Thrombocytopenia ROBERT L

Home , Bleeding, Hematology, Purpura, Thrombocytopenia

Thrombocytopenia ROBERT L. GAUER, MD, Womack Army Medical Center Family Medicine Residency, Fort Bragg, North Carolina MICHAEL M. BRAUN, DO, 1st Special Forces Group, Fort Lewis, Washington

Thrombocytopenia is defined as a platelet count of less than 150× 103 per µL. It is often discovered incidentally when obtaining a complete blood count during an office visit. The etiology usually is not obvious, and additional investigation is required. Patients with platelet counts greater than 50 × 103 per µL rarely have symptoms. A platelet count from 30 to 50 × 103 per µL rarely manifests as purpura. A count from 10 to 30 × 103 per µL may cause bleeding with minimal trauma. A platelet count less than 5 × 103 per µL may cause spontaneous bleeding and constitutes a hematologic emergency. Patients who present with thrombocytopenia as part of a multisystem disorder usually are ill and require urgent evaluation and treatment. These patients most likely have an acute infection, heparin-induced thrombocytopenia, liver disease, thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, disseminated intravascular coagulation, or a hematologic disorder. During pregnancy, preeclampsia and the HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome are associated with thrombocytopenia. Patients with isolated thrombocytopenia commonly have drug-induced thrombocytopenia, immune thrombocytopenic purpura, pseudothrombocytopenia, or if pregnant, gestational thrombocytopenia. A history, physical examination, and laboratory studies can differentiate patients who require immediate intervention from those who can be treated in the outpatient setting. Treatment is based on the etiology and, in some cases, treating the secondary cause results in normalization of platelet counts. Consultation with a hematologist should be considered if patients require hospitalization, if there is evidence of systemic disease, or if thrombocytopenia worsens despite initial treatment. (Am Fam Physician. 2012;85(6):612- 622. Copyright © 2012 American Academy of Family Physicians.) ▲ Patient information: amily physicians often see patients (5 × 109 per L), and is considered a hemato- A handout on low platelet who present with a low platelet count. logic emergency.2 count, written by the authors of this article, is Although further inquiry may elicit provided on page 623. additional signs and symptoms of Initial Evaluation F systemic disease, the etiology of thrombocy- Thrombocytopenia can result from decreased topenia usually is not immediately apparent. platelet production, increased platelet con- A low platelet count may be the only hema- sumption, or sequestration (Table 13-6). Com- tologic abnormality. In adults, thrombocyto- mon etiologies with clinical findings and penia is a platelet count less than 150 × 103 suggested treatment are listed in Table 2,7-14 per µL (150 × 109 per L). Cases are considered and clinical considerations to aid in diagno- mild if counts are between 70 and 150 × 103 sis are listed in Table 3. A systematic approach per µL (70 to 150 × 109 per L) and severe if less should be used to evaluate incidental throm- than 20 × 103 per µL (20 × 109 per L).1 Patients bocytopenia. During the patient history, phy- with a platelet count greater than 50 × 103 per sicians should inquire about easy bruising or µL (50 × 109 per L) often are asymptomatic. petechiae, melena, rashes, fevers, and bleeding. Patients with a count from 30 to 50 × 103 per They also should inquire about medication µL (30 to 50 × 109 per L) rarely present with use, immunizations, recent travel, transfusion purpura, although they may have excessive history, family history, and medical history. bleeding with trauma. However, counts from A history of acute and chronic alcohol use 10 to 30 × 103 per µL (10 to 30 × 109 per L) may should be obtained. Any recent hospitalization cause bleeding with minimal trauma, and or heparin exposure should raise the possibil- counts less than 10 × 103 per µL increase the ity of heparin-induced thrombocytopenia. risk of spontaneous bleeding, petechiae, and Pregnant patients with visual symptoms, bruising. Spontaneous bleeding (i.e., muco- headaches, abdominal pain, or influenza-like sal, intracranial, gastrointestinal, and geni- symptoms may have preeclampsia or HELLP tourinary bleeding) is more likely in patients (hemolysis, elevated liver enzymes, and low with platelet counts less than 5 × 103 per µL platelet count) syndrome.

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SORT: KEY RECOMMENDATION FOR PRACTICE

Evidence Clinical recommendation rating References Comments

Corticosteroids are first-line treatment for immune C 2, 21 Treatment is rarely indicated in patients thrombocytopenic purpura. with platelet counts greater than 50 × 103 per µL (50 × 109 per L). Patients older than 60 years with thrombocytopenia should be C 2, 21 Patients with myelodysplastic syndrome evaluated for myelodysplastic syndrome or lymphoproliferative usually will present with anemia and disorders. lymphoma with lymphadenopathy. Pregnant patients with platelet counts greater than 115 × 103 C 9, 37 Gestational thrombocytopenia is per µL (115 × 109 per L) and no evidence of preeclampsia or common and does not pose a risk to HELLP (hemolysis, elevated liver enzymes, and low platelet the fetus or mother. count) syndrome do not require further evaluation. Patients with mild thrombocytopenia (i.e., platelet counts of C 16 Any change in clinical health or evidence 100 to 150 × 103 per µL [100 to 150 × 109 per L]) who are of bleeding before repeat testing asymptomatic should have a platelet count repeated in two to should prompt immediate reevaluation. four weeks. Patients with stable thrombocytopenia (platelet counts greater C 39, 41, 42 The information is based on long-term than 50 × 103 per µL) generally do not require activity outcomes from patients with chronic restrictions and are able to tolerate most invasive procedures. immune thrombocytopenic purpura.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.xml.

