Eduovisual
Blood & Lymphoreticular
Pancytopenia: workup algorithm
— Hemoglobin <12 g/dL (women) or <13 g/dL (men)
— Absolute neutrophil count (ANC) <1.8 ×10⁹/L
— Platelets <150 ×10⁹/L
— Severe: ANC <500, platelets <20, Hgb <8 with reticulocytopenia
— Very severe aplastic anemia: ANC <200
— Decreased production (hypocellular marrow): aplastic anemia, MDS, leukemia infiltration, B12/folate deficiency, drugs, viral suppression, radiation, fibrosis
— Increased destruction/sequestration (normo- or hypercellular marrow): hypersplenism, PNH, autoimmune (SLE), DIC, TTP/HUS, HLH
— Outpatient: fatigue + easy bruising + recurrent infections in same patient
— Incidental CBC abnormality on a routine medication monitoring panel (methotrexate, azathioprine, carbimazole, clozapine, TMP-SMX, linezolid, chemo)
— Post-viral (parvovirus B19, EBV, CMV, HIV, hepatitis), post-chemo nadir at 7–14 days
— Returning traveler with fevers (visceral leishmaniasis, brucellosis, malaria)
— Febrile neutropenia (T ≥38.3°C once or ≥38.0°C sustained with ANC <500)
— Bleeding with platelets <10–20
— Symptomatic anemia with CP, dyspnea, or hemodynamic instability
— Blasts on smear, schistocytes, or nucleated RBCs
Step 3 management: First branch point at the visit is isolated mild cytopenias vs. true pancytopenia with end-organ symptoms. If febrile and neutropenic, do not wait for marrow biopsy — draw cultures, start empiric cefepime within 1 hour, then proceed with workup. The outpatient with stable mild pancytopenia gets a structured ambulatory workup (smear, retic, B12/folate, LFTs, HIV, hepatitis, ANA, TSH) before hematology referral.
Board pearl: Pancytopenia + macrocytosis + hypersegmented neutrophils = B12/folate until proven otherwise — cheap fix before invasive workup.
— Anemia → fatigue, dyspnea on exertion, pallor, postural lightheadedness, angina in CAD patients
— Thrombocytopenia → petechiae, gum bleeding, epistaxis, menorrhagia, easy bruising
— Neutropenia → fevers, mucositis, perianal pain, recurrent sinopulmonary infections
— Acute (days–weeks): acute leukemia, drug reaction, viral suppression, TTP, HLH
— Subacute (weeks–months): MDS, aplastic anemia, megaloblastic anemia
— Chronic with prior abnormal CBCs: MDS, hypersplenism, congenital marrow failure (Fanconi, dyskeratosis congenita)
— Drug exposure: chemo, methotrexate, sulfa drugs, antiepileptics (carbamazepine, phenytoin, valproate), clozapine, ticlopidine, PTU/methimazole, linezolid, ganciclovir, chloramphenicol, NSAIDs, allopurinol, PPIs (B12)
— Toxins: benzene, pesticides, gold, arsenic, radiation
— Diet/EtOH: vegan diet (B12), alcohol use disorder (folate, marrow suppression, hypersplenism)
— Infections: HIV risk factors, hepatitis exposure, recent viral illness, TB risk, travel
— Autoimmune review of systems: rash, arthralgias, oral ulcers, sicca, photosensitivity
— Family history: marrow failure syndromes, early gray hair (dyskeratosis), nail dystrophy, café-au-lait spots (Fanconi)
— Bleeding/clotting history: dark urine in morning, abdominal/portal thrombosis (PNH)
— B symptoms: weight loss, night sweats, fevers — lymphoma, leukemia, TB, HLH
Key distinction: Bleeding with normal platelet count points away from pancytopenia toward coagulopathy (liver disease, DIC, vWD) — but in pancytopenia, expect bleeding to track with platelet count and platelet function.
Board pearl: A patient on methimazole presenting with fever and sore throat — check CBC immediately. Agranulocytosis can precede pancytopenia and is the highest-yield drug-induced marrow toxicity stem on Step 3.
