Blood & Lymphoreticular

Thrombocytopenia: workup algorithm

Clinical Overview and When to Suspect Thrombocytopenia

— Mild: 100–149K — usually outpatient workup, often incidental.

— Moderate: 50–99K — procedural caution, no spontaneous bleed.

— Severe: <50K — bleeding risk rises; <20K → spontaneous mucocutaneous bleeding; <10K → intracranial hemorrhage risk.

— Petechiae, purpura, wet purpura (oral blood blisters), epistaxis, menorrhagia, GI bleed in a previously healthy patient.

— New medication exposure (heparin, vancomycin, linezolid, quinine, sulfonamides, valproate, GPIIb/IIIa inhibitors).

— Recent viral illness, HIV/HCV risk factors, pregnancy, chemotherapy, alcohol use, liver disease.

— Microangiopathic features: fever, neuro changes, AKI, dark urine → think TTP/HUS/DIC.

— Young woman + isolated low platelets + mucocutaneous bleeding → ITP.

— Hospitalized patient day 5–10 of heparin + 50% drop → HIT.

— Pregnant patient near term + mild drop → gestational thrombocytopenia.

— Cirrhotic + splenomegaly → sequestration.

Board pearl: A patient with platelets 80K and no bleeding does not need urgent transfusion — assess mechanism first; transfusion can be harmful in HIT and TTP.

Definition: platelet count <150,000/µL; clinically meaningful bleeding risk generally emerges at <50,000/µL, and spontaneous bleeding at <10,000–20,000/µL.

Severity tiers (memorize for Step 3 triage decisions):

When to suspect even before the CBC returns:

Step 3 framing: the question is rarely "what is the platelet count" — it is "is this isolated thrombocytopenia, multilineage cytopenia, or a microangiopathy?" This branch point drives the entire algorithm.

Incidental thrombocytopenia in ambulatory clinic: repeat CBC with peripheral smear and citrate tube (to exclude pseudothrombocytopenia from EDTA-induced clumping) before any further workup.

Pretest probability anchors:

Presentation Patterns and Key History

— Platelet-type bleeding (thrombocytopenia or platelet dysfunction): petechiae, purpura, epistaxis, gingival bleeding, menorrhagia, GI bleed, immediate post-procedural oozing.

— Coagulation-factor bleeding (hemophilia, warfarin, DIC late): hemarthrosis, deep muscle hematomas, delayed bleeding after trauma. If you see this picture, thrombocytopenia is not the whole story.

— Full med list including OTC, supplements (quinine in tonic water, herbals), recent antibiotics.

— Heparin within 5–14 days (HIT) or re-exposure within 100 days (rapid-onset HIT).

— Recent vaccines, viral syndromes (EBV, CMV, HIV, HCV, dengue, parvovirus, COVID-19).

— Travel and tick exposure (anaplasmosis, ehrlichiosis, babesiosis, RMSF, malaria).

— Diet/alcohol (folate, B12 deficiency; alcohol marrow suppression).

— Pregnancy status and trimester.

— Family history (von Willebrand, MYH9 disorders, Wiskott-Aldrich, congenital macrothrombocytopenias).

— Prior platelet counts — was this new or chronic and stable?

— B symptoms, lymphadenopathy → lymphoma, leukemia.

— Joint pain, rash, photosensitivity → SLE, APS.

— Hepatitis risk factors, ascites → cirrhosis with hypersplenism.

— Mental status changes + fever → TTP until proven otherwise.

— Dyspnea + DVT in setting of falling platelets → HIT with thrombosis.

Key distinction: Petechiae spare the soles in ITP but are prominent on the feet and ankles in vasculitis — a clue when the smear is "normal" except for low platelets.

Bleeding phenotype localizes the defect:

Targeted history (Step 3 loves the medication reconciliation):

Review of systems triggers:

Timeline matters: abrupt drop over days suggests immune destruction, drug effect, DIC, or TTP; gradual drift over months suggests marrow process, MDS, or chronic liver disease.

Physical Exam Findings and Hemodynamic Assessment

— Petechiae: pinpoint, non-blanching, dependent areas (ankles, dorsum of feet) — favor mucocutaneous/platelet etiology.

— Purpura and ecchymoses without trauma — quantify and photograph.

— Wet purpura (hemorrhagic bullae on buccal/palatal mucosa) → impending serious bleed, marker for transfusion in severe ITP.

— Palpable purpura → vasculitis, not isolated thrombocytopenia.

— Splenomegaly argues against ITP and toward lymphoma, CLL, infection (EBV, malaria), portal hypertension, or storage disease.

— Lymphadenopathy → infection or hematologic malignancy workup.

— New limb ischemia, DVT, or skin necrosis at heparin injection sites in hospitalized patient → HIT.

— Mechanical valve or LVAD → consider mechanical hemolysis.

— Tachycardia, hypotension, orthostasis, drop in Hb → active hemorrhage; resuscitate before workup.

— Fever + hypotension + thrombocytopenia + DIC labs → septic DIC.