Table 1. Etiologies of Thrombocytopenia

Decreased platelet production Increased platelet consumption (continued) Bone marrow failure (e.g., aplastic anemia, paroxysmal nocturnal Heparin-induced thrombocytopenia hemoglobinuria, Shwachman-Diamond syndrome) Immune thrombocytopenic purpura* Bone marrow suppression (e.g., from medication, chemotherapy, or Infection† (e.g., cytomegalovirus, Epstein-Barr virus, irradiation) hepatitis C virus, HIV, mumps, parvovirus B19, Chronic alcohol abuse* rickettsia, rubella, varicella-zoster virus) Congenital macrothrombocytopenias (e.g., Alport syndrome, Bernard- Mechanical destruction (e.g., aortic valve, mechanical Soulier syndrome, Fanconi anemia, platelet-type or pseudo–von Willebrand valve, extracorporeal bypass) disease, Wiskott-Aldrich syndrome) Preeclampsia/HELLP syndrome Infection† (e.g., cytomegalovirus, Epstein-Barr virus, hepatitis C virus, HIV, Thrombotic thrombocytopenic purpura/hemolytic uremic mumps, parvovirus B19, rickettsia, rubella, varicella-zoster virus) syndrome Myelodysplastic syndrome Sequestration/other Neoplastic marrow infiltration Chronic alcohol abuse* Nutritional deficiencies (vitamin B and folate) 12 Dilutional thrombocytopenia (e.g., hemorrhage, Increased platelet consumption excessive crystalloid infusion) Alloimmune destruction (e.g., posttransfusion, neonatal, posttransplantation) Gestational thrombocytopenia Autoimmune syndromes (e.g., antiphospholipid syndrome, systemic lupus Hypersplenism (e.g., distributional thrombocytopenia) erythematosus, sarcoidosis) Liver disease (e.g., cirrhosis, fibrosis, portal hypertension) Disseminated intravascular coagulation*/severe sepsis* Pseudothrombocytopenia Drug-induced thrombocytopenia Pulmonary emboli Pulmonary hypertension

HELLP = hemolysis, elevated liver enzymes, and low platelet count; HIV = human immunodeficiency virus. *—More than one mechanism of action. †—Thrombocytopenia with infection is usually caused by bone marrow suppression. In some cases, the thrombocytopenia is also immune-mediated. Information from references 3 through 6.

March 15, 2012 ◆ Volume 85, Number 6 www.aafp.org/afp American Family Physician 613 Table 2. Common Etiologies of Thrombocytopenia with Clinical Findings and Suggested Treatment

Etiology Severity Clinical presentation Evaluation Treatment Comments

Bone marrow suppression by Moderate to severe History of exposure, comorbid preexisting disease, or malignancy Directed by preexisting diagnosis, specific Based on underlying etiology Usually affects all cell lines irradiation, chemotherapy, Acute leukemias present with fatigue, weakness, bruising, hepatosplenomegaly cancer markers or neoplasia Abnormal blood smear or bone marrow biopsy

Chronic alcohol abuse Mild to moderate Findings range from normal to evidence of cirrhosis or hepatic failure Positive screening questionnaire, abnormal Cessation of alcohol use, vitamin Cessation of alcohol use may lead to platelet liver function tests (AST/ALT > 2, GGT), and nutritional replacement rebound (> 500 × 103 per µL [500 × 109 per L]) at macrocytosis, folate deficiency, hepatic imaging one to two weeks as clinically indicated

Chronic liver disease Mild to severe Symptoms are variable based on evidence of cirrhosis, liver dysfunction, Abnormal intrinsic liver function testing, Based on etiology; often Hypersplenism often is present contributing to gastrointestinal bleeding, ascites, hepatomegaly, and jaundice imaging and liver biopsy as clinically indicated supportive thrombocytopenia

Congenital thrombocytopenia Mild to moderate Long history of abnormal platelet count or family history of thrombocytopenia Many disorders associated with giant platelets, Varies depending on primary Often asymptomatic when there is no bleeding neutrophil inclusions, or other congenital abnormality diathesis anomalies

Disseminated intravascular Severe Acute illness; bleeding, acute renal failure, hepatic and respiratory dysfunction, and Prolonged coagulation activation, elevated Supportive treatment with Mortality rates exceed 20 percent; prognosis is coagulation shock are common clinical manifestations fibrin markers, and accelerated fibrinolysis platelet and clotting factor based on treating the underlying disorder Secondary to other comorbid conditions, such as sepsis, trauma, burns, or malignancy (low fibrinogen levels) replacement therapy

Drug-induced Moderate to severe Can range from asymptomatic to evidence of clinical bleeding Detailed history of recent prescription Removal of offending agent May be initially indistinguishable from ITP thrombocytopenia medications, nutritional supplements, and Serial platelet monitoring until Often resolves within seven to 14 days after agent is over-the-counter agents normalization discontinued

