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Home , Bone marrow suppression, Neutropenia, Thrombocytopenia

ONLINE EXCLUSIVE

Richard W. Temple, MD, and FAAFP; Brittany Burns, DO Camp Lejeune Family Residency, Naval Medical : A structured Center Camp Lejeune, NC (Dr. Temple); Naval Hospital approach to evaluation Pensacola, Fla (Dr. Burns) richard.w.temple2.mil@ mail.mil.

These algorithms and tables will help you quickly assess The authors reported no potential conflict of interest the severity of the 2 abnormalities and delineate relevant to this article. between life-threatening and benign causes.

hrombocytopenia and neutropenia are commonly PRACTICE encountered laboratory abnormalities. The presence RECOMMENDATIONS of either requires that you promptly evaluate for life- ❯ Employ a systematic T threatening causes and identify the appropriate etiology. This approach to the diagnosis and article identifies key questions to ask. It also includes algo- treatment of thrombocytope- rithms and tables that will facilitate your evaluation of patients nia and neutropenia. C with isolated thrombocytopenia or isolated neutropenia and ❯ Do not transfuse in speed the way toward appropriate treatment. patients with counts >10,000/mcL who are stable and are not undergoing an Thrombocytopenia: invasive procedure. C A look at the numbers ❯ Monitor patients on Thrombocytopenia is defined as a platelet count <150,000/mcL.1 heparin therapy for >4 days The blood abnormality is either suspected based on the pa- for -induced tient’s signs or symptoms, such as ecchymoses, petechiae, pur- thrombocytopenia. C pura, epistaxis, gingival , or , or it is incidentally ❯ Monitor (for life) patients discovered during review of a (CBC). with a history of gastric The development of clinical symptoms is closely related bypass for the development of to the severity of the thrombocytopenia, with platelet counts nutritional neutropenias. C <30,000/mcL more likely to result in clinical symptoms with

Strength of recommendation (SOR) minor trauma and counts <5,000/mcL potentially resulting in A Good-quality patient-oriented spontaneous bleeding. While most patients will have asymp- evidence tomatic, incidentally-found thrombocytopenia, and likely a B Inconsistent or limited-quality patient-oriented evidence benign etiology, those with the signs/symptoms just described,  C Consensus, usual practice, evidence of , or are more likely to have a opinion, disease-oriented serious etiology and require an expedited work-up. Although evidence, case series pregnancy may be associated with thrombocytopenia, this re- view confines itself to the causes of thrombocytopenia in non- pregnant adults.

Rule out pseudothrombocytopenia When isolated thrombocytopenia is discovered incidentally in an asymptomatic person, the first step is to perform a repeat

