ONLINE EXCLUSIVE Richard W. Temple, MD, Thrombocytopenia and FAAFP; Brittany Burns, DO Camp Lejeune Family Medicine Residency, Naval Medical neutropenia: 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 blood 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 platelets in speed the way toward appropriate treatment. patients with platelet 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 heparin-induced tient’s signs or symptoms, such as ecchymoses, petechiae, pur- thrombocytopenia. C pura, epistaxis, gingival bleeding, or melena, or it is incidentally ❯ Monitor (for life) patients discovered during review of a complete blood count (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 infection, or thrombosis 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 • Abciximab • Gentamicin calcium chelator in the ethylenediaminetet- • Captopril • Hydrochlorothiazide/ raacetic anticoagulant 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 • Phenytoin from a citrated or heparinized tube avoids • Dactinomycin/ • Piperacillin actinomycin this phenomenon. • Quinine • 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, • Eptifibatide • Trimethoprim/ sulfamethoxazole for potential causes of drug-induced throm- • Famotidine Immune- bocytopenia. DITP can be either immune- • Vancomycin • Fluconazole mediated mediated or nonimmune-mediated. • Vaccines: Hepatitis B drug-induced ❚ Immune-mediated DITP typically oc- • Furosemide and influenza 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 coagulation, hemolytic uremic syndrome, offending drug. (HIT) is a unique form of immune-mediated thrombotic thrombocytopenic purpura, DITP in that it is caused by antibody 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 therapy. 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- ❚ Acute and chronic alcohol use. Al- questration, or to bone marrow suppression. though alcohol is not a drug per se, it can also TABLE 31,9-11 lists common infections 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 folate lori can cause asymptomatic thrombocytope- 12 deficiency, further contributing to the devel- nia via an immune-mediated mechanism. 1 opment of the blood abnormality. Eradication of H pylori results in a variable E2 THE JOURNAL OF FAMILY PRACTICE | JULY 2018 | VOL 67, NO 7 THROMBOCYTOPENIA/NEUTROPENIA TABLE 2 Thrombocytopenia associated with thrombosis4,6-9 Diagnosis Clinical setting Laboratory findings Treatment Disseminated intravascular Sepsis fibrinogen Treat underlying cause coagulation Malignancy d-dimer Cryoprecipitate Trauma Prolonged PT, aPTT Fresh frozen plasma Hemolytic uremic syndrome Kidney injury Creatinine Supportive Shiga-toxin-producing Anemia Dialysis Escherichia coli infection Schistocytes Thrombotic Neurologic deficit LDH Plasmapheresis thrombocytopenic purpura Anemia Schistocytes ADAMTS13 gene Heparin-induced Current or past heparin + serotonin release assay Anticoagulation (non-heparin) thrombocytopenia exposure Antibodies to heparin-platelet factor 4 complex Antiphospholipid antibody Vascular thrombosis Anticardiolipin antibody Anticoagulation syndrome Pregnancy complications Lupus 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 pancytopenia? thrombocytopenia A review of the peripheral smear, with atten- Viral Cytomegalovirus, Epstein-Barr tion to abnormalities in other cell lines, may virus, hepatitis B and C, human assist in arriving at a diagnosis. If the periph- immunodeficiency virus, parvovirus B19 eral smear reveals pancytopenia, then, in addition to many of the etiologies described Bacterial Ehrlichiosis, Helicobacter pylori, Rocky Mountain spotted fever earlier, one should also consider vitamin B12 or folate deficiency, copper deficiency, drug- and viral-induced aplastic anemia, paroxys- (HIT, H pylori infection, etc). Consider ITP if, mal nocturnal hemoglobinuria, leukemias, 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 cirrhosis.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