— Tachycardia, orthostasis, narrow pulse pressure → significant anemia or bleeding
— Fever in neutropenia → treat as sepsis until proven otherwise
— Hypotension + petechiae + fever + altered mental status → consider TTP, DIC, septic shock, HLH
— Petechiae (dependent areas, palate), purpura, ecchymoses
— Pallor of conjunctivae, palmar creases, nail beds
— Jaundice → hemolysis (PNH, autoimmune), liver disease with hypersplenism
— Café-au-lait spots, hypopigmented macules → Fanconi anemia
— Nail dystrophy, oral leukoplakia, reticular skin pigmentation → dyskeratosis congenita
— Glossitis (smooth, beefy tongue) → B12/folate deficiency
— Mucositis, gingival hypertrophy → AML (especially M4/M5)
— Diffuse lymphadenopathy → leukemia, lymphoma, HIV, infectious mononucleosis
— Splenomegaly → hypersplenism, lymphoproliferative disease, infections (EBV, malaria, leishmaniasis), portal hypertension, myelofibrosis, hairy cell leukemia
— Hepatomegaly with stigmata of cirrhosis → portal HTN-driven hypersplenism
— Subacute combined degeneration (posterior columns, lateral corticospinal) → B12 deficiency
— Confusion, focal deficits in setting of thrombocytopenia + schistocytes → TTP
CCS pearl: On a CCS case, order vitals q4h, type and screen, peripheral IV access, and place the patient on neutropenic precautions if ANC <500 before drilling into the etiology. Transfuse platelets if <10 (or <20 with fever/bleeding risk) and packed RBCs for symptomatic anemia.
Board pearl: Splenomegaly + pancytopenia in an otherwise well middle-aged smoker → hairy cell leukemia (dry tap on aspirate, TRAP+, BRAF V600E).
— CBC with differential, MCV, MCH, RDW
— Peripheral blood smear (highest-yield single test — review personally or insist on hematopathologist read)
— Reticulocyte count with reticulocyte production index (RPI <2 = inadequate marrow response)
— Comprehensive metabolic panel (LFTs, BUN/Cr)
— LDH, indirect bilirubin, haptoglobin (hemolysis screen)
— Vitamin B12 and folate (RBC folate if recently treated)
— Iron studies, ferritin
— TSH
— HIV, hepatitis B and C serologies
— ANA, dsDNA if autoimmune features
— Coagulation panel (PT/INR, aPTT, fibrinogen, D-dimer if DIC suspected)
— Pregnancy test in reproductive-age women
— Type and screen
— Blasts → urgent leukemia workup, flow cytometry, marrow biopsy
— Schistocytes → TTP/HUS/DIC (check ADAMTS13)
— Hypersegmented neutrophils, macro-ovalocytes → B12/folate
— Teardrop cells, leukoerythroblastic picture (nucleated RBCs + immature myeloid) → marrow infiltration, myelofibrosis
— Dysplastic granulocytes (Pelger-Huët, hypogranular) → MDS
— Atypical lymphocytes → EBV, CMV, HIV
— Hairy cells → hairy cell leukemia
— Macrocytic: B12/folate, MDS, liver disease, hypothyroid, drugs (hydroxyurea, AZT)
— Normocytic: aplastic anemia, infiltration, early MDS
— Microcytic: less common in true pancytopenia; consider combined deficiency
Step 3 management: If the smear shows blasts or schistocytes, this is no longer an outpatient workup — admit. Otherwise, complete the ambulatory panel and book hematology within 1–2 weeks.
Board pearl: A normal reticulocyte count in the face of anemia is inappropriately low — the marrow should respond. Treat low RPI as marrow failure until proven otherwise.
— Initial workup is non-diagnostic
— Smear shows blasts, dysplasia, or leukoerythroblastic features
— Suspected MDS, aplastic anemia, leukemia, lymphoma, myeloma, infiltrative process
— Persistent unexplained cytopenias >2–4 weeks
— Hypocellular (<25% cellularity, fatty marrow): aplastic anemia, hypoplastic MDS, drug toxicity
— Hypercellular with dysplasia: MDS (need ≥10% dysplasia in a lineage + cytogenetics)
— Hypercellular with blasts ≥20%: acute leukemia
— Fibrosis (reticulin stain): primary myelofibrosis, metastatic carcinoma
— Granulomas: TB, fungal, sarcoid
— Hemophagocytosis: HLH
— "Dry tap": myelofibrosis, hairy cell leukemia, densely packed marrow
— Flow cytometry (lineage, clonality, blast phenotype)
— Cytogenetics/karyotype (del 5q, monosomy 7, complex karyotype → MDS prognosis)
— FISH and molecular panel (JAK2, CALR, MPL, FLT3, NPM1, TP53)
— PNH flow (CD55/CD59 deficiency, FLAER assay) — order in any aplastic anemia or unexplained pancytopenia with hemolysis/thrombosis
— HLH: ferritin >500 (often >10,000), fasting triglycerides, fibrinogen, soluble IL-2R, NK cell function
— Copper/zinc levels: in patients with bariatric surgery or zinc supplementation (copper deficiency mimics MDS)
— Parvovirus B19 PCR: especially in immunocompromised or chronic hemolytic anemia
— Chromosome breakage (diepoxybutane) test: young patient → Fanconi anemia
— Telomere length: dyskeratosis congenita
CCS pearl: Order "bone marrow biopsy with aspirate, flow cytometry, cytogenetics, and FISH panel" as a single bundle — splitting them wastes CCS clock and risks missing the diagnostic window before transfusion alters marrow.