MDEDGE.COM/JFPONLINE VOL 67, NO 7 | JULY 2018 | THE JOURNAL OF FAMILY PRACTICE E1 CBC with a peripheral smear to confirm the TABLE 1 presence of thrombocytopenia, rule out labo- Medications that can induce ratory error, and assess for platelet clumping. 3 If thrombocytopenia is confirmed and plate- thrombocytopenia let clumping is present, it may be due to the • • Gentamicin calcium chelator in the ethylenediaminetet- • Captopril • Hydrochlorothiazide/ raacetic contained within the triamterene • Cilastatin/imipenem laboratory transport tube; this cause of pseu- • Meropenem dothrombocytopenia occurs in up to 0.29% • Clopidogrel of the population.1 Obtaining a platelet count • from a citrated or heparinized tube avoids • Dactinomycin/ • actinomycin this phenomenon. • • Digoxin • Spironolactone Is the patient’s thrombocytopenia • Dipyridamole drug induced? • Tirofiban Once true thrombocytopenia is confirmed, the • Drospirenone/ • TNF-alpha/INF- ethinylestradiol next step is to review the patient’s prescribed gamma medications, as well as any illicit drugs used, • • / sulfamethoxazole for potential causes of drug-induced throm- • Famotidine Immune- bocytopenia. DITP can be either immune- • • mediated mediated or nonimmune-mediated. • Vaccines: B drug-induced ❚ Immune-mediated DITP typically oc- • Furosemide and thrombocyto- curs within 1 to 2 weeks of medication ex- penia typically posure and begins to improve within 1 to occurs within 2 days of stopping the offending drug.2 (See Is there thrombosis? 1 to 2 weeks TABLE 13 for a list of medications that can in- In addition to exploring a connection be- of medication duce thrombocytopenia.) It should be noted tween thrombocytopenia and the drugs a exposure and that most patients who take the medications patient is taking, it’s also important to look begins to listed in TABLE 1 do not experience thrombo- for evidence of thrombosis. The causes of improve within cytopenia; nonetheless, it is a potential risk thrombocytopenia that paradoxically result 1 to 2 days associated with their use. in thrombosis are: disseminated intravascu- of stopping the ❚ Heparin-induced thrombocytopenia lar , hemolytic uremic syndrome, offending drug. (HIT) is a unique form of immune-mediated thrombotic thrombocytopenic , DITP in that it is caused by complex- catastrophic antiphospholipid antibody syn- es, resulting in platelet activation, clumping, drome, and the previously mentioned HIT. and thrombotic events.4 HIT occurs in <1% of TABLE 24,6-9 outlines the clinical settings, labo- patients in intensive care units, but can occur ratory findings, and treatments of thrombo- in any patient on long-term heparin . cytopenia associated with thrombosis. It manifests as a >50% drop in platelet count within 5 to 14 days of the introduction of hep- Is an infectious cause to blame? arin; however, in those previously exposed to If the patient is ill, consider infectious causes heparin, it can occur within 24 hours.4,5 of thrombocytopenia. Thrombocytopenia as- ❚ Non-immune-mediated DITP, result- sociated with infection may result from an ing from myelosuppression, chemotherapeu- immune-mediated response to an illness it- tic agents, or valproic acid, is less common.1,2 self, to treatment of an illness, to splenic se- ❚ and chronic alcohol use. Al- questration, or to suppression. though alcohol is not a drug per se, it can also TABLE 31,9-11 lists common that may result in thrombocytopenia. The mechanism cause thrombocytopenia. is the direct suppression of bone marrow, Of note, infection with Helicobacter py- although alcohol also causes B12 and lori can cause asymptomatic thrombocytope- deficiency, further contributing to the devel- nia via an immune-mediated mechanism.12 opment of the blood abnormality.1 Eradication of H pylori results in a variable

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TABLE 2 Thrombocytopenia associated with thrombosis4,6-9

Diagnosis Clinical setting Laboratory findings Treatment Disseminated intravascular  fibrinogen Treat underlying cause coagulation  d-dimer Cryoprecipitate Trauma Prolonged PT, aPTT Fresh frozen plasma Hemolytic uremic syndrome Kidney injury  Creatinine Supportive Shiga-toxin-producing Dialysis infection Thrombotic Neurologic deficit  LDH Anemia Schistocytes  ADAMTS13 gene Heparin-induced Current or past heparin + serotonin release assay Anticoagulation (non-heparin) thrombocytopenia exposure to heparin-platelet factor 4 complex Antiphospholipid antibody Vascular thrombosis Anticardiolipin antibody Anticoagulation syndrome Pregnancy complications anticoagulant Anti-beta2 glycoprotein aPTT, activated partial thromboplastin time; ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; LDH, lactate dehydrogenase; PT, prothrombin time.

elevation in platelets, on average 30,000/mcL TABLE 3 in 50% of patients with the infection.13 Common infectious causes of 1,9-11 Is there ? thrombocytopenia A review of the peripheral smear, with atten- Viral , Epstein-Barr tion to abnormalities in other cell lines, may , hepatitis B and C, human assist in arriving at a diagnosis. If the periph- virus, eral smear reveals pancytopenia, then, in addition to many of the etiologies described Bacterial , Helicobacter pylori, Rocky Mountain spotted earlier, one should also consider or , deficiency, drug- and viral-induced , paroxys- (HIT, H pylori infection, etc). Consider ITP if, mal nocturnal hemoglobinuria, , after a thorough work-up, a cause of isolated myelodysplastic disorders, and systemic thrombocytopenia is not identified.16 Treat- lupus erythematosis.14 Pancytopenia is also ment for ITP is outlined in TABLE 4.16 FIGURE 1 seen with hypersplenism, which is often as- is an algorithm for the complete evaluation of sociated with .15 If the etiology isn’t thrombocytopenia in adults. readily apparent, a bone marrow biopsy may be required. Treatment: Platelet transfusions Is immune thrombocytopenia to blame? In general, patients who are not actively Immune thrombocytopenia (ITP) is an auto- bleeding are considered stable and do not re- immune disorder resulting in the destruction quire platelet transfusions to minimize their of normal platelets and may be primary or risk of bleeding or prevent bleeding during secondary to processes described previously a planned procedure unless their platelet

