ITP Practice Guideline didnot recommend antiplatelet antibody studies in patients thought to have ITP [1], and there is still


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no evidence that antiplatelet antibody studies are important for the diagnosis of ITP. Thisrecommendation is different from the common practice of many physicians, but is consistentwith the absence of data that platelet antibody testing affects management decisions [2]. Thelack of clinical value of antiplatelet antibody testing reflects limitations of laboratorymethodology. The absence of detectable antiplatelet antibodies does not imply the absence of

autoantibodies as the underlying pathogenesis of ITP.The lack of value of antibody testing can be illustrated by the following observations:

A small study compared patients with ITP to patients initially suspected of having ITP in whoman alternative diagnosis was subsequently made [68]. Commonly used commercial tests for both platelet-bound IgG and serum platelet-bindable IgG had no predictive value.

A larger series included 90 patients with a clinical diagnosis of ITP and 160 patients with aclinical diagnosis of incidental thrombocytopenia of pregnancy (gestational thrombocytopenia);four laboratories with expertise in platelet antibody testing were involved and eight differentassays for antiplatelet antibodies were used [69]. There was no difference between these twogroups with six of the tests; a seventh test had a statistically significant distinction, but thedifference was clinically unimportant because there was almost complete overlap amongindividual patients.

A subset of 40 patients in the preceding study had a statistically significant distinction whenglycoprotein-specific antiplatelet antibodies were assayed [69]. In another report, however, therewere variable results with platelet glycoprotein-specific antiplatelet antibody tests when thesame samples from patients with ITP were studied in eight different laboratories [70].

In reviews of four prospective studies, antiplatelet antibody tests were positive in 49 to 66percent of patients with ITP, but were also positive in 7 to 28 percent of patients with apparentlynonimmune etiologies (eg, gestational thrombocytopenia, myelodysplastic syndrome,familial/congenital thrombocytopenia) [57,71].

Two studies of newer techniques demonstrated only 53 to 55 percent sensitivity for making the

diagnosis of ITP and 82 to 84 percent specificity [71,72].These data provide support for the concept that thrombocytopenia in ITP is mediated byautoantibodies, but the frequency of false negative and false positive results limits the value of these tests for making clinical decisions [65].Results of platelet antibody testing in ITP are also different from the standard practice inautoimmune hemolytic anemia, which is defined by the presence of a positive antibody test (ie,direct antiglobulin test [DAT], direct Coombs test). In many cases of ITP, what is beingmeasured is "platelet-associated IgG", which may reflect plasma IgG acquired by plateletpincytosis rather than antiplatelet antibodies [73].At this time, platelet antibody tests are notnecessary for management decisions in patients with suspected ITP. Specifically, currentlyavailable tests do not distinguish ITP from secondary thrombocytopenic purpura, and a negativetest does not rule out the diagnosis of ITP [2,68,71,72,74,75].Clinically apparent associated conditions Patients with thrombocytopenia and a clinicallyapparent associated condition causing the thrombocytopenia may have a disorder comparableto ITP. However, these patients can be distinguished from those with ITP because the clinicalcourse is often dominated by the associated condition. Examples include:


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Chronic lymphocytic leukemia and other lymphoproliferative disorders. (See "Autoimmunecomplications following purine analog therapy" and "Overview of the complications of chroniclymphocytic leukemia".)

Thrombocytopenia associated with HIV infection. (See "Hematologic manifestations of HIVinfection: Thrombocytopenia and coagulation abnormalities", section on 'Thrombocytopenia'.)

Systemic lupus erythematosus and other autoimmune disorders. Approximately 3 to 15percent of patients with apparently isolated ITP go on to develop systemic lupus erythematosus(SLE). In one series of 115 patients who underwent splenectomy for ITP, 14 (12.5 percent)subsequently developed SLE [76]. (See "Hematologic manifestations of systemic lupuserythematosus in adults", section on 'Thrombocytopenia'.)In the definition of ITP, the emphasis on excluding only clinically apparent associated conditionsis important, because patients with typical ITP often have isolated abnormalities on serologictests without symptoms of a systemic disorder. As an example, up to 40 percent of otherwisetypical patients with ITP have positive tests for antinuclear antibodies [77] or antiphospholipidantibodies [78-81].ITP and other autoimmune phenomena (eg, autoimmune hemolytic anemia,pernicious anemia) are often seen in patients with common variable immunodeficiency (CVI)[82]. The diagnosis of ITP may be made before, at the time of, or following the diagnosis of CVI[83]. Testing for immunoglobulin levels has been suggested as a way to determine whichpatients with ITP also suffer from CVI. Treatment of ITP with agents resulting in further immunosuppression is relatively contraindicated when these conditions co-exist. (See "Clinicalmanifestations and epidemiology of common variable immunodeficiency", section on'Autoimmune disease'.)The presence of antinuclear antibodies does not appear to affect the overall clinical course of these patients, but antiphospholipid antibodies are associated with a high incidence of thrombosis and/or fetal loss over the subsequent five years [84]. Patients should be alertedabout this increased risk. (See "Clinical manifestations of the antiphospholipid syndrome",

section on 'Hematologic manifestations' and "Treatment of the antiphospholipid syndrome",section on 'Prophylaxis'.)Bone marrow aspiration and biopsy In the typical patient with ITP, overall bone marrowcellularity is normal, with normal erythropoiesis and myelopoiesis. Megakaryocytes are presentin normal to increased numbers. In some patients, a shift towards younger megakaryocytes withlesser degrees of nuclear polyploidy and less evidence of platelet production may be noted.(See "Megakaryocyte biology and the production of platelets", section on 'Immunethrombocytopenic purpura'.)Bone marrow examination is not required in most patients withisolated thrombocytopenia and suspected ITP [1,3,85]. However, it should be performed inpatients over the age of 60, because of concern for the presence of myelodysplasia [86]. (See"Clinical manifestations and diagnosis of the myelodysplastic syndromes", section on'Thrombocytopenia' and 'Myelodysplasia' below.) Marrow examination is also of criticalimportance in making a diagnosis of the rare condition, acquired pure megakaryocytic aplasia(amegakaryocytic thrombocytopenia), in which megakaryocytes are either severely reduced innumber, or absent (see 'Differential diagnosis' below and "Recombinant hematopoietic growthfactors in inherited bone marrow failure syndromes", section on 'Amegakaryocyticthrombocytopenia').