Step 3 management: A hemodynamically unstable thrombocytopenic patient with active bleeding gets simultaneous type-and-cross, platelet transfusion (unless TTP/HIT suspected), and source control — do not wait for the smear. In suspected TTP/HIT, avoid platelets unless life-threatening bleeding.

Skin and mucosa (highest yield):

Lymph nodes and spleen:

Hepatic stigmata: spider angiomas, palmar erythema, caput medusae, ascites → cirrhosis with hypersplenism + decreased thrombopoietin.

Neurologic exam: focal deficits, confusion, seizure → TTP pentad (fever, MAHA, thrombocytopenia, renal dysfunction, neuro changes) — though full pentad is rare; MAHA + thrombocytopenia alone is enough to act.

Cardiopulmonary and vascular:

Hemodynamic assessment:

Obstetric exam: fundal height, BP, reflexes, edema, RUQ tenderness → preeclampsia/HELLP.

Diagnostic Workup — Initial Labs

— Repeat CBC; review smear for platelet clumping (pseudothrombocytopenia from EDTA-dependent agglutinins).

— Redraw in citrate (blue top) or heparin tube; if count normalizes, no further workup.

— CBC with differential: WBC, Hgb, MCV, reticulocyte count.

— Isolated thrombocytopenia → ITP, drug-induced, early HIT, gestational.

— Bi/tricytopenia → marrow failure (aplastic anemia, MDS, leukemia, B12/folate, alcohol, infiltration).

— Schistocytes → microangiopathy: TTP, HUS, DIC, HELLP, malignant HTN, mechanical valve.

— Large/giant platelets → ITP, congenital macrothrombocytopenia (MYH9), recovery phase.

— Blasts → acute leukemia → urgent heme consult.

— Teardrop cells, leukoerythroblastic picture → marrow infiltration/myelofibrosis.

— Hypersegmented neutrophils → B12/folate deficiency.

— Spherocytes → Evans syndrome (AIHA + ITP).

— Intracellular parasites → malaria, babesiosis, anaplasmosis.

— PT/INR, aPTT, fibrinogen, D-dimer → DIC has ↑PT/PTT, ↓fibrinogen, ↑D-dimer; TTP/HUS have normal coags.

— LDH, indirect bilirubin, haptoglobin, reticulocytes, direct Coombs.

Board pearl: Normal PT/PTT/fibrinogen + schistocytes + thrombocytopenia = TTP/HUS, not DIC. This single distinction drives whether you start plasma exchange or treat the underlying sepsis.

Step 1 — Confirm the count is real:

Step 2 — Determine if isolated or part of pancytopenia:

Step 3 — Peripheral smear (the highest-yield test):

Step 4 — Coagulation and hemolysis panel (always when microangiopathy possible):

Step 5 — Etiology-targeted screens: HIV, HCV, HBV (treatable, ITP mimics), TSH, ANA, LFTs, BMP, pregnancy test in reproductive-age women, H. pylori (chronic ITP).

Diagnostic Workup — Advanced or Confirmatory Studies

— PLASMIC score components: platelets <30K, hemolysis, no active cancer, no transplant, MCV <90, INR <1.5, creatinine <2.

— Thrombocytopenia magnitude, Timing (5–10 days), Thrombosis, oTher causes.

— Score ≥4 → send PF4-heparin ELISA (anti-PF4/heparin antibody); if positive, confirm with serotonin release assay (SRA) — functional gold standard.

— Stop all heparin (including flushes, LMWH) immediately; start non-heparin anticoagulant (argatroban, bivalirudin, fondaparinux, or DOAC).

— Age >60 with new thrombocytopenia (rule out MDS).

— Multilineage cytopenia, abnormal smear (blasts, dysplasia, teardrops).

— Splenomegaly without clear cause.

— ITP not responding to first-line therapy.

— Findings: increased megakaryocytes → peripheral destruction (ITP); decreased → marrow failure.

— Antiphospholipid antibodies (lupus anticoagulant, anti-β2GP1, anticardiolipin) if thrombosis or recurrent miscarriage.

— ANA, dsDNA if SLE features.

— H. pylori stool antigen or breath test in adult ITP — eradication can raise platelets.

— HIV, HCV viral loads.

Key distinction: A positive PF4 ELISA alone is not HIT — many patients seroconvert without disease. The SRA (functional assay) confirms; clinical 4T score drives initial action.

ADAMTS13 activity: order before plasma exchange when TTP suspected; activity <10% confirms TTP. Do not delay PLEX waiting for the result if PLASMIC score is high (≥6).

HIT workup — 4T score first, then labs:

Bone marrow biopsy — indications:

Immune/infectious add-ons:

Genetic testing: lifelong thrombocytopenia, family history, giant platelets, hearing loss/nephritis (MYH9), eczema/immunodeficiency (Wiskott-Aldrich).

Imaging: abdominal ultrasound for splenomegaly/portal HTN; CT if lymphoma suspected.

