When to intubate in GCS?

GCS ≤ 8 requires intubation for airway protection. The patient cannot protect their own airway at this level of consciousness. Motor score is the most prognostically important component.

What is the best initial fluid for sepsis resuscitation?

Lactated Ringer's (LR) is the preferred resuscitation fluid. The SMART trial (2018) showed balanced crystalloids reduced death, new renal failure, and persistent renal dysfunction compared to normal saline.

When to start vasopressors in septic shock?

Start norepinephrine (first-line vasopressor) if MAP remains < 65 mmHg after initial 30 mL/kg crystalloid resuscitation, or earlier if patient is profoundly hypotensive. Do not delay pressors to complete full fluid resuscitation.

Why can serum uric acid be normal during acute gout?

During acute inflammation, IL-6 increases renal urate excretion and redistributes urate from plasma to tissues. Up to 40% of acute gout flares have normal serum uric acid. Joint aspiration with polarized microscopy is needed for definitive diagnosis.

How do you distinguish lupus flare from infection in SLE?

Key clues: CRP is low/normal in flare but elevated in infection. Complement (C3/C4) drops in flare but is normal/elevated in infection. Procalcitonin is elevated in bacterial infection but normal in flare. Anti-dsDNA rises in flare, stable in infection.

What is the difference between DKA and HHS?

DKA features acidosis (pH 600), hyperosmolality (> 320), and minimal ketosis -typically in Type 2 DM. DKA requires insulin drip; HHS requires aggressive fluid resuscitation first.

When to give tPA in acute ischemic stroke?

IV alteplase (tPA) can be given within 4.5 hours of last known well time in eligible patients. CT head must rule out hemorrhage first. For large vessel occlusion, mechanical thrombectomy can be performed up to 24 hours with favorable imaging.

What antibiotics for community-acquired pneumonia?

Inpatient non-ICU: ceftriaxone + azithromycin. ICU: ceftriaxone + azithromycin (add vancomycin if MRSA risk). Outpatient healthy: amoxicillin. Outpatient with comorbidities: augmentin + azithromycin or respiratory fluoroquinolone. Duration: 5 days if clinically stable for 48 hours.

How to interpret iron studies?

Iron deficiency: low ferritin (< 30), high TIBC, low iron, low transferrin saturation (< 20%). Anemia of chronic disease: normal/high ferritin (acute phase reactant), low TIBC, low iron. A ferritin of 50-100 in an inflamed patient may still represent iron deficiency.

What is the correction rate for hyponatremia?

Correct sodium no more than 8 mEq/L in 24 hours to avoid osmotic demyelination syndrome (ODS). For symptomatic severe hyponatremia with seizures, give 3% hypertonic saline 100-150 mL bolus over 10-20 minutes. If overcorrected, use D5W + DDAVP rescue protocol.

When to start antibiotics in meningitis?

Within 30-60 minutes. Do NOT delay antibiotics for LP or CT. Draw blood cultures, start empiric antibiotics (vancomycin + ceftriaxone ± ampicillin if > 50 or immunocompromised), then perform LP when possible. Dexamethasone should be given before or with the first antibiotic dose.

DOACs vs warfarin in antiphospholipid syndrome?

DOACs are contraindicated in APS. The TRAPS trial (2018) showed rivaroxaban was inferior to warfarin with more thrombotic events in triple-positive APS patients. Warfarin with INR target 2-3 is the standard for APS, indefinitely.

How to manage scleroderma renal crisis?

ACE inhibitors (captopril) are life-saving -start immediately and titrate aggressively. Do NOT hold for rising creatinine. Steroids > 15 mg prednisone per day precipitate scleroderma renal crisis. ARBs are NOT a substitute -evidence is only for ACEi.

What are the 4 pillars of heart failure treatment?

Guideline-directed medical therapy (GDMT) for HFrEF: (1) ARNI or ACEi/ARB, (2) beta-blocker (carvedilol, metoprolol succinate, or bisoprolol), (3) MRA (spironolactone or eplerenone), (4) SGLT2 inhibitor (dapagliflozin or empagliflozin). All four should be initiated and titrated to target doses.

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TTP / HUS

Thrombotic microangiopathies -ADAMTS13 deficiency (TTP) or complement-mediated (aHUS). Thrombocytopenia + MAHA + organ damage with NORMAL coags. Untreated TTP mortality > 90%. Plasma exchange saves lives. Never transfuse platelets.

🔍 Overview

TTP vs HUS

PLASMIC Score (Predicts ADAMTS13 < 10%)

Feature	TTP	Typical HUS	Atypical HUS
Mechanism	ADAMTS13 < 10% → ultra-large vWF → platelet aggregation	Shiga toxin (E. coli O157:H7)	Complement dysregulation
Key features	Neuro predominant (confusion, seizures)	Renal failure + bloody diarrhea (children)	Renal failure
Coags	NORMAL (PT, aPTT, fibrinogen all normal)	Normal	Normal
Treatment	Plasma exchange + steroids + caplacizumab	Supportive (abx CONTRAINDICATED)	Eculizumab (anti-C5)

Criterion	1 Point Each
P	Platelet < 30,000
L	Hemolysis (retic > 2.5%, hapto undetectable, or indirect bili > 2)
A	No active cancer
S	No stem cell/organ transplant
M	MCV < 90
I	INR < 1.5
C	Creatinine < 2.0

≥ 5: high probability → start plasma exchange. Don't wait for ADAMTS13 results.

🚨 Management

Plasma exchange

Daily TPE until platelets > 150K × 2 days. Removes antibodies + ultra-large vWF, replaces ADAMTS13. FFP as bridge if TPE delayed.

Steroids

Methylprednisolone 1g IV × 3 days → prednisone 1 mg/kg. Rituximab if refractory/relapsing.

Caplacizumab

Anti-vWF nanobody. HERCULES, 2019: 74% reduction in death + recurrence. Now standard alongside TPE + steroids.

NEVER transfuse platelets in TTP

🧪 Workup

Workup

CBC + peripheral smear -severe thrombocytopenia (often < 30K) + schistocytes. Schistocytes are REQUIRED for diagnosis.
ADAMTS13 activity level -send immediately but do NOT wait for results to start PLEX. ADAMTS13 < 10% = TTP. Takes 2-5 days to result. ADAMTS13 Discovery Study, 2004
PLASMIC score -7-variable clinical prediction score. Score 6-7 = high probability of ADAMTS13 < 10% → start PLEX empirically. Components: platelet count < 30K, hemolysis (retic > 2.5%, haptoglobin undetectable, indirect bili > 2), no active cancer, no transplant, MCV < 90, INR < 1.5, Cr < 2. PLASMIC Score Derivation, 2017
LDH -markedly elevated (often > 1000). Trends with disease activity -single best marker to follow during treatment.
Haptoglobin -undetectable (consumed by free hemoglobin binding)
Reticulocyte count -elevated (bone marrow compensating for hemolysis)
Indirect bilirubin -elevated (hemolysis)
Fibrinogen -NORMAL in TTP. This is the key differentiator from DIC (where fibrinogen is low). If fibrinogen is low, reconsider DIC.
Direct Coombs (DAT) -negative. Rules out autoimmune hemolytic anemia.
Cr -mild elevation typical. If Cr markedly elevated (> 3), consider HUS over TTP (renal-dominant TMA).
Coags (PT/INR) -should be normal. If elevated → think DIC, not TTP.

💊 Medications

Medications

Drug	Dose	Route	Notes
Therapeutic plasma exchange (PLEX)	1-1.5 plasma volumes daily	Apheresis	Cornerstone of treatment. Removes anti-ADAMTS13 antibodies and ultra-large vWF multimers, replaces ADAMTS13. Continue daily until platelet count > 150K × 2 consecutive days, then taper. Canadian TTP PLEX Trial, 1991
Methylprednisolone	1g IV daily × 3 days	IV	Then transition to prednisone 1 mg/kg daily with taper. Immunosuppression to reduce anti-ADAMTS13 antibody production.
Caplacizumab	11 mg IV first dose → 11 mg SQ daily	IV/SQ	Anti-vWF nanobody -prevents platelet-vWF binding. 74% reduction in composite of death + recurrence + major thromboembolic event. HERCULES, 2019. Continue for 30 days after last PLEX. Monitor for bleeding (mucocutaneous).
Rituximab	375 mg/m² IV weekly × 4 doses	IV	For refractory TTP (no response after 5-7 days PLEX) or relapsing TTP. Depletes anti-ADAMTS13-producing B cells. Response in 1-3 weeks. Increasingly used upfront in severe cases.
DO NOT give platelets	-	-	CONTRAINDICATED (unless life-threatening hemorrhage). Transfused platelets are consumed by ultra-large vWF multimers → fuels microthrombosis → clinical deterioration. "Adding fuel to the fire."
Folate	1 mg daily	PO	Support RBC production during ongoing hemolysis.

📋 On Rounds

Why are platelets contraindicated in TTP?

Ultra-large vWF multimers (uncleaved by absent ADAMTS13) create a thrombotic environment. Transfused platelets bind immediately → more microthrombi → worsened organ ischemia. The platelet count may be 5,000 but the patient is at risk from thrombosis, not bleeding. Treatment = remove the cause (plasma exchange), not add substrate (platelets).

Why should you NEVER transfuse platelets in TTP?

In TTP, platelet microthrombi are the pathology -transfusing platelets is like adding fuel to a fire. The ultra-large vWF multimers (from ADAMTS13 deficiency) recruit and consume platelets into microthrombi in small vessels, causing ischemic organ damage (brain, kidneys). Adding more platelets → more substrate for thrombus formation → worse organ damage.

What is caplacizumab and why was it a breakthrough for TTP?

Caplacizumab is an anti-von Willebrand factor nanobody that blocks the interaction between ultra-large vWF multimers and platelets → prevents platelet adhesion and microthrombus formation. HERCULES, 2019: caplacizumab + standard therapy (PLEX + steroids) vs placebo: faster platelet normalization, fewer thromboembolic events, fewer TTP-related deaths. Dose: 11 mg IV before first PLEX, then 11 mg SQ daily until 30 days after last PLEX.

What is the PLASMIC score and how does it guide your decision to start PLEX?

PLASMIC score predicts ADAMTS13 < 10% (which confirms TTP). Components: Platelet count < 30K (+1), combined hemolysis variables (reticulocyte > 2.5%, haptoglobin undetectable, indirect bilirubin > 2) (+1), no active cancer (+1), no solid organ or stem cell transplant (+1), MCV < 90 (+1), INR < 1.5 (+1), Cr < 2.0 (+1). Score 0-4: low probability TTP → consider other MAHA causes (DIC, HUS).

❓ What is the classic pentad of TTP and how often is it complete?

The classic pentad: (1) thrombocytopenia, (2) microangiopathic hemolytic anemia (schistocytes), (3) neurological symptoms, (4) renal impairment, (5) fever. However, the full pentad is present in < 5% of cases. Most present with only thrombocytopenia + MAHA. Waiting for the pentad delays treatment and increases mortality. Treat on clinical suspicion.

❓ What is ADAMTS13 and why is it deficient in TTP?

ADAMTS13 is a metalloprotease that cleaves ultra-large von Willebrand factor (vWF) multimers into smaller fragments. In immune TTP, autoantibodies against ADAMTS13 cause acquired deficiency (< 10% activity). Without ADAMTS13, ultra-large vWF multimers accumulate → spontaneous platelet aggregation → microvascular thrombosis throughout the body. Congenital TTP (Upshaw-Schulman) is genetic ADAMTS13 deficiency.

❓ Why are platelets contraindicated in TTP?

Transfused platelets are immediately consumed by the ultra-large vWF multimers that are pathologically accumulated in the microvasculature. This fuels more microthrombosis rather than raising the platelet count -"adding fuel to the fire." Only give platelets if there is life-threatening hemorrhage (which is rare in TTP because the thrombocytopenia is consumptive, not due to production failure).

❓ When would you give rituximab in TTP?

Refractory TTP (no response after 5-7 days of daily PLEX), relapsing TTP, or preemptive treatment when ADAMTS13 falls < 10% during remission monitoring (before clinical relapse). Some centers use rituximab upfront in severe presentations. Rituximab depletes the B cells producing anti-ADAMTS13 antibodies. Response in 1-3 weeks. TTP Rituximab Study, 2011

Clinical Examples

📋 Case 1, Classic Acquired TTP

Patient: 34F with confusion, petechiae, fatigue × 3 days. Hgb 7.2, platelets 11K, Cr 1.6, LDH 1800, haptoglobin < 10, indirect bili 4.2. Smear: abundant schistocytes. PLASMIC score 7 (high risk).

Key findings: Microangiopathic hemolytic anemia (MAHA) + thrombocytopenia = TMA. High PLASMIC score (> 5) = high probability of TTP (ADAMTS13 < 10%). Do NOT wait for ADAMTS13 result to start treatment.

Management:

Send ADAMTS13 activity + inhibitor BEFORE starting PLEX (plasma dilutes the sample)
Emergent therapeutic plasma exchange (PLEX), daily until platelets > 150K × 2 days
Caplacizumab 11 mg IV bolus before first PLEX → 11 mg SQ daily (anti-vWF nanobody, faster platelet recovery) HERCULES, 2019
Prednisone 1 mg/kg daily (suppress autoantibody production)
Do NOT transfuse platelets (fuels microvascular thrombosis, "adding fuel to the fire")

Teaching point: TTP is a clinical emergency, mortality untreated is > 90%. Start PLEX empirically based on PLASMIC score. Platelet transfusion is contraindicated unless life-threatening bleeding, it worsens microvascular thrombosis.

📋 Case 2, TTP vs HUS Differentiation

Patient: 4-year-old boy with bloody diarrhea × 5 days after eating undercooked hamburger. Now oliguric, pallor. Hgb 6.8, platelets 28K, Cr 4.8, LDH 920. Smear: schistocytes. Stool: Shiga toxin positive.

Key findings: Typical HUS (Shiga toxin-associated): MAHA + thrombocytopenia + AKI after bloody diarrhea with Shiga toxin-producing E. coli (usually O157:H7). Renal involvement is predominant (unlike TTP where neuro predominates).

Management:

Supportive care is mainstay, NO antibiotics (may increase Shiga toxin release and worsen HUS)
IVF resuscitation, monitor UOP strictly, dialysis if needed for renal failure
Transfuse pRBCs for symptomatic anemia (unlike TTP, platelet transfusion is not as clearly contraindicated)
PLEX is NOT standard for typical HUS (unlike TTP)
Most children recover renal function (90%+), but 5-10% develop ESRD

Teaching point: The key differentiator: TTP = neurologic predominance + ADAMTS13 < 10%. HUS = renal predominance + Shiga toxin + normal ADAMTS13. Atypical HUS (complement-mediated, no diarrhea) is treated with eculizumab (anti-C5).

📋 Case 3, Relapsing TTP with ADAMTS13 Monitoring

Patient: 42F with history of TTP 18 months ago (achieved remission with PLEX + steroids). Routine ADAMTS13 monitoring: activity dropped from 45% → 8% over 3 months. Asymptomatic, platelets 180K, LDH normal.

Key findings: Falling ADAMTS13 without clinical relapse, "subclinical relapse." ADAMTS13 < 10% predicts imminent clinical relapse with MAHA, thrombocytopenia, and end-organ damage.

Management:

Preemptive rituximab 375 mg/m² weekly × 4 (prevent clinical relapse before it occurs)
Monitor ADAMTS13 q2 weeks during rituximab treatment, expect recovery to > 20% within 4-8 weeks
Continue ADAMTS13 monitoring q3 months indefinitely (relapse risk is lifelong)
No PLEX needed if asymptomatic with normal counts, rituximab alone is sufficient preemptively
Caplacizumab course (30 days after PLEX) reduces relapse rate in the initial treatment period

Teaching point: ADAMTS13 monitoring after TTP allows preemptive treatment before clinical relapse. A falling ADAMTS13 < 10% is an actionable finding, rituximab at this point prevents the life-threatening clinical episode. This is why lifelong monitoring is essential.

📣 Sample Presentation

One-Liner

"Ms. Wilson is a 36-year-old presenting with confusion, petechiae, Hgb 7.8, platelets 12K, Cr 1.8, LDH 1,400, and schistocytes on peripheral smear. PLASMIC score 7. ADAMTS13