Blood & Lymphoreticular

Hemolytic uremic syndrome in adults

Clinical Overview and When to Suspect HUS in Adults

— Shiga toxin–producing E. coli (STEC-HUS): O157:H7 or O104:H4, follows bloody diarrhea ~5–10 days

— Atypical HUS (aHUS): complement alternative pathway dysregulation (CFH, CFI, MCP, C3, CFB mutations or anti-CFH antibodies)

— Secondary HUS: pregnancy/postpartum, malignant hypertension, drugs (calcineurin inhibitors, gemcitabine, quinine, VEGF inhibitors, mitomycin), HIV, transplant, autoimmune disease, cobalamin C deficiency

Board pearl: In adults, always send ADAMTS13 activity before starting empiric plasma exchange — TTP (ADAMTS13 <10%) is the chief mimic, and the management diverges sharply once results return. While awaiting results in a critically ill TMA patient, start PLEX empirically because untreated TTP mortality approaches 90%.

Step 3 management: First clinic/ED move is a CBC with smear, LDH, haptoglobin, bilirubin (direct/indirect), creatinine, urinalysis, coags, Coombs, and ADAMTS13 — then triage to hematology and nephrology simultaneously. Do not wait for confirmatory tests to admit; TMA is an inpatient diagnosis until proven otherwise.

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA) defined by the triad of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and acute kidney injury (AKI).

Adult HUS is less common than pediatric Shiga toxin HUS and more likely to represent atypical HUS (aHUS) from complement dysregulation, secondary HUS, or be mistaken for TTP.

Core categories to keep mentally separated:

Suspect HUS in any adult with unexplained AKI plus anemia and low platelets, especially when a peripheral smear shows schistocytes.

Key supporting features: elevated LDH, low haptoglobin, indirect hyperbilirubinemia, negative direct Coombs, normal PT/PTT (distinguishes from DIC).

Renal involvement typically dominates in HUS, while neurologic involvement dominates in TTP — but overlap exists and ADAMTS13 testing is mandatory.

Presentation Patterns and Key History

— Diarrhea begins ~3–4 days post-exposure; HUS emerges 5–10 days into the illness, often as diarrhea is improving

— Adults with STEC-HUS tend to have worse outcomes than children, including higher rates of dialysis and death

— Triggers include infections (URI, influenza, COVID, pneumococcus), pregnancy, surgery, or transplant

— Family history of unexplained renal failure or TMA suggests inherited complement mutation

— Recurrent episodes after partial recovery are a hallmark

— Recent gemcitabine, mitomycin C, bevacizumab/sunitinib, tacrolimus, cyclosporine, quinine, oral contraceptives

— Pregnancy-associated TMA (especially postpartum, distinct from HELLP/preeclampsia which resolves within 48–72 hr of delivery)

— Severe hypertension with target-organ damage (malignant HTN can cause TMA)

— Bone marrow transplant or solid organ transplant history

— Disseminated malignancy (mucin-producing adenocarcinomas)

Key distinction: STEC-HUS = preceding bloody diarrhea; aHUS = often no diarrhea, may have family history or trigger; TTP = neurologic and febrile prominence with relatively preserved renal function. None of these are absolute, which is why ADAMTS13 and stool studies are obligatory.

Board pearl: A postpartum woman with persistent TMA >72 hours after delivery despite controlled BP and resolving LFTs has aHUS until proven otherwise — start eculizumab workup.

STEC-HUS in adults classically follows a prodrome of bloody diarrhea from undercooked ground beef, unpasteurized dairy, contaminated produce (sprouts, leafy greens), petting zoos, or daycare contacts.

Atypical HUS often presents without a diarrheal prodrome:

Secondary HUS clues in the history:

Symptoms patients report: fatigue, pallor, dyspnea, decreased urine output, dark/cola urine, edema, abdominal pain, easy bruising, petechiae, headache or confusion.

Physical Exam Findings and Hemodynamic Assessment

— Tachycardia from anemia and volume shifts

— Crackles, elevated JVP, S3 if volume-overloaded or uremic

— Pericardial rub in advanced uremia (rare at presentation)

— Hypertension is common and may be severe/malignant, especially in aHUS

— Hypovolemia from diarrheal losses early in STEC-HUS

— Once oligoanuric AKI develops, patients shift to euvolemia or hypervolemia

— Daily weights, strict I/Os, orthostatics, and bedside ultrasound (IVC, lung B-lines) guide fluid decisions

CCS pearl: On CCS, order vital signs q4h, daily weight, strict I/O, continuous telemetry (electrolyte shifts → arrhythmia risk), and neuro checks q4h. Repeat physical exam after each major intervention (fluid bolus, transfusion, dialysis run).