Risk Stratification and First-Line Management Logic

— Schistocytes present? → TTP/HUS/DIC pathway → coags, LDH, ADAMTS13, PLASMIC score; emergent hematology consult.

— On heparin? → 4T score → if ≥4, stop heparin, start argatroban, send PF4 antibody.

— Pregnant? → gestational vs ITP vs preeclampsia/HELLP vs AFLP pathway.

— Pancytopenia? → marrow evaluation.

— Isolated, no smear abnormalities, otherwise well? → ITP is a diagnosis of exclusion.

— >50K, asymptomatic: outpatient workup, no transfusion, safe for most procedures except neurosurgery/ocular.

— 30–50K: workup expedited; avoid antiplatelets/anticoagulants if possible.

— 20–30K: admit if uncertain etiology or bleeding risk; treat ITP.

— <20K or any bleeding: treat immediately (steroids ± IVIG for ITP; PLEX for TTP).

— <10K: prophylactic platelet transfusion in marrow failure/chemo; not in ITP/TTP/HIT unless life-threatening bleed.

— Minor procedures, central line: >20–50K.

— Major surgery: >50K.

— Neurosurgery, posterior eye surgery: >100K.

— Epidural/spinal anesthesia: >70–80K.

— Lumbar puncture: >40–50K (>20K if urgent).

— TTP, HIT, ITP without bleeding → platelets can worsen thrombosis or be ineffective; reserve for life-threatening hemorrhage.

Step 3 management: For asymptomatic platelets of 60K discovered on routine labs in a stable outpatient, the next step is repeat CBC with peripheral smear and citrate tube, not hospital admission or transfusion.

Algorithmic branch points (memorize):

Platelet threshold–based action:

Procedural thresholds (Step 3 perioperative favorite):

Transfusion contraindications/cautions:

Pharmacotherapy — First-Line Drug Regimen

— Corticosteroids:

— Prednisone 1 mg/kg/day × 1–2 weeks then taper, or

— Dexamethasone 40 mg daily × 4 days (preferred — faster response, shorter exposure, higher sustained response).

— IVIG 1 g/kg × 1–2 days — when rapid rise needed (bleeding, pre-procedure, platelets <20K), pregnancy, steroid contraindication. Onset 24–48h.

— Anti-D immunoglobulin — Rh-positive, non-splenectomized, non-anemic patients; boxed warning for intravascular hemolysis.

— Platelet transfusion only for life-threatening bleeding; give with IVIG/steroids since transfused platelets are also destroyed.

— Thrombopoietin receptor agonists: romiplostim (SC weekly), eltrombopag (PO daily, avoid with food/calcium), avatrombopag.

— Rituximab 375 mg/m² weekly × 4.

— Fostamatinib (SYK inhibitor) for chronic refractory.

— Splenectomy — durable remission ~60%; vaccinate against encapsulated organisms (S. pneumoniae, H. influenzae, N. meningitidis) ≥2 weeks pre-op.

— Stop all heparin (UFH, LMWH, flushes, heparin-coated catheters).

— Argatroban (hepatic clearance — preferred in renal failure), bivalirudin, or fondaparinux.

— Transition to warfarin only after platelets recover >150K and with ≥5-day overlap to prevent warfarin-induced skin necrosis/venous limb gangrene.

— DOACs increasingly used once stable.

Board pearl: Never bridge HIT patients with warfarin alone — protein C drops faster than factors II/VII/IX/X, causing warfarin-induced venous limb gangrene.

Immune thrombocytopenia (ITP) — adult first-line:

Second-line ITP (chronic/refractory):

HIT pharmacotherapy:

TTP: urgent plasma exchange + corticosteroids; add caplacizumab (anti-vWF nanobody) and rituximab for immune TTP.

DIC: treat underlying cause; supportive blood products only if bleeding.

Procedures and Expanded Pharmacologic Management

— Initiate within 4–8 hours of suspicion; do not wait for ADAMTS13.

— Daily 1–1.5 plasma volume exchanges with FFP replacement until platelets >150K × 2 days and LDH normalizing.

— Adjunct: methylprednisolone 1 g/day × 3, caplacizumab (reduces refractoriness and mortality), rituximab for relapse prevention.

— Indication: ITP refractory to ≥1 line of therapy, persistent for ≥12 months.

— Pre-op: vaccinate ≥14 days prior against pneumococcus (PCV20 or PCV15→PPSV23), meningococcus (ACWY + B), Hib, annual influenza.

— Post-op: lifelong awareness of overwhelming post-splenectomy infection (OPSI); patient carries antibiotic standby.

— 1 apheresis unit ≈ 6 pooled random-donor units → expected rise ~30–50K.

— Corrected count increment (CCI) at 1h <7,500 suggests refractoriness — workup HLA antibodies, consider HLA-matched products.

— Use leukoreduced (CMV-safe, reduces alloimmunization) and irradiated (immunocompromised, intrauterine, BMT) when indicated.

— Eltrombopag: separate from polyvalent cations (dairy, antacids, iron) by 4 hours; monitor LFTs.

