Immune Thrombocytopenia and Posttransfusion Purpura

Howard A. Liebman

Douglas B. Cines

James B. Bussel

IMMUNE THROMBOCYTOPENIA

Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disorder characterized by thrombocytopenia with or without mucocutaneous bleeding manifestations. Because of its complex pathophysiology and association with a variety of other disorders, ITP is best characterized as a syndrome sharing the common clinical phenotype of immune-mediated thrombocytopenia.¹ While the clinical manifestations of ITP have been known for over a century, only in the last 20 years has our increased understanding of normal immune regulation led to better understanding of the pathophysiology of ITP involving aberrant interactions of antigen presenting cells, B lymphocytes, and regulatory thymic lymphocytes leading to increased platelet destruction and ineffective platelet production.²^,³ This new understanding has resulted in new therapeutic interventions with improved treatment outcomes, particularly for patients refractory to traditional therapies.

Definition and Epidemiology

ITP is an acquired disorder characterized by isolated thrombocytopenia with a peripheral blood platelet count <100 × 10⁹/L in the absence of any obvious other initiating or underlying cause, although ITP may be associated with other predisposing conditions (see “Secondary ITP”).⁴ This definition was the result of a recent consensus opinion by an International Working Group of ITP experts.⁴ Therefore, the diagnosis of ITP is one of exclusion and is based principally on patient history, physical examination, complete blood count, and review of the peripheral blood smear.⁵ Historically, the disorder was defined as either acute, with resolution of thrombocytopenia occurring within 6 months, or chronic persisting >6 months.⁵ Acute ITP was a disorder observed predominately in children and chronic ITP (CITP) in adults. However, the recent International Working Group in ITP consensus report has divided the disorder into three phases: newly diagnosed ITP with a duration up to 3 months, persistent ITP 3 months to 1 year, and CITP >1 year.⁴ During the time period encompassing newly diagnosed and persistent ITP, 85% of children and approximately 15% of adults will have a spontaneous remission. Spontaneous remissions are rare beyond a year.

ITP can be further characterized as either primary (idiopathic) or secondary to a number of associated disorders such as immunodeficiency diseases, autoimmune-rheumatologic disorders, lymphoproliferative diseases, and certain chronic infections.⁴ It is estimated that approximately 20% of ITP cases in the United States are secondary to other disorders.¹ However, the incidence of secondary ITP worldwide may vary greatly, particularly in populations with high incidence of human immunodeficiency virus (HIV), hepatitis C virus (HCV), or Helicobacter pylori (H. pylori) infection. There are few data on the incidence or prevalence of ITP in populations other than in North America and Europe. The prevalence of ITP in adults is significantly greater than that of children due to the chronic nature of the disease in adults. The incidence of newly diagnosed ITP in adults ranges from 1.6 to 3.9 per 100,000 persons per year.⁶^,⁷^,⁸ While older retrospective studies suggested a younger peak incidence for CITP in adult patients, more recent studies find an increased incidence and prevalence with advancing age.⁶^,⁷^,⁹ In nearly all studies, the female-to-male ratio ranges from 1.2 to 1.9, with the female predominance more evident among young to middle age adults.⁶^,⁷^,⁸^,⁹

Pathophysiology of ITP

Antiplatelet Autoantibodies

Harrington et al. were the first to provide experimental evidence that a plasma factor, later shown to be an antibody, was responsible for premature platelet destruction in ITP.²^,¹⁰^,¹¹ Early assays designed to detect platelet-bound antibodies were very sensitive, but had inadequate specificity. Using newer assays specific for platelet autoantibodies directed against specific platelet glycoproteins, such antibodies can be detected in 40% to 80% of patients with clinical ITP.²^,¹²^,¹³ However, absence of detectable antibodies does not rule out a diagnosis of ITP, since many patients without detectable antibodies respond to traditional ITP therapies and antibodies may occur in patients with liver disease and other conditions without clinical ITP.

The antigenic target for these antiplatelet autoantibodies are prevalent platelet glycoproteins such as platelet GPIIb/IIIa in nearly two-thirds of patients, platelet GPIb/IX in approximately 20% of patients and in the remaining patients, antibodies are directed against both of these platelet glycoprotein complexes or other platelet antigens.¹³ The B- and T-cell response against these common platelet glycoproteins can be directed against various antigenic sequences on same protein resulting in a polyclonal and polyspecific response. Also, antibodies against specific antigenic sequences on certain platelet glycoproteins may have different pathogenic properties. For example, a unique autoantibody observed in patients with HIV-associated ITP directed against platelet GPIIIa amino acid residues 49 to 66 appears capable of inducing platelet fragmentation by generating platelet superoxides, at least in vitro.¹⁴ As stated above, some patients with assumed ITP may not have detectable antibodies due to a misdiagnosis such as early myelodysplasia in an older patient; antibodies directed against a less prevalent platelet antigen; low titer of antibody; clearance of the autoantibodies
with treatment; or the thrombocytopenia resulting from T lymphocyte-mediated platelet cytotoxicity.¹⁵ In view of the variability of antibody detection in patients with suspected ITP, current guidelines do not recommend screening patients for platelet antibodies to make an initial diagnosis.

The spleen, in addition to being the major site of antibody-mediated platelet destruction, is a major site of autoantibody production as shown by in vitro studies where ITP splenic cells produced IgG that bound to platelets¹⁶^,¹⁷^,¹⁸ and megakaryocytes.¹⁹ Since in some ITP patients, autoantibody persists after splenectomy, there must be additional production sites, for example, bone marrow-derived B lymphocytes.²⁰

Role of the Thymic Lymphocyte in ITP

Production of autoreactive IgG against a protein antigen, like all immunoglobulin isotype-switched IgG antibody responses, is initiated by activated T helper cells that recognize their antigens on antigen presenting MHC class II positive dendritic cells (DCs) or macrophages.³^,²¹^,²²^,²³ DCs from patients with ITP have upregulated costimulatory molecules enhancing autoreactive T- and B-cell responses against platelets.³ The ongoing process of macrophage-mediated platelet destruction and further presentation of new platelet proteins to T and B lymphocytes contributes to the epitope spreading observed over time in patients with ITP and may contribute to a more refractory disease in patients with ITP of longer duration.¹

Adults and children with CITP have a serum cytokine profile (IL2/IL10/interferon gamma) suggesting a Th0/Th1 activation pattern.²⁴^,²⁵^,²⁶^,²⁷^,²⁸^,²⁹ Oligoclonal accumulation of CD4+ T helper cells that frequently use Vβ3, 6, 10 and 13.1 to 14 genes for their T-cell receptors have been found in the peripheral blood of patients with CITP by some investigators.³⁰ These studies suggest that CITP is accompanied by a loss of T lymphocyte tolerance against platelet antigens with the accumulation of abnormal T lymphocyte clones that can direct autoreactive B cells to differentiate and secrete IgG autoantibodies.³⁰ Recent studies have clearly demonstrated that ITP patients have significant defects in immune self-tolerance.¹^,³ Autoreactive cytotoxic CD8-expressing T lymphocyte clones capable of directly damaging platelets and possibly megakaryocytes have also been demonstrated¹⁵ and are likely to proliferate under the influence of similar T helper lymphocytes.

A distinct population of T lymphocytes, essential to maintaining peripheral self-tolerance, preventing autoimmune disease, and limiting chronic inflammatory diseases,³¹ termed Tregs, are usually reduced in number and/or function in patients with ITP.³²^,³³ Quantitative and qualitative defects in the Treg population appear to correlate with persistence of CITP. For example, an association between an improvement in the peripheral blood Treg number and function and remission induction with ITP treatment has been reported.³⁴

One of the many factors responsible for maintaining proliferation of B lymphocytes is B cell-activating factor (BAFF).³⁵^,³⁶ BAFF is a member of the tumor necrosis factor family and binds to several receptors, one of which, BR3 is important for B cell-dependent Th1 responses. BAFF mRNA is increased in patients with active ITP compared to healthy controls, and values return to normal during remission. Addition of BAFF to cocultures of ITP lymphocytes and platelets reduced apoptosis of both B and T lymphocytes in patients with ITP, but not in normal subjects.³⁷ Apoptosis was prevented by the addition of a soluble decoy of the BAFF receptor. Also, in cocultures of ITP platelets and ITP B cells, addition of BAFF increased platelet apoptosis, which was again ameliorated using the decoy receptor.³⁷

Suppression of Platelet Production

The dogma of ITP as exclusively a disorder of accelerated platelet destruction was challenged in the early 1980s by a number of investigators.³⁸^,³⁹^,⁴⁰ Using indium-111-labeled autologous platelets, these investigators found evidence not only of increased platelet clearance, but also impaired platelet production.³⁸^,³⁹^,⁴⁰ Recent studies have demonstrated inhibition of in vitro megakaryocyte growth and maturation by antibodies from some ITP patients.⁴¹^,⁴² Evidence that patients with ITP have autoreactive cytotoxic thymic (T) lymphocytes capable of directly lysing platelets suggests that these lymphocytes may also induce megakaryocyte injury and contribute to defective platelet production.¹⁵ While megakaryocyte numbers and appearance in bone marrow specimens appear normal in most patients with ITP when viewed under light microscopy, electron microscope studies of bone marrows from ITP patients show extensive damage in the majority of megakaryocytes.⁴³^,⁴⁴

Thrombopoietin (TPO) is the major physiologic regulator of megakaryocyte growth and differentiation.⁴⁵^,⁴⁶ TPO is synthesized and secreted by the liver and production is constant with no translational or posttranslational regulation.⁴⁷ When TPO is released into the circulation, most of the protein binds to TPO receptors on platelets and is cleared with the platelets with the remaining TPO binding to receptors on bone marrow precursors.⁴⁸ TPO levels are not increased above the normal range in the majority of patients with ITP and this observation provided the theoretical basis for treatment with TPO-receptor agonists.⁴⁵^,⁴⁸^,⁴⁹

Clinical Presentation and Natural History of ITP in Adults

Adult patients with ITP are more likely to manifest disease with a chronic course. Overall, approximately 15% of patients remit within a year after disease onset, but rare late remissions occur, even among patients who have failed splenectomy.⁷^,⁵⁰^,⁵¹^,⁵² While bleeding manifestations are the most common presenting symptoms in patients with ITP, the increased use of automated blood counts results in the frequent identification of asymptomatic patients or patients with minimal bleeding. Therefore, it is uncertain whether there is a period of mild-to-moderate thrombocytopenia in adults prior to the development of severe thrombocytopenia with bleeding. In a study of 217 healthy individuals with incidentally discovered thrombocytopenia and platelet counts between 100 × 10⁹/L and 150 × 10⁹/L, the 10-year probability of developing ITP as defined by platelet counts <100 × 10⁹/L was 6.9% (95% CI 4.0% to 12.0%). The 10-year probability of developing autoimmune disorders other than ITP was 12% (95% CI 6.9% to 20.8%).⁵³

Bleeding manifestations vary widely among patients. Mucocutaneous bleeding, including petechiae, purpura, epistaxis, and gum bleeding, is the most common initial manifestation. The feared complications of internal bleeding or fatal intracranial hemorrhage are rare and more likely to occur in older individuals with additional comorbidities.⁷^,⁵⁰^,⁵¹^,⁵² Symptomatic bleeding is to certain degree related to the platelet count, with nearly all major bleeding occurring with platelet counts under 30 × 10⁹/L.
Only in patients with hepatitis C-related thrombocytopenia does major bleeding appear to occur with some frequency at higher platelet counts.⁵⁴

The risk of bleeding and fatal hemorrhage in adults with severe CITP, defined as a platelet count of <30 × 10⁹/L at least 1 year following diagnosis, was analyzed in a pooled analysis of published clinical series comprising 1,800 patients.⁵⁵ The annual incidence of fatal hemorrhage was 1.6 to 3.9 cases per 100 patient years, with a lower risk in patients under 40 years of age (0.4% per year) compared to patients >60 years of age (13% per year).⁵⁵ The risk of nonfatal hemorrhage was estimated to be 3% per year in patients <40 years of age and 71% per year for patients >60 years of age. However, it should be noted that this case series dated from 1954 to 1991 and therefore, did not include patients treated with newer agents (rituximab, TPO receptor agonists) or managed with laparoscopic splenectomy that has a documented lower complication risk.

The prognosis of ITP in adults may be better than previously thought, with a majority of patients eventually obtaining a safe platelet count off treatment. In an Italian study of 310 children and adults (median age 40 years; range 8 to 87 years) with CITP, defined as a platelet count <150 × 10⁹/L 6 months after diagnosis, only 34 (11%) patients continued to have a platelet count under 30 × 10⁹/L with a median follow-up of 121 months (range 7 to 434 months); 19 of the severely thrombocytopenic patients were receiving no treatment.⁵⁶ Major bleeding occurred in 9 (3%) patients with only 1 fatal intracranial hemorrhage.⁵⁶ While only 26 (8%) patients who received medical therapy alone achieved a sustained complete remission, 125 patients were able to maintain a platelet count over 50 × 10⁹/L with low-dose prednisone or other treatments. Of the 109 patients who underwent splenectomy, 72 (66%) had a sustained response and 37 were either refractory or relapsed later.⁵⁶

A single institution study of 152 adult ITP patients accrued over a 20-year period reported a complete response (defined as a platelet count over 100 × 10⁹/L at 2 years off all treatment) in 90 (59%) patients and 114 (75%) had a platelet count >30 × 10⁹/L.⁵¹ Among the patients who had a complete response, 46/90 (51%) underwent splenectomy to obtain remission. Only nine of these patients had a relapse during an extended follow-up. Four patients with severe thrombocytopenia died during the first 2 years of observation. Only one patient died of a bleeding complication (intracerebral bleed) and three from infectious complications (two with gram-negative sepsis and one with cytomegalovirus pneumonia); all four of these patients were older than 65 years. Compared to the age-matched general population, the mortality risk in adults with ITP was estimated at 1.5% (95% CI 1.1 to 2.2).⁵¹ Patients with secondary ITP had a higher risk of dying of 6.0% (95% CI 2.5 to 14.5), most likely reflecting the morbidity and mortality associated with the underlying diseases. Patients with severe thrombocytopenia (platelets <30 × 10⁹/L) were more likely to require hospitalization, averaging 1.2 hospital admissions during the first 2 years following diagnosis.⁵¹

ITP diagnosed in elderly patients (age >65 years) is generally believed to be more refractory and associated with an increased risk of major bleeding, as well as higher mortality.⁵⁷ However, a recent retrospective single institution study of 178 consecutive elderly patients (age >65 years) presenting over a 17-year period appears to refute some of the earlier observations.⁵⁰ All patients had platelet counts <150 × 10⁹/L and clinical and bone marrow studies consistent with a diagnosis of ITP. One hundred twelve patients (63%) were not treated at presentation and 90 patients (50.6%), including 12 patients (6.8%) with platelet counts <50 × 10⁹/L, received no treatment for the duration of their follow-up.⁵⁰ Five untreated patients had a spontaneous complete remission. Eleven untreated patients developed other pathology during a median follow-up of 47 months (range 2 to 96 months). This included antiphospholipid antibody syndrome (APLS) (four patients); myelodysplastic syndrome (three patients); gastric lymphoma (one patient); rheumatoid arthritis (one patient); monoclonal gammopathy (one patient); and ovarian carcinoma (one patient). Therapy with low dose prednisone was initiated in 66 patients (37%) on presentation. The mean platelet count in these patients was 15 × 10⁹/L (range 1-43 × 10⁹/L). Within 1 month of treatment 49 patients (63.6%) increased their platelet count to over 50 × 10⁹/L, with 16 patients attaining a complete remission. Eighteen of the 49 patients (36.7%) relapsed during the period of follow-up.⁵⁰ Only one nonresponding patient died of intracerebral bleed. As in other studies, the risk of bleeding appeared to be greatest among the patients with platelet counts persistently <30 × 10⁹/L.³⁴

In a prospective analysis of 183 patients (25 children and 158 adults) treated with splenectomy during a 10-year period, 53 patients (29%) were refractory to this treatment.⁵⁸ The single significant clinical prognostic factor predictive of refractoriness to splenectomy was a platelet count below 50 × 10⁹/L 10 days after surgery (P < 0.001). Of the 53 patients, 6 were lost to follow-up; there after, 47 refractory patients (26.6%) were followed prospectively for a median of 7.5 years (5 to 15 years). Thirty seven refractory patients (77%) achieved a durable platelet count >100 × 10⁹/L, 9 without treatment and 27 with low-dose corticosteroids or azathioprine. Six patients (13%) continued to have moderate thrombocytopenia with platelet counts of 35 × 10⁹/L to 100 × 10⁹/L and five patients failed to respond to any treatment and had platelet counts <20 × 10⁹/L. Three of the five severely refractory patients died of bleeding.⁵⁸

McMillan and Durette⁵² reported on the long-term outcome of 114 adult patients who failed to obtain a stable platelet count >30 × 10⁹/L after splenectomy; 105 patients were available for long-term follow-up. With a median follow-up of 110 months, a majority of patients (71.4%) achieved a complete or stable partial remission with a median of 46 months. Thirty patients (29.6%) remained unresponsive to treatment, failing to obtain a platelet count over 30 × 10⁹/L. Eleven patients (10.2%) died of bleeding due to refractory thrombocytopenia. Six patients (5.6%) died of treatment-related complications, most often infection.⁵²

A systemic review of the literature on the efficacy of splenectomy in ITP reported a 64% complete durable response with a mean follow-up of 7.25 years (range 5 to 12.75 years) with few late relapses.⁵⁹ Therefore, extrapolating from the studies of Bourgeois et al. and McMillan and Durette, an estimated 95% of adult patients with ITP can achieve a safe platelet count when splenectomy is incorporated into the ITP treatment algorithm. Except in the highly refractory patients (persistent platelet counts <30 × 10⁹/L), the risk of fatal hemorrhage is quite low and morbidity appears to reflect a combination of nonfatal hemorrhage and treatment-related toxicities.

Clinical Presentation and Natural History of ITP in Children

The peak age of presentation of ITP in children is between 5 and 6 years with 70% of cases presenting between ages of 1 and 10 years.⁶⁰ Approximately 50% to 60% of children will have a febrile illness that preceded the discovery of thrombocytopenia. Numerous viral infections, including rubella, varicella, mumps, rubeola, and Epstein-Barr virus, as well as immunizations with MMR vaccine have been associated with the subsequent development of ITP in children.¹^,⁶⁰^,⁶¹^,⁶² As with adults, review of the blood smear is essential. Signs of mucocutaneous bleeding most often occur without other systemic symptoms and the child frequently does not appear ill.⁶³^,⁶⁴ Bleeding manifestations vary from little or none, to the typical findings of purpura, petechiae, epistaxis, and menorrhagia in older females.⁶³^,⁶⁴^,⁶⁵^,⁶⁶ Most children present with platelet counts under 20 × 10⁹/L.⁶⁶ In a study of 863 children with newly diagnosed ITP, no or mild bleeding manifestations were reported in 77% of patients, moderate bleeding occurred in 20%, and severe bleeding in 3%.⁶⁶ Life-threatening bleeding is rare and the estimated risk of intracranial hemorrhage is between 0.1% and 0.5% in newly diagnosed cases.⁶⁰^,⁶⁶^,⁶⁷ A retrospective systematic review of medical literature to ascertain the characteristics of children with intracranial hemorrhage in acute CITP found the median time to a hemorrhagic event from diagnosis was 32 days (range 0 to 8 years), with 72% occurring within the first 6 months and with 71.5% of the children having platelet counts <10 × 10⁹/L at the time of the bleed.⁶⁸

Most children have a spontaneous resolution of thrombocytopenia within weeks irrespective of treatment.⁶⁹^,⁷⁰ However, therapy may shorten the duration of severe thrombocytopenia. Approximately 65% to 70% of children remit by 6 months and another 15% to 20% by 12 months.⁶⁰^,⁷¹ Only 5% to 10% of children develop chronic disease. Children who develop CITP tend to be older, are more often female, and usually present with a higher platelet count.⁶⁹^,⁷⁰^,⁷¹^,⁷²^,⁷³ Severe or life-threatening bleeding manifestations are rare in children with CITP.⁶⁹^,⁷³

Diagnostic Approach to Patients with Suspected ITP

In almost all cases, a presumptive diagnosis of ITP can be made by a careful history, physical examination, complete blood count, and review of the blood smear.⁵^,⁷⁴ Response to initial treatment with corticosteroids, intravenous immunoglobulin (IVIG), or anti-RhD supports the diagnosis and confirms the immune nature of the thrombocytopenia. However, additional investigation is necessary to exclude secondary ITP and provide additional information to assist with patient management.

Patient history should be directed toward excluding non-immune disorders associated with thrombocytopenia, such as primary bone marrow disorders, active infection, cirrhotic liver disease with portal hypertension, drugs, and supplements. A careful drug history should be taken since a large number of medications have been associated with thrombocytopenia (see Chapter 62).⁷⁵ A family history of thrombocytopenia or a bleeding disorder may suggest inherited thrombocytopenia (see Chapter 63). A history of recurrent infections may suggest an underlying immune deficiency disorder that may be a contraindication to immunosuppressive therapy. A history of diabetes or psychiatric disorder may be a contraindication to high-dose corticosteroid treatment. Any constitutional symptoms such as fever, night sweats, or weight loss suggest an alternate diagnosis or a secondary cause of ITP.

Physical examination may reveal bleeding manifestations consistent with the severity of the thrombocytopenia, but should otherwise be normal. Finding splenomegaly, hepatomegaly, or adenopathy strongly suggests a diagnosis other than primary ITP. Some physical findings such as a malar rash or joint abnormalities may suggest that thrombocytopenia is secondary to an autoimmune-rheumatologic disorder.

A complete blood count should reveal isolated thrombocytopenia with normal white and red blood cell numbers. Anemia may exist if there has been significant bleeding and findings consistent with a microcytic anemia due to iron deficiency may exist in a female due to excessive menstrual blood loss. In patients with anemia, a reticulocyte count should be performed to determine whether anemia is due to recent blood loss or decreased red cell production. In some patients, concomitant autoimmune hemolytic anemia (Evan syndrome) may be diagnosed by finding an increased reticulocyte count, an elevated MCHC, and spherocytes on the peripheral blood smear.

A careful review of the peripheral blood smear is mandatory to exclude abnormalities in other cellular elements of the blood. Abnormalities in erythrocyte or leukocyte morphology may suggest an underlying bone marrow disorder, such as the myelodysplastic syndrome, or a congenital cause of thrombocytopenia. For example, the presence of a MYH9-related disorder may be suggested by finding leukocyte inclusion bodies. Many congenital thrombocytopenic disorders are associated with very large platelets (macrothrombocytopenia) that may also be reflected in an abnormally high mean platelet volume. Increased numbers of small lymphocytes may suggest a diagnosis of chronic lymphocytic leukemia (CLL) with secondary ITP. Increased numbers of lymphocytes with granular inclusions can suggest a diagnosis of large granular lymphocytic leukemia with secondary ITP. Pseudothrombocytopenia due to platelet clumping should be excluded: if platelet clumping is seen on the blood smear, a repeat platelet count using a blood sample collected in citrate or heparin rather than EDTA should be performed. Thrombocytopenia resulting from thrombotic thrombocytopenic purpura or hemolytic uremic syndrome must be considered if the blood smear shows significant numbers of schistocytes.

The International Working Group on ITP recommended a number of additional laboratory tests to further assist in the diagnosis and management of patients with primary ITP.⁷⁴ These recommendations are listed in Table 61.1. Bone marrow examination has been recommended in patients refractory to ITP-therapy or who relapse after an initial remission, patients with systemic symptoms or atypical physical findings, and prior to splenectomy.⁷⁴ A bone marrow aspirate and biopsy should be performed in patients older than 60 years and include cytogenetic studies and flow cytometry.⁷⁴

Three chronic infections are commonly associated with the development of secondary ITP and their identification and treatment may affect the clinical outcome.¹^,⁷⁴^,⁷⁶^,⁷⁷^,⁷⁸ Helicobacter pylori infection, as detected by either the urea breath test or stool antigen, is recommended in all patients with a presumptive diagnosis of ITP. If these tests are unavailable or if patients are receiving proton pump inhibitors for ulcer treatment or prophylaxis, serologic detection can be considered if the patient has
not received recent treatment with IVIG. Testing in children is not supported by the literature.⁷⁴

Table 61.1 International ITP working group consensus recommendations for the diagnosis of ITP in children and adults

Basic Initial Evaluation	Addition Studies of Potential Value	Studies of Unproven Benefit
Patient history	APLAs (patients with history of thrombosis or fetal loss)	TPO assay
Family history	TSH or antithyroid antibodies	Reticulated platelets
Medication history	ANA in children	Platelet-associated immunoglobulins
Physical examination	Pregnancy test in women of child bearing years	Serum complement
Complete blood count	Viral PCR for parvovirus and CMV (selected refractory, febrile or leukopenic patients)	Bleeding time
Quantitative immunoglobulins	Platelet glycoprotein-specific antibodies	Platelet survival studies
Blood group (Rh)
DAT
Helicobacter pylori
HIV
HCV
Bone marrow (in selected patients)
Adapted from Glanz J, France E, Xu S, et al. A population-based, multisite cohort study of the predictors of chronic idiopathic thrombocytopenic purpura in children. Pediatrics 2008;121:e506-e512.

Thrombocytopenia associated with infection with the HIV or the HCV can result in thrombocytopenia years before the development of viral-related symptoms. Thrombocytopenia associated with both viruses is indistinguishable from primary ITP and can response to standard ITP treatments. However, optimal treatment for HIV- and HCV-related thrombocytopenia should be directed toward treatment of the viral infection. Since both infections may be silent in early stages, screening for these infections is recommended regardless of patient background or reported lifestyle.⁷⁴ Patients should also be screened for hepatitis B infection since treatment with prednisone and/or rituximab may result in viral reactivation and fulminant hepatitis.

The international ITP working group recommends obtaining baseline immunoglobulin levels (IgG, IgM, and IgA). Low levels can be found in patients with common variable immunodeficiency, which is accompanied by a surprisingly high incidence of autoimmune complications including immune thyroid disease, autoimmune hemolytic anemia, and ITP.⁷⁹ Immune suppression in these patients should be avoided as should splenectomy, if possible. Selective IgA deficiency can also be associated with the development of ITP, with many patients lacking a history of recurrent or chronic infection. If required to treat ITP, these patients should receive IVIG preparations that are IgA depleted to avoid severe infusion reactions.

A direct antiglobulin test (DAT, direct Coomb test) should be considered if there is evidence of unexplained anemia associated with a high reticulocyte count. A positive DAT has been reported in up to 22% in patients with ITP, most often without overt evidence of hemolysis.⁷⁰ Therefore, it should also be performed along with red cell Rh typing in patients who are to be treated with anti-RhD, since the presence of a pretreatment antibody on the red cell could increase the risk of intravascular hemolysis.⁷⁴^,⁸⁰

Several other tests have been suggested in the consensus reports that may be of clinical utility in some patients (Table 61.1).⁷⁴ Screening for antiphospholipid antibodies (APLAs) (lupus anti-coagulant [LA], anticardiolipin [ACL] and anti-β₂-glycoprotein antibodies) should be considered in any patient with a prior history of thrombosis or fetal loss. While APLAs can be found in up to 40% of ITP patients, they have no apparent effect on the outcome of ITP treatment and the majority of patients with such antibodies do not develop clinical manifestations of the APLS.⁷⁶ Therefore, routine testing for these antibodies is not recommended unless there is a history suggestive of the APLS. A positive antinuclear antibody assay (ANA) may be present in 15% to 25% of patients with ITP, however independent of patients with clinical systemic lupus erythematosus, a positive test in primary ITP has not been shown to predict response to treatment or prognosis in adults.⁸¹ Therefore, an ANA test is not routinely recommended in adults. However, a positive ANA test may be a predictor of chronicity in childhood ITP.⁸²

Clinical hypo- and hyperthyroidism is reported in up to 20% of patients with ITP and antithyroid antibodies are present in nearly 40% of patients.⁸¹^,⁸³ Mild to moderate thrombocytopenia has been reported in patients with both hypothyroidism and hyperthyroidism and platelet counts return to normal when patients become euthyroid.⁸³ Also, patients with ITP and clinical hypo- or hyperthyroidism maybe refractory to standard ITP treatment and only become responsive when their thyroid disease is treated.⁸³ Therefore, it can be useful to screen refractory patients with an assay for thyroid stimulating hormone (TSH)
to rule out associated thyroid disease.⁷⁴^,⁸³ In selected patient populations, testing for antibodies to thyroglobulin or other thyroid antigens may identify patients at risk of developing clinical thyroid disease.⁷⁴

Secondary ITP

CITP has been classified either as a primary autoimmune disorder (idiopathic thrombocytopenic purpura) or as secondary to a number of underlying disorders.⁴ Common conditions associated with secondary ITP include immunodeficiency disorders, lymphoproliferative disorders, and chronic infection with HIV, H. pylori, and HCV.¹^,⁴^,⁷⁶^,⁷⁷^,⁸¹ Other autoimmune rheumatologic disorders are associated with secondary ITP, of which systemic lupus erythematosus (SLE) and APLS are the most common.¹^,⁴^,⁷⁶^,⁷⁷^,⁸¹

Systemic Lupus Erythematosus

Although laboratory evidence of autoimmunity, such as a positive ANA, is common in ITP, few patients are likely to develop SLE or related conditions.¹^,⁸⁴ The pathophysiology of ITP in SLE and APLS is similar to that of primary ITP and in most cases is mediated by antiplatelet glycoprotein autoantibodies. Decreased platelet production, as observed in primary ITP, may also be involved in the pathogenesis of ITP in patients with this secondary form of the disorder.¹^,³⁸

SLE is a systemic inflammatory disease that can affect any organ system, including the hematologic system, which is 1 of 11 criteria for diagnosis.⁸⁴ Hematologic manifestations include leukopenia, hemolytic anemia, and thrombocytopenia, any or all of which can be present at the onset of the disease or can develop later. Twenty to twenty-five percent of patients with SLE have platelet counts <100 × 10⁹/dL, although <10% of patients have platelet counts <30 × 10⁹/L.⁸⁵^,⁸⁶ A recent study from China reported an incidence of significant thrombocytopenia in SLE of 24.2%.⁸⁷ In patients with SLE, thrombocytopenia with platelet counts <100 × 10⁹/L is more prevalent when patients have high titer ACL antibodies.⁸⁸ However, it is unclear whether these patients also fulfill criteria for APLS.

Potential mechanisms for the pathogenesis of thrombocytopenia in patients with SLE include antibody-mediated platelet destruction by anti-GPIIb/IIIa and anti-GPIb/IX antibodies or antiplatelet glycoprotein autoantibodies that induce megakaryocyte apoptosis.² Lupus vasculitis, thrombotic microangiopathy, and hemophagocytosis are immunopathologic disorders associated with SLE in which platelets are destroyed secondary to a microvascular inflammatory process. Thrombocytopenia in these disorders reverses with correction of the primary process. There are no studies of plasma TPO levels in patients with SLE and thrombocytopenia, but it can be assumed that they are similar to those reported in patients with ITP.⁸⁹

A low platelet count in SLE can also result from mechanisms other than autoimmunity. These include drug-induced thrombocytopenia and infection. Antimalarial agents, commonly used to treat SLE, have been reported to induce thrombocytopenia, although recent data suggest improvement of platelet counts with hydroxychloroquine.⁶⁰^,⁹⁰ Infections with H. pylori, HCV, HIV, and other viral illnesses can further contribute to the risk of developing thrombocytopenia.¹ Two disorders associated with thrombocytopenia, Evans syndrome and Graves disease, are both reported to be more frequent in patients with SLE compared to the general population.²^,⁹¹ Thrombocytopenia in pregnant patients with SLE can result from the HELLP syndrome; in the postpartum period, SLE flares can add to the difficulty in diagnosis.⁹²

When patients with SLE have associated ITP, corticosteroids remain the primary treatment modality, although every effort should be made to switch to a steroid-sparing therapy to minimize the long-term exposure. Immunosuppressive agents such as methotrexate, azathioprine, leflunomide, dapsone, cyclosporine, mycophenolate mofetil, and cyclophosphamide are often used as disease modifying and steroid-sparing agents in SLE.⁹³ Each of these agents has also been used to treat patients with CITP.⁵^,⁵⁹ Several case series indicate that B lymphocyte depletion with rituximab, an agent with documented responses in refractory ITP, is also of clinical benefit in patients with refractory SLE.⁹⁴ Splenectomy, if possible, should be avoided, particularly in patients with active SLE who will require further immunosuppressive therapy and therefore be at risk of infection.

Antiphospholipid Antibody Syndrome

APLS is characterized by recurrent fetal loss and recurrent venous and/or arterial thromboembolic events.⁹⁵ In the most severe form, catastrophic antiphospholipid syndrome, multiple organ dysfunction occurs.⁹⁵ Although frequently associated with SLE, over half of the patients with APLS do not have clinical evidence of SLE.⁹⁶^,⁹⁷

Thrombocytopenia in association with APLS is more common in patients with SLE than in primary APLS (PAPS), although it is well described in both.⁹⁸ The reported incidence of thrombocytopenia varies between 22% and 42%.²^,⁹⁶^,⁹⁷^,⁹⁸^,⁹⁹ Thrombocytopenia in APLS tends to be less severe than that seen with ITP; platelet counts usually range from 70 to 120K and it does not usually require intervention.⁹⁹ Accordingly, it is less commonly associated with bleeding manifestations than ITP. APLS may present with isolated thrombocytopenia without other signs and symptoms. The presence of thrombocytopenia does not seem to affect the thromboembolic complications of the disorder, as rates of thrombosis are similar with and without thrombocytopenia.⁹⁶^,¹⁰⁰ While the findings of cardiac valvular vegetations and myocardial infarction are not associated with thrombocytopenia, there is a strong statistical association between valvular leaflet thickening and thrombocytopenia.⁹⁷ Chorea, arthritis, and livido reticularis, other clinical manifestations of APLS, are also associated with the presence of thrombocytopenia.⁹⁷

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