Step 3 management: Severe hypertension in HUS is treated with IV agents (labetalol, nicardipine); avoid ACEi/ARB acutely during AKI but plan to introduce them later for renoprotection. Do not aggressively volume-resuscitate an oligoanuric HUS patient — you'll precipitate pulmonary edema; instead, address with early renal replacement therapy if indicated.

General appearance: pale, ill-appearing, often volume overloaded from AKI; may be hypertensive (renal microvascular injury and volume retention).

Skin: petechiae and ecchymoses from thrombocytopenia; jaundice from hemolysis; pallor of conjunctivae and palmar creases.

Cardiopulmonary:

Abdomen: tenderness, especially RLQ in STEC colitis; rebound or guarding suggests bowel necrosis or intussusception (more in kids but possible in adults); hepatosplenomegaly is uncommon.

Neuro: usually mild — headache, irritability; focal deficits, seizures, or coma should push you toward TTP or severe aHUS with CNS involvement.

Volume status assessment is critical:

Diagnostic Workup — Initial Labs

— Anemia (often Hgb <8 g/dL), thrombocytopenia (typically 20–100k), schistocytes ≥2 per high-power field confirms MAHA

— Reticulocytosis reflects marrow response

— LDH markedly elevated (often >1000)

— Haptoglobin undetectable

— Indirect hyperbilirubinemia

— Direct Coombs NEGATIVE (positive Coombs suggests autoimmune hemolytic anemia, not TMA)

— Elevated creatinine and BUN, hyperkalemia, metabolic acidosis, hyperphosphatemia

— Urinalysis: hematuria, proteinuria, RBC casts may appear; nephrotic-range proteinuria is uncommon

— PT, aPTT, fibrinogen are normal in HUS/TTP — abnormal coags point to DIC

— D-dimer may be mildly elevated but not the wildly deranged pattern of DIC

Board pearl: Normal PT/PTT with thrombocytopenia + MAHA = TMA (HUS/TTP), not DIC. The Coombs-negative hemolysis with schistocytes is the defining biochemical signature.

Step 3 management: Order labs as a bundle on initial encounter — CBC w/ smear, BMP, LFTs, LDH, haptoglobin, retic, Coombs, PT/PTT/fibrinogen, UA, ADAMTS13, stool Shiga toxin, complement levels, HIV, pregnancy test. Do not space these out across days.

CBC with peripheral smear — the cornerstone:

Hemolysis panel:

Renal panel:

Coagulation studies:

Stool studies if diarrhea: Shiga toxin EIA + stool culture for E. coli O157:H7 on sorbitol-MacConkey agar; also PCR for stx1/stx2 genes

Pregnancy test in reproductive-age women — pregnancy-associated TMA changes the differential dramatically

HIV test, complement C3/C4, ANA as part of secondary workup

Type and screen in anticipation of transfusion

Diagnostic Workup — Advanced and Confirmatory Studies

— <10% activity = TTP (acquired or congenital)

— >10% with TMA features = HUS spectrum (STEC-HUS, aHUS, secondary)

— Always draw before plasma exchange — exogenous plasma will falsely normalize the result

— C3 may be low (alternative pathway activation), C4 typically normal

— Soluble C5b-9 (sC5b-9) often elevated

— Genetic panel for CFH, CFI, CFB, C3, MCP (CD46), THBD, DGKE

— Anti–factor H autoantibodies (especially in younger adults)

Key distinction: A PLASMIC score ≥6 or French score can predict severe ADAMTS13 deficiency at the bedside while awaiting confirmation — useful for prioritizing empiric PLEX in undifferentiated TMA.

Board pearl: aHUS is a diagnosis of exclusion — you cannot definitively call it aHUS until you have ruled out TTP (ADAMTS13 >10%), STEC (negative Shiga toxin), and major secondary causes.

ADAMTS13 activity (and inhibitor): the single most important send-out test in any adult TMA.

Shiga toxin testing: stool EIA, stool culture (sorbitol-MacConkey for O157:H7), and PCR for stx1/stx2. Sensitivity falls after several days of illness, so test early.

Complement evaluation for suspected aHUS:

Kidney biopsy: not required for diagnosis but can confirm TMA when picture is ambiguous; shows glomerular endothelial swelling, fibrin thrombi, fragmented RBCs, double contours, arteriolar onion-skinning.

Imaging: abdominal CT if mesenteric ischemia or perforation is suspected in STEC colitis; head CT/MRI if neurologic signs.

Rule-outs: ANA, dsDNA, antiphospholipid antibodies (catastrophic APS mimics TMA), B12 and homocysteine/methylmalonic acid (cobalamin C deficiency in young adults), HIV, hepatitis serologies.