— Romiplostim: weekly SC, titrate to platelets 50–200K.

CCS pearl: In a CCS case of suspected TTP, the correct sequence is "Consult hematology, order ADAMTS13, initiate plasma exchange, IV methylprednisolone, caplacizumab" — moving the clock forward before PLEX is wrong even by hours.

Plasma exchange (PLEX) for TTP:

Splenectomy:

Platelet transfusion technique:

TPO-receptor agonist counseling:

Anticoagulation in HIT after recovery: continue non-heparin agent for minimum 4 weeks if isolated HIT, 3 months if HIT with thrombosis.

Procedural prophylaxis: for invasive procedures in ITP, IVIG + steroids 24–48h pre-op preferred over transfusion.

Special Populations — Elderly and Renal/Hepatic Impairment

— Higher pretest probability of MDS, CLL, monoclonal gammopathy, drug-induced thrombocytopenia, and occult malignancy.

— Bone marrow biopsy threshold is lower — strongly consider in any new persistent thrombocytopenia >60 years.

— ITP in elderly: more bleeding (especially intracranial), more steroid morbidity (hyperglycemia, osteoporosis, delirium, infection); prefer shorter dexamethasone pulse over prolonged prednisone, lower threshold for TPO-RA.

— Polypharmacy review is critical: check linezolid, valproate, thiazides, H2 blockers, vancomycin, sulfonamides, statins, gold, quinine.

— Uremia → qualitative platelet dysfunction (bleeding with normal count); treat with desmopressin (DDAVP), cryoprecipitate, dialysis, conjugated estrogens.

— HUS more common with renal involvement; atypical HUS → eculizumab (vaccinate against meningococcus).

— Argatroban preferred over bivalirudin in renal failure (hepatic clearance); avoid fondaparinux if CrCl <30.

— LMWH accumulates → bleeding risk; dose-adjust or switch to UFH.

— Cirrhosis: thrombocytopenia from splenic sequestration, reduced thrombopoietin production, alcohol marrow toxicity, HCV.

— Pre-procedure in cirrhosis: avastrombopag or lusutrombopag raises platelets without prothrombotic risk of FFP/platelets.

— Avoid argatroban in hepatic failure (hepatic clearance) — use bivalirudin or reduced-dose argatroban.

— Remember rebalanced hemostasis: low platelets do not equal bleeding risk equivalent to non-cirrhotic.

Step 3 management: A 72-year-old with platelets 95K stable over 3 months, MCV 104, mild neutropenia, and 2% blasts on smear → next step is bone marrow biopsy with cytogenetics, not steroids.

Elderly (>60) with new thrombocytopenia:

Renal impairment:

Hepatic impairment:

Special Populations — Pregnancy and Pediatrics

— Gestational thrombocytopenia (most common, ~75% of cases): mild (>70K, usually >100K), late 2nd–3rd trimester, no maternal/fetal sequelae, resolves postpartum. No treatment.

— ITP: any trimester, often <100K, may predate pregnancy. Treat if <30K or bleeding or pre-delivery; steroids or IVIG first-line. Avoid rituximab, TPO-RAs (limited safety data). Neonate may have transient thrombocytopenia from transplacental antibody → check cord blood.

— Preeclampsia/HELLP: ≥20 weeks, HTN, proteinuria, elevated AST/ALT, hemolysis. Definitive treatment is delivery; magnesium for seizure prophylaxis.

— Acute fatty liver of pregnancy (AFLP): 3rd trimester, hypoglycemia, coagulopathy, DIC.

— TTP: can mimic HELLP; ADAMTS13 <10% distinguishes; treat with PLEX.

— Antiphospholipid syndrome: thrombocytopenia + recurrent loss + thrombosis.

— Typically post-viral, abrupt onset, age 2–6, otherwise well child.

— Self-limited in ~80% within 6 months — observation alone is preferred for asymptomatic or minor bleeding regardless of count.

— Treat (IVIG preferred, or anti-D, or steroids) for significant mucosal bleeding or count <20K with bleeding.

— Avoid platelet transfusion unless life-threatening bleed.

— Bone marrow biopsy not required before steroids in classic presentation per current ASH guidelines.

Board pearl: Platelets 110K in a 36-week pregnant woman, asymptomatic, normal BP, normal LFTs = gestational thrombocytopenia — no workup, no treatment, recheck postpartum.

Pregnancy differential (timing-based):

Delivery thresholds: vaginal delivery >50K; cesarean >50K; epidural/spinal >70–80K.

Pediatric ITP:

Neonatal alloimmune thrombocytopenia (NAIT): maternal antibodies to fetal HPA-1a → severe neonatal thrombocytopenia + risk of in utero ICH; treat with maternal IVIG antenatally, washed maternal platelets postnatally.

Complications and Adverse Outcomes

— Intracranial hemorrhage — feared outcome, <1% in ITP but mortality 25–50%; risk rises with platelets <10K, age >60, antiplatelet/anticoagulant use, HTN, prior bleeding.