Gestational thrombocytopenia Mild Asymptomatic with platelet counts rarely < 70 × 103 per µL (70 × 109 per L) Identified during initial prenatal CBC No treatment indicated Possible immunologic etiology No associated fetal thrombocytopenia Platelet counts approaching 50 × May be difficult to distinguish from ITP before delivery Spontaneous resolution after delivery 103 per µL (50 × 109 per L) often Up to 15 percent of infants with thrombocytopenia are considered ITP and treated are born to women with ITP with corticosteroids or IVIG

Heparin-induced Mild to moderate Thrombocytopenia or a 50 percent reduction after exposure to heparin or low- History of heparin use; erythema or necrosis at Immediate withdrawal of Warfarin (Coumadin) monotherapy may induce thrombocytopenia molecular-weight heparin site of injection; thrombosis; ELISA test for heparin; treatment with thrombosis and is contraindicated in the acute Arterial and venous thrombosis presence of platelet factor 4 antibodies nonheparin anticoagulant setting

Immune thrombocytopenic Moderate to severe Often asymptomatic, although symptoms can range from petechiae and easy Remainder of CBC normal; normal peripheral Corticosteroids, IVIG, rituximab Diagnosis of exclusion purpura bruising to severe bleeding diathesis (rare) blood smear; absence of clinically associated (Rituxan), splenectomy Patients older than 60 years should have bone Secondary ITP may present in patients with autoimmune disorders, infections (e.g., conditions Treatment not indicated for marrow biopsy to rule out myelodysplastic cytomegalovirus, Epstein-Barr virus, Helicobacter pylori, hepatitis C virus, human Secondary ITP causes should be investigated as platelet counts > 50 × 103 per syndrome or lymphoproliferative disorder immunodeficiency virus, varicella-zoster virus), and lymphoproliferative disorders clinically indicated µL unless active bleeding MMR vaccination causes one case of ITP per Secondary ITP also requires 40,000 doses treatment of underlying cause

Infections (viral or rickettsial) Mild to moderate Viral: prodrome or asymptomatic; known viruses include cytomegalovirus, Epstein- Viral: diagnosis based on viral etiology; directed Viral: based on viral etiology; Viral: varicella (live) and influenza A (H1N1) Barr virus, hepatitis B and C viruses, human immunodeficiency virus, parvovirus antiviral titer testing if available most self-limited viral vaccinations have been reported to cause mild B19, varicella-zoster virus Rickettsial: ELISA testing may be useful infections are supportive transient thrombocytopenia Rickettsial: Lyme disease, Rocky Mountain spotted fever, ehrlichiosis; tick-borne Rickettsial: doxycycline is Rickettsial: ehrlichiosis causes more severe illnesses present with fever, headache, malaise, arthralgias, and rash recommended in symptomatic thrombocytopenia than Rocky Mountain spotted tick-borne disease fever and Lyme disease

Preeclampsia/HELLP syndrome Mild to moderate Elevated blood pressure, visual symptoms, headache, right upper quadrant abdominal CBC, liver function test, urine protein level, Delivering the fetus; intravenous Recovery usually is within three days of delivery pain, influenza-like symptoms increased uric acid level, increased LDH level, magnesium sulfate If persistent beyond the third day after delivery, basic metabolic panel presume thrombotic thrombocytopenic purpura

Pseudothrombocytopenia Factitious Asymptomatic; in vitro agglutination of platelets Repeat CBC using non-EDTA anticoagulant No treatment indicated Peripheral blood smear will demonstrate clumping

Thrombotic thrombocytopenic Moderate to severe Most common presentation is nonspecific and includes abdominal pain, nausea/ Microangiopathic hemolytic anemia; impaired Plasma exchange 10 to 30 percent mortality despite treatment; in purpura/hemolytic uremic vomiting, and weakness; patients with thrombotic thrombocytopenic purpura renal function; neurologic abnormalities; children, hemolytic uremic syndrome presents with syndrome may have neurologic abnormalities at presentation proteinuria; increased LDH, increased gastroenteritis (bloody diarrhea) and 60 percent bilirubin, and decreased haptoglobin levels will have thrombocytopenia

ALT = alanine transaminase; AST = aspartate transaminase; CBC = complete blood count; EDTA = ethylenediaminetetraacetic acid; ELISA = enzyme- linked immunosorbent assay; GGT = γ-glutamyltransferase; HELLP = hemolysis, elevated liver enzymes, and low platelet count; ITP = immune thrombocytopenic purpura; IVIG = intravenous immune globulin; LDH = lactate dehydrogenase; MMR = measles, mumps, and rubella. Information from references 7 through 14. Table 2. Common Etiologies of Thrombocytopenia with Clinical Findings and Suggested Treatment

Etiology Severity Clinical presentation Evaluation Treatment Comments

Pseudothrombocytopenia Factitious Asymptomatic; in vitro agglutination of platelets Repeat CBC using non-EDTA anticoagulant No treatment indicated Peripheral blood smear will demonstrate clumping