Risk Stratification and First-Line Management Logic

— If TTP cannot be excluded and patient is critically ill, initiate plasma exchange (PLEX) within 4–6 hours of suspicion — mortality benefit is time-dependent

— Add glucocorticoids (methylprednisolone 1 mg/kg/day) for presumed immune TTP

— Once ADAMTS13 returns >10%, stop PLEX and pivot

— STEC-HUS: supportive care is the mainstay — IV fluids cautiously, electrolyte correction, transfusion as needed, dialysis when indicated. Avoid antibiotics (may increase Shiga toxin release), avoid antimotility agents, avoid platelet transfusions unless bleeding or pre-procedure

— aHUS: eculizumab or ravulizumab (anti-C5 monoclonals) — first-line, started as soon as aHUS is likely

— Secondary HUS: remove the trigger (discontinue offending drug, treat underlying disease, deliver baby in pregnancy-associated forms)

— pRBCs for symptomatic anemia (Hgb <7 generally)

— Platelets only if active bleeding or invasive procedure — otherwise risk worsening microthrombi

Step 3 management: Before giving eculizumab, vaccinate against Neisseria meningitidis (MenACWY + MenB) and give prophylactic penicillin or ciprofloxacin for 2 weeks if vaccination cannot be given ≥2 weeks in advance — meningococcal sepsis is a black-box risk.

Board pearl: In STEC-HUS, antibiotics are contraindicated because they lyse bacteria and release more Shiga toxin, worsening disease.

Step 1 — Stabilize: admit to monitored bed (often ICU), correct life-threatening electrolytes (hyperkalemia, acidosis), control BP, manage volume.

Step 2 — Empiric therapy for undifferentiated TMA:

Step 3 — Subtype-directed therapy:

Indications for renal replacement therapy (same as general AKI): AEIOU — Acidosis, Electrolytes (refractory hyperkalemia), Ingestions, Overload, Uremia.

Transfusion strategy:

Pharmacotherapy — First-Line Regimens

— Dosing: 900 mg IV weekly × 4 weeks, then 1200 mg week 5, then 1200 mg every 2 weeks

— Blocks terminal complement (C5 → C5a + C5b–9)

— Hematologic response in days to weeks; renal recovery slower

— Black box: meningococcal infection — vaccinate ≥2 weeks prior or give prophylactic abx

— Monitor for breakthrough hemolysis, infusion reactions

— Mainstay for TTP, not for aHUS once diagnosis is established

— In aHUS, PLEX may be used as bridge until eculizumab is available, or for anti-CFH antibody disease along with immunosuppression

— 1.0–1.5 plasma volumes daily with FFP replacement

— Antihypertensives: IV labetalol/nicardipine acutely; transition to amlodipine; add ACEi/ARB once AKI stable for proteinuria/CKD protection

— Phosphate binders, sodium bicarbonate for metabolic complications

— Erythropoiesis-stimulating agents if anemia persists with CKD

Board pearl: Eculizumab is continued indefinitely in most genetic aHUS patients due to relapse risk; discontinuation trials require expert nephrology guidance, frequent monitoring, and patient counseling on relapse signs.

Step 3 management: Always counsel patients on early warning signs of meningococcal disease (fever, neck stiffness, headache, rash) and provide a wallet card stating they are on a complement inhibitor — this is testable Step 3 patient safety material.

Eculizumab (anti-C5 monoclonal) — first-line for aHUS:

Ravulizumab: longer-acting C5 inhibitor, dosed every 8 weeks after loading — improves adherence and quality of life; equivalent efficacy.

Plasma exchange (PLEX):

Glucocorticoids: adjunct in immune TTP and anti-CFH antibody HUS; not standard for STEC-HUS.

Immunosuppression for anti-CFH antibody aHUS: corticosteroids + rituximab or mycophenolate.

Supportive pharmacotherapy:

Procedures and Expanded Management

— Requires large-bore central venous access (often vascath in internal jugular or femoral)

— 1.0–1.5 plasma volumes per session with FFP as replacement fluid

— Complications: line infection, pneumothorax, citrate-induced hypocalcemia (tetany, paresthesias), allergic reactions, hypotension

— Daily until platelets >150k and LDH normalizing for 2 consecutive days (TTP); not the default for aHUS once eculizumab started

— ~50–60% of adult HUS patients require dialysis acutely

— CRRT preferred in hemodynamically unstable ICU patients

— Transition to intermittent HD as stable; outpatient HD if recovery is delayed >4–6 weeks

— Historically high recurrence (50–90%) without prophylaxis

— Now standard to give prophylactic eculizumab peri-transplant in genetic aHUS

— MCP (CD46) mutations: lower recurrence because the protein is membrane-bound on donor kidney — transplant alone may suffice

— CFH/CFI mutations: high recurrence — consider combined liver-kidney transplant historically, now usually eculizumab prophylaxis

CCS pearl: When you order PLEX, also order calcium gluconate available at bedside, type and crossmatch FFP, and post-procedure CBC, ionized Ca, fibrinogen.

Board pearl: In a patient with aHUS heading to kidney transplant, start eculizumab pre-operatively and continue post-op to prevent allograft TMA — this is a high-yield transition-of-care fact.

Plasma exchange (PLEX) procedural details:

Hemodialysis / CRRT:

Central venous access: ultrasound-guided IJ preferred; consent for line placement and document indication.

Renal biopsy: percutaneous, ultrasound-guided; hold for platelets >50k, normal coags, controlled BP <160/90; risk of bleeding, AV fistula.

Kidney transplantation in end-stage aHUS:

Special Populations — Elderly and Renal/Hepatic Impairment

— Higher likelihood of secondary HUS (malignancy, drug-induced) and TTP than STEC-HUS

— Cancer-associated TMA: think gastric, breast, pancreatic, lung adenocarcinomas; often DIC overlap with bone marrow infiltration

— Higher baseline CKD complicates AKI assessment — review prior creatinine

— Polypharmacy: review for calcineurin inhibitors, gemcitabine, quinine, clopidogrel, ticagrelor

— Eculizumab and ravulizumab: no renal dose adjustment

— Antihypertensives: avoid ACEi/ARB until AKI stable; renal-dose β-blockers (atenolol accumulates; prefer metoprolol or carvedilol)

— LMWH: avoid in CrCl <30; use unfractionated heparin for VTE prophylaxis on dialysis

— Contrast imaging: balance against worsening AKI; use only if essential

— Cobalamin C deficiency–related TMA can present with hepatic involvement in young adults — rare but testable

— Avoid acetaminophen >2 g/day in cirrhosis; avoid NSAIDs universally in HUS (worsen AKI, bleed risk)

Step 3 management: In an elderly patient with new TMA, always include a malignancy screen — age-appropriate cancer screening, CT chest/abdomen/pelvis, SPEP/UPEP, and consider bone marrow biopsy if cytopenias are out of proportion.

Board pearl: Gemcitabine-induced TMA classically presents 6–8 months into therapy with hypertension, AKI, and MAHA — discontinue the drug and consider eculizumab; this is a recognized indication for complement blockade in secondary HUS.

Elderly adults (>65) with TMA:

Dose considerations in renal impairment:

Hepatic impairment:

Geriatric-specific concerns: delirium during ICU stay, pressure ulcers from immobility on dialysis, falls risk with anemia and orthostasis, polypharmacy reconciliation at discharge.

Special Populations — Pregnancy and Other Subgroups

— Preeclampsia/HELLP: HTN, proteinuria, elevated LFTs, low platelets, MAHA — resolves within 48–72 hours of delivery

— Acute fatty liver of pregnancy (AFLP): hypoglycemia, coagulopathy, elevated ammonia

— TTP in pregnancy: ADAMTS13 falls physiologically in pregnancy; severe deficiency presents most commonly in 2nd–3rd trimester

— Pregnancy-associated aHUS: most often postpartum (60–80%), persists >72 hr after delivery

— Deliver if HELLP/preeclampsia and viable

— PLEX for TTP, including during pregnancy

— Eculizumab is considered safe in pregnancy and lactation (no transplacental passage of full IgG2/4 monoclonal in measurable amounts); used for aHUS in pregnancy

— Calcineurin inhibitor (tacrolimus, cyclosporine) TMA: dose-reduce or switch to belatacept/mTOR inhibitor

— De novo TMA after kidney transplant can be aHUS unmasked by ischemia-reperfusion injury

Key distinction: >72 hours postpartum with persistent TMA = pregnancy-associated aHUS until proven otherwise. Start complement workup and prepare for eculizumab.

Board pearl: In a 28-year-old with a 2nd-trimester TMA and normal LFTs, TTP is highest on the list — send ADAMTS13 and start PLEX while pregnant.

Pregnancy-associated TMA is a critical Step 3 differential:

Management of pregnancy-associated TMA:

Postpartum follow-up: women with pregnancy-associated aHUS have high risk of recurrence in subsequent pregnancies — preconception counseling and high-risk MFM involvement essential.

Transplant recipients:

HIV-associated TMA: less common in ART era; check viral load and start/optimize ART.

Cobalamin C deficiency in young adults: methylmalonic acid and homocysteine elevated; treat with hydroxocobalamin, betaine, folate.

Complications and Adverse Outcomes

— AKI requiring dialysis in 50–60% of adult HUS patients

— Persistent oliguria/anuria >2 weeks predicts CKD

— Hyperkalemia, metabolic acidosis, uremia, volume overload, pericarditis

— ~25–40% of adult STEC-HUS survivors develop CKD or hypertension long-term

— aHUS without complement inhibition progresses to ESRD in 50% within 1 year

— Proteinuria, hypertension, and decreased eGFR persist; lifelong nephrology follow-up

— Seizures, stroke, posterior reversible encephalopathy syndrome (PRES), cortical blindness, coma

— More common in aHUS and severe STEC-HUS (~30%)

— Myocardial microthrombi → troponin elevation, heart failure, arrhythmia

— Pericarditis from uremia

— Hemorrhagic colitis, bowel necrosis, perforation, intussusception, toxic megacolon

— Pancreatitis, transient diabetes (islet ischemia)

— Severe anemia requiring transfusion

— Bleeding from thrombocytopenia (rarely life-threatening)

— Iron overload from chronic transfusion

— Meningococcal sepsis on complement inhibitors

— Line infections from PLEX/HD catheters

— Citrate toxicity, transfusion reactions

Board pearl: PRES in an HUS patient — recognize with headache, visual changes, seizures, and posterior white matter edema on MRI; treat by aggressive BP control. Often reversible.

Step 3 management: At discharge from index hospitalization, schedule nephrology within 1–2 weeks, document baseline eGFR, urine protein:creatinine ratio, and BP plan — this is a Step 3 transition-of-care touchpoint.

Acute renal complications:

Chronic kidney disease and ESRD:

Neurologic complications:

Cardiac:

GI complications in STEC-HUS:

Hematologic:

Treatment-related:

When to Escalate Care — ICU, Consult, Inpatient Triage

— Hemodynamic instability, severe hypertensive emergency

— Altered mental status, seizures, focal neurologic deficits

— Need for PLEX with central venous access

— Severe AKI requiring CRRT or urgent HD

— Severe anemia (Hgb <6) or active bleeding

— Respiratory failure, pulmonary edema, MI from microvascular thrombosis

— Hematology — drives PLEX initiation, ADAMTS13 interpretation, transfusion strategy

— Nephrology — manages AKI, dialysis, eculizumab planning, biopsy

— Infectious disease if STEC complications or pre-eculizumab vaccination

— MFM/OB if pregnant or postpartum

— Transplant nephrology for transplant recipients

— Transfer to tertiary center if PLEX, complement inhibitor access, or transplant nephrology unavailable

— Stabilize first: BP, volume, electrolytes; do not delay PLEX in TTP for transfer logistics

— Discuss early in elderly or malignancy-associated cases

— Younger aHUS patients usually have excellent prognosis with eculizumab — pursue aggressive care

CCS pearl: On CCS, the sequence is: admit to ICU → consult heme and nephro → place central line → start PLEX empirically → vaccinate for meningococcus → start eculizumab when aHUS likely → initiate dialysis if AEIOU criteria met. Move the clock forward in 2–4 hour increments and recheck CBC, BMP, LDH, haptoglobin.

Board pearl: Delay in initiating PLEX by even 12–24 hours in suspected TTP is associated with higher mortality — do not wait for confirmatory ADAMTS13 to act.

All adults with suspected TMA need inpatient admission — outpatient management is not appropriate.

ICU admission criteria:

Mandatory consults:

Inter-facility transfer:

Code status / goals of care:

Key Differentials — Same-Category TMA Causes

— ADAMTS13 <10% (severe deficiency)

— Pentad (fever, MAHA, thrombocytopenia, AKI, neuro) only ~5% — don't wait for all five

— Neurologic prominence, less severe AKI than HUS

— Treatment: PLEX + steroids + caplacizumab, rituximab for relapse

— STEC: diarrheal prodrome, positive Shiga toxin, supportive care

— aHUS: no diarrhea, complement dysregulation, eculizumab

— Abnormal PT/PTT, low fibrinogen, elevated D-dimer

— Usually has identifiable trigger (sepsis, trauma, obstetric emergency, malignancy)

— Treat underlying cause; replace factors

— Quinine (classic, immune-mediated), gemcitabine, mitomycin, calcineurin inhibitors, mTOR inhibitors, VEGF inhibitors, oxaliplatin, clopidogrel, ticagrelor, oral contraceptives

— Stop the drug; eculizumab considered in severe cases

— Multi-organ thrombosis in ≤1 week, antiphospholipid antibodies positive

— Triple therapy: anticoagulation + steroids + PLEX/IVIG

— Pregnant patient, resolves with delivery; LFTs elevated, RUQ pain

— Severe HTN with TMA, controls with BP management; resolves with BP control

Key distinction: DIC has coagulopathy (abnormal PT/PTT/fibrinogen); TMA preserves PT/PTT/fibrinogen — this single laboratory pattern is the most discriminating board factoid.

Board pearl: Quinine-induced TMA classically occurs after tonic water consumption for leg cramps in an elderly patient — stop quinine and recovery is typical.

Thrombotic thrombocytopenic purpura (TTP):

STEC-HUS vs aHUS:

DIC:

Drug-induced TMA:

Catastrophic antiphospholipid syndrome (CAPS):

HELLP / preeclampsia:

Malignant hypertension:

Key Differentials — Other-Category Mimics

— Direct Coombs POSITIVE, no schistocytes (spherocytes instead)

— Treat with steroids ± rituximab

— AIHA + ITP — Coombs positive, no MAHA pattern

— Pancytopenia, MAHA-like smear (schistocytes from ineffective erythropoiesis), elevated LDH and indirect bili

— Methylmalonic acid and homocysteine elevated; treat with B12 replacement

— Critical mimic — don't start PLEX or eculizumab without checking B12 in suggestive cases

— Hypotension, coagulopathy, multi-organ failure; cultures positive

— Prosthetic heart valves (paravalvular leak), ECMO, ventricular assist devices

— Schistocytes present but no thrombocytopenia or AKI from microthrombi

— Fever, cytopenias, ferritin >10,000, hepatosplenomegaly, hypertriglyceridemia, hypofibrinogenemia

— Leukoerythroblastic smear, mucin-producing adenocarcinomas

— Severe HTN, AKI, MAHA in patient with scleroderma — treat with ACE inhibitor (captopril) even in AKI

Board pearl: Scleroderma renal crisis is the one TMA where you start an ACE inhibitor immediately despite AKI — captopril is the agent of choice and is life-saving.

Step 3 management: Always check B12 and reticulocyte count in adult TMA — a brisk retic argues for true hemolysis; a low retic with pancytopenia and MAHA-pattern smear should trigger B12 testing before PLEX.

Autoimmune hemolytic anemia (AIHA):

Evans syndrome:

Severe vitamin B12 deficiency (pseudo-TMA):

Severe sepsis with DIC:

Mechanical hemolysis:

Acute glomerulonephritis with hemolysis: rare but RPGN can mimic — check ANCA, anti-GBM, complement

Hemophagocytic lymphohistiocytosis (HLH):

Disseminated malignancy with bone marrow infiltration:

Scleroderma renal crisis:

Secondary Prevention and Long-Term Plan

— Lifelong annual BP, urinalysis (proteinuria), and creatinine — late CKD risk persists decades

— Counsel on food safety: cook beef to 160°F (71°C), avoid unpasteurized dairy/juice, wash produce, hand hygiene around farm animals

— Public health reporting required (next chunk)

— Indefinite eculizumab/ravulizumab in most genetic forms; selected MCP-mutation patients may not need maintenance

— Meningococcal vaccination updates every 5 years (MenACWY) and per MenB schedule

— Prophylactic penicillin V 500 mg BID or alternative considered during complement inhibitor therapy in some protocols

— Monitor for breakthrough TMA: LDH, CBC, creatinine every 4–8 weeks

— Patient must carry wallet card identifying complement inhibitor use

— Target <130/80 in CKD

— ACEi/ARB once renal function stable for proteinuria reduction

— SGLT2 inhibitor (dapagliflozin/empagliflozin) for CKD with proteinuria

— Phosphate, PTH, vitamin D, bicarbonate monitoring

— Anemia management (iron, ESA as needed)

— Avoid NSAIDs, IV contrast when avoidable

Board pearl: Eculizumab raises the risk of meningococcal disease ~1000–2000× even in vaccinated patients — fever in a complement-inhibitor patient is a medical emergency warranting empiric ceftriaxone and admission.

Step 3 management: At discharge, write specific orders: MenACWY + MenB vaccination dates, penicillin prophylaxis duration, eculizumab infusion schedule, nephrology in 1–2 weeks, BP cuff at home, urinalysis q3 months, wallet card issued.

STEC-HUS survivors:

aHUS survivors:

Blood pressure control:

CKD management:

Vaccinations: annual influenza, pneumococcal (PCV20 or PCV15+PPSV23), COVID-19, hepatitis B, meningococcal as above

Family screening in inherited aHUS — genetic counseling and testing of first-degree relatives

Follow-Up, Monitoring, Rehab, and Counseling

— Nephrology: 1–2 weeks post-discharge, then monthly × 3, then every 3 months

— Hematology: 2 weeks, then every 1–3 months while on complement inhibitor

— Primary care: 1 week post-discharge for med reconciliation, BP, mental health screen

— CBC with smear, BMP, LDH, haptoglobin, UA with protein:Cr ratio — every 2–4 weeks initially, then quarterly when stable

— Spot any rise in LDH, drop in platelets, rise in Cr as potential breakthrough TMA — early action prevents organ damage

— Eculizumab trough levels and CH50 in select centers

— Low-sodium diet (<2 g/day), DASH-style eating

— Hydration appropriate to CKD stage

— Smoking cessation, alcohol moderation

— Exercise as tolerated; cardiac rehab if MI complicated course

— Women of childbearing age with aHUS should have preconception planning with MFM and nephrology

— Pregnancy possible on eculizumab with appropriate monitoring

Step 3 management: Use a structured discharge summary including diagnosis, eculizumab plan, vaccinations given, follow-up appointments scheduled, red-flag symptoms, and contact numbers — Step 3 frequently tests transition-of-care completeness.

Board pearl: Persistent proteinuria >1 g/day at 6 months post-HUS predicts long-term CKD progression — escalate ACEi/ARB and add SGLT2 inhibitor.

Outpatient cadence:

Monitoring labs:

BP monitoring: home cuff, log readings, aim <130/80; report sustained >140/90

Lifestyle counseling:

Mental health: post-ICU PTSD, depression, and anxiety are common after critical TMA — screen with PHQ-9 and GAD-7 at follow-up

Reproductive counseling:

Driving/work: clearance after neurologic recovery; many patients return to work within weeks if no major sequelae

Ethical, Legal, and Patient Safety Considerations

— STEC infection (E. coli O157:H7 and other Shiga-toxin–producing serotypes) is a reportable disease in all US states

— Report to local health department; failure to report is a regulatory violation

— Health department will perform contact tracing, source identification (food, water, daycare, restaurants)

— Eculizumab consent must specifically include meningococcal disease risk, indefinite duration, and cost (one of the most expensive drugs in the US — financial counseling required)

— PLEX consent covers central line risks, transfusion reactions, citrate toxicity

— Capacity assessment if patient is encephalopathic — surrogate decision-maker per state hierarchy

— Eculizumab >$500,000/year; prior authorization, manufacturer patient assistance programs (Soliris OneSource), and case management referral are part of standard care

— Document discussions about cost and adherence barriers

— High-risk handoffs: ICU → floor (med rec for eculizumab schedule), hospital → home (vaccine status, prophylactic abx, follow-up appointments confirmed before discharge)

— Medication reconciliation to remove offending drugs (quinine, gemcitabine, etc.) and add prophylactic antimicrobials

— Counsel on implications for family members, insurance (GINA protections but not life/disability insurance)

— Offer cascade testing to first-degree relatives

Board pearl: STEC outbreaks require immediate health department notification — Step 3 may present a cluster of cases from a single restaurant/event and ask about next step: report to public health.

Step 3 management: Before complement inhibitor therapy, document vaccination status, give patient a wallet card, prescribe prophylactic antibiotic if vaccinated <2 weeks ago, and provide written fever-action plan.

Mandatory public health reporting:

Informed consent edge cases:

Cost-of-care and access:

Transition-of-care safety:

Disclosure of medical errors: if antibiotics were inadvertently given in STEC-HUS, disclose to patient/family per institutional policy

Genetic testing ethics in aHUS:

High-Yield Associations and Rapid-Fire Facts

Board pearl: When you see "5 days after bloody diarrhea, an adult presents with anemia, thrombocytopenia, and rising creatinine" — diagnosis is STEC-HUS; management is supportive; do not give antibiotics.

Key distinction: TTP = ADAMTS13 deficiency, PLEX; aHUS = complement dysregulation, eculizumab; STEC-HUS = Shiga toxin, supportive care.

STEC-HUS: O157:H7 most common (US); O104:H4 caused the 2011 German sprout outbreak with high adult mortality.

Triad: MAHA + thrombocytopenia + AKI.

Schistocytes ≥2/HPF required for MAHA.

Normal PT/PTT/fibrinogen distinguishes TMA from DIC.

Coombs negative distinguishes from AIHA.

ADAMTS13 <10% = TTP; >10% with TMA = HUS spectrum.

PLASMIC score ≥6 predicts severe ADAMTS13 deficiency.

STEC-HUS treatment: supportive — NO antibiotics, NO antimotility agents, NO empiric platelet transfusion.

aHUS treatment: eculizumab or ravulizumab — vaccinate for meningococcus first.

Eculizumab black box: meningococcal infection — vaccinate ≥2 weeks prior or give prophylactic antibiotics.

Gemcitabine, quinine, calcineurin inhibitors, VEGF inhibitors, mitomycin = classic drug causes.

Scleroderma renal crisis: ACEi (captopril) is treatment of choice despite AKI.

Pregnancy-associated aHUS: most often postpartum, persists >72 hr after delivery.

HELLP: resolves within 48–72 hours of delivery.

Cobalamin C deficiency: young adult TMA with elevated MMA and homocysteine.

B12 deficiency can produce pseudo-TMA — check before PLEX.

Kidney transplant in aHUS: eculizumab prophylaxis prevents recurrence except in MCP mutation.

Public health reporting: STEC is reportable.

Food safety: cook ground beef to 160°F, avoid unpasteurized products.

Adults with STEC-HUS have worse outcomes than children.

Board Question Stem Patterns

Board pearl: Pay attention to time course (days vs weeks postpartum), diarrhea history, drug list, and ADAMTS13 number — these four features sort 80% of TMA stems on Step 3.

Step 3 management: When the stem provides an offending drug, the answer is almost always discontinue the drug first, then specific therapy.

Pattern 1 — STEC-HUS: "32-year-old develops oliguria, pallor, and bruising 7 days after bloody diarrhea following a backyard barbecue. Cr 4.2, plt 45k, Hgb 7.8, schistocytes on smear, LDH 1400, haptoglobin undetectable, Coombs negative, PT/PTT normal." Answer: supportive care, IV fluids, dialysis as needed; AVOID antibiotics and antimotility agents.

Pattern 2 — aHUS: "27-year-old woman 5 days postpartum with persistent thrombocytopenia, AKI, MAHA; LFTs normal, BP controlled, no diarrhea. ADAMTS13 65%." Answer: vaccinate for meningococcus and start eculizumab.

Pattern 3 — TTP mimicker: "45-year-old with fever, headache, platelets 12k, schistocytes, Cr 1.4. ADAMTS13 pending." Answer: start PLEX empirically with glucocorticoids; await ADAMTS13.

Pattern 4 — Drug-induced TMA: "62-year-old on gemcitabine for pancreatic cancer presents with new HTN, AKI, MAHA." Answer: stop gemcitabine; consider eculizumab.

Pattern 5 — Scleroderma renal crisis: "55-year-old with diffuse scleroderma, BP 220/130, Cr 3.0, schistocytes." Answer: captopril, even with AKI.

Pattern 6 — B12 deficiency mimic: "70-year-old vegan with pancytopenia, schistocytes, LDH 2000, low reticulocyte count." Answer: check B12, MMA, homocysteine before PLEX.

Pattern 7 — Eculizumab safety: "aHUS patient on eculizumab with fever and headache." Answer: empiric ceftriaxone for possible meningococcal disease; admit.

Pattern 8 — Public health: "Three adults from same wedding develop bloody diarrhea then HUS." Answer: report to local health department.

Pattern 9 — Post-transplant: "Kidney transplant patient on tacrolimus with new TMA." Answer: reduce/discontinue tacrolimus; consider belatacept or mTOR switch.

One-Line Recap

Adult HUS is a thrombotic microangiopathy defined by Coombs-negative MAHA, thrombocytopenia, and AKI with normal coagulation, requiring urgent ADAMTS13 testing to exclude TTP, then targeted therapy: supportive care for STEC-HUS (no antibiotics), eculizumab for atypical HUS (after meningococcal vaccination), and removal of trigger for secondary causes.

Board pearl: Three numbers sort adult TMA on Step 3: ADAMTS13 (<10% = TTP), Shiga toxin (positive = STEC-HUS), and time since delivery (>72 hr postpartum = aHUS). Memorize the algorithm and the management diverges cleanly.

Step 3 management: Every HUS patient leaves the hospital with a documented eGFR baseline, BP plan, vaccination record, follow-up appointments confirmed, and red-flag symptom education — this completeness is what Step 3 rewards.

Diagnose: CBC with smear (schistocytes), LDH↑, haptoglobin↓, Coombs negative, normal PT/PTT/fibrinogen, AKI; send ADAMTS13 before PLEX; stool Shiga toxin if diarrhea; complement workup if no clear cause.

Triage: empiric PLEX if TTP possible (ADAMTS13 pending and critically ill); supportive care if STEC-HUS confirmed; eculizumab for aHUS after MenACWY/MenB vaccination or with prophylactic penicillin bridge.

Avoid: antibiotics and antimotility agents in STEC-HUS, platelet transfusions unless bleeding or pre-procedure, NSAIDs, ACEi/ARB during active AKI (except scleroderma renal crisis where captopril is the answer).

Long-term: indefinite complement inhibition for most genetic aHUS, lifelong BP/proteinuria monitoring, vaccinations, wallet card for complement inhibitor use, nephrology follow-up at 1–2 weeks then quarterly, family genetic counseling, and public health reporting for STEC.