— GI bleeding, menorrhagia (iron deficiency over time), retinal hemorrhage.

— Wet purpura is a clinical predictor of impending serious bleeding.

— HIT thrombosis: 30–50% of HIT patients develop VTE, arterial thrombosis, limb gangrene, adrenal hemorrhage (bilateral adrenal vein thrombosis → Addisonian crisis), skin necrosis at injection sites.

— TTP: microvascular thrombosis → stroke, MI, mesenteric ischemia, AKI.

— APS: thrombosis with thrombocytopenia.

— Steroids: hyperglycemia, osteoporosis, AVN, mood disturbance, infection, weight gain, adrenal suppression.

— IVIG: aseptic meningitis, AKI (sucrose-containing preparations), thrombosis, volume overload, anaphylaxis in IgA-deficient patients.

— Rituximab: HBV reactivation (screen HBsAg/anti-HBc first), PML, infusion reactions, hypogammaglobulinemia.

— Splenectomy: OPSI (lifelong risk), portal vein thrombosis, surgical complications.

— TPO-RAs: thromboembolism, hepatotoxicity (eltrombopag), marrow reticulin fibrosis.

— Alloimmune platelet refractoriness from prior transfusions/pregnancies → HLA antibodies; manage with HLA-matched or crossmatched platelets, leukoreduction prevention.

Key distinction: A drop in platelets with a new thrombosis is HIT until proven otherwise — do not wait for ELISA; stop heparin and start argatroban based on 4T score alone.

Hemorrhagic complications:

Thrombotic complications (paradoxical but classic):

Treatment-related complications:

Refractoriness:

Iron deficiency from chronic menorrhagia or GI losses — supplement and address source.

When to Escalate Care — ICU, Consult, Inpatient Triage

— Any active bleeding with platelets <50K.

— Platelets <20K regardless of bleeding (especially new diagnosis).

— Suspected TTP, HUS, HIT, DIC, acute leukemia.

— Pregnancy with preeclampsia/HELLP features.

— Neurologic, cardiac, or GI symptoms with thrombocytopenia.

— Hemodynamic instability from hemorrhage.

— TTP undergoing PLEX with end-organ damage (stroke, MI).

— DIC with multi-organ failure or massive transfusion.

— Intracranial hemorrhage.

— HIT with massive PE, limb ischemia, or adrenal crisis.

— Suspected TTP (PLASMIC ≥5), HIT, acute leukemia, severe ITP with bleeding.

— Refractory ITP needing second-line therapy.

— Diagnostic uncertainty requiring bone marrow biopsy.

— Splenectomy candidates.

— Pregnant patients near term with thrombocytopenia <80K for delivery planning and neuraxial decisions.

— Acute abdomen with cytopenia (splenic rupture, mesenteric thrombosis).

— Platelets 50–100K, no bleeding, no smear abnormalities, stable trend, reliable patient.

— Schedule repeat CBC, smear, and targeted labs within 1–2 weeks.

— Counsel on activity restriction (avoid contact sports, NSAIDs, antiplatelets).

— Discharge instructions: bleeding precautions, when to return (headache, melena, neuro symptoms), medication list with platelet-affecting drugs removed.

CCS pearl: In a CCS case, ordering "platelet count" daily during ITP treatment, "hematology consult" early, and adding "advance directive discussion" when bleeding risk is high earns full management credit.

Admit immediately:

ICU criteria:

Hematology consult (urgent within hours):

Surgical/OB-GYN consult:

Outpatient/ambulatory pathway acceptable:

Transitions of care:

Key Differentials — Same-Category Causes (Decreased Production and Destruction)

— Aplastic anemia — pancytopenia, hypocellular marrow; causes: idiopathic, drugs (chloramphenicol, carbamazepine), hepatitis-associated, radiation.

— Myelodysplastic syndrome (MDS) — older adults, macrocytosis, dysplastic cells, blasts <20%; cytogenetics drive prognosis (IPSS-R).

— Acute leukemia — blasts on smear, bi/pancytopenia, urgent marrow.

— Marrow infiltration — metastatic cancer, lymphoma, myelofibrosis, granulomatous disease, mycobacterial infection → leukoerythroblastic smear.

— Nutritional: B12, folate, severe iron deficiency, copper deficiency.

— Drugs: chemotherapy, linezolid (especially >14 days), valproate, methotrexate, alcohol.

— Viral suppression: HIV, HCV, HBV, EBV, CMV, parvovirus B19, dengue, hantavirus.

— Primary ITP — diagnosis of exclusion.

— Secondary ITP — SLE, CLL, lymphoma, HIV, HCV, common variable immunodeficiency, post-vaccination.

— Drug-induced immune thrombocytopenia (DITP) — quinine, sulfonamides, vancomycin, rifampin, ceftriaxone, GPIIb/IIIa inhibitors (abciximab, tirofiban).

— HIT — IgG against PF4-heparin complex.