Key distinction: Aplastic anemia = hypocellular marrow without dysplasia or fibrosis. Hypoplastic MDS = hypocellular with dysplasia and often abnormal cytogenetics. PNH flow distinguishes overlap.
1. Is the patient hemodynamically stable?
2. Is there active bleeding or febrile neutropenia?
3. Is there evidence of leukemia, TTP, DIC, or HLH on smear?
— Outpatient workup acceptable: ANC >1.0, platelets >50, Hgb >9, no bleeding, no fever, stable trend
— Admission required: ANC <500, platelets <20, symptomatic anemia, fever, blasts/schistocytes, suspected TTP/HLH/DIC
— ICU: hemodynamic instability, TTP with neuro symptoms, DIC with bleeding, febrile neutropenia with sepsis
— ANC <500
— Platelets <20
— Reticulocyte count <60 ×10⁹/L (or <1%)
— Transfuse RBCs for symptomatic anemia or Hgb <7 (or <8 in CAD); use irradiated, leukoreduced, CMV-safe products if transplant candidate
— Platelets if <10 (prophylactic) or <20 with fever, <50 with bleeding/procedures
— Avoid HLA alloimmunization — minimize transfusions in potential transplant candidates
— Neutropenic precautions, avoid raw foods, no rectal exams or suppositories
— Hold offending drugs immediately
— Cefepime, piperacillin-tazobactam, or meropenem within 1 hour of fever
— Add vancomycin if catheter-related infection, mucositis, hemodynamic instability, or prior MRSA
— Antifungal (voriconazole, micafungin) if fever persists >4–7 days
— TTP → plasma exchange + steroids + caplacizumab
— HLH → HLH-94 protocol (etoposide + dexamethasone)
— B12 → IM cyanocobalamin
— Aplastic anemia → HSCT (young, HLA-matched sibling) vs. ATG + cyclosporine + eltrombopag
Step 3 management: Don't transfuse a stable asymptomatic patient with Hgb 8 just because it's low — over-transfusion in aplastic anemia worsens iron overload and alloimmunization, jeopardizing future transplant.
— HSCT for patients <50 with matched sibling donor → curative
— Immunosuppressive therapy (IST) for older or no donor: horse ATG + cyclosporine + eltrombopag
— Response rates ~70% with triple therapy; monitor for serum sickness (ATG), nephrotoxicity (cyclosporine), hepatotoxicity (eltrombopag)
— Lower-risk (IPSS-R low/intermediate): erythropoiesis-stimulating agents (epoetin/darbepoetin) if EPO <500
— Lenalidomide for del(5q) MDS — dramatic response
— Luspatercept for ring sideroblast MDS or ESA failure
— Higher-risk: hypomethylating agents (azacitidine, decitabine) — improve survival, bridge to transplant
— Allogeneic HSCT — only curative option
— IM cyanocobalamin 1000 mcg daily ×1 week, then weekly ×4 weeks, then monthly indefinitely (lifelong if pernicious anemia)
— Oral 1000–2000 mcg daily acceptable if no neuro symptoms and absorption preserved
— Replete folate simultaneously to avoid worsening neuro deficits
— Eculizumab or ravulizumab (anti-C5) — vaccinate against N. meningitidis (MenACWY + MenB) ≥2 weeks before therapy
Board pearl: Always vaccinate against encapsulated organisms (meningococcus, pneumococcus, Hib) at least 2 weeks before starting eculizumab or splenectomy — Step 3 loves this delayed-consequence question.
Key distinction: Erythropoietin works in MDS only if endogenous EPO is low (<500 mU/mL) and transfusion need is modest.
— Posterior superior iliac spine is standard site
— Sternal aspiration only — never biopsy (risk of cardiac perforation)
— Hold anticoagulation per agent-specific guidance; reverse if INR >1.5; platelets >20 acceptable (transfuse if lower and procedure urgent)
— Allogeneic for severe aplastic anemia (<50 yo, matched sibling preferred), high-risk MDS, acute leukemia, severe PNH
— Conditioning: cyclophosphamide ± ATG for aplastic anemia; reduced-intensity for older patients
— Pre-transplant: HLA typing of patient and siblings, CMV serology, dental clearance, cardiac/pulmonary evaluation, viral hepatitis screen
— Post-transplant complications: GVHD (acute <100 days, chronic >100 days), CMV reactivation, sinusoidal obstruction syndrome, secondary malignancy, infertility
— TTP: daily until platelets >150 for 2 consecutive days and LDH normalizes
— Replace with FFP (provides ADAMTS13)
— Rarely first-line in pancytopenia; consider in hairy cell leukemia (now usually cladribine instead), refractory ITP, hypersplenism with severe symptomatic cytopenias from cirrhosis or lymphoma
— Pre-op vaccines (≥2 weeks prior): pneumococcal (PCV20 or PCV15+PPSV23), meningococcal (ACWY + B), Hib, annual influenza
— Lifelong asplenia counseling: emergency antibiotics for febrile illness, medical alert bracelet
CCS pearl: When ordering HSCT workup on CCS, sequence is: HLA typing → infectious disease screen → cardiac/pulm function → dental → conditioning → transplant → monitor engraftment (ANC >500 ×3 days). Don't skip the dental clearance.
— MDS is the dominant etiology — incidence rises sharply after 70
— Lower threshold for marrow biopsy when CBC abnormalities persist
— Reduced bone marrow reserve → slower recovery from chemo, drugs
— B12 deficiency increasingly common (atrophic gastritis, PPI use, metformin)
— Anemia of chronic disease, CKD-related anemia mimic primary marrow disease
— HSCT generally not offered above 70–75; reduced-intensity conditioning extends eligibility
— Goals-of-care conversations early — transfusion dependence and treatment burden matter
— Erythropoietin deficiency contributes to anemia; check EPO level
— Dose-adjust: cyclosporine (monitor levels, nephrotoxic), allopurinol (reduce in tumor lysis prophylaxis), antibiotics (cefepime — risk of neurotoxicity if not adjusted)
— Methotrexate contraindicated in CrCl <30
— Avoid NSAIDs (worsen renal function, bleeding risk)
— Eltrombopag dosing affected by hepatic but not renal function
— Cirrhosis causes pancytopenia via hypersplenism (portal HTN) + decreased thrombopoietin synthesis
— Treat the liver disease (TIPS for portal HTN, transplant); splenectomy rarely indicated
— Avoid hepatotoxic drugs (azathioprine, methotrexate)
— Reduce dose: cyclophosphamide, vincristine, doxorubicin
— Watch for HBV reactivation when starting immunosuppression — screen HBsAg, anti-HBc, HBV DNA; prophylactic entecavir if positive
Step 3 management: In an 82-year-old with newly diagnosed lower-risk MDS, start with epoetin if EPO <500 and transfuse as needed — don't reflexively offer hypomethylating agents. Quality of life and transfusion independence are the realistic goals.
Board pearl: Cirrhosis + pancytopenia + splenomegaly doesn't need a marrow biopsy — it needs imaging for portal HTN and hepatology referral.
— Gestational thrombocytopenia is common but isolated; true pancytopenia is rare and needs workup
— Pancytopenia in pregnancy → consider HELLP, TTP, AFLP, aplastic anemia (rare, may be pregnancy-triggered), folate deficiency (megaloblastic)
— Folate supplementation 400–800 mcg daily preconception; 4 mg if prior NTD
— Avoid teratogenic agents: methotrexate, hydroxyurea (relative), thalidomide, azacitidine
— Eculizumab is safe in pregnancy for PNH (and reduces thrombotic risk, which spikes peripartum)
— ATG/cyclosporine can be used if aplastic anemia diagnosed during pregnancy
— Plasma exchange remains first-line for TTP in pregnancy
— Fanconi anemia: café-au-lait spots, short stature, radial/thumb anomalies, renal anomalies, increased AML/SCC risk; diagnose with chromosome breakage (DEB/MMC) test
— Dyskeratosis congenita: nail dystrophy, oral leukoplakia, reticular skin pigmentation, pulmonary fibrosis; short telomeres
— Shwachman-Diamond: pancreatic insufficiency + neutropenia + skeletal abnormalities
— Diamond-Blackfan: pure red cell aplasia, can progress; thumb anomalies, craniofacial
— Pearson syndrome: mitochondrial, sideroblastic anemia + pancreatic insufficiency
— Viral (parvovirus B19 in sickle cell → aplastic crisis), EBV, HHV-6
— ALL is the most common pediatric malignancy presenting with pancytopenia
— Autoimmune lymphoproliferative syndrome (ALPS)
— Consider HIV, anorexia nervosa (marrow gelatinous transformation), eating disorders, anabolic steroid abuse
Key distinction: Pure red cell aplasia (isolated anemia with reticulocytopenia) is not pancytopenia — but parvovirus B19 in immunocompromised hosts can cause pancytopenia and is treatable with IVIG.
Board pearl: A child with thumb anomalies, short stature, and pancytopenia → Fanconi anemia. Order chromosome breakage test before any marrow biopsy.
— Febrile neutropenia → bacteremia, fungal infection (invasive aspergillosis if neutropenia >7–10 days), typhlitis (neutropenic enterocolitis — RLQ pain, fever, bowel wall thickening on CT)
— Reactivation of latent infections: HBV, HCV, TB, CMV, HSV, VZV
— Pneumocystis jirovecii in prolonged immunosuppression — prophylax with TMP-SMX
— Intracranial hemorrhage (highest mortality) — platelets <10 with hypertension or trauma
— GI bleed, pulmonary hemorrhage, retinal hemorrhage with vision loss
— Iron overload → cardiac (heart failure, arrhythmias), hepatic (cirrhosis), endocrine (diabetes, hypogonadism, hypothyroidism)
— Alloimmunization → refractoriness to platelet transfusions
— TRALI, TACO, transfusion reactions, transmission of infections
— GVHD from non-irradiated products in immunosuppressed (use irradiated blood)
— Aplastic anemia → clonal evolution to MDS/AML (~15% at 10 years) or PNH
— MDS → AML transformation (varies by IPSS-R risk)
— Lower-risk MDS can still kill via infection/bleeding before transformation
— ATG: serum sickness (fever, rash, arthralgia, days 7–14)
— Cyclosporine: hypertension, nephrotoxicity, gingival hyperplasia, hirsutism, tremor
— Eltrombopag: hepatotoxicity, cataracts, thromboembolism
— Hypomethylating agents: cytopenias worse before better (3–4 cycles to assess response)
— HSCT: GVHD, infection, infertility, secondary malignancy, sinusoidal obstruction syndrome
— Treatment fatigue, financial toxicity, depression, sexual dysfunction post-transplant
Step 3 management: Suspect typhlitis in a neutropenic patient with abdominal pain — get CT abdomen, hold neutropenic diet, broad-spectrum antibiotics with anaerobic coverage, avoid surgery unless perforation or refractory bleeding.
Board pearl: Fever + RUQ pain + hepatomegaly + jaundice + weight gain post-HSCT → sinusoidal obstruction syndrome (VOD). Treat with defibrotide.
— Septic shock from febrile neutropenia (lactate >4, MAP <65 despite fluids, pressor requirement)
— TTP with neurologic symptoms or cardiac involvement
— DIC with active bleeding
— HLH with multiorgan dysfunction
— Intracranial hemorrhage
— Tumor lysis syndrome with acute kidney injury or arrhythmia
— Hyperleukocytosis (WBC >100, blast crisis) with leukostasis — order leukapheresis
— ANC <500 with fever (febrile neutropenia)
— Platelets <10 or <20 with bleeding
— Symptomatic anemia requiring transfusion + active workup
— New diagnosis of leukemia, suspected MDS requiring marrow, suspected aplastic anemia
— Initiation of chemotherapy or immunosuppression
— Hematology/oncology — required for any unexplained pancytopenia, all marrow biopsies, all transfusion-dependent patients
— Infectious disease — persistent neutropenic fever, suspected fungal infection, HSCT candidate
— Transplant hematology — early referral for severe aplastic anemia, high-risk MDS, AML
— Hepatology — cirrhosis with hypersplenism
— Genetic counseling — suspected congenital marrow failure
— Palliative care — transfusion-dependent older MDS, refractory AML, transition to comfort
— If your facility lacks plasma exchange capability and you suspect TTP, transfer urgently after starting steroids
— Pediatric pancytopenia warrants tertiary pediatric heme/onc center
— HSCT requires transplant-capable center
CCS pearl: On CCS, "consult hematology" early — but you must still order the workup yourself. The consult doesn't substitute for the marrow biopsy order, the transfusion orders, or the antibiotic order.
Key distinction: Febrile neutropenia is always a medical emergency even if the patient looks well — start antibiotics within 1 hour, not after cultures return.
— Hypocellular marrow (<25%), no dysplasia, no fibrosis
— Idiopathic 70%, drug-induced, viral (hepatitis non-A non-B non-C), radiation, benzene
— Severity by Camitta criteria
— Hypercellular (usually) marrow with dysplasia in ≥1 lineage ≥10%, cytogenetic abnormalities
— IPSS-R risk stratification: cytogenetics, blast %, cytopenias, hemoglobin
— Higher-risk lesions: del(7q), monosomy 7, complex karyotype, TP53 mutation
— ≥20% blasts in marrow or peripheral blood
— AML: Auer rods, MPO+; APML subtype (t(15;17), PML-RARA) → DIC, ATRA emergency
— ALL: TdT+, more common in children; CNS prophylaxis
— Leukoerythroblastic smear, teardrop cells, dry tap, splenomegaly, JAK2/CALR/MPL
— Ruxolitinib for symptoms
— Pancytopenia + monocytopenia + splenomegaly + dry tap; TRAP+, BRAF V600E; cladribine
— Macrocytic, hypersegs, mild pancytopenia with hemolysis pattern (intramedullary hemolysis)
— Hemolytic anemia + thrombosis (atypical sites: hepatic, cerebral) + cytopenias; CD55/CD59 deficient
— Anemia + renal failure + hypercalcemia + bone lesions; SPEP/UPEP, free light chains
— Breast, prostate, lung, stomach, neuroblastoma; leukoerythroblastic picture
Board pearl: Pancytopenia + monocytopenia is nearly pathognomonic for hairy cell leukemia. Most marrow disorders cause monocytosis, not monocytopenia.
Key distinction: MDS vs aplastic anemia → both can be hypocellular, but MDS has dysplasia and clonal cytogenetics; PNH flow and FISH panel separate them.
— Hypersplenism from any cause: cirrhosis, portal vein thrombosis, lymphoma, infections (malaria, schistosomiasis, leishmaniasis, EBV), Gaucher disease, sarcoidosis
— Autoimmune cytopenias: SLE (can cause autoimmune hemolytic anemia + ITP + autoimmune neutropenia = Evans syndrome variant), RA with Felty syndrome (RA + splenomegaly + neutropenia)
— Drug-induced immune cytopenias: quinine, heparin, vancomycin
— DIC: sepsis, malignancy, OB emergencies, snake bite
— TTP/HUS: ADAMTS13 deficiency or Shiga toxin; schistocytes, MAHA
— Viral: HIV (multifactorial — direct, drug-induced, opportunistic), CMV, EBV, parvovirus B19, hepatitis viruses, dengue
— Bacterial: overwhelming sepsis, mycobacteria (disseminated TB, MAC in HIV), brucellosis, ehrlichiosis, rickettsia
— Parasitic: malaria, visceral leishmaniasis (kala-azar)
— Fungal: disseminated histoplasmosis (marrow granulomas in HIV)
— B12, folate, copper deficiency (post-bariatric surgery, zinc supplementation)
— Anorexia nervosa with gelatinous marrow transformation
— Severe alcohol use (direct marrow suppression + folate + hypersplenism)
— Benzene, chemotherapy, radiation, arsenic, gold, NSAIDs
— Hypothyroidism (usually anemia alone, occasionally pancytopenia)
— Adrenal insufficiency (rarely)
Step 3 management: In any HIV patient with new pancytopenia, the differential expands enormously — drugs (AZT, ganciclovir, TMP-SMX), opportunistic infections (MAC, histo, CMV, parvovirus), lymphoma, and HIV itself. Marrow biopsy with cultures and stains is high-yield.
Board pearl: Copper deficiency post-gastric bypass perfectly mimics MDS on marrow morphology — check copper and ceruloplasmin before labeling a bariatric patient with MDS.
— B12 deficiency from pernicious anemia: lifelong IM B12 monthly or high-dose oral daily; monitor CBC, MCV, B12 levels
— Aplastic anemia post-IST: cyclosporine taper over 12+ months (rapid taper risks relapse); eltrombopag continuation; surveillance for clonal evolution (annual marrow, PNH flow)
— MDS: ESAs, transfusion support, iron chelation when ferritin >1000 or >20 units RBCs; consider transplant evaluation if eligible
— PNH: lifelong eculizumab/ravulizumab with meningococcal vaccination and prophylactic penicillin in pediatric patients
— Drug-induced: strict avoidance of offending agent, MedicAlert documentation
— Annual influenza (inactivated only — no live vaccines in immunosuppressed)
— PCV20 (or PCV15 + PPSV23 sequence), MenACWY + MenB, Hib for asplenic or complement-deficient (eculizumab) patients
— Hold live vaccines (MMR, varicella, zoster live, yellow fever) during active immunosuppression
— Recombinant zoster vaccine (Shingrix) acceptable and recommended
— TMP-SMX for PCP in prolonged steroid/immunosuppressant therapy
— Acyclovir for HSV/VZV during chemo/HSCT
— Fluconazole or posaconazole during high-risk neutropenia
— Deferasirox PO daily; monitor renal/hepatic function, ferritin q3 months, cardiac MRI T2* annually in chronically transfused
— Soft toothbrush, electric razor, avoid NSAIDs/aspirin
— Hormonal suppression of menses for severe thrombocytopenia
— Post-HSCT and Fanconi patients have increased SCC, AML, MDS risk — routine derm and oral exams
Step 3 management: At every visit with a chronically transfused patient, document ferritin, vaccine status, and discuss transplant eligibility. Step 3 rewards longitudinal management.
— Severe aplastic anemia on IST: CBC twice weekly initially, then weekly, then monthly after response
— MDS on hypomethylating agents: CBC weekly during cycle, before each cycle; response assessment after 4–6 cycles
— Stable lower-risk MDS: CBC every 1–3 months
— Drug-induced (recovering): CBC weekly until normalized
— Post-HSCT: CBC weekly for 100 days, then tapering
— Cyclosporine: trough levels, BP, Cr, magnesium, potassium, LFTs
— Eltrombopag: LFTs every 2 weeks initially, then monthly; eye exam annually
— Iron chelation: monthly Cr, urinalysis, LFTs, monthly ferritin
— PNH on eculizumab: LDH (should normalize), hemoglobin, reticulocyte count, meningococcal vaccine boosters
— MDS clonal evolution: annual or symptom-triggered marrow biopsy
— Aplastic anemia: PNH flow annually (risk of late PNH clone)
— Fever protocol: any T ≥38°C → call hematologist, go to ED for cultures and antibiotics
— Bleeding warning signs: headache, vision change, melena, hematuria
— Medication adherence and interactions (cyclosporine + statins, azoles, grapefruit juice)
— Reproductive counseling: fertility preservation pre-chemo/transplant
— Travel: avoid endemic areas during deep immunosuppression
— Diet: neutropenic precautions controversial; emphasize food safety, well-cooked foods
— Screen for depression, fatigue, financial toxicity
— Rehabilitation post-HSCT: physical therapy, nutrition, return-to-work planning
Step 3 management: A patient on cyclosporine with new edema and rising Cr — check trough level, reduce dose, recheck Cr in 1 week, consider switching to tacrolimus if intolerant.
Board pearl: A post-aplastic anemia patient years out who develops new hemolysis and abdominal pain — think PNH clonal evolution with hepatic vein thrombosis (Budd-Chiari).
— Risks: bleeding, infection, pain, rare cardiac event with sternal aspirate
— Document blood-product consent separately; specifically address Jehovah's Witness patients
— Jehovah's Witnesses: erythropoietin, IV iron, B12/folate, eltrombopag, romiplostim, anti-fibrinolytics (tranexamic acid), cell salvage — build a bloodless management plan; document advance directive
— Sibling donor consent: voluntary, free from coercion, separate counseling; minor donors require ethics review
— Fertility preservation discussion before initiating cytotoxic therapy — sperm banking, oocyte/embryo cryopreservation, ovarian tissue preservation
— Disclosure of treatment-related mortality (HSCT can be 10–30% at 1 year)
— Newly diagnosed leukemia and MDS → state cancer registry
— Suspected occupational benzene exposure → OSHA reporting, workers' compensation
— Suspected medication error causing agranulocytosis → institutional safety event reporting (e.g., clozapine REMS noncompliance)
— Pancytopenic patients discharged on multiple immunosuppressants are high-risk for readmission — confirm primary care follow-up within 7 days, hematology within 2 weeks
— Medication reconciliation: stop offending agents and clearly document allergies/intolerances
— Communicate fever protocol in writing to patient AND PCP
— Clozapine: ANC monitoring required; do not dispense if ANC criteria not met
— Lenalidomide, thalidomide: REMS pregnancy prevention program (two contraceptive methods, monthly pregnancy tests)
— Transfusion-dependent older MDS without transplant option — discuss goals; transfusions can continue as palliation but home hospice often discontinues
— Document code status before each admission
Step 3 management: A 17-year-old needing HSCT with sibling donor — donor consent requires ethics consultation, independent advocate, and capacity assessment separate from the recipient's medical team.
Board pearl: Clozapine + new fever + sore throat — immediate ANC check, discontinue clozapine if ANC <1000; never rechallenge if true agranulocytosis.
— Pancytopenia + dry tap + splenomegaly + monocytopenia → hairy cell leukemia (cladribine)
— Pancytopenia + Auer rods + DIC → APML (ATRA + arsenic, emergency)
— Pancytopenia + hypocellular marrow in young adult → aplastic anemia
— Pancytopenia + macro-ovalocytes + hypersegs + glossitis + neuro signs → B12 deficiency
— Pancytopenia + schistocytes + neuro + renal + fever → TTP
— Pancytopenia + ferritin >10,000 + fever + hepatosplenomegaly → HLH
— Pancytopenia + dark morning urine + atypical-site thrombosis → PNH
— Pancytopenia + café-au-lait + thumb anomaly in child → Fanconi anemia
— Pancytopenia + teardrop cells + leukoerythroblastic + splenomegaly → myelofibrosis
— Pancytopenia + bone pain + hypercalcemia + renal failure → multiple myeloma
— Pancytopenia + rheumatoid arthritis + splenomegaly → Felty syndrome
— Pancytopenia + nail dystrophy + oral leukoplakia → dyskeratosis congenita
— Pancytopenia + pancreatic insufficiency in child → Shwachman-Diamond
— MCV >115 → almost always B12/folate, MDS, or drug
— Reticulocyte index <2 with anemia → marrow failure
— LDH very high + low haptoglobin + indirect bili high → hemolysis (intra- or extravascular)
— Hgb F elevated in adult → suggests MDS, aplastic anemia
— Chemo (predictable), chloramphenicol (idiosyncratic aplasia), carbamazepine, phenytoin, clozapine, methimazole/PTU, sulfasalazine, TMP-SMX, linezolid, ticlopidine, gold, NSAIDs
Board pearl: If the stem mentions "atypical-site thrombosis" (Budd-Chiari, mesenteric, cerebral venous sinus) with hemolysis, the answer is PNH — order flow cytometry for CD55/CD59 (or FLAER).
— Answer: Stop methimazole, draw cultures, start empiric cefepime, admit. Next best step ≠ G-CSF first; antibiotics come first.
— Answer: Start ATRA immediately before genetic confirmation; transfuse cryoprecipitate, platelets, plasma. Do not wait for cytogenetics.
— Answer: HLA-type patient and siblings; if <50 with matched sibling → HSCT; otherwise ATG + cyclosporine + eltrombopag.
— Answer: IM cyanocobalamin loading dose; recheck CBC at 1–2 weeks (expect retic surge).
— Answer: Cladribine.
— Answer: Flow cytometry for CD55/CD59 → eculizumab after meningococcal vaccine.
— Answer: HLH-94 protocol; treat EBV.
— Answer: Methotrexate or rituximab; G-CSF for symptomatic neutropenia.
— Answer: Lenalidomide.
Step 3 management: Stems mentioning "next best step" almost always want the cheapest, safest, most informative test before the marrow biopsy — usually the peripheral smear or a targeted lab (B12, retic, HIV).
Pancytopenia is approached by first stabilizing the patient and then dichotomizing into decreased marrow production (hypocellular: aplastic anemia, MDS, drugs, B12) versus increased peripheral destruction/sequestration (TTP, DIC, hypersplenism, autoimmune), guided by the peripheral smear, reticulocyte index, and ultimately a bone marrow biopsy with cytogenetics and flow cytometry.
Board pearl: When in doubt, the peripheral blood smear and reticulocyte count are the two highest-yield, lowest-cost tests that direct the entire downstream workup — order them before anything fancy.