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A systematic review of published case reports of drug-induced thrombocytopenia presented acomprehensive database on the level of clinical evidence supporting a causal relationship of thedrug to thrombocytopenia [64]. This database, updated through October 2008, is available at.Infection Viral and bacterial infections commonly cause thrombocytopenia, which may be

acute (eg, rubella, infectious mononucleosis, ehrlichiosis, hepatitis) or chronic and persistent(eg, HIV infection, HCV infection) [92]. (See "Hematologic manifestations of HIV infection:Thrombocytopenia and coagulation abnormalities", section on 'Thrombocytopenia' and"Extrahepatic manifestations of hepatitis C virus infection", section on 'Autoimmunethrombocytopenic purpura and hemolytic anemia'.)Hypersplenism Hypersplenism due to portal hypertension caused by chronic liver disease ischaracteristically associated with mild thrombocytopenia secondary to increased pooling of platelets in the splenic sinusoids [93]. Diminished production of thrombopoietin may play acontributory role [94]. Other signs of portal hypertension are typically present and the spleen isusually palpable; however, these signs are not apparent in some patients. (See "Extrinsicnonimmune hemolytic anemia due to mechanical damage: Fragmentation hemolysis andhypersplenism", section on 'Extravascular nonimmune hemolysis due to hypersplenism'.)Myelodysplasia Myelodysplasia (MDS) in elderly patients may present initially with purethrombocytopenia [66,67]. This constitutes the rationale noted above for examination of thebone marrow in elderly patients with suspected ITP.This was shown in a retrospective study of interphase FISH analysis for del(20q) on thawed frozen bone marrow cell pellets from 23 adultpatients with ITP. These patients had bone marrow examination performed mostly because of age >60 and/or failure to respond to ITP therapy, including splenectomy. While bone marrowmorphology, cellularity, and karyotype were normal in all of the cases, del(20q) was present in12 (52 percent) [86,95]. (See "Clinical manifestations and diagnosis of the myelodysplasticsyndromes", section on 'Thrombocytopenia'.)

Congenital thrombocytopenias Congenital, familial thrombocytopenia should be consideredin patients with persistent thrombocytopenia unaffected by treatment [96-98]. Although somereports suggest that the platelets in patients with ITP are larger than normal, truly giant plateletsapproaching the diameter of red blood cells do not occur in ITP. Their presence on theperipheral smear or automated cell counters strongly suggests the presence of congenital,familial thrombocytopenia (picture 5).

As an example, in a study of 35 patients with inherited macrothrombocytopenias and 56 withITP, a mean platelet volume >12.4 fL had a sensitivity and specificity of 83 and 89 percent,respectively, in separating the former from the latter [99].

Among children, congenital thrombocytopenias are often initially misdiagnosed as ITP. Some of these are discussed elsewhere in the program. (See "Approach to the adult patient withthrombocytopenia", section on 'Abnormal platelet morphology' and "Congenital and acquireddisorders of platelet function", section on 'Inherited disorders of platelet function'.)The most common of these and their typical clinical characteristics include:

von Willebrand disease type 2B, with greater than expected bleeding for the degree of thrombocytopenia. (See "Clinical presentation and diagnosis of von Willebrand disease", sectionon 'Type 2B'.)


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Wiskott-Aldrich syndrome and its variant, X-linked thrombocytopenia, with small platelets andrecurrent infections. (See "Wiskott-Aldrich syndrome".)

Alport syndrome (hereditary nephritis) variants, with giant platelets, renal failure, and hearingloss [100]. (See "Genetics, pathogenesis, and pathology of hereditary nephritis (Alportsyndrome)".)

May-Hegglin anomaly, with giant platelets and Dhle bodies in granulocytes, and other manifestations of MYH9 gene mutations (the gene encoding the nonmuscle myosin heavy chainIIA) [101]. (See "Approach to the adult patient with thrombocytopenia", section on 'May-Hegglinanomaly'.)

Fanconi syndrome, with short stature, anemia, and neutropenia. (See "Inherited aplasticanemia in children", section on 'Fanconi anemia'.)

Bernard-Soulier syndrome, with giant platelets and greater than expected bleeding for thedegree of thrombocytopenia. (See "Approach to the adult patient with thrombocytopenia",section on 'Bernard-Soulier syndrome'.)

Thrombocytopenia with absent radius (TAR) syndrome, with skeletal abnormalities. (See"Neonatal thrombocytopenia", section on 'Thrombocytopenia-absent radius syndrome'.)

Acquired pure megakaryocytic aplasia Patients with the rare disorder acquired puremegakaryocytic aplasia (acquired amegakaryocytic thrombocytopenia) are clinicallyindistinguishable from patients with ITP, except for the absence of bone marrowmegakaryocytes. (See "Recombinant hematopoietic growth factors in inherited bone marrowfailure syndromes", section on 'Amegakaryocytic thrombocytopenia'.)

ADDITIONAL INFORMATION Additional information concerning thrombocytopenicconditions (ie, drug-induced, ITP, TTP-HUS, and thrombocytopenia in pregnancy) can be foundon a database maintained by Dr. James N. George at the University of Oklahoma HealthSciences Center. This database is updated regularly and is available at.

SUMMARY AND RECOMMENDATIONSMaking the diagnosis There is no "gold standard" test that can establish the diagnosis of ITP.The diagnosis is in part one of exclusion, requiring that other causes of thrombocytopenia beruled out (table 2).

A presumptive diagnosis of ITP is made when the history (eg, lack of ingestion of a drug thatcan cause thrombocytopenia), physical examination, complete blood count, and examination of the peripheral blood smear do not suggest other etiologies for the patient'sisolated thrombocytopenia.Recommended testing Few diagnostic studies other than the history, physical examination,complete blood count, and examination of the blood smear are necessary. The onlyrecommended further tests in such patients include [1]:

HIV and HCV testing in patients at risk for these infections Bone marrow aspiration in patients over 60 years of age to rule out one of the myelodysplastic

syndromes (see 'Myelodysplasia' above)When to obtain hematologic consultation

For patients with presumed ITP, severe thrombocytopenia, and/or clinical bleeding, urgenthematologic consultation is most appropriate.


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For asymptomatic patients with modest degrees of thrombocytopenia, consultation is lessurgent, but should be pursued in order to establish a clinical and laboratory baseline, shouldtreatment be required in the future. (See "Treatment and prognosis of immune (idiopathic)thrombocytopenic purpura in adults", section on 'General therapeutic principles'.)

Treatment and prognosis of immune (idiopathic) thrombocytopenic purpura in adults Author James N George, MD Section Editor Lawrence LK Leung, MD Deputy Editor Stephen A Landaw, MD, PhDLast literature review version 18.2: May 2010 | This topic last updated: June 9, 2010 (More)INTRODUCTION Immune (idiopathic) thrombocytopenic purpura (ITP) is an acquireddisorder. Only two criteria are required for its diagnosis [1-5]:

Thrombocytopenia, with an otherwise normal complete blood count and white blood celldifferential, including a normal peripheral blood smear (except when coincidental abnormalitiesare also present, such as concomitant iron deficiency).

No clinically apparent associated condition(s) or medications (including herbal preparations,quinine-containing beverages) that may cause thrombocytopenia are present.The pathogenesis of ITP is presumed to be related to increased platelet destruction along withinhibition of platelet production via the production of specific autoantibodies. However, suchantibodies are not easily demonstrable in all patients, and assays for antiplatelet antibodieshave not been important for management decisions. (See "Clinical manifestations and diagnosis

of immune (idiopathic) thrombocytopenic purpura in adults", section on 'Pathogenesis'.)The initial treatment and prognosis of ITP in adults will be reviewed here. The approach iscompatible with guidelines for ITP issued by the British Committee for Standards inHaematology General Haematology Task Force in 2003 [1], and an international consensusreport in 2009 [2].Treatment of chronic, refractory ITP, the clinical manifestations, diagnosis, and differentialdiagnosis of ITP in adults, and issues related to ITP in children are discussed separately. (See"Chronic refractory immune (idiopathic) thrombocytopenic purpura in adults" and "Clinicalmanifestations and diagnosis of immune (idiopathic) thrombocytopenic purpura in adults" and"Clinical manifestations and diagnosis of immune (idiopathic) thrombocytopenic purpura inchildren".)GENERAL THERAPEUTIC PRINCIPLES Major bleeding is rare in patients with ITP,primarily occurring in those with platelet counts below 10,000/microL (figure 1) [6]. The goal for treatment of ITP is to provide a safe platelet count to prevent major bleeding, rather thanreturning the platelet count to normal [3,5]. This involves the following critical concepts (see'Patient selection' below:


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Adults with severe thrombocytopenia (ie, a platelet count below 30,000/microL) at the time of diagnosis are always treated even if they are asymptomatic or have only minor bleedingsymptoms, because the course of the disease and the risk for future bleeding cannot be known.

Avoid unnecessary treatment of asymptomatic patients with mild to moderatethrombocytopenia (ie, a platelet count greater than 30,000 to 50,000/microL).

The efficacy of continued therapy is uncertain among asymptomatic patients with chronicsevere thrombocytopenia who have had no or only a partial response to treatment. Suchpatients often report that the morbidity from side effects of therapy exceeds any problemscaused by their ITP [7].Natural history An understanding of the natural history of untreated ITP, which differsbetween children and adults, provides part of the rationale for deciding which patients should betreated. Many children receive no specific therapy, since 70 to 80 percent have a spontaneouscomplete remission of the disease within six months. (See "Clinical manifestations anddiagnosis of immune (idiopathic) thrombocytopenic purpura in children".)Spontaneous remissions are unusual in adults, occurring in 9 percent in one series [8]. Thenecessity for treatment in adults varies with the severity of the thrombocytopenia:

Adults with severe thrombocytopenia (platelet count below 30,000/microL) at the time of diagnosis are treated, most often with glucocorticoids. However, most do not maintain a normalplatelet count after glucocorticoids are discontinued [8,9]. (See 'Initial treatment' below.)

Most adults presenting with platelet counts greater than 30,000 to 50,000/microL have a stableand benign course without treatment [8,10-12]. Data from case series suggest that 15 percentor less of such patients develop more severe thrombocytopenia and require treatment duringthree to seven years of follow-up [8,10,11].The frequency of spontaneous remissions in adults after a prolonged duration of ITP is lessclear. The incidence of major bleeding and death from bleeding is also unknown, although theseevents are thought to be rare. The absence of firm data on these important clinical outcomes

impairs all management decisions. The following observations suggest that ITP may be a morebenign disease than previously thought, and may be best approached by a conservativetreatment program in the majority of patients [8,11,12].In a report of 208 adults with ITP who were followed for a median of 92 months, the followingfindings were noted [8]:

42 percent had a platelet count above 50,000/microL and were not treated; these patients hada spontaneous remission rate of 9 percent. Fifteen percent of patients had a subsequent fall inplatelet count to less than 50,000/microL and were treated with prednisone.

At last follow-up in 95 treated patients, 43 were in complete remission without therapy and 52were still being treated.

Five deaths were attributable to thrombocytopenia. A second series evaluated long-term morbidity and mortality in 152 patients who were followedfor a median duration of 9.5 years [11]:

The long-term mortality risk was equal to that in the general population. Six patients died of ITP-related causes: two from disease-related causes (eg, intracranial

hemorrhage); and four from complications of treatment (eg, infection related toimmunosuppressive therapy or previous splenectomy).


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Morbidity from splenectomy in 78 patients was 26 percent (eg, postoperative complicationsresulting in prolonged hospitalization or readmission).These data suggest caution in the therapeutic approach to ITP, reserving aggressive treatmentfor patients with severe and symptomatic thrombocytopenia.INITIAL TREATMENT There are few prospective, controlled trials concerning the

effectiveness of different therapies for ITP on long-term outcomes [2,3]. Nevertheless, sincespontaneous remissions are unusual in adults with ITP, treatment to increase the platelet countis always initiated in patients with a platelet count below 30,000/microL, which is severe enoughto constitute a risk for bleeding.Some adults who present with an abrupt onset of purpura and severe thrombocytopenia have aself-limited course, possibly caused by an inapparent infection or an adverse drug reaction. In acohort study from England, for example, 28 of 343 patients (8 percent) initially registered ashaving ITP were subsequently determined to have had drug-induced thrombocytopenia [12].Quinine was the most commonly implicated agent (13 patients). Three patients hadsplenectomy before the drug-induced etiology was recognized.Patient selection The above observations reinforce the importance of appropriate patientselection for treatment of the ITP:

All patients with severe thrombocytopenia (platelet count less than 30,000/microL) should betreated because they are at risk of bleeding. This is especially true in the patient withcomorbidities (eg, older patient, hypertension), in whom the bleeding might be fatal.

Patients with mild to moderate asymptomatic thrombocytopenia that is discovered incidentallyon a routine blood count should not be treated.

As noted above, among patients with initial platelet counts above 30,000 to 50,000/microL,fewer than 15 percent of untreated patients develop more severe thrombocytopenia that requiretreatment after three to seven years of follow-up [8,10,11]. These data suggest that suchpatients require careful follow-up but no specific initial therapy [1,13].

When treatment is given, it should be limited in duration unless symptomaticthrombocytopenia persists.

Asymptomatic patients with even lower platelet counts may be carefully followed without specifictreatment, since experience in patients who have ITP [6], aplastic anemia [14], andthrombocytopenia due to chemotherapy-induced marrow suppression [15] suggests that major bleeding does not occur unless the platelet count is


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Medical conditions and medications increasing the risk of thrombocytopenia, bleeding, and/or infection, especially if myelosuppressive or immunosuppressive agents are to be employed

Accordingly, the decision to treat should be a shared one between the clinician and the patient.Patients may be bothered by side effects of treatment much more than their physicianappreciates. On the other hand, physicians may be more concerned about the risk for bleeding

than their patients [7]. A scheme for the sequence of treatment divides treatment into three sequential steps (algorithm1).Glucocorticoids The goal of initial glucocorticoid treatment is not to "cure" the ITP, but tosupport the platelet count in a safe range with minimal and tolerable side effects until aspontaneous remission occurs, or until more definitive management establishes a durableremission.Prednisone In adults, a standard practice for many decades has been to initiate treatmentwith oral prednisone, 1 mg/kg given as a single daily dose. Most adults with ITP respond toprednisone treatment within two weeks, with the majority responding within the first week. Theduration of initial prednisone treatment is determined by the platelet count response. If theplatelet count recovers promptly to normal, the prednisone dose is tapered and discontinued;there is no standard regimen for tapering the prednisone dose. Some hematologists feel that avery gradual tapering schedule increases the chance for a durable remission; others feel that amore rapid tapering schedule is better, in order to diminish glucocorticoid side effects and todetermine if further treatment is actually required. A reasonable course is to taper anddiscontinue prednisone over four to six weeks after achieving a normal platelet count. Thisschedule includes the time period during which most spontaneous remissions might otherwiseoccur. (See "Glucocorticoid withdrawal".) Patients with persistent symptomatic and severethrombocytopenia (usually described as a platelet count


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largest of these studies are discussed below. A brief course of high-dose dexamethasone (40mg/day orally for four consecutive days) was given to 157 consecutive patients with either aplatelet count


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High-dose methylprednisolone High-dose methylprednisolone (HDMP) has generally beenused in children and in adults resistant to conventional doses of prednisone. However, onestudy evaluated the efficacy of HDMP as first-line therapy for 21 adults with severethrombocytopenia and severe or persistent mucosal or vaginal bleeding. Results werecompared with 36 patients with a less severe presentation who were treated with conventional

doses of prednisone [22]. HDMP was given in a dose of 30 mg/kg intravenously over the courseof one hour initially and tapered every third day to 1 mg/kg once daily. Patients treated withHDMP responded more rapidly (4.7 versus 8.4 days) and had a higher response rate (80 versus53 percent) despite presenting with more severe clinical disease. Three of the 12nonresponders to conventional doses of prednisone responded to a subsequent course of HDMP. There was no difference between the two groups in the frequency of complete or persistent remission. Further studies are required to assess the utility of this approach, whichemployed a high dose of this agent not usually employed in adults. (See 'Methylprednisoloneversus IVIG' below and 'Emergency treatment of life-threatening bleeding' below.)Intravenous immunoglobulin The platelet count can be temporarily supported by the use of intravenous immune globulin (IVIG) or by anti-Rh(D) (Rho(D) immune globulin, anti-D,WinRho ) in patients whose red cells are Rh(D) positive and who have not had a splenectomy.Both of these agents increase the platelet count in most patients with ITP within several days,with an effect that may last for several weeks [3,23,24]. (See "Intravenous immune globulin inhematologic disorders", section on Idiopathic thrombocytopenic purpura.)

A prospective, multicenter trial randomly assigned 35 consecutive adult patients with ITP (meanplatelet count 26,000/microL) to receive IVIG at an initial total dose of either 0.5 or 1.0 g/kg over a period of 4 to 12 hours on day 1 [25]. Non-responders received additional IVIG in divideddoses on days 4 and 5 to reach a total intravenous dose of 2.0 g/kg. Results of this studyincluded the following:

Responses (an increase in platelet count to 80,000/microL to at least twice the initial platelet

count) to the lower (0.5) and higher (1.0) IVIG doses were seen in 6 and 28 percent on day 2,24 and 61 percent on day 3, and 24 and 67 percent on day 4, respectively.

Eleven of the 13 non-responders to the 0.5 g/kg dose, and two of the six non-responders tothe 1.0 g/kg dose, responded by day 8 to a total dose of 2.0 g/kg, for an overall response rate of 78 percent.

Transient and reversible intolerance to IVIG was seen in two patients in the low dose group,and consisted of hypertension and headache in one, and chills, vomiting, and hypotension in theother.

Anti-D is effective only in Rh-positive patients in whom the immunoglobulin binds to theerythrocyte D antigen, and is also apparently effective only in patients who have not hadsplenectomy. Immune-mediated clearance of the sensitized erythrocytes occupies the Fcgamma receptors in the reticuloendothelial system, minimizing removal of antibody-coatedplatelets [26-28]. Accordingly a modest amount of hemolysis is expected with the use of thisagent, although more severe degrees of hemolysis have been reported following use of thisagent (see below) [29,30]. The response rate to anti-D in one series was 70 percent, with theincrease in platelet count lasting more than 21 days in 50 percent of the responders [24].Standard intravenous regimens for these products are [31]:

IVIG 1 g/kg per day, given for one to two days


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Anti-D 50 to 75 mcg/kg per day, given onceNeither modality is expected to induce a long-term remission. However, these agents may bevaluable in a patient with life-threatening bleeding, or in preparing for splenectomy or other surgical procedures (see 'Emergency treatment of life-threatening bleeding' below and'Splenectomy' below).

Side effects IVIG and anti-D can cause mild alloimmune hemolysis and IVIG may also causeheadache, nausea, and vomiting, symptoms that may cause concern for the possibleoccurrence of intracranial hemorrhage [32]. Some sucrose-containing products may also beassociated with acute renal failure [33].If an Rh(D)-positive patient who received anti-D requires a red cell transfusion, Rh(D)-negativered cells should be used, to avoid worsening ongoing hemolysis. Caution should also beexercised if the patient receives platelets from an Rh(D)-positive donor, since thesepreparations may contain significant quantities of red cells. Additional information on thesetopics can be obtained from the revised package insert and the Food and Drug Administrationwebsite [34].Intravascular hemolysis from anti-D Unpublished data from anti-D clinical trials for thetreatment of ITP have revealed an estimated incidence of intravascular hemolysis of 0.7 percent[35,36]. Signs and symptoms consistent with intravascular hemolysis, including back pain,shaking chills, and/or hemoglobinuria, occurred within four hours of anti-D administration.Severe complications included anemia, requiring transfusion and ending fatally in one case,acute onset or exacerbation of renal insufficiency, requiring dialysis in two cases [37], and sixcases of disseminated intravascular coagulation (DIC) associated with acute hemoglobinemia or hemoglobinuria, five of which were fatal [38]. Estimates for the risk of development of intravascular hemolysis or DIC are less than 1/1000 and 1/10,000, respectively.The etiology of intravascular hemolysis following anti-D administration is unknown [39]. No riskfactors associated with this adverse event have been identified, including age, gender, renal

function prior to treatment, hemoglobin concentration, concomitantly administered packed redcells, or dose. Some of the patients in whom DIC occurred had tolerated previous doses of thedrug. A "black box" warning indicates that patients receiving anti-D should be monitored for hemoglobinuria/hematuria/renal function during the 8 hours following use of this agent, and thatthis agent not be used in patients with evidence of, or at high risk for, hemolysis (eg,reticulocytosis, positive Coombs test) [40,41].Methylprednisolone versus IVIG The relative efficacy of high-dose intravenousmethylprednisolone (MP, 15 mg/kg per day on days 1 to 3) versus IVIG (0.7 g/kg per day ondays 1 to 3) was studied in a prospective randomized trial in 122 patients with previouslyuntreated severe acute ITP (ie, platelet count 20,000/microL) [42]. In a second randomization,patients received either placebo or oral prednisone (1 mg/kg per day) on days 4 to 21. Major study results included:

The percent of patients with a platelet count >50,000/microL on days 2 and 5 was slightlygreater for those receiving IVIG (7 and 79 percent, respectively) than for those receiving MP (2and 60 percent).

Use of prednisone was significantly more effective than placebo for all short-term studyendpoints (eg, days with platelet count >50,000/microL, highest platelet count, platelet count at21 days, and time to relapse).


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The remission rate at one year was not affected by the initial treatment (IVIG versus MP); useof prednisone did not prevent progression to chronic ITP.SECOND-LINE MANAGEMENT AFTER FAILURE OF INITIAL THERAPYOverview Second-line management should be reserved for patients with persistentsymptomatic thrombocytopenia following treatment with glucocorticoids, typically those with

platelet counts


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patients [43]. Patient outcomes were consistent across many years and many differentcountries. Sixty-six percent of 2623 patients achieved a complete remission, defined by anormal platelet count with no subsequent treatment. An additional 22 percent had a partialresponse, defined by a platelet count over 50,000/microL, with or without treatment [43].Follow-up after splenectomy in these 47 case series varied from 1 to 153 months (median: 29

months) and demonstrated that the percent of patients remaining in complete remission was notrelated to the duration of follow-up (figure 2) [43].These data suggest that in most of the two-thirds of patients who achieve a complete remissionfollowing splenectomy, the remission is durable.Indications and results Important considerations affecting the decision for splenectomyinclude:

The severity of bleeding or thrombocytopenia and the assumed risk for major bleeding.Splenectomy is not appropriate for patients with mild or moderate thrombocytopenia and minor bleeding.

The patient's lifestyle related to risk for bleeding. The duration of ITP. Since ITP can remit spontaneously in a small percent of patients,

splenectomy is usually deferred for four to six weeks after diagnosis. A 2010 review hassuggested that splenectomy be deferred for six months after diagnosis [2]. However, manypatients with persistent severe and symptomatic thrombocytopenia in spite of initialglucocorticoid treatment will require consideration of splenectomy much sooner than six months.

The probability that splenectomy will provide a complete remission from ITP. The bestestimate for a complete remission following splenectomy is 66 percent [43]. Some studies, bothin adults and children, have suggested that splenic sequestration of radiolabeled platelets[47] or a response to IVIG [48,49] may predict a favorable response to splenectomy; however,the data are not consistent and study of the sequestration of radiolabeled platelets remains aninvestigational procedure [43,50-54].

The only clinical parameter that predicts a favorable response to splenectomy is patient age;younger patients respond better [3,43,47,55]. However, a specific age cut-off for thisobservation could not be determined in our literature review [43].

The potential risks from the surgical procedure. In a healthy, young, thin patient, splenectomyis a low risk procedure. Surgical risk is increased in older or obese patients with other medicalproblems.

The morbidity and mortality from splenectomy appear to be less with laparoscopic techniquesthan with standard laparotomy [56-59]. One case series reported that 26 percent of 78 patientsundergoing splenectomy by standard laparotomy suffered postoperative complications, resultingin prolonged hospitalization or readmission [11]. In the author's review of over 3000 suchprocedures, morbidity was 9.6 versus 12.9 percent and mortality 0.2 versus 1.0 percent for laparoscopic and laparotomy splenectomies, respectively [43]. Patients who achieve a completeremission following splenectomy typically do so within the first two weeks after surgery; somemay have an immediate post-operative "surge" in their platelet counts [58]. This promptresponse is consistent with the concept that the spleen is the major site of destruction of antibody-sensitized platelets, and is supported by studies of infusion of plasma from patientswith ITP into normal volunteers [46]. Infusion of such plasma caused thrombocytopenia innormal subjects, while in splenectomized subjects much larger doses were required to induce


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thrombocytopenia [46]. A longer-term benefit of splenectomy is this procedure's removal of themajor site of autoantibody production.Complications The risks of splenectomy include those of the surgical procedure plusincreased susceptibility to serious infection. With respect to surgical risk, patients should have aplatelet count >50,000/microL when undergoing splenectomy, usually after response to

treatment with glucocorticoids, IVIG, anti-D, and/or platelet transfusions. However, somepatients with ITP undergo splenectomy with more severe thrombocytopenia (ie, platelet counts


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At a median follow-up of 20 months, the rates of relapse (ie, a platelet count 50,000/microL) have been seen in approximately 50 percent, with completeremissions (ie, platelet counts >150,000/microL) in about one-third. (See "Treatment and

prognosis of immune (idiopathic) thrombocytopenic purpura in children", section on 'Treatmentof refractory chronic ITP'.)

In two reports, 16 of 18 patients achieving complete remission maintained that status at amedian observation period of 72 weeks [74] and 17 of 31 patients with responses lasting morethan one year maintained that response for a total of five years [76].

In a third report in 26 patients with relapsed or refractory ITP and active, symptomatic disease,complete and partial responses to rituximab were seen in 14 and 4 subjects, respectively [79].Nine of the 18 responding patients relapsed after a median of 21 months (range: 8 to 66months).Two systematic reviews of case series describing rituximab treatment of five or more patientswith chronic refractory ITP have documented a short-term 30 to 43 percent rate of completeremission with this agent [63,80]. This remission rate is similar to that noted in a prospectivecohort study of children with chronic ITP; 11 of 30 children (37 percent) responded with asustained platelet count >100,000/microL for at least 4 consecutive weeks [81]. The durability of these responses is uncertain; the systematic review mentioned above noted that the medianfollow-up of patients in the available series was only 9.5 months [63].None of the studies included in one of the systematic reviews of rituximab employed a controlgroup and the quality of such data was considered to be poor [63]. The finding of significant


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toxicity of rituximab in this review, including death in 2.9 percent of cases, suggests caution inits use. Although many of the deaths may have been related to long courses of complextreatment regimens for patients with advanced disease, some of the nine reported deaths mayhave been attributable to toxicity of rituximab [63]. Rituximab might be preferred by thosepatients who are not good candidates for surgery or who wish to avoid surgery. However,

accumulating experience shows that rituxan response may be less durable than the response tosplenectomy. The use of rituximab as initial second-line treatment after failure of steroids maynot avoid surgery, but may only prolong the period before the more definitive splenectomy isdone. Although rituximab has been studied in combination with dexamethasone in previouslyuntreated patients, it is not recommended for initial treatment.Thrombopoiesis-stimulating agents Thrombopoiesis- stimulating agents (TPO mimetics) areapproved by the United States FDA for use in ITP in adults "with insufficient response tocorticosteroids, immunoglobulins, or splenectomy", and have been advocated for second-linetreatment of ITP in a 2010 review [2]. The basis for this recommendation is that these agentsare the only treatments for ITP with efficacy supported by randomized clinical trials, althoughthey are also the only treatments for ITP that have been extensively evaluated by randomizedclinical trials as a required part of their approval process. (See "Chronic refractory immune(idiopathic) thrombocytopenic purpura in adults", section on 'Thrombopoiesis-stimulatingagents'.) We do not recommend the use of thrombopoiesis-stimulating agents as second-linetreatment until other treatments to achieve a durable remission have failed. Thrombopoiesis-stimulating agents are expensive, only support an increased platelet count as long as they arecontinued, do not induce a remission, and their long-term side effects are not fully known. Our recommendation is similar to that of the European medicines evaluation agency (EMEA), whichhas approved these agents for "splenectomized adults who are refractory to other treatments."CHRONIC REFRACTORY ITP Approximately 10 percent of all adult patients diagnosed withITP do not respond adequately to combinations of the above therapeutic measures (eg,

glucocorticoids, IVIG, splenectomy) and go on to have chronic, symptomatic thrombocytopenia[82]. The management of such patients (chronic refractory ITP) is discussed separately. (See"Chronic refractory immune (idiopathic) thrombocytopenic purpura in adults".)EMERGENCY TREATMENT OF LIFE-THREATENING BLEEDING Although rare,intracerebral bleeding, severe gastrointestinal bleeding, and death from bleeding can occur inITP [8]. Life-threatening bleeding may be seen at any age and at any time during the course of this disease, but appears to be more common in older patients [10,16]. In one report, for example, the rates of severe hemorrhagic complications in patients >60 or


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Platelet transfusions Although patients with ITP may have rapid destruction of circulatingplatelets, clinical experience with platelet transfusion demonstrates that many patients havehigher platelet count increments that last for durations longer than anticipated [84,85]. In onereport, for example, 13 of 31 (42 percent) platelet transfusions raised the platelet count to>20,000/microL; next day platelet counts remained elevated in five of the seven responders

[84]. Even if the platelet response is limited, transfused platelets, alone or in conjunction with theuse of IVIG, may provide critical temporary hemostatic support [86]. (See "Clinical andlaboratory aspects of platelet transfusion therapy", section on 'Immune thrombocytopenia'.)Factor VIIa If critical bleeding continues after initial management with platelet transfusions,IVIG, and methylprednisolone, intravenous recombinant human factor VIIa may be effective [87-90]. (See "Therapeutic uses of recombinant coagulation factor VIIa", section on 'Off-labelexperience'.)ITP DURING PREGNANCY AND NEONATAL THROMBOCYTOPENIA Plateletautoantibodies in pregnant patients with ITP can cross the placenta and producethrombocytopenia in the infant. Issues related to the treatment of the pregnant patient with ITPand her newborn are discussed separately, but are briefly reviewed here. (See"Thrombocytopenia in pregnancy", section on 'ITP during pregnancy and delivery'.)The following observations have been made with respect to the incidence of and risk factors for neonatal thrombocytopenia:

The incidence of fetal thrombocytopenia with platelet counts


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LONG-TERM OUTCOMES As with many aspects of ITP, there are better data for ITP inchildren than in adults. Case series with long follow-up in children support a conservativeapproach to treatment, since most children eventually achieve a spontaneous remission fromITP if they are followed for 10 to 20 years [102]. Appreciation of this benign outcome hasmarkedly diminished the frequency of splenectomy in children to


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Thus, the life-long incidence of major bleeding and death from bleeding in patients with ITP ismost likely substantially


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If splenectomy is being considered, it should be deferred for at least four to six weeks after initialdiagnosis, unless the patient has severe and symptomatic thrombocytopenia unresponsive toinitial treatment with glucocorticoids. We prefer the laparoscopic approach to open splenectomybecause of its lower morbidity and mortality. (See 'Splenectomy' above.)Continued treatment failure Patients with persistent and severe thrombocytopenia

( 20,000/microL) after treatment with prednisone, splenectomy, and rituximab, who have acontinuing requirement for therapies to increase and/or sustain the platelet count, areconsidered to have chronic refractory ITP. Management of such patients is challenging and isdiscussed separately. (See "Chronic refractory immune (idiopathic) thrombocytopenic purpura inadults".)Life-threatening bleeding Life-threatening bleeding requires immediate intervention. After conventional critical care measures are underway, emergent platelet transfusion should beinitiated. This should be combined with other rapidly-acting interventions (eg, intravenous pulsemethylprednisolone, intravenous immunoglobulin, splenectomy).Intravenous recombinant human factor VIIa is an option if all other treatments have failed tocontrol the bleeding. (See 'Emergency treatment of life-threatening bleeding' above.)


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Approach to the adult patient with thrombocytopenia

AuthorsStephen A Landaw, MD, PhDJames N George, MD Section Editor

Lawrence LK Leung, MD Deputy Editor Stephen A Landaw, MD, PhDLast literature review version 18.2: May 2010 | This topic last updated: March 23, 2010 (More)

INTRODUCTION The clinician is frequently faced by a patient presenting with a low plateletcount, the cause of which is not immediately apparent. This topic will provide a structure throughwhich the cause(s) of such thrombocytopenia can be assessed. A related topic describes themost common outpatient and inpatient presentations of adults with newly recognizedisolated thrombocytopenia (ie, patients in whom the remainder of the blood count is normal, andwho may or may not have signs of systemic disease) and provides a general guideline for theevaluation and management of thrombocytopenic patients in the office and hospital settings.(See "Evaluation and management of thrombocytopenia by primary care physicians".)Other issues related to thrombocytopenia are presented separately:

Thrombocytopenia in pregnancy. (See "Thrombocytopenia in pregnancy".) Evaluation of the patient with a bleeding diathesis. (See "Approach to the adult patient with a

bleeding diathesis".)

DEFINITIONS The normal platelet count in adults ranges from 150,000 to 450,000/microL,with mean values of 237,000 and 266,000/microL in males and females, respectively [1].Thrombocytopenia is defined as a platelet count less than 150,000/microL (150 x 10(9)/L),keeping in mind that 2.5 percent of the normal population will have a platelet count lower than

this. A recent fall in the platelet count by one-half, while still in the normal range, may heraldsevere clinical problems (see below), and requires active follow-up. However, thrombocytopeniais not usually detected clinically (see below) until the platelet count has fallen to levelssignificantly below 100,000/microL.Variation of the platelet count in a given individual is limited; differences in the absolute plateletcount greater than 70 to 90,000/microL will occur by chance less than 1 percent of the time [1].

As an example, even if the patient's platelet count is within the normal range, if the count hasrecently fallen 50 percent or more from a prior value, this should immediately raise thepossibility of heparin-induced thrombocytopenia in any patient begun on heparin therapy withinthe preceding 5 to 10 days. If confirmed, this constitutes a medical emergency, requiringappropriate urgent action. (See "Heparin-induced thrombocytopenia".)Surgical bleeding due solely to a reduction in the number of platelets does not generally occur until the platelet count is less than 50,000/microL, and clinical or spontaneous bleeding does notoccur until the platelet count is less than 10,000 to 20,000/microL. In a study of patients withidiopathic thrombocytopenic purpura, for example, minimal bleeding after trauma wasuncommon unless the platelet count was less than 60,000/microL, whereas self-limitedbleeding, spontaneous bleeding requiring special attention (eg, nasal packing for epistaxis), and


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severe life threatening bleeding did not occur until platelet counts were


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MECHANISMS OF THROMBOCYTOPENIA Analogous to the red blood cell system, themajor mechanisms for a reduced platelet count are decreased production and increaseddestruction. Two additional mechanisms include dilutional or distributional thrombocytopenia.However, before the evaluation of the mechanism of thrombocytopenia is considered, it isimperative to validate the platelet count to exclude the possibility of spurious or

pseudothrombocytopenia and be certain that actual thrombocytopenia exists.

Pseudothrombocytopenia The platelet count can be falsely low in a number of clinicalsituations:

If anticoagulation of the blood sample is inadequate, the resulting thrombin-induced plateletclumps can be counted as leukocytes by automated cell counters. In these circumstances, theWBC count is rarely increased by more than 10 percent and there is usually an associatedspurious thrombocytopenia [10].