MDEDGE.COM/JFPONLINE VOL 67, NO 7 | JULY 2018 | THE JOURNAL OF FAMILY PRACTICE E3 TABLE 4 Treatment of primary immune thrombocytopenia16

Signs/symptoms Treatment Asymptomatic patient, threshold for Prednisone 1 mg/kg/d until platelets >50,000/mcL, then treatment: platelet count <30,000/mcL taper over 4 weeks (response typically in 1 week) Symptomatic patient, bleeding, or Single dose of IVIg 1 g/kg initially (response typically in platelet count <5000/mcL 24-48 hours) or a single dose of anti-D 75 mcg/kg if the patient is Rh positive, has a spleen, and has a negative Coombs test Refractory to prednisone and/or IVIg vs receptor agonists Anti-D, anti-D immunoglobulin; IVIg, intravenous immunoglobulin.

TABLE 5 Consider platelet transfusions in these situations17 Platelet count/mcL Patient's status 10,000 Stable, not bleeding 20,000 Undergoing central venous line placement 50,000 Undergoing elective lumbar puncture or major elective nonneuraxial Heparin-induced thrombocyto- penia occurs in <1% of patients count falls below the levels specified in and Nutrition Examination Survey 1999 to in intensive care TABLE 5.17 For patients who are actively bleed- 2004, the prevalence was 4.5%, 0.79%, and units and ing, a more aggressive approach may be re- 0.38% in black, white, and Mexican-American typically is quired. Locally-derived transfusion protocols participants, respectively.19 FIGURE 2 outlines manifested by typically guide transfusions for the actively the outpatient work-up of adult patients with a ≥50% drop in hemorrhaging patient. The American Asso- neutropenia not related to . platelet count ciation of Blood Banks has put forth evidence- within 5 to based guidelines for platelet transfusions Is the patient severely ill? 14 days of when a patient is given a diagnosis of throm- The prognosis of the patient is related both introducing bocytopenia (see TABLE 5).17 Single-donor to the etiology of the neutropenia, as well heparin. platelets have a shelf life of 3 to 5 days, and one as to the nadir of the count. Pa- unit will raise platelets 30,000 to 50,000/mcL. tients who have an ANC <500 cells/mcL or who have inadequate bone marrow reserves are at highest risk for an overwhelming in- Neutropenia: fection.20,21 The absence of oral ulcers and Prevalence varies by ethnicity and/or the presence of purulent An absolute neutrophil count (ANC) of material at the site of an infection are signs of <1500 cells/mcL traditionally defines neutro- adequate bone marrow reserves. penia, with an ANC of 1000 to 1500 cells/mcL Additionally, neutropenia may be the constituting mild neutropenia; 500 to 999 source—or the result—of a serious life- cells/mcL, moderate; and <500 cells/mcL, threatening illness. This distinction may not severe.18 Similar to the evaluation of throm- be readily apparent at the time of the patient’s bocytopenia, it is important to repeat the presentation. If signs or symptoms of a se- CBC prior to initiating a work-up in order to vere illness are apparent (fever, , confirm that the neutropenia is not a labora- tachycardia, ANC <500 cells/mcL), admit the tory error. Additionally, patients with signs or patient to the hospital for evaluation and ini- symptoms of infection should be worked up tiation of . expeditiously. The prevalence of neutropenia varies by Is the neutropenia chronic? ethnicity. According to the National Health A review of previous CBCs will identify

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FIGURE 1 Algorithm for the work-up of thrombocytopenia in adults

Thrombocytopenia

Use Yes citrated/heparinized Clumping? tube No No True thrombocytopenia Normal platelet count?

Yes Yes Medications causing See TABLE 1 Pseudothrombocytopenia thrombocytopenia? No

Concurrent Yes DIC HUS thrombosis? TTP HIT Hepatitis B, C No Yes Concurrent APS HIV illness? EBV No Yes CMV Pancytopenia? B12 deficiency H pylori Folate deficiency No Parvovirus B19 RMSF Paroxysmal nocturnal hemoglobinuria Immune Ehrlichiosis thrombocytopenia Automimmune diseases (SLE) Hypersplenism Cirrhosis No

Consider bone marrow biopsy (aplastic anemia, , myelodysplastic disorders)

APS, antiphospholipid syndrome; CMV, cytomegalovirus; DIC, disseminated intravascular coagulation; EBV, Epstein-Barr virus; HIT, heparin-induced thrombocytopenia; HIV, human immunodeficiency virus; HUS, hemolytic-uremic syndrome; RMSF, Rocky Mountain spotted fever; SLE, systemic lupus erythematosus; TTP, thrombotic thrombocytopenic purpura.

whether this condition is new or chronic. nadir of the neutrophil count. The diagnosis A persistent, mild neutropenia (ANC 1000- is established by obtaining serial CBCs twice 1500 cells/mcL) in a healthy individual is weekly for 4 to 6 weeks, which reflect cycling consistent with benign familial or ethnic of the neutrophil count.20,22 neutropenia (see TABLE 6).20 If prior CBCs are unavailable, then a diagnosis of chronic neu- Are any medications tropenia may be established by verifying the contributing to the neutropenia? persistence of mild neutropenia over time. Medications that suppress bone marrow or ❚ is a periodic neu- that interfere with other immune-mediated tropenia (occurring every 2-5 weeks) associ- processes are the most common cause of ated with mild illnesses that are related to the acquired neutropenia.23 Drug-induced

MDEDGE.COM/JFPONLINE VOL 67, NO 7 | JULY 2018 | THE JOURNAL OF FAMILY PRACTICE E5 TABLE 6 Congenital causes of neutropenia20

Constitutional/ethnic neutropenia -Mild, chronic (ANC >1000/mcL) -No history of recurrent infections -Mediterranean or African ancestry Benign familial neutropenia -Similar to constitutional, but not ethnically linked Cyclic neutropenia -Self-limited infections associated with nadir of neutropenia -Recurrence q2-5 weeks -Autosomal dominant ANC, absolute neutrophil count.

TABLE 7 Medications that can be associated with agranulocytosis25 Drug class Drug name Analgesics Diclofenac, diflunisal, ibuprofen Antiarrhythmics Disopyramide, procainamide, quinidine A persistent, Antibiotics Ampicillin, cefotaxime, cefuroxime, imipenem-cilastatin, , oxa- mild cillin, penicillin G, quinine, ticarcillin neutropenia Anticonvulsants Carbamazepine, phenytoin, in a healthy Antirheumatics individual is consistent with Antithyroid drugs Propylthiouracil benign familial Cardiovascular drugs Clopidogrel, , ramipril, spironolactone or ethnic Gastrointestinal drugs Cimetidine, metoclopramide neutropenia. Psychotropics Chlorpromazine, , fluoxetine

TABLE 8 Infectious causes of neutropenia23,27-29 Bacterial , paratyphoid, pertussis, , tularemia, typhoid Rickettsial: Ehrlichiosis, Rocky Mountain spotted fever Parasitic Plasmodium vivax, P falciparum Viral Cytomegalovirus, Epstein-Barr, human immunodeficiency, hepatitis, influenza, parvovirus B19

is defined as an ANC <500 imab, sulfasalazine, and ticlopidine), and cells/mcL due to exposure to a drug that results fatality rates were higher (10% vs 3%) among in immunologic or cytotoxic destruction of those patients with a nadir <100 cells/mcL.25 neutrophils.24 TABLE 725 lists medications that can be as- A systematic review of case reports sociated with agranulocytosis. Depending of drug-induced agranulocytosis (a de- on prior exposure to a drug, neutropenia/ crease in peripheral neutrophil count to agranulocytosis can occur within hours to <500 cells/mcL) revealed that although at least months of exposure to the causal drug and 125 drugs were probably related to agranu- can take a few days to 3 weeks to resolve after locytosis, only 11 drugs were responsible cessation.25,26 for 50% of cases (carbimazole, clozapine, dapsone, dipyrone, methimazole, penicil- Has the patient had any recent illnesses? lin G, procainamide, propylthiouracil, ritux- The usual response to an infection is an

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FIGURE 2 Algorithm for the outpatient work-up of neutropenia in adult patients who aren't receiving chemotherapy

ANC <1500 cells/mcL

Yes Febrile Yes Admit to hospital for IV Signs/symptoms antibiotics and work-up severe illness? Hypotensive Tachycardic Altered mental status ANC <500 cells/mcL No

Yes Is this chronic? See TABLE 6

No If mild neutropenia (ANC >1000 cells/ Yes mcL) and no apparent etiology: Medications causing See TABLE 7 • Monitor CBC q2 weeks for neutropenia? 2 months, then if stable q3 months for 1 year. If stable, No then monitor CBC periodically, Yes as needed, for illness/fever. Recent illness? See TABLE 8

No

Yes At risk for nutritional Check for a deficiency deficiencies? of B12, folate, copper No Yes Symptoms of connective Check for ANA, anti-CCP tissue disease? antibodies, RF No

Collaborate with Check for: for consideration of flow • cytometry or bone • marrow biopsy • Large granular lymphocyte leukemia • Aplastic anemia

ANA, antinuclear antibodies; ANC, absolute neutrophil count; anti-CCP, anti-cyclic citrullinated peptide; CBC, complete blood count; IV, intrave- nous; RF, rheumatoid factor. increase in neutrophil count. However, cer- overwhelming bacterial infection results from tain bacterial, rickettsial, parasitic, and vi- the depletion of bone marrow reserves.23,27 ral infections can result in neutropenia (see TABLE 823,27-29). Viral infections may cause tran- Do you suspect a nutritional deficiency? sient neutropenia because of either bone Patients with a nutritional deficiency of B12, marrow suppression or increased peripheral folate, or copper are likely to exhibit a defi- destruction, while neutropenia related to an ciency in more than just .23,27 In

MDEDGE.COM/JFPONLINE VOL 67, NO 7 | JULY 2018 | THE JOURNAL OF FAMILY PRACTICE E7 developed countries, people with neutrope- N Engl J Med. 2007;357:580-587. 3. University of Oklahoma Health Sciences Center. Database for nia may have a history of malnutrition due Drug–induced thrombocytopenia from group patient reports: an to a disease (eg, anorexia nervosa) or surgery update. Available at: http://www.ouhsc.edu/platelets/Internet- PostingGroupFrames2014.htm. Accessed May 7, 2018. (eg, gastric bypass) that causes severe calorie 4. Sniecinski RM, Hursting MJ, Paidas MJ, et al. Etiology and assess- restriction.20 ment of hypercoagulability with lessons from heparin-induced thrombocytopenia. Anesth Analg. 2011;112:46-58. 5. Warkentin TE. Heparin-induced thrombocytopenia in critically ill Does your patient have symptoms patients. Crit Care Clin. 2011;27:805-823. 6. Connell NT, Sweeney JD. Does my patient have life- or limb- of a connective tissue disease? threatening thrombocytopenia? Hematol Oncol Clin North Am. Neutropenia, in association with arthralgias, 2012;26:369-382. 7. George JN, Nester CM. Syndromes of thrombotic microangiopathy. joint swelling, , or rash may be N Engl J Med. 2014;371:654-666. a manifestation of an underlying collagen 8. Hanly JG. Antiphospholipid syndrome: an overview. CMAJ. 2003;168:1675-1682. vascular disorder, such as rheumatoid ar- 9. Sekhon SS, Roy V. Thrombocytopenia in adults: a practical approach thritis (RA) or systemic lupus erythematosus to evaluation and management. South Med J. 2006;99:491-498. 20 10. Gauer RL, Braun MM. Thrombocytopenia. Am Fam . (SLE). If the clinical scenario supports one 2012;85:612-622. of these diagnoses, undertake or refer the pa- 11. Bratton RL, Corey R. Tick-borne disease. Am Fam Physician. tient for a rheumatologic evaluation. This may 2005;71:2323-2330. 12. Yeh JJ, Tsai S, Wu DC, et al. P-selectin-dependent platelet aggrega- include studies of anti-cyclic citrullinated tion and apoptosis may explain the decrease in platelet count dur- peptide antibodies, rheumatoid factor to ing Helicobacter pylori infection. Blood. 2010;115:4247-4253. 13. Stasi R, Sarpatwari A, Segal JB, et al. Effects of eradication of Helico- evaluate for RA, and/or antinuclear antibod- bacter pylori infection in patients with immune thrombocytopenic In developed ies to evaluate for SLE.30,31 While most neutro- purpura: a systemic review. Blood. 2009;113:1231-1240. 14. Weinzierl EP, Arber DA. The differential diagnosis and bone mar- countries, penias associated with autoimmune disease row evaluation of new-onset pancytopenia. Am J Clin Pathol. are mild, neutropenia associated with Felty 2013;139:9-29. people with 15. Peck-Radosavljevic M. Hypersplenism. Eur J Gastroenterol Hepatol. neutropenia may syndrome (RA, splenomegaly, and neutrope- 2001;13:317-323. nia) may be severe (ANC <100 cells/mcL).20,23 16. Neunert C, Lim W, Crowther M, et al. The American Society of have a history of Hematology 2011 evidence-based practice guideline for immune malnutrition due thrombocytopenia. Blood. 2011;117:4190-4207. Is the etiology unclear? 17. Kaufman RM, Djulbegovic B, Gernsheimer T, et al. Platelet trans- to a disease fusion: a clinical practice guideline from the AABB. Ann Int Med. (eg, anorexia Patients with moderate to severe neutropenia 2015;162:205-213. without an apparent etiology, in the setting of 18. Palmblad J, Dufour C, Papadaki HA. How we diagnose neutro- nervosa) or penia in the adult and elderly patient. Haematologica. 2014;99: surgery aplastic anemia, or in the presence of sple- 1130-1133. nomegaly and/or lymphadenopathy, should 19. Hsieh MM, Everhart JE, Byrd-Holt DD, et al. Prevalence of neutro- (eg, gastric penia in the U.S. population: age, sex, smoking status, and ethnic bypass) that undergo a hematologic evaluation and/or differences.Ann Intern Med. 2007;146:486-492. bone marrow biopsy, given that hematologic 20. Gibson C, Berliner N. How we evaluate and treat neutropenia in causes severe adults. Blood. 2014;124:1251-1258. 20,27 calorie malignancy is a potential cause. 21. Urabe A. Clinical features of the neutropenic host: definitions and restriction. ❚ The treatment of neutropenia hinges initial evaluation. CID. 2004;39(suppl 1):S53-S55. 22. Dale DC, Hammond WP 4th. Cyclic neutropenia: a clinical review. on correctly identifying the etiology of the Blood Rev. 1988;2:178-185. diminished neutrophil count. If the cause is 23. Munshi HG, Montgomery RB. Severe neutropenia: a diagnostic ap- a medication, infection, underlying rheuma- proach. West J Med. 2000;172:248-252. 24. Pisciotta AV. Drug-induced agranulocytosis peripheral destruction tologic condition, or nutritional deficiency, of polymorphonuclear leukocytes and their marrow precursors. Blood Rev. 1990;4:226-237. then either treating the entity or withdraw- 25. Andersohn F, Konzen C, Garbe E. Systematic review: agranulo- ing the offending medication should result in cytosis induced by nonchemotherapy drugs. Ann Intern Med. 2007;146:657-665. resolution of the neutropenia. If the cause is 26. Bhatt V, Saleem A. Review: drug-induced neutropenia – patho- determined to be familial or ethnic, then pa- physiology, clinical features, and management. Ann Clin Lab Sci. 2004;34:131-137. JFP tient reassurance is all that is required. 27. Newburger PE, Dale DC. Evaluation and management of patients with isolated neutropenia. Semin Hematol. 2013;50:198-206. CORRESPONDENCE 28. Bakken JS, Krueth J, Wilson-Nordskog C, et al. Clinical and labo- Richard W. Temple, MD, FAAFP, CDR MC USN, Camp Lejeune ratory characteristics of human granulcytic ehrlichiosis. JAMA. Residency, Naval Medical Center Camp 1996;275:199-205. Lejeune, 100 Brewster Blvd, Camp Lejeune, NC 28547-2538; 29. Hall GW, Schwartz RP. White count and differential in [email protected]. Rocky Mountain spotted fever. NC Med J. 1979;40:212-214. 30. Nishimura K, Sugiyama D, Kogata Y, et al. Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for . Ann Intern Med. 2007;146:797-808. References 31. Petri M, Orbai AM, Alarcón GS, et al. Derivation and validation of 1. Wong EY, Rose MG. Why does my patient have thrombocytope- the Systemic Lupus International Collaborating Clinics classifica- nia? Hematol Oncol Clin North Am. 2012;26:231-252. tion criteria for systemic lupus erythematosus. Arthritis Rheum. 2. Aster RH, Bougie DW. Drug-induced immune thrombocytopenia. 2012; 64:2677-2686.

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