ALT = alanine transaminase; AST = aspartate transaminase; CBC = complete blood count; EDTA = ethylenediaminetetraacetic acid; ELISA = enzyme- linked immunosorbent assay; GGT = γ-glutamyltransferase; HELLP = hemolysis, elevated liver enzymes, and low platelet count; ITP = immune thrombocytopenic purpura; IVIG = intravenous immune globulin; LDH = lactate dehydrogenase; MMR = measles, mumps, and rubella. Information from references 7 through 14. Thrombocytopenia Table 3. Clinical Considerations to Aid in Diagnosis of Thrombocytopenia

Clinical consideration Possible diagnosis management) or nonemergent (outpatient Timing management). Some syndromes may fall Acute Acute infection (primarily viral), acute leukemias, aplastic anemia, chemotherapy or irradiation, drug-induced in either category based on the severity of thrombocytopenia, HELLP syndrome/preeclampsia, thrombocytopenia. heparin-induced thrombocytopenia, ITP, malignancies A peripheral blood smear can provide with marrow infiltration, myelofibrosis, TTP/HUS diagnostic information on a variety of white Chronic Chronic alcohol abuse, congenital syndromes, ITP, blood cell disorders, hemolytic anemias, and liver disease, myelodysplastic syndrome thrombocytopenia.15 A blood smear should History be obtained during the initial evaluation. Family history Congenital thrombocytopenia Table 4 lists common findings on peripheral Liver disease Chronic alcohol abuse, chronic liver disease blood smear and their associated diagnoses. Pregnancy Gestational thrombocytopenia, HELLP syndrome/ preeclampsia Long-term Outcomes of Incidental Recent change in Drug-induced thrombocytopenia medication Thrombocytopenia Recent hospitalization Heparin-induced thrombocytopenia The findings of isolated thrombocytope- Recent immunization MMR, varicella, influenza A (H1N1) nia in an outpatient setting have prognostic Recent transfusion or Alloimmune destruction, posttransfusion purpura, implications. A prospective study evaluated high-risk behavior viral infection (HCV, HIV) the long-term outcomes of patients with Recent travel Dengue fever, malaria, rickettsial diseases incidental thrombocytopenia. The study fol- Recent valve Mechanical destruction lowed 217 persons with platelet counts from replacement surgery 100 to 150 × 103 per µL (100 to 150 × 109 Symptoms per L) over a 10-year period. In 64 percent Abdominal pain HELLP syndrome/preeclampsia, HUS, platelet of patients, platelet counts normalized or sequestration remained stable. The probability of develop- Recent fever Viral infections (CMV, EBV, HIV, influenza A [H1N1], parvovirus B19), TTP, rickettsial diseases ing immune thrombocytopenic purpura or Weight loss or night HIV, malignancies (acute leukemias, myelodysplastic an autoimmune disorder was approximately sweats syndrome) 7 and 12 percent, respectively. Four cases Physical examination of myelodysplastic syndrome were diag- Acute rash Rickettsial diseases, SLE, viral infections nosed (2 percent), all of which were in older 16 Generalized Viral infections (CMV, EBV, HIV), SLE, myeloproliferative patients. lymphadenopathy disorders, lymphoproliferative disorders Hepatomegaly Chronic liver disease, acute leukemias, viral infections Factitious Thrombocytopenia (CMV, EBV, HBV, HCV) Pseudothrombocytopenia is secondary to Neurologic TTP platelet clumping and has no clinical sig- Splenomegaly* Autoimmune (SLE, sarcoidosis), hypersplenism, viral nificance. It occurs in one in 1,000 per- infections sons in the general population, and can be 3 CMV = cytomegalovirus; EBV = Epstein-Barr virus; HBV = hepatitis B virus; HCV = hepatitis confirmed by a peripheral blood smear. C virus; HELLP = hemolysis, elevated liver enzymes, and low platelet count; HIV = human Causes include use of abciximab (Reopro) or immunodeficiency virus; HUS = hemolytic uremic syndrome; ITP = immune thrombocyto- ethylenediaminetetraacetic acid–dependent penic purpura; MMR = measles, mumps, and rubella; SLE = systemic lupus erythemato- 17,18 sus; TTP = thrombotic thrombocytopenic purpura. agglutinins. The platelet count should *—Ultrasonography may be useful in patients who are obese. be repeated by collecting blood in a tube with a non-ethylenediaminetetraacetic acid anticoagulant, such as heparin or sodium The physical examination should include the eyes citrate. If the complete blood count still shows thrombo- (e.g., hemorrhage is suggestive of central nervous system cytopenia, other causes should be investigated. bleeding), abdomen (e.g., splenomegaly, hepatomegaly), lymph nodes (e.g., lymphadenopathy), skin (e.g., Emergent Thrombocytopenia petechiae, purpura, bruising), and neurologic system. IMMUNE (IDIOPATHIC) THROMBOCYTOPENIC PURPURA Bleeding (e.g., epistaxis, mucosal, gastrointestinal, geni- Immune thrombocytopenic purpura is an acquired tourinary) also should be assessed. Thrombocytopenia immune-mediated disorder characterized by isolated can be classified as emergent (usually requires inpatient thrombocytopenia and the absence of other conditions

616 American Family Physician www.aafp.org/afp Volume 85, Number 6 ◆ March 15, 2012 Thrombocytopenia Table 4. Common Peripheral Blood Smear Findings and Possible Diagnoses

Smear findings Possible diagnosis Comments

Atypical lymphocytosis Viral infection (e.g., Epstein-Barr virus, Abundant cytoplasm cytomegalovirus)

Basophilic stippling Thalassemia, chronic alcohol use, lead or metal Ribosomal precipitate (appears as blue granules) poisoning throughout the cytoplasm of the red blood cell

Cryoglobulin Cryoglobulinemia, mycoplasma pneumonia, Proteins that precipitate when blood is below normal multiple myeloma, some autoimmune disorders body temperature

Giant platelets Congenital thrombocytopenias, immune Caused by increased platelet turnover or release of thrombocytopenic purpura immature forms into the circulation

Megakaryocyte fragments Myelofibrosis Presence of large platelets

Nucleated red blood cells Severe hemolysis, myelofibrosis Immature red blood cells secondary to accelerated erythropoiesis

Oval macrocytosis Vitamin B12 and folate deficiencies Suggests impaired bone marrow synthesis

Platelet agglutination Pseudothrombocytopenia Clumping of platelets in patients with EDTA-activated antiplatelet antibodies

Platelet hypogranularity Myelodysplastic syndrome, myelofibrosis Suggests impaired bone marrow synthesis

Round macrocytosis Myelodysplastic syndrome, myelofibrosis, chronic Suggests impaired bone marrow synthesis liver disease

Schistocytosis Thrombotic thrombocytopenic purpura, hemolytic Fragmented erythrocytes uremic syndrome, disseminated intravascular coagulation, defective prosthetic heart valve

Target cells Chronic liver disease, hemoglobinopathies Excess hemoglobin in the center of the red blood cell

EDTA = ethylenediaminetetraacetic acid. or agents known to induce thrombocytopenia. The inci- antiphospholipid antibodies without having an under- dence is 100 cases per 1 million persons annually, and lying autoimmune syndrome.20 Treatment is generally approximately 50 percent of cases occur in children.2 restricted to those with severe thrombocytopenia and Immune thrombocytopenic purpura in children often is rarely indicated when platelet counts are greater than resolves spontaneously but tends to be more insidious 50 × 103 per µL unless there is evidence of active bleed- and chronic in adults. The risk of bleeding correlates to ing. Corticosteroids are considered first-line treatment the severity of thrombocytopenia. Patients may pres- and increase platelet counts usually within one week of ent without symptoms, with minimal bleeding, or with initiation.2,21 Intravenous immune globulin and ritux- serious hemorrhage (e.g., mucosal, intracranial, gastro- imab (Rituxan) also have been used for initial treatment intestinal, genitourinary). Older patients, patients on of immune thrombocytopenic purpura. Second-line antiplatelet therapy, and patients with comorbid condi- treatment includes thrombopoietin-receptor agonists tions may have more severe bleeding manifestations.19 and splenectomy. Any patient older than 60 years pre- Secondary immune thrombocytopenic purpura is senting with isolated thrombocytopenia should be associated with other underlying conditions, such as evaluated for myelodysplastic syndrome and lympho- autoimmune disorders (e.g., systemic lupus erythema- proliferative disorders.2,21 tosus, antiphospholipid syndrome, Graves disease, sarcoidosis), lymphoproliferative disorders, and infections HEPARIN-INDUCED THROMBOCYTOPENIA (e.g., human immunodeficiency virus, Epstein-Barr Heparin-induced thrombocytopenia should be sus- virus, cytomegalovirus, varicella-zoster virus, hepa- pected in patients recently treated with heparin. Plate- titis C virus, Helicobacter pylori). Testing to rule out let counts decline within five to 10 days in patients with other causes should be performed as clinically indi- no previous exposure to heparin and may decline pre- cated. Forty percent of patients with immune throm- cipitously (within hours) in patients with recent heparin bocytopenic purpura test positive for antinuclear or exposure. This life-threatening disorder is characterized

March 15, 2012 ◆ Volume 85, Number 6 www.aafp.org/afp American Family Physician 617 Thrombocytopenia

by the presence of platelet-activating antibodies recog- diarrhea, and/or abdominal pain. Shiga toxin-producing nizing multimolecular complexes bound to unfraction- Escherichia coli is the most common causative organism ated heparin or low-molecular-weight heparin. Patients in hemolytic uremic syndrome.26 with heparin-induced thrombocytopenia present with mild thrombocytopenia or a 50 percent decrease in PREECLAMPSIA AND HELLP SYNDROME platelet count from baseline.22 The incidence is higher Pregnant patients beyond 20 weeks’ gestation with throm- among surgical patients than medical patients. Throm- bocytopenia or signs and symptoms such as headache, bosis complications (termed heparin-induced thrombo- visual disturbances, right upper quadrant abdominal cytopenia with thrombosis) develop in 20 to 50 percent pain, or elevated blood pressure should be evaluated for of patients and may affect arterial and venous systems, preeclampsia and HELLP syndrome. Laboratory abnor- even after heparin is discontinued.23 malities may include anemia, elevated liver enzymes, Characteristic features are erythematous or necrotiz- elevated lactate dehydrogenase, and proteinuria.27 Treat- ing skin reactions at the site of injection or severe mani- ment is intravenous magnesium sulfate and active man- festations, such as deep venous thrombosis, pulmonary agement to deliver the fetus.28 Pregnant patients also can emboli, stroke, or myocardial infarction. The most widely present with other causes of thrombocytopenia, includ- available diagnostic test is an enzyme-linked immunosor- ing disseminated intravascular coagulation (as seen with bent assay with platelet sepsis and placenta abruptio) and thrombotic thrombo- factor 4/anion complex cytopenic purpura, which can mimic HELLP syndrome. Drug-induced thrombo- as the antigen. This test cytopenia is one of the has a high sensitivity OTHER CAUSES most common types of (greater than 97 per- Aplastic anemia, chemotherapy, irradiation, acute leuke- thrombocytopenia in cent) but a lower speci- mias, and myelodysplastic disorders may result in severe the outpatient setting. ficity (74 to 86 percent) or symptomatic thrombocytopenia. Paroxysmal noctur- because of the presence nal hemoglobinuria is associated with hemolysis, renal of platelet factor 4 antibodies in patients without heparin- disease, and thrombosis complications. Hospitalized induced thrombocytopenia.22,24 If the clinical diagnosis patients with comorbid conditions, such as sepsis, trauma, is suspected or confirmed by laboratory analysis, hepa- burns, or malignancy, can develop disseminated intra- rin should be stopped immediately and treatment should vascular coagulation with resultant thrombocytopenia. be changed to a nonheparin anticoagulant. One study showed that patients who developed heparin-induced Nonemergent Thrombocytopenia thrombocytopenia had a 20 percent in-hospital mortality DRUG-INDUCED THROMBOCYTOPENIA rate, regardless of thrombosis development.25 One of the most common types of thrombocytopenia in the outpatient setting is drug-induced thrombocytope- THROMBOTIC THROMBOCYTOPENIC PURPURA nia. An epidemiologic study from Europe and the United Patients presenting with thrombocytopenia and micro- States showed an annual incidence of 10 cases per 1 mil- angiopathic hemolytic anemia should be admitted to lion persons, but numbers could be higher in older persons the hospital with a presumptive diagnosis of thrombotic and in hospitalized patients.29 Drug-induced thrombo- thrombocytopenic purpura. Renal manifestations, neu- cytopenia should be suspected in all patients presenting rologic changes, and fever also may be present. Severity with an acute drop in platelet count. Most patients with is reflected by the extent of microvascular aggregation drug-induced thrombocytopenia have moderate to severe of platelets resulting in ischemia and necrosis of tissue thrombocytopenia reaching a nadir platelet count of cells. The incidence of thrombotic thrombocytopenic 20 × 103 per µL.8 Physicians should ask specific questions purpura is four to 11 patients per 1 million annually in about the use of any medications, including nutritional the United States. 7 The condition often is caused by the supplements and over-the-counter remedies. Quinine is absence or deficiency of a disintegrin and metallopro- a common cause of drug-induced thrombocytopenia and teinase with thrombospondin type 1 motif, member 13.7 often is missed in the patient history. It is fatal without treatment; prompt initiation of plasma Table 5 lists common medications that may cause exchange is critical. Thrombotic thrombocytopenic pur- thrombocytopenia.8 A comprehensive list of all case pura occurs primarily in adults. Hemolytic uremic syn- reports describing drug-induced thrombocytopenia drome is thrombotic thrombocytopenic purpura found is available at http://www.ouhsc.edu/platelets. Drug- in children presenting with acute renal failure, bloody induced thrombocytopenia typically occurs within five

618 American Family Physician www.aafp.org/afp Volume 85, Number 6 ◆ March 15, 2012 Thrombocytopenia

in 14 percent of hospitalized patients with Table 5. Medications/Substances Commonly Associated influenza A (H1N1) virus.31 Platelet counts with Drug-Induced Thrombocytopenia usually recover in patients with a self-limited viral infection. If the patient has a recent Proposed mechanism travel history, especially to South America Medication/substance Drug class of action or Mexico, dengue fever and malaria should Abciximab (Reopro) Glycoprotein IIb/IIIa Drug-specific antibody be considered. Other travel-associated infec- inhibitor tions, such as typhoid fever, can cause throm- Alcohol Ethanol Suppression of bocytopenia.32 Ehrlichiosis, Rocky Mountain megakaryocyte spotted fever, and Lyme disease are common production tick-borne illnesses that can cause transient Carbamazepine (Tegretol) Anticonvulsant Unknown thrombocytopenia.33 Cephalosporins Antibiotic Hapten-dependent

Cimetidine (Tagamet) Histamine H2 blocker Unknown LIVER DISEASE Eptifibatide (Integrilin) Glycoprotein IIb/IIIa Drug-specific antibody inhibitor Chronic liver disease usually causes per- Gold salts Antirheumatic Autoantibody sistent thrombocytopenia, and manifests Heparin Anticoagulant Platelet factor 4/heparin as cirrhosis, fibrosis, and portal hyperten- antibody sion. The most common cause is chronic Hydrochlorothiazide Antihypertensive Suppression of alcohol abuse; however, other etiologies megakaryocyte include infectious hepatitis, drug-induced production liver disease, nonalcoholic liver disease, and Interferon Antiviral Drug-specific antibody metabolic disorders. Patients who consume Measles, mumps, and Vaccine Vaccine-specific antibody rubella vaccine excessive amounts of alcohol can present Phenytoin (Dilantin) Anticonvulsant Unknown with varying degrees of liver impairment Procainamide Antiarrhythmic Autoantibody ranging from asymptomatic fatty liver to Quinidine/quinine Cinchona alkaloid Drug-glycoprotein end-stage liver disease. Thrombocytopenia complex results from direct toxic marrow suppres- Rifampin Antibiotic Autoantibody sion and splenic sequestration. Folic acid Sulfasalazine (Azulfidine) Anti-inflammatory Drug-specific antibody deficiency (related to malnutrition) often Trimethoprim/ Antibiotic Drug-glycoprotein coexists with alcohol abuse. Abstinence and sulfamethoxazole complex (Bactrim, Septra) nutritional replacement often lead to platelet Vancomycin Antibiotic Drug-specific antibody normalization in three to four weeks in the absence of chronic liver disease.34 Adapted with permission from Kenney B, Stack G. Drug-induced thrombocytopenia. Arch Pathol Lab Med. 2009;133(2):314. Copyright 2009. College of American GESTATIONAL THROMBOCYTOPENIA Pathologists. Gestational thrombocytopenia is the most common diagnosis of thrombocytopenia in pregnancy, occurring in 8 percent of preg- to seven days of exposure to the causative agent and usu- nancies.9,10 Its etiology is thought to be hemodilution ally resolves within seven to 14 days after discontinua- and accelerated platelet clearance. Gestational thrombo- tion.30 If drug-induced thrombocytopenia is suspected, cytopenia is characterized by mild thrombocytopenia, the causative medication should be discontinued and the no history of thrombocytopenia, no association of fetal patient’s platelet count should be repeated in one week. thrombocytopenia, and spontaneous resolution after delivery.35,36 Gestational thrombocytopenia is a benign INFECTIONS clinical condition not associated with maternal or neona- Infections may cause thrombocytopenia by direct bone tal morbidity or mortality. marrow suppression or increased peripheral platelet con- Recommendations for the initial evaluation of throm- sumption. Common viruses include hepatitis B and C, bocytopenia in pregnancy include a complete blood human immunodeficiency virus, Epstein-Barr, cyto- count and peripheral blood smear.10 Additional studies megalovirus, parvovirus B19, varicella-zoster, rubella, are determined on the basis of history and physical exam- and mumps. Recent studies found thrombocytopenia ination. Pregnant patients with platelet counts greater

March 15, 2012 ◆ Volume 85, Number 6 www.aafp.org/afp American Family Physician 619 Management of Thrombocytopenia

Complete blood count results abnormal with decreased platelets

Yes Other indices abnormal? Associated anemia, Consider hematology referral leukopenia, or No leukocytosis*

Thrombocytopenia

Yes Childhood history or family Congenital thrombocytopenia history of thrombocytopenia?

Perform peripheral blood smear†

Yes Clinical manifestation? Bleeding, petechiae, bruising‡ Consider hematology referral

Asymptomatic

Repeat platelet count in non-EDTA anticoagulant

Normal Abnormal

Pseudothrombocytopenia True thrombocytopenia§

Obtain history; perform physical examination Obtain platelet count

Platelet count less than 50 × 103 Platelet count 50 to 100 × 103 Platelet count 100 to 150 × 103 per µL (50 × 109 per L) per µL (50 to 100 × 109 per L) per µL (100 to 150 × 109 per L)

Consider hematology referral Repeat in one to two weeks Repeat in two to four weeks

Platelet count less Platelet count 50 to Platelet count 100 to Platelet count greater than 50 × 103 per µL 100 × 103 per µL 150 × 103 per µL than 150 × 103 per µL

Consider hematology referral Follow up and refer if count decreases Follow up until count normalizes No further evaluation needed

*—Bone marrow suppression, hematologic or infiltrative malignancy, TTP/HUS, liver disease, DIC, viral/rickettsial infection, nutritional deficiency, preeclampsia/HELLP syndrome (in pregnancy). †—Giant platelets suggest congenital thrombocytopenia. Clumping is seen in pseudothrombocytopenia. Fragmented red blood cells suggest microangiopathic hemolytic anemia (TTP/HUS, DIC). ‡—ITP, TTP/HUS, heparin-induced thrombocytopenia if exposed, hypersplenism, viral/rickettsial infection, DIC, mechanical destruction, preeclampsia/ HELLP syndrome (in pregnancy). §—ITP, heparin-induced thrombocytopenia if exposed, drug-induced thrombocytopenia, hypersplenism, viral/rickettsial infection, mechanical destruction, gestational thrombocytopenia (in pregnancy).

Figure 1. Algorithm for the management of thrombocytopenia. (DIC = disseminated intravascular coagulation; EDTA = ethylenediaminetetraacetic acid; HELLP = hemolysis, elevated liver enzymes, and low platelet count; HUS = hemolytic uremic syndrome; ITP = immune thrombocytopenic purpura; TTP = thrombotic thrombocytopenic purpura.) Information from reference 4. Thrombocytopenia

than 115 × 103 per µL (115 × 109 per L) and no evidence Most surgical and invasive procedures can be per- of preeclampsia or HELLP syndrome do not require fur- formed safely in patients with platelet counts greater ther evaluation.9,37 than 50 × 103 per µL. Other procedures, such as bone Mild immune thrombocytopenic purpura and ges- marrow biopsy, bronchoscopy, and endoscopy, can be tational thrombocytopenia often are indistinguishable completed safely in patients with platelet counts greater and cannot be differentiated on the basis of antiplatelet than 20 × 103 per µL, provided that no other bleeding antibody screening; however, 12 to 15 percent of neo- abnormalities are noted.41,42 The American College of nates delivered to women with immune thrombocyto- Obstetricians and Gynecologists recommendations state penic purpura will develop platelet counts of less than that epidural anesthesia in pregnancy is safe in patients 50 × 103 per µL.38 The platelet count in infants should be with platelet counts between 50 and 100 × 103 per µL.10 monitored when immune thrombocytopenic purpura is Data Sources: The authors searched OvidSP, UpToDate, American suspected in the mother. Academy of Family Physicians, American College of Obstetricians and Gynecologists, American Society of Clinical Oncology Practice Guidelines, Management Hematology/Oncology Clinics or North America, Harrison’s Principles A suggested algorithm for the management of thrombo- of Internal Medicine (17th edition), Agency of Healthcare Research and 4 Quality Evidence Reports, National Guidelines Clearinghouse, Cochrane cytopenia is shown in Figure 1. Symptomatic patients Database of Systematic Reviews, and the Centre for Reviews and Dis- require immediate evaluation. Patients with inciden- semination. Key words included: thrombocytopenia, review, treatment, tal thrombocytopenia (i.e., platelet counts of 50 to idiopathic (immune) thrombocytopenic purpura, thrombocytopenia in 150 × 103 per µL) who are asymptomatic should have pregnancy, thrombotic thrombocytopenic purpura, heparin-induced thrombocytopenia, hemolytic uremic syndrome, preeclampsia, HELLP a platelet count repeated in one to four weeks depend- syndrome, gestational thrombocytopenia, pseudothrombocytopenia, ing on the severity of thrombocytopenia.16 Reassessment myelodysplastic syndrome, microangiopathic hemoglobinopathies, drug- should be performed immediately if patients become induced thrombocytopenia, platelet transfusion, inherited thrombocy- symptomatic during the surveillance period. Additional topenias, antiphospholipid antibodies, and viral infections. Information published between 1996 and June 2010 was included. Original search laboratory evaluation should be performed as clinically dates: April 5 and June 16, 2010. Final search date: November 23, 2011. indicated, and a trial of discontinuing agents known to The authors thank Penelope Harris, MD, for her assistance with the decrease platelet counts is recommended. Patients with manuscript. chronic alcohol abuse or known nutritional deficiencies The opinions and assertions contained herein are the private views of the with stable thrombocytopenia can be treated by a pri- authors and are not to be construed as official or as reflecting the views mary care physician. Rickettsial diseases and most viral of the U.S. Army Medical Department or the U.S. Army at large. infections causing transient thrombocytopenia also can be managed by a primary care physician. Patients with The Authors unexplained severe thrombocytopenia, decreasing platelet counts, additional hematologic abnormalities, or ROBERT L. GAUER, MD, is a faculty physician at Womack Army Medical Center Family Medicine Residency at Fort Bragg, N.C., where he serves associated bleeding complications should be referred to as the research and scholarship advisor. He also is an assistant professor a hematologist. of family medicine at the Uniformed Services University of the Health Sci- ences in Bethesda, Md. Activity Participation and Invasive Procedures MICHAEL M. BRAUN, DO, is the 3rd Battalion Surgeon for the 1st Special General recommendations for activity participation Forces Group based at Fort Lewis, Wash. have been based on historical data from patients with Address correspondence to Robert L. Gauer, MD, Womack Army Medi- chronic severe thrombocytopenia.39,40 A platelet count cal Center, Bldg. 4-2817, Riley Rd., Fort Bragg, NC 28310 (e-mail: Robert. greater than 50 × 103 per µL is adequate for hemosta- [email protected]). Reprints are not available from the authors. sis and is unlikely to be clinically recognized. Patients Author disclosure: No relevant financial affiliations to disclose. with a platelet count greater than this level can engage in most activities, but should use caution if participat- REFERENCES ing in contact sports.16,40 Patients with platelet counts less 1. Buckley MF, James JW, Brown DE, et al. A novel approach to the assess- 3 than 10 × 10 per µL should be restricted from contact ment of variations in the human platelet count. Thromb Haemost. 2000; sports and other potentially traumatic activities. In one 83(3):480-484. study, 42 percent of patients with platelet counts less than 2. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl 10 × 103 per µL had spontaneous bleeding requiring inter- J Med. 2002;346(13):995-1008. 3. Veneri D, Franchini M, Randon F, Nichele I, Pizzolo G, Ambrosetti A. vention (e.g., nasal packing) compared with 6 percent of Thrombocytopenias: a clinical point of view. 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