— Post-transfusion purpura — HPA-1a antibodies, 7–10 days post transfusion.

— Evans syndrome — AIHA + ITP.

— TTP, HUS (Shiga toxin, atypical complement-mediated), DIC, HELLP, mechanical valves, malignant hypertension, eclampsia, large hemangiomas (Kasabach-Merritt).

Board pearl: When isolated thrombocytopenia presents with normal smear, normal coags, and no splenomegaly in a young woman → ITP. Any deviation (splenomegaly, schistocytes, blasts, coag abnormality) means it is not ITP.

Decreased production (marrow process):

Increased destruction — immune:

Increased destruction — non-immune (consumption):

Key Differentials — Other-Category Causes (Sequestration, Dilution, Pseudo)

— Hypersplenism from any cause of splenomegaly: cirrhosis with portal hypertension, lymphoma, CLL, myeloproliferative disorders, Gaucher disease, sarcoidosis, chronic infection (malaria, leishmaniasis, EBV).

— Mechanism: up to 90% of platelets can pool in enlarged spleen (normal ~30%).

— Counts typically 50–100K, rarely <50K from sequestration alone.

— Treatment is of underlying cause; TIPS, splenectomy, or splenic artery embolization in selected cases.

— Massive transfusion (>10 units PRBC in 24h) without platelet replacement → use 1:1:1 ratio (PRBC:FFP:platelets).

— Massive fluid resuscitation in trauma or burns.

— EDTA-induced platelet agglutination — autoantibody causes clumping in vitro only.

— Diagnosis: smear shows clumps; redraw in citrate or heparin tube — count normalizes.

— Glycoprotein IIb/IIIa inhibitor–induced pseudothrombocytopenia is similar mechanism.

— Platelet satellitism (platelets rosette around neutrophils) — same management.

— Antiphospholipid syndrome.

— Vasculitides (GPA, MPA, IgA vasculitis — though usually normal counts).

— Hemophagocytic lymphohistiocytosis (HLH) — fever, splenomegaly, cytopenias, ferritin >10,000, triglycerides ↑, fibrinogen ↓.

— Sepsis without overt DIC — direct platelet activation and consumption.

— Vaccine-induced immune thrombotic thrombocytopenia (VITT) — adenoviral vector COVID vaccines + thrombosis (cerebral venous sinus) — anti-PF4 antibodies, treat like HIT (avoid heparin, IVIG, non-heparin anticoagulant).

Key distinction: Falsely low platelets from EDTA clumping is the most missed diagnosis — always inspect the smear before launching a thrombocytopenia workup.

Sequestration:

Dilutional:

Pseudothrombocytopenia (lab artifact):

Other systemic conditions:

Secondary Prevention, Discharge Medications, Long-Term Plan

— Define remission: platelets >100K off therapy ≥12 months.

— Monitor for relapse with CBC every 1–3 months initially; space out if stable.

— Vaccinate before rituximab or splenectomy; live vaccines deferred during immunosuppression.

— Eradicate H. pylori if positive — can produce durable remissions.

— Counsel: avoid aspirin, NSAIDs, fish oil, ginkgo, contact sports while platelets <50K.

— Iron supplementation if menorrhagia caused iron deficiency anemia; consider hormonal suppression of menses.

— Documented allergy/alert in chart — no heparin (including flushes) ever again unless emergent and antibodies have cleared (>100 days, with re-testing).

— Continue non-heparin anticoagulation: 4 weeks (isolated HIT) or 3 months (HIT with thrombosis); DOAC reasonable after platelet recovery.

— Medical alert bracelet.

— Lifelong relapse surveillance with CBC and ADAMTS13 every 3–6 months; rising ADAMTS13 antibody titer predicts relapse.

— Pre-emptive rituximab if ADAMTS13 falls <10% off therapy.

— Avoid pregnancy until in remission; pregnancy can precipitate relapse.

— Annual influenza, pneumococcal (PCV20 or PCV15→PPSV23 every 5 years), meningococcal ACWY (every 5 years) + B, Hib boosters.

— Patient carries standby antibiotic (amoxicillin-clavulanate or levofloxacin) for febrile illness, start immediately, seek care.

— Travel counseling for malaria (high risk in asplenia).

Step 3 management: Every HIT patient leaves the hospital with a chart allergy alert to all heparins and a medical alert ID — this is the single most exam-relevant safety transition.

ITP long-term plan:

Post-HIT:

Post-TTP:

Post-splenectomy (functional asplenia):

Cirrhosis-related: treat underlying liver disease, manage portal hypertension, avastrombopag pre-procedure.

Follow-Up, Monitoring Parameters, Rehab/Counseling

— Acute phase: CBC every 2–3 days while titrating therapy.

— After response: weekly × 2–4 weeks, then every 2–4 weeks, then every 1–3 months once stable.

— On TPO-RA: weekly CBC during titration, then monthly; LFTs monthly on eltrombopag.

— On rituximab: screen HBV, monitor IgG levels, watch for infections.

— Daily platelets until recovery >150K and on stable non-heparin anticoagulant.