Approximately 0.1 percent of normal subjects have EDTA- dependent agglutinins which canlead to platelet clumping and spurious thrombocytopenia and spurious leukocytosis. This isthought to result from a "naturally occurring" platelet autoantibody directed against a normallyconcealed epitope on the platelet membrane glycoprotein (GP) IIb/IIIa, which becomes exposedby EDTA-induced dissociation of GP IIb/IIIa [11-17]. Pseudothrombocytopenia then occursbecause EDTA is the anticoagulant employed in the tubes used for routine complete bloodcounts.

Pseudothrombocytopenia can also occur after the administration of the murine monoclonalantibody abciximab, which is directed against the GP IIb/IIIa receptor [18]. (See "Drug-inducedthrombocytopenia", section on 'Glycoprotein IIb/IIIa inhibitors'.)EDTA-induced platelet clumping can be diagnosed by examination of the peripheral smear (picture 3). This is an established routine for laboratory technologists, but sometimes thephysician only receives the report of the falsely low platelet count number, without the note

about clumping or a repeat count in a non-EDTA anticoagulant.If platelet clumping is observed, the platelet count is repeated using heparin or sodium citrate asan anticoagulant. If citrate is used, one should remember to correct the platelet count for dilutioncaused by the amount of citrate solution used; no such correction is needed for heparin.

Alternatively, one can use freshly-shed non-anticoagulated blood pipetted directly into plateletcounting diluent fluid.Decreased platelet production Platelet production by the bone marrow can be impaired whenthe marrow is suppressed or damaged. In almost all disorders caused by marrow suppressionor damage, white cell and red cell production are also affected. Examples include:

After viral infections (eg, rubella, mumps, varicella, parvovirus, hepatitis C, and Epstein-Barr virus). Decreased platelet counts also regularly occur in children receiving live attenuatedmeasles vaccination, but the thrombocytopenia is rarely clinically important [19]. However, whenviral infections occur in a patient who already has marrow suppression from another etiology,such as chemotherapy, the ensuing thrombocytopenia may be severe.

Certain infectious agents are capable of damaging megakaryocytes directly, such as thehuman immunodeficiency virus. (See "Hematologic manifestations of HIV infection:Thrombocytopenia and coagulation abnormalities", section on 'Ineffective platelet production'.)


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Following chemotherapy or radiation therapy to sites of platelet production (eg, total nodalirradiation).

In cases of congenital or acquired bone marrow aplasia or hypoplasia, such as Fanconianemia, acquired pure megakaryocytic aplasia, and thrombocytopenia with absent radius (TAR)syndrome. Although congenital thrombocytopenias are more commonly diagnosed in children,

many conditions are mild and not recognized until an adult has a routine blood count including aplatelet count. (See "Aplastic anemia: Pathogenesis; clinical manifestations; and diagnosis" and"Recombinant hematopoietic growth factors in inherited bone marrow failure syndromes",section on 'Amegakaryocytic thrombocytopenia'.)

Direct alcohol toxicity. (See "Alcohol abuse and hematologic disorders".) Vitamin B12 and folic acid deficiency. (See "Etiology and clinical manifestations of vitamin B12

and folic acid deficiency".)

Increased platelet destruction Increased platelet destruction is seen in a number of conditions, including:

Idiopathic thrombocytopenic purpura (ITP) and systemic lupus erythematosus, in which themechanism in many cases is presumed to be due to the presence of autoimmune anti-plateletantibodies. However, ineffective platelet production may also contribute to thrombocytopenia inpatients with ITP [20]. This observation has led to the develop of new treatments for ITP thatstimulate platelet production. (See "Clinical manifestations and diagnosis of immune (idiopathic)thrombocytopenic purpura in adults", section on 'Pathogenesis' and "Hematologicmanifestations of systemic lupus erythematosus in adults", section on 'Thrombocytopenia' and"Chronic refractory immune (idiopathic) thrombocytopenic purpura in adults", section on'Thrombopoiesis-stimulating agents'.)

Alloimmune destruction (posttransfusion, neonatal, post- transplantation [21,22]) Disseminated intravascular coagulation (DIC, (table 1)

Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) (see "Causesof thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults")

The antiphospholipid syndrome (see "Clinical manifestations of the antiphospholipidsyndrome")

The HELLP syndrome (hemolytic anemia, elevated liver function tests, and low platelet count)in pregnant women (see "HELLP syndrome")

Certain drugs, most notably heparin, quinine, quinidine, and valproic acid (see below) (see"Heparin-induced thrombocytopenia" and "Drug-induced thrombocytopenia")

Following certain infections (eg, infectious mononucleosis, cytomegalovirus) Patients infected with HIV have a high incidence of thrombocytopenia, which bears a similarity

to ITP (see "Hematologic manifestations of HIV infection: Thrombocytopenia and coagulationabnormalities", section on 'Primary HIV-associated thrombocytopenia')

Physical destruction of platelets during cardiopulmonary bypass, within giant cavernoushemangiomata (Kasabach-Merritt syndrome), occasionally in large aortic aneurysms, and rarelyin intravascular or intracardiac metastatic lesions [23].

Dilutional thrombocytopenia Patients who have had massive blood loss and transfusionalsupport with packed RBC will have dilutional thrombocytopenia due to absence of viable


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platelets in packed RBC products. The usual platelet count in patients receiving 15 or 20 redblood cell units in 24 hours is 47,000 to 100,000/microL and 25,000 to 61,000/microL,respectively [24,25]. This problem can be obviated by giving platelet concentrates to patientsreceiving more than 20 units of packed RBC in a 24 hour period.

Distributional thrombocytopenia caused by splenomegaly Normally, about one-third of circulating platelets are sequestered in the spleen, where they are in equilibrium with circulatingplatelets. Splenic sequestration of platelets can be increased to as high as 90 percent inpatients with congestive splenomegaly due to portal hypertension (figure 2), although totalplatelet mass and overall platelet survival remain relatively normal [6]. Thus, patients withcirrhosis, portal hypertension, and splenomegaly may have significant degrees of "apparent"thrombocytopenia (with or without leukopenia and anemia), but rarely have clinical bleeding,since their total available platelet mass is usually normal.

CLINICAL PRESENTATION Patients with thrombocytopenia may be asymptomatic andthrombocytopenia may be first detected on a routine complete blood count. The symptomaticpresentation of thrombocytopenia is bleeding, characteristically mucosal and cutaneous.Mucosal bleeding may be manifest as epistaxis and gingival bleeding, and large bulloushemorrhages may appear on the buccal mucosa due to the lack of vessel protection afforded bythe submucosal tissue. Bleeding into the skin is manifested as petechiae or superficialecchymoses. (See "Clinical manifestations and diagnosis of immune (idiopathic)thrombocytopenic purpura in adults".)

Menorrhagia (menstrual flow that does not taper after more than three days) and metrorrhagia(uterine bleeding between periods) are also common and there may be persistent, profusebleeding from superficial cuts. Patients with thrombocytopenia tend to bleed immediately after

vascular trauma; they do not experience the delayed bleeding that is characteristic of patientswith coagulation disorders such as hemophilia. Posttraumatic or postoperative surgical bleedingusually responds to local measures, but may persist for hours or days after small injuries.Bleeding into the central nervous system rarely occurs; when it does there is often precedingtrauma, but it is the most common cause of death due to thrombocytopenia. The pattern of bleeding in patients with thrombocytopenia (and in patients with disordered platelet function)differs from that seen in patients with coagulation disorders such as hemophilia, in that the latter group has delayed bleeding that begins several hours or a day after trauma, because normalplatelet function can provide temporary hemostasis. Patients with coagulation disorders alsohave deep bleeding (into tissues, muscles, and joints), minimal bleeding after minor cuts, moredelayed bleeding, more postsurgical bleeding, and tend not to have petechiae (table 2).

Petechiae Petechiae are pinhead sized, red, flat, discrete lesions often occurring in crops independent areas (picture 4); they are most dense on the feet and ankles, where the hydrostaticpressure on the small superficial vessels is greatest, and fewer are present on the legs.Petechiae are not found on the sole of the foot where the vessels are protected by the strongsubcutaneous tissue. Petechiae are due to the presence of red cells which have extravasatedfrom capillaries; they are nontender and do not blanch under pressure. They are asymptomatic


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and not palpable, and should be distinguished from small telangiectasias, angiomas, andvasculitic purpura (picture 5).

Purpura Purpura is a purplish discoloration of the skin due to the presence of confluentpetechiae. Two types of purpura are generally recognized:

Dry purpura is the term used when the only bleeding is in the skin, as in frame A of the picture(picture 4).

Wet purpura is the term used when there is extensive mucous membrane bleeding, as inframe B of the picture (picture 4).It is generally felt that the presence of wet purpura is the more serious, and is a prognostic signfor potentially life-threatening hemorrhage.

Ecchymoses Ecchymoses are nontender areas of bleeding into the skin, usually associatedwith multiple colors, due to the presence of extravasated blood (red, purple) plus the colors dueto breakdown of heme pigment by skin macrophages (green, orange, yellow). Ecchymoticlesions characteristically are small, multiple, and superficial. They usually develop withoutnoticeable trauma and do not spread into deeper tissues.

INITIAL APPROACH There is no substitute for an accurate history and physical examination.However, a platelet count that does not make sense within the context of the clinical pictureshould be repeated before extensive evaluation is undertaken. For extremely low platelet countsin symptomatic patients, such re-testing should be performed immediately; for asymptomaticpatients with modest reductions in platelet count (eg, 75,000 to 100,000/microL), testing may berepeated in one to two weeks, provided that the patient is advised to immediately report anychanges in clinical status during this interval.If, after initial evaluation and retesting, the cause of the thrombocytopenia is not apparent,

hematologic consultation is warranted.The general history Certain conditions associated with thrombocytopenia are obvious andcan be immediately recognized by the clinician:

Recent viral or rickettsial infection Previously diagnosed hematologic disease (eg, acute and chronic leukemias, chronic

myeloproliferative or myelodysplastic diseases) Nonhematologic diseases known to decrease platelet counts (eg, eclampsia, sepsis, DIC,

anaphylactic shock, hypothermia, massive transfusions) A positive family history of bleeding and/or thrombocytopenia Recent live virus vaccination

Poor nutritional status, especially in the elderly and alcoholics Pregnancy, especially late in the third trimester or at onset of labor (see below), but also with

a prior history of ITP or TTP-HUS, or with preeclampsia or eclampsia (see "Thrombocytopeniain pregnancy").

Recent organ transplantation from a donor sensitized to platelet alloantigens [21] Recent transfusion of a platelet-containing product in an allosensitized recipient (see

"Immunologic blood transfusion reactions", section on 'Posttransfusion purpura')


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Medications It is critical to review the list of ALL medications taken by the patient which mightbe associated with the development of thrombocytopenia (table 3A-C). This list should alsoinclude any over-the-counter and herbal products, quinine containing beverages, aspirin andnon-steroidal antiinflammatory agents. (See "Drug-induced thrombocytopenia" and 'Drugingestion' below.)

Recent travel Fever and thrombocytopenia in an adult or child with a history of recent travelmay indicate infection; malaria or dengue virus infection are common causes [26,27]. Other infections which may be associated with recent travel and thrombocytopenia includeleptospirosis, meningococcemia, rat-bite fever, rickettsial infections, hantavirus, and other viralhemorrhagic fevers (eg, Ebola, Lassa fever). (See "Clinical presentation and diagnosis of dengue virus infections", section on 'Laboratory findings' and "Evaluation of fever in thereturning traveler", section on 'Differential diagnosis'.)

The bleeding history Patients with a suspected bleeding disorder should be questioned aboutpast bleeding problems, a history of iron-responsive anemia, bleeding outcomes with surgicalprocedures and tooth extractions, history of transfusion, character of menses, and dietary habitsor antibiotic use which might predispose to deficiencies of vitamin K, vitamin B12, and folic acid.(See "Approach to the adult patient with a bleeding diathesis", section on 'Patient history' and"Preoperative assessment of hemostasis", section on 'Patient questionnaires'.)

Drug ingestion Medications may cause thrombocytopenia via induction of peripheral plateletdestruction or production of bone marrow aplasia or hypoplasia. Some drugs can alsoexacerbate an underlying platelet disorder. Examples include the platelet dysfunction inducedby aspirin and many other antiinflammatory drugs; and the co-ingestion of drugs that potentiatethe anticoagulant effects of warfarin. (See "Nonselective NSAIDs: Overview of adverse effects".)

The timing of onset of clinical bleeding or first recognition of the thrombocytopenia with use of medications should be explored in depth, since it may focus attention on the most likelyagent(s). Explicit questions about over-the-counter medicines, medicines taken irregularly or notprescribed by a physician (eg, medicines prescribed for a friend or a family member but takenby the patient), and herbal remedies are required, because patients are often reluctant to reporttheir use of these medicines. It is good practice to review each of the patient's medications for the possibility of drug-induced thrombocytopenia, especially if the drug has been recentlyintroduced and/or its side effects are not generally known.The spectrum of drugs reported as causing drug-induced thrombocytopenia is broadening andchanging progressively, reflecting changes in drug consumption. A complete list and analysis of all published reports of drug-induced thrombocytopenia is available [28]. (See "Drug-inducedthrombocytopenia", for a continuously updated table of drugs causing thrombocytopenia).

As an example, the list of thrombocytopenia-inducing agents in Denmark contains 110 differentdrugs (excluding cytotoxic drugs); 20 percent of reported cases concerned drugs not previouslylisted, and 25 percent were caused by drugs which appeared on the list only sporadically [29].Some of the most commonly cited agents causing thrombocytopenia include:

Heparin (see "Heparin-induced thrombocytopenia") Valproic acid


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Gold salts (see "Major side effects of gold") Quinine and quinidine Trimethoprim-sulfamethoxazole and other sulfonamides Interferons Measles-mumps-rubella vaccine

Glycoprotein IIb/IIIa inhibitors (eg, abciximab)

Hospitalized patients often do not know what medications have been prescribed

clinical manifestations and diagnosis of immune

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