Immune Thrombocytopenia

I. What every physician needs to know.

Immune Thrombocytopenia (ITP) in the past has been called Idiopathic Thrombocytopenia Purpura and Immune Thrombocytopenic Purpura. The new nomenclature is reflective of the fact that this is an autoimmune disease. Furthermore, few patients demonstrate purpuric skin lesions. Until recently most cases of ITP were felt to be related to the production of antibodies with the resultant destruction of otherwise normal platelets which was more rapid than new platelet production. However, the success of the newer thrombopoietic agents point to the fact that ITP is also related to the inhibition of platelet production. In reality, ITP is a heterogeneous group of diseases that not only effects B-cells, but also, megakaryocytes and effective thrombopoiesis as well as T-cells.

ITP is now defined as a quantitative decrease in platelet count related to any immune process. When there is no secondary disease, it is known as primary ITP which accounts for 80% of cases. Common causes of secondary ITP are systemic lupus erythematosus (SLE), drugs, Hepatitis C, human immunodeficiency virus (HIV), Helicobacter Pylori, Chronic Lymphocytic Leukemia and other lymphoproliferative diseases, the Antiphospholipid Syndrome, vaccines (Measles/Mumps/Rubella [MMR] most commonly), and Common Variable Immunodeficiency Disease (CVID) as well as other viruses, post-transfusion purpura, and Evans syndrome. These secondary causes account for approximately 20% of cases of ITP.

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Proper nomenclature for secondary causes of ITP is, “secondary ITP” with the cause in parentheses, for example, secondary ITP (Helicobacter Pylori-associated). If a patient does not have clinical manifestations of the secondary disease but is instead a carrier of antibodies such as the antiphospholipid antibodies or antinuclear antibody (ANA), this is considered primary ITP.

ITP has been categorized into new onset for those diagnosed within the last 3 months, persistent for those diagnosed between 3 and 12 months, and chronic in those who have had the disease for greater than one year. Treatment options differ depending on these categories.

ITP tends to differ between adults and children. In adults the disease process tends to be insidious in onset without any precipitating factors and it tends to be chronic in duration. In children the course tends to be more self limiting with approximately 2/3 having complete remission. A large number of pediatric patients with ITP have an identifiable precipitating viral infection or an exposure to a vaccination (most commonly MMR). This chapter will be limited to a discussion of ITP in adults.

II. Diagnostic Confirmation: Are you sure your patient has Immune Thrombocytopenia?

ITP is largely a diagnosis of exclusion. All other causes for thrombocytopenia must be ruled out first in order to confirm that your patient has ITP. The only inclusion criterion is that the patient must have an isolated platelet count of less than 100,000 cells/microliter. Unfortunately, there is no single laboratory value that defines ITP.

A careful history and physical examination with carefully selected labs must be performed in order to rule out a potential competing diagnosis. The best assurance that the patient has ITP, is an adequate response to the treatment modalities administered.

A. History Part I: Pattern Recognition:

The typical patient with ITP presents with either asymptomatic thrombocytopenia or with a bleeding disorder. Rarely, the patient presents with a life-threatening gastrointestinal, genitourinary or intracranial bleed. Most commonly the patient will present with minor episodes of bleeding or increased bruising. Small pinpoint hemorrhages in the skin are known as petechiae and these usually present in dependent portions of the body or in mucosal gingiva. Areas with firm subcutaneous tissue such as the soles of the feet tend to be spared. When confluent, these lesions are called purpura. The purpura is not palpable.

Other common manifestations include: heavy menstrual bleeding, gingival bleeding, epistaxis, and easy bruising. Intra-articular hemorrhage is not common in ITP and is more indicative of a deficiency or inhibitor of hematologic clotting factors.

Patients who have thrombocytopenia with constitutional or B symptoms such as fevers, sweats, or weight loss should be evaluated for an alternative diagnosis such as HIV, a lymphoproliferative process, or an underlying infection or other malignancy. Further, the patient with ITP should not have bony tenderness or joint pain. A family history of low platelets is indicative of an inherited platelet disorder. A family history of bleeding disorders or easy bruising is unlikely.

B. History Part 2: Prevalence:

Not unlike most auto-immune diseases, ITP was felt to be a disease most prevalent in younger females. However, it is now known that it is also prevalent in an older population and it is equal in frequency amongst males and females in this older population. Since many patients are asymptomatic, there are probably a large number of undiagnosed patients; therefore the true incidence of the disease is not known.

C. History Part 3: Competing diagnoses that can mimic Immune Thrombocytopenia.

The most common competing diagnoses for primary ITP are those diseases that cause secondary ITP such as antiphospholipid syndrome, SLE, HIV, hepatitis C, medications, and lymphoproliferative diseases.

Some of the more common drugs that can cause a secondary ITP are the following: quinine which is also a flavor component of tonic water. Other drugs include sulfonamides, nonsteroidal anti-inflammatory drugs (NSAIDS), gold and vancomycin. Alemtuzumab and purine analogs may also cause ITP. The best proof that a drug is the inciting agent is a rapid rise in the platelet count, usually within 10 days of stopping the drug.

Heparin Induced thrombocytopenia (HIT) in patients who have not yet developed thrombosis share many of the same characteristics as ITP except that the patient has been exposed to heparin. Peripheral blood smear tends to show more clumping of platelets in HIT. Although HIT is immune-mediated this remains a separate disease entity.

HIV is a common cause for secondary ITP. HIV infection can present initially as thrombocytopenia. Alternatively, ITP can manifest in patients with acquired immunodeficiency syndrome (AIDS).

Evans syndrome is a form of secondary ITP whereby autoantibodies are directed against both red blood cells as well as platelets. These patients exhibit both hemolytic anemia and thrombocytopenia. In Evans Syndrome the red cell antibody is directed at the Rhesus (Rh) locus and may appear indistinguishable from the hemolytic anemia in patients who have received intravenous (IV) anti-D treatment. Elution studies can help to differentiate the source of these antibodies.

Although hepatitis C can cause thrombocytopenia from ITP, thrombocytopenia may arise from other mechanisms including but not limited to: decreased production of thrombopoietin, infection of megakaryocytes and, hence, decreased production of platelets, or splenic sequestration.

Myelodysplastic syndrome usually affects other cell lineages but patients may be limited to thrombocytopenia only. Other lymphoproliferative diseases including leukemias, myelofibrosis, and aplastic anemia may cause secondary ITP or thrombocytopenia secondary to bone marrow infiltration. Acquired pure megakaryocytic aplasia is rare but clinically distinguishable by the absence of bone marrow megakaryocytes.

Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic Uremic Syndrome (HUS) may only have mild anemia and thrombocytopenia which can be confused with ITP in patients who have combined ITP and severe iron deficiency anemia. In mild forms of TTP or HUS the physician may falsely attribute the anemia to intermittent bleeding secondary to the low platelet counts from ITP. A large number of schistocytes associated with the hemolytic process should be seen in the former disease processes.

One must rule out thrombocytopenia secondary to an acute viral infection (to include CMV, varicella, EBV, rubella) or sepsis with or without Disseminated Intravascular Coagulopathy (DIC).

Patients with unidentified cirrhosis might not always be identifiable through careful physical examination. Further, patients who consume large quantities of alcohol may suffer myelosuppression that may in fact be limited to thrombocytopenia.

Patients who require large volume red blood cell (RBC) transfusions may develop a thrombocytopenia secondary to the dilutional effects of the transfusion. Alternatively, they may develop a secondary form of ITP with or without purpura.

Patients with inherited thrombocytopenia often have an uneventful history and unremarkable physical exam not unlike ITP which emphasizes the importance of looking at trends in platelet counts. Prior platelet counts can be invaluable in distinguishing inherited from acquired thrombocytopenias.

Pseudothrombocytopenia secondary to Ethylenediaminetetraacetic acid (EDTA) within collecting tubes might look like ITP. One can order a citrated platelet count to help better differentiate.

Thrombocytopenia secondary to pregnancy, also known as, gestational thrombocytopenia occurs in up to 5% of females near the end of pregnancy. The platelet counts usually remain greater than 70,000 and spontaneously resolve after delivery. Other more serious causes of thrombocytopenia in pregnancy need to be excluded: eclampsia, hemolysis elevated, liver enzymes, and low platelets (HELLP) syndrome, and Disseminated Intravascular Coagulopathy (DIC).

Rarely, disorders of platelet production secondary to either B12 or folate deficiency may mimic ITP.

D. Physical Examination Findings.

Patients generally have a normal physical examination except for possible bleeding manifestations related to the low platelet count. Common manifestations are petechiae, purpura, and gingival bleeding.

Splenomegaly might suggest underlying cirrhosis with splenic sequestration of platelets. The platelet volume remains normal but platelets are sequestered within the spleen. Further, one should look for other stigmata of underlying liver disease to include: palmar erythema, spider telangiectasias, gynecomastia, and testicular atrophy. Alternatively, splenomegaly in patients with thrombocytopenia might be indicative of an underlying lymphoproliferative process, an underlying viral infection (cytomegavirus [CMV], HIV, hepatitis, parvovirus), bacterial endocarditis, other infections, or an autoimmune process including SLE.

Lymphadenopathy might be suggestive of an underlying lymphoproliferative disease, HIV, underlying infection or malignancy.

E. What diagnostic tests should be performed?

A careful history and physical should always be performed.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

All patients should have a peripheral blood smear examined. On peripheral smear one would expect to see a quantitatively small number of platelets that tend to be larger in size without any evidence of clumping. These relatively large sized platelets tend to be younger and more hemostatically active and thus, major life threatening bleeding tends to be very rare as compared to other diseases with thrombocytopenia. Thus, clinically apparent bleeding is rare in those whose platelet counts are greater than 10,000 cells/microliter. Extremely large platelets would raise the suspicion of an inherited genetic cause for thrombocytopenia.

In ITP other cell lineages are preserved with the exception of some patients who have an apparent reason to have iron deficiency anemia, as they may have hypochromic and microcytic red blood cells. Other abnormalities on peripheral smear may point to other causes for thrombocytopenia. Schistocytes and other fragmented cells raise the suspicion of a hemolytic process to include but not limited to Thrombotic Thrombocytopenic Purpura, Hemolytic Uremic Syndrome, DIC, and HELLP syndrome. Hypersegmented neutrophils can point toward an alternative diagnosis of B12 or folate deficiency.

A bone marrow examination is not routinely required. However, it should be considered in the presence of other unexplained cytopenias, suspected dysplasia, concern for malignancy, or uncertainty about the diagnosis. On bone marrow evaluation one typically sees an increase in megakaryocyte number without any other marrow abnormalities.

As the treatments are different for those with secondary ITP, consideration should be given to testing all patients for HIV, hepatititis C, and Helicobacter Pylori. Eradication of Helicobacter pylori especially in countries with a high prevalence of Helicobacter pylori has been shown to reverse the thrombocytopenia, and thus, testing for Helicobacter Pylori should be done through fecal antigen testing, carbon 13 breath testing, or via gastric biopsy. Routine Helicobacter pylori antibody screening is not indicated.

Many patients with primary ITP manifest anti-nuclear antibodies as well as antiphospholipid antibodies including anticardiolipin antibodies and lupus anticoagulant with a small number going on to develop SLE or antiphospholipid Syndrome. However, routine antibody testing when patients do not meet clinical criteria for these diseases remains controversial and does not affect the disease management.

Quantitative immunoglobulins should be obtained to rule out Common Variable Immunodeficiency Disease or isolated immunoglobulin A (IgA) deficiency. Further, it can effect treatment options as one needs to carefully use immunosuppression agents in patients with CVID.

Rh blood type and direct antibody testing (Coomb’s testing) needs to be obtained especially when the use of Intravenous anti-D is considered (as hemolytic anemia is a known complication of this therapy). Hepatitis B surface antigen and antibody testing should be performed in patients being considered for Rituximab as this therapy can result in reactivation of hepatitis B.

All females of childbearing age should receive pregnancy testing.

Patients with other signs of infection should undergo appropriate workup to include ruling out DIC when indicated. Parvovirus and CMV can cause isolated thrombocytopenia and consideration for polymerase chain reaction (PCR) testing in select patients should be considered.

Any patient with potential exposure to heparin should be ruled out for Heparin Induced Thrombocytopenia with antibody testing to platelet factor-4.

Antithyroid antibody testing and thyroid function should be obtained in patients with ITP as approximately 10% of patients with ITP develop clinical hyperthyroidism when followed over the course of time.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

No imaging tests are required to establish the diagnosis.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Ordering anti-platelet antibodies is not sensitive or specific for the disease entity and do not change the diagnosis, prognosis, or treatment and thus, is not recommended. Antibodies are detected in less than 60% of patients. Thrombopoietin levels add little value to treatment efficacy even when anti thrombopoietin agents are used. Bleeding times and tests of platelet function add little value.

III. Default Management.

Priority needs to be given to those with a life threatening bleed or those patients who have a low platelet count and in need of emergent surgical intervention.

A. Immediate management.

For the patient with a life threatening bleed secondary to a gastrointestinal, genitourinary or central nervous system (CNS) hemorrhage, one would provide basic life sustaining supportive treatment as indicated. In the event of altered level of consciousness from an intracranial bleed or if the patient lacks airway protection from a large gastrointestinal bleed, endotracheal intubation may be indicated. The hypotensive patient who is actively bleeding will need RBC transfusions in order to maintain oxygen delivery capacity. Consultation with clinical hematology should be considered for all patients with ITP.

Platelet transfusions are generally contraindicated in ITP (due to their rapid destruction by the underlying auto-immune process). However, transfused platelets may provide at least temporary hemostatic benefit in the event of serious or life-threatening bleeding. One of the early goals will be to raise platelets to an adequate level to prevent bleeding and thus, platelets should be transfused in order to maintain a platelet count of at least 50,000. Although one would expect rapid consumption of platelets post-transfusion, clinical experience suggests such patients may gain clinical benefit for hemostasis. Slowing the rate of platelet transfusion may extend their hemostatic effect.

Medications that should be considered acutely are intravenous immunoglobulin (IVI) as 1gram/kilogram (g/kg) as a one time dose; alternatively, many will prescribe 1-2g/kg in divided doses over 3 to 5 days alongside intravenous methylprednisolone (1g) daily for 3 days. Alternatively, intravenous anti-D (75 micrograms/kg) may be used (in non-splenectomized, RH+ patients). Both IVIG and intravenous anti-D show an initial response within 1-3 days. Alternatively, one may consider antifibrinolytic agents such as aminocaproic acid (1-4g every 4-6hours) or transexamic acid (1g, 3 times daily orally) which are extremely effective in controlling oral bleeding or epistaxis, but the data supporting its efficacy in ITP is limited.

Other procoagulant therapies such as recombinant factor VIIa and/or immune therapies might be considered in consultation with a clinical hematologist.

Emergent splenectomy can be used as a last effort keeping in mind the effects of unplanned surgery, the high risk of bleeding in a patient whose bleeding otherwise couldn’t be controlled, and high infection rate given the lack of time for immunization. Progestational agents may be needed to manage menorrhagia. Any agent that can cause bleeding such as NSAIDS, aspirin, warfarin and other anticoagulants, clopidogrel and other anti-platelet agents should be discontinued at the time of admission. Use of vitamin K in those who have prolonged prothrombin time or protamine in those patients on heparin may be considered. Emergent plasmapharesis is not indicated for ITP.

Patients who may need to undergo emergent surgery may also need immediate treatment in order to ensure that the patient has an adequate platelet count for surgical hemostasis.

B. Physical Examination Tips to Guide Management.

As the patient with ITP ordinarily has a normal physical examination, the physical examination does not guide treatment options. However, in the patient with active bleeding, the hospitalist will need to assess the severity of the bleed to determine how aggressively to treat in order to control the bleeding source. Resolution of bleeding and hemodynamic stability will indicate successful immediate management.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Adequate response to treatment can be monitored by showing that bleeding has stopped and that the patient has reached their target platelet count. Patients with severe bleeding who have not reached an adequate platelet count to ensure hemostasis may benefit from repeat platelet transfusions as frequently as every 30 minutes.

D. Long-term management.

The major goal of treatment is to ensure an adequate platelet level in order to prevent a significant or life-threatening bleed. Although not evidence-based, treatment consideration usually begins when the platelet count falls below 30,000 cells/microliter or higher in the event of active bleeding or prior to surgical intervention. However, one always needs to weigh the risk and benefits of potential treatments in accordance with the patient’s wishes and life style.

Although not in the guidelines, asymptomatic patients with lower counts may be carefully followed as major bleeding usually does not occur until the platelet count falls below 10,000 cells/microliter. One can consider “on demand” treatment for when the patient is at higher risk of bleeding episodes, e.g., prior to surgical intervention. However, one must be aware that there is currently no validated tool to assess bleeding risk. Patients who are highly engaged in contact physical activities are at higher risk of bleeding with asymptomatic thrombocytopenia.

Patient’s other co-morbid diseases may impact treatment options as patients with hypertension may be at higher risk for an intracranial bleed. Patients who are greater than 60 years of age are also at much higher risk for bleeding and may require more aggressive treatments. Other co-morbid conditions that are suggestive for a higher risk of bleeding may need more aggressive treatments such as a history of a prior bleed, hypertension, peptic ulcer disease cerebrovascular disease and other disorders which require the patient to be on anti-platelet agents or anticoagulation.

Other factors in choosing therapy include cost and long-term convenience of the treatment. ITP can be a challenging disease to treat as many patients will experience multiple relapses and can become less responsive to standard therapies.

Unfortunately, it is difficult to assess the effectiveness of one treatment as compared to another as most studies have used different definitions to define a successful response. Henceforth, standard terms have been established by an International work group (Vicenza Consensus Conference).

A complete response is defined as a platelet count greater than 100,000 cells/microliter after treatment measures on two successive occasions at least 7 days apart without any evidence of bleeding. A partial response is a platelet count between 30,000 and 100,000 cells/microliter to include at least a doubling in the number of platelets on two occasions at least 7 days apart without any evidence of bleeding. Duration is the time from complete or partial response to the loss of such response. Severe ITP has been defined as patients with ITP and bleeding that requires new or escalation of treatment. Refractory ITP is defined as severe ITP after splenectomy.

Glucocorticoids remain the standard, first-line therapy for ITP. Traditionally, prednisone has been used and most commonly dosed at 1 mg/kg with the latest evidenced-based clinical guidelines recommending treatment for 21 days followed by tapering. There are no standard recommendations on how to taper, but generally, the tapering should be gradual (often over weeks).

High dose intravenous methylprednisolone (15 mg/kg/day) for 3 days followed by prednisone on days 4-21 may be considered especially for those who fail standard steroid management or those with emergent bleeding. When a more immediate increase in platelet count is required, IVIG (1 -2 gm/kg) over 3-5 days in addition to steroids should be considered. IVIG as single drug therapy or intravenous anti-D (for patients with a spleen who are Rh+) are first line treatments in patients where steroids are contraindicated. Steroid dependence is defined as the need for ongoing or recurrent treatments with prednisone in order to maintain a response. The goal of first line therapy tends not to be a cure or remission but rather to maintain a safe platelet count that will prevent bleeding while minimizing the side effects of the medications.

Second line treatment options include: rituximab, thrombopoietin agonists, splenectomy, danazol or other immunosuppressive agents to include azathioprine, cyclosporine A, cyclophosphamide, mycophenolate mofetil, dapsone and vinblastine. In rare circumstances, a hematopoietic stem cell transplantation may be considered for chronic, refractory ITP.

Rituximab is an anti-CD20 monoclonal antibody which may kill B cell clones producing the autoimmune antibody. Rituximab (375 mg/meter2 [mg/m2 ]) weekly for 4 weeks may be considered with or without short term dexamethasone for second line therapy. One study showed a higher response rate with the addition of rituximab than in a dexamethasone alone group. One problem with this study is that it is not entirely clear how rituximab and short term dexamethasone compare with long term standard prednisone treatment. Alternatively rituximab may be considered as single drug therapy in any patient who fails first line treatment. Another study looked at adult ITP patients who were treated with rituximab (375 mg/m2 weekly for 4 weeks) and followed for a mean of 82 months. This group demonstrated a long-term response rate of approximately 40%.

Splenectomy remains the treatment with the highest likelihood of sustained remission. Up to 66% of patients may have a durable response. Splenectomy is recommended for patients who have failed first line treatments with steroids. (However, given that splenectomy is not necessarily curative and can have significant side effects, some would reserve this intervention for patients who are refractory to other treatments.) Open and laparoscopic splenectomy appear to have similar effectiveness but laparoscopic procedures have slightly lower associated morbidity and mortality.

Splenectomy removes the site at which antibody covered platelets are trapped and destroyed. Further, as the spleen contains lymphoid tissue, splenectomy likely results in decreased anti-platelet antibody production. Most defer surgery for 6 months after diagnosis of ITP is made. Platelet count should be at least 50,000 cells/microliter prior to the procedure. Splenectomy may fail in some patients who have an accessory spleen. Other patients may grow an accessory spleen secondary to cells that are not removed or shed at the time of surgery.

The thrombopoietin agonists such as romiplostim and eltrombopag are the most recent therapeutic options that may be considered for ITP. They may induce significant remissions, however, they must generally be continued in order to sustain desirable platelet counts.

At this time, the choice between rituximab, the thrombopoieten agonists, or splenectomy remains a patient-centered decision based on cost, convenience, lifestyle, and varying surgical risk based on co-morbidities.

Recommendations for patients who are about to undergo minor surgery, including complex dental extractions, should have a platelet count greater than 50,000 cells/microliter, for major surgery greater than 80,000 cells/microliter, and greater than 100,000 cells/microliter for neurosurgery.

E. Common Pitfalls and Side-Effects of Management.

Steroids have many common complications including: osteoporosis, diabetes, hypertension, weight gain, psychosis and depression. Other serious side effects include adrenal insufficiency upon discontinuation, risk of infection and reactivation of tuberculosis, and myopathy.

Intravenous anti-D has a risk of severe hemolysis and thus, should be avoided in patients who are Coomb’s test positive. Patients need to be Rh-positive. It is contraindicated in patients who have had a splenectomy. Patient’s who need transfusions after receiving this medication should receive only Rh(D) negative blood in order to avoid hemolysis. Symptoms of severe hemolysis include: fever, rigors, back pain and may result in acute kidney injury, DIC, or death. The drug is cheaper than IVIG and easier to administer. Other severe side effects include: thrombotic events, and transfusion related acute lung injury.

Intravenous immunoglobulin may cause the following serious side effects: renal failure, anaphylaxis, hemolysis, transfusion related acute lung injury, pulmonary edema and thrombosis.

Splenectomy patients run the life-long risk of severe sepsis especially with encapsulated organisms such as Streptococcus pneumoniae, Neiseria meningitidis, and Haemophilus influenzae. Lifelong antibiotic prophylaxis is not warranted. One needs to consider basic surgical complications to include the associated risk of anaesthesia, infections, bleeding, adhesions, and deep vein thrombosis or pulmonary embolism. Patients should be immunized with both the pneumococcal and meningococcal vaccines 2 weeks prior to surgery if possible. Haemophilus influenza type b is not contraindicated prior to surgery.

Chronic complications due to splenectomy may include atherosclerosis, pulmonary hypertension, and immunodeficiency. Patients may consider wearing bracelets that state that they are asplenic. Patients may be given home antibiotics for prophylaxis in the event of a fever.

The immunosuppressive agents run the risk of infection, lymphoproliferative and other malignancies, hypertension, and liver toxicity as well as other drug specific complications that will not be discussed here.

Thrombopoietin receptor agonists can cause immediate rebound in thrombocytopenia upon discontinuation and thus, need to be used life-long. There is a possible risk of portal vein thrombosis with eltrombopag especially in patients with underlying liver disease. Both agents have shown an increase in marrow reticulin and thus the theoretical risk of fibrosis. Neither agent has been shown to cause other major thrombotic events; however, these drugs are relatively new.

Romiplostim was associated with a transient but reversible rise in circulating blasts but to date there is no increased risk for leukemic transformation and thus it carries a warning that it may increase the progression of myelodysplastic syndrome (MDS). Eltrombopag has a black box label warning calling for monitoring of liver function tests. Eltrombopag has been shown to cause cataracts in rodents and thus, ophthalmic examinations may be advisable. As thrombopoietic agents are growth hormones they can theoretically increase the risk of progression of malignancies.

Rituximab may cause progressive multifocal leukoencephalopathy. The drug is a potent immunosuppressive drug. Severe effects may include respiratory distress secondary to bronchospasm, anaphylaxis, pulmonary embolism, serum sickness, renal artery thrombosis, fatal mucocutaneous skin reactions, bowel obstruction or perforation, tumor lysis syndrome and infection. Overall it has fewer side effects than splenectomy. It is contraindicated in patients with active hepatitis B. It may cause fatal renal toxicity in patients with hematologic malignancies.

IV. Management with Co-Morbidities.

Pregnant patients with ITP, if treatment is warranted, still receive steroids as first line therapy with or without IVIG depending on the necessity for a rapid increase in platelet count. Alternatively, intravenous IVIG or intravenous anti-D may be considered as alternatives. Steroids may cause the additional risk of gestational diabetes and postpartum depression.

If required, splenectomy is safest during the second trimester. Patients in the first trimester are at increased risk of preterm labor and those in the third trimester present a technical challenge to the surgeon. Rituximab has been used to treat non-Hodgkins lymphoma in pregnant patients and may be considered for second line therapy.

The method of delivery should be tailored according to the obstetrical indication and platelet counts should be at least 50,000 cells/microliter prior to delivery in order to allow for Cesarean section. The disease should be treated in close consultation with Hematology and High-risk Obstetrics. Because pregnancy is a procoagulant state, these patients may in part be protected from the bleeding complications of ITP. There is no indication to monitor fetal platelet counts.

Neonates are at increased risk for thrombocytopenia as a result of the anti-platelet antibodies crossing the placenta. Treatment of the mother does not alter the incidence of neonatal thrombocytopenia. However, neonates have extremely low rates of severe bleeding. Such neonates should be treated by a neonatologist who may order cord blood platelet count and a transcranial ultrasound. Neonates with severe bleeding may benefit from a single dose of IVIG (1g/kg).

A. Renal Insufficiency.

Patients with severe renal disease have impaired platelets or uremic platelets and thus, may be at increased risk of bleeding with higher platelet counts. If uremic platelets are suspected then one may consider using desmopression or conjugated estrogens.

Placement of any renal catheters would be considered a minor surgical procedure and thus, a platelet count of 50,000 cells/microliter would be desirable.

IVIG should be avoided in patients with a creatinine clearance < 10 ml/min, and should be used in caution with patients with renal insufficiency.

B. Liver Insufficiency.

Patients with hepatic insufficiency may have decreased production of clotting factors and thus, they may be at increased risk of bleeding in comparison to others without hepatic insufficiency with similar platelet counts. Platelet counts may be decreased secondary to other factors including decreased production of thrombopoietin or a stunned marrow in those who have hepatic disease secondary to the effects of alcohol. Low platelet counts may also be secondary to splenic sequestration.

In patients with active hepatitis B, rituximab is contraindicated. Patients with hepatitis C may have an increase in platelets with antiviral treatment to include ribavarin and interferon with or without bocepravir. As ribavarin can cause severe thrombocytopenia it is contraindicated in patients with platelet counts less than 75,000 cells/microliter. Steroids are contraindicated in patients with hepatitis C as it can cause an increase in viral load. IVIG and intravenous anti-D when not contraindicated are first line options. Alternatively these patients can undergo splenectomy.

C. Systolic and Diastolic Heart Failure.

IVIG should not be used in decompensated heart failure. Rituximab and prednisone can cause an increase in edema and thus, worsening of congestive heart failure symptoms.

D. Coronary Artery Disease or Peripheral Vascular Disease.

Most patients with coronary artery disease (CAD) or peripheral vascular disease (PVD) will require anti-platelet agents chronically and thus, may be at increased risk of bleeding with ITP. Further, such patients may require an intensified anticoagulation regimen in the event of an acute crisis.

Rituximab and IVIG should be used with caution in patients with CAD. IVIG can increase the risk of thrombotic events. Prednisone may increase the risk of myocardial rupture.

Prior to splenectomy, a thorough pre-operative evaluation should occur.

E. Diabetes or other Endocrine issues.

IVIG should be used with caution in patients with diabetes as it may precipitate renal failure. Steroids can cause worsening of hyperglycemia. Rituximab may cause hyperglycemia or alternatively, it can enhance the effect of hypoglycemic agents and cause hypoglycemia.

F. Malignancy.

Rituximab can precipitate tumor lysis syndrome in certain lymphoid malignancies. The thrombopoietin receptor agonists which are growth factors, may cause progression of cancer.

Many patients with malignancy will have imbalances in their procoagulant state versus their risk for bleeding. IVIG can increase the risk of thrombosis.

G. Immunosuppression (HIV, chronic steroids, etc).

Patients with ITP secondary to HIV may have a complete response with highly active antiretroviral therapy (HAART). Steroids do not worsen the viral load in HIV; however, caution needs to be exercised in those with low CD4 counts as it can cause reemergence of opportunistic infections and reactivation of tuberculosis. For patients with HIV, steroids with or without IVIG, IVIG as single drug therapy or intravenous anti-D are first line options. Splenectomy is an effective treatment for patients who fail first line therapy. These patients should be co-managed with a specialist in infectious diseases.

Patients with CVID may be treated with high dose IVIG followed by lifelong maintenance dosing (0.3- 0.4 g/kg every 3-4 weeks).

IVIG, rituximab, and prednisone may all increase the risk for serious infections.

H. Primary Lung Disease (COPD, Asthma, ILD).

IVIG is associated with exacerbation of asthma and rituximab should be used with caution in patients with underlying respiratory problems. Patients with severe COPD may already be exposed long term to the detrimental toxic effects of steroids and thus, one may consider shortening the exposure of steroids as much as possible.

I. Gastrointestinal or Nutrition Issues.

As noted above all patients should be screened for Helicobacter Pylori and treated appropriately if screening is positive.

Patients with prior history of gastrointestinal bleeds secondary to peptic ulcer disease, esophageal varices, hemorrhoids, diverticulosis, malignancy or any other pathologic cause may be at increased risk of bleeding with ITP. In the event of a new bleed, these patients need to be treated as any other patient with a gastrointestinal bleed would be treated and as such one may consider both upper and lower endoscopy for both diagnostic and therapeutic purposes.

Prednisone can increase the risk of perforation in patients with underlying diverticulosis, peptic ulcer disease, and ulcerative colitis. Rituximab can cause bowel perforation and thus, acute abdominal pain needs to be thoroughly evaluated in patients taking Rituximab.

J. Hematologic or Coagulation Issues.

In all patients on anticoagulation, one always needs to weigh closely the risks of bleeding versus the benefits of the treatments especially as the platelet counts become lower. IVIG and intravenous anti-D may both cause a hemolytic anemia. Intravenous anti-D is contraindicated in patients who are Coomb’s positive.

K. Dementia or Psychiatric Illness/Treatment.

Steroids may exacerbate or cause psychosis or depression.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

One must check the complete blood count (CBC) as frequently as needed in a patient who is actively bleeding in order to ensure that their need for transfusions is being met. Patients may need to be transfused so that oxygen delivery capacity meets oxygen requirements. Those patients who are symptomatic with acute coronary syndrome or acute stroke will have a higher transfusion threshold which will be institution dependent. If the patient’s bleeding intensifies see emergency management above.

B. Anticipated Length of Stay.

Patients are usually hospitalized if they have either bleeding or an arbitrarily extremely low platelet count usually less than 10,000 cells/microliter or slightly higher if the patient has risk factors for bleeding or needs an immediate surgical intervention. Most other cases of ITP can be managed as an outpatient. One would expect an adequate rise in platelet counts that can control bleeding within 3 days.

C. When is the Patient Ready for Discharge.

Patients will be ready for discharge after the bleeding has stopped and their platelet count has risen to an adequate level to ensure further protection from bleeding usually greater than 50,000 cells/microliter.

D. Arranging for Clinic Follow-up.

This disease entity can be primarily treated as an outpatient.

1. When should clinic follow up be arranged and with whom.

The Hospitalist should ensure that the patient is seen by a hematologist within 1 week of discharge with a follow-up CBC.

2. What tests should be conducted prior to discharge to enable best clinic first visit.


3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

CBC looking at both the platelet count as well as hemoglobin level.

E. Placement Considerations.

This would be dependent on other co-morbid conditions.

F. Prognosis and Patient Counseling.

The disease is one that has an extremely high relapse rate. Risk of mortality depends greatly on age and co-morbidity status.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

There are no Joint Commission Core indicators that are referable to this Disease.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

All patients with ITP when not contraindicated should undergo vaccination against Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae as a large number of these patients will eventually need to undergo splenectomy.

Patients will need to be educated as to all signs and symptoms of bleeding. Minor manifestations of bleeding such as menorrhagia, petechiae, purpura, and bruising should be reported to their primary care physician immediately. Patients with more significant bleeding to include melena, bright red blood from rectum, large genitourinary bleeds or those with chest pain, dyspnea, or signs of a stroke will need to be instructed to report to the nearest Emergency Department immediately.

VII. What's the evidence?

Andemariam, B, Bussel, J. “New therapies for immune thrombocytopenic purpura”. Current Opinion in Hematology. vol. 14. 2007. pp. 427-431.

Cines, D, Bussel, J, Liebman, H, Prak, E. “The ITP syndrome: pathogenic and clinical diversity”. Blood. vol. 113. 2009. pp. 6511-6521.

Cuker, A, Cines, D. “Immune thrombocytopenia”. Hematology. vol. 2010. 2010. pp. 377-384.

Handin, R, Kasper, D. “Disorders of the Platelet and vessel wall”. Harrison's Principles of Internal Medicine. 2005. pp. 673-676.

Neunert, C, Lim, W, Crowther, M. “the American Society of Hematology 2011 evidenced-based practice guideline for immune thrombocytopenia”. Blood. vol. 117. 2011. pp. 4190-4207.

Provan, D, Stasi, R. “International concensus report on the investigation and management of primary immune thrombocytopenia”. Blood. vol. 115. 2010. pp. 168-186.

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

Zaja, F. “Long-term follow-up analysis after rituximab salvage therapy in adult patients with immune thrombocytopenia”. . vol. 87. 2012. pp. 886-9.

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