— Doppler bilateral lower extremities at diagnosis (silent DVT in ~50%).

— Document seroconversion timeline for future heparin re-exposure decisions.

— Daily platelets, LDH, creatinine, hemoglobin, neurologic exam during PLEX.

— Taper PLEX after platelets >150K × 2 days.

— ADAMTS13 every 3 months for first year, then every 6–12 months.

— Soft-bristled toothbrush, electric razor, avoid contact sports/skiing/horseback riding while <50K.

— No IM injections; SC and IV acceptable.

— Avoid antiplatelets, NSAIDs, anticoagulants unless essential — and then with hematology input.

— Fall prevention especially in elderly on steroids.

Board pearl: A patient on chronic prednisone ≥20 mg for >4 weeks needs PJP prophylaxis (TMP-SMX), calcium/vitamin D, bone density screening, and PPI if also on NSAID/anticoagulant — these are favorite Step 3 add-ons.

ITP monitoring cadence:

HIT monitoring:

TTP monitoring:

Bleeding-precaution counseling:

Steroid taper counseling: never abrupt stop after >2 weeks; teach stress-dose recognition; bone health (calcium, vitamin D, DEXA if prolonged), glucose monitoring, PJP prophylaxis if prednisone ≥20 mg/day >4 weeks.

Vaccination tracking: maintain registry; coordinate boosters with PCP and pharmacy.

Mental health and quality of life: chronic ITP linked to fatigue and anxiety; screen and refer.

Ethical, Legal, and Patient Safety Considerations

— Jehovah's Witnesses and platelet transfusion: blood products including platelets generally refused; document advance directive, explore acceptable alternatives (IVIG, steroids, TPO-RAs, antifibrinolytics like tranexamic acid, recombinant factor VIIa in extremis). Respect autonomy even when life-threatening.

— Capacity assessment: a thrombocytopenic patient with intracranial bleed may lack capacity → identify surrogate per state hierarchy.

— Pediatric ITP: parental refusal of platelets in life-threatening bleed → court intervention may be required (best interest standard).

— HIT is a high-stakes adverse drug event — disclose to patient, document in allergy field, and report to institutional pharmacovigilance.

— Transfusion reactions, TRALI, alloimmunization → report to blood bank.

— Suspected NSAID/antiplatelet–induced bleeding in elderly → consider Beers Criteria review.

— Heparin allergy/alert not transferred between hospitals → re-exposure risk. Always send updated medication and allergy reconciliation with discharge summary; verbally communicate to receiving provider.

— Splenectomy patients: vaccination status, antibiotic standby, medical alert ID — explicit handoff to PCP.

— Anticoagulation transitions (argatroban → warfarin/DOAC) demand written plan, lab follow-up, and bridging instructions.

— Two-patient-identifier check before platelet transfusion.

— Look-alike/sound-alike medication errors: argatroban vs apixaban, heparin vs hetastarch.

— Never events: ABO-incompatible transfusion, wrong-patient transfusion.

Step 3 management: A Jehovah's Witness with ITP and platelets 8K plus mucosal bleeding gets high-dose dexamethasone + IVIG + tranexamic acid as first-line — not platelet transfusion — with clear documentation of advance directive.

Informed consent edge cases:

Mandatory reporting and disclosure:

Transitions of care (Step 3 favorite):

Patient safety systems:

Disclosure of medical error: if heparin given to known HIT patient, prompt apology and disclosure per institutional policy; document and analyze through root cause analysis.

High-Yield Associations and Rapid-Fire Clinical Facts

— Young woman + isolated thrombocytopenia + mucocutaneous bleed → ITP.

— Heparin day 5–10 + 50% platelet drop ± new thrombosis → HIT.

— Schistocytes + neuro changes + AKI + fever + thrombocytopenia → TTP.

— Child + bloody diarrhea (E. coli O157:H7) + AKI + thrombocytopenia → typical HUS.

— Pregnant + 3rd trimester + HTN + ↑LFTs + ↓platelets → HELLP.

— Sepsis + ↑PT/PTT + ↓fibrinogen + ↑D-dimer + ↓platelets → DIC.

— COVID vaccine (adenoviral vector) + cerebral venous sinus thrombosis + thrombocytopenia → VITT — treat like HIT.

— Splenomegaly + cytopenia + cirrhosis → hypersplenism.

— Recurrent miscarriage + thrombosis + thrombocytopenia → APS.

— Eczema + immunodeficiency + thrombocytopenia + male child → Wiskott-Aldrich.

— Giant platelets + nephritis + deafness → MYH9-related disorder (Alport-like).

— Absent radii + thrombocytopenia → TAR syndrome.

— Mucocutaneous bleeding + giant platelets + absent ristocetin aggregation → Bernard-Soulier (GPIb deficiency).

— Bleeding + normal platelet count but abnormal aggregation to all agonists except ristocetin → Glanzmann (GPIIb/IIIa).

— Dexamethasone 40 mg × 4 days = preferred ITP induction.

— IVIG = rapid rise, pregnancy-friendly, pre-procedure.

— Anti-D = Rh+, non-splenectomized, non-anemic only.

— Never warfarin alone in HIT.

— Never platelets in TTP/HIT unless life-threatening bleed.

— Avastrombopag/lusutrombopag for cirrhotic pre-procedure.

— Procedure thresholds: 50K major, 100K neuro/eye, 70–80K epidural, 20K minor.

— TTP cutoff: ADAMTS13 <10%.

— PLASMIC ≥6 high risk.

— 4T ≥4 → send HIT antibody.

Key distinction: DIC has abnormal coags; TTP/HUS do not. This single lab pattern distinguishes the two most dangerous microangiopathies.

Classic associations (one-liners):

Treatment pearls:

Numbers to memorize:

Board Question Stem Patterns

"Asymptomatic 45-year-old with routine CBC platelets 40K, normal smear shows clumping." → Next step: redraw in citrate tube. Trap: starting steroids or admitting.

"28-year-old woman, petechiae, platelets 8K, normal smear except large platelets, normal WBC and Hgb, no splenomegaly." → Diagnosis: ITP. Treatment: dexamethasone 40 mg × 4 days ± IVIG. Trap: bone marrow biopsy (not required in classic presentation).

"Post-op day 7 patient on UFH prophylaxis, platelets drop from 250K → 110K, new DVT." → 4T score 6 → stop heparin, start argatroban, send PF4 ELISA. Trap: switching to LMWH (cross-reacts) or starting warfarin alone.

"35-year-old with fever, confusion, AKI, platelets 12K, schistocytes, LDH 1500, normal PT/PTT." → Plasma exchange + steroids + caplacizumab, send ADAMTS13. Trap: platelet transfusion, waiting for ADAMTS13 before PLEX.

"Septic patient, platelets 40K, INR 2.1, fibrinogen 90, D-dimer >10,000." → Treat underlying sepsis, transfuse only if bleeding. Trap: heparin without source control.

"37-week pregnant, platelets 105K, asymptomatic, normal BP, no prior history." → Gestational thrombocytopenia, no treatment. Trap: IVIG/steroids.

"32-week pregnant, BP 165/105, AST 220, platelets 78K, schistocytes." → Magnesium + deliver. Trap: dexamethasone for ITP.

"Patient on TMP-SMX for 10 days, platelets drop from 220 → 18." → Stop drug, supportive; IVIG/steroids if bleeding.

"72-year-old, platelets 80K, MCV 108, neutropenia, dysplastic cells on smear." → Bone marrow biopsy with cytogenetics.

Board pearl: When the stem gives you timing of heparin exposure, count the days carefully — day 5–10 is HIT; day 1 with prior exposure within 100 days is rapid-onset HIT.

Stem 1 — Pseudothrombocytopenia:

Stem 2 — Classic ITP:

Stem 3 — HIT:

Stem 4 — TTP:

Stem 5 — DIC:

Stem 6 — Gestational vs ITP:

Stem 7 — HELLP:

Stem 8 — Drug-induced:

Stem 9 — Elderly MDS:

One-Line Recap

Thrombocytopenia workup is a structured algorithm: confirm the count is real (smear and citrate redraw), classify the mechanism (decreased production, increased destruction, sequestration, dilution), recognize the four emergencies (TTP, HIT, DIC, severe ITP with bleeding), and tailor therapy to the specific mechanism rather than the number alone.

— Repeat CBC + peripheral smear + citrate tube is always step one in asymptomatic thrombocytopenia.

— Smear findings drive the next branch: schistocytes → microangiopathy; blasts → leukemia; giant platelets → ITP or congenital; teardrops → marrow infiltration.

— Normal PT/PTT/fibrinogen with schistocytes = TTP/HUS, not DIC.

— TTP: start PLEX before ADAMTS13 returns when PLASMIC ≥6.

— HIT: stop heparin and start non-heparin anticoagulant based on 4T ≥4 alone.

— Severe bleeding with platelets <20K: simultaneous IVIG + steroids ± transfusion.

— Never transfuse platelets in TTP or HIT unless life-threatening bleed.

— Never use warfarin alone in HIT — bridge with non-heparin anticoagulant ≥5 days until platelets >150K.

— Vaccinate splenectomy and rituximab candidates ≥2 weeks ahead.

— Pre-procedure thresholds: 50K major surgery, 70–80K neuraxial, 100K neurosurgery/eye.

— Heparin allergy alert and medical ID for HIT patients.

— Pneumococcal/meningococcal/Hib vaccination tracking for asplenic patients.

— Steroid taper plans with PJP prophylaxis, bone health, glucose monitoring.

Step 3 management: When in doubt, the peripheral smear is the highest-yield, lowest-cost test in all of thrombocytopenia — order it before any expensive workup or empiric therapy.

Algorithm anchors:

Emergencies that cannot wait for labs:

Do-not-miss safety rules:

Transition-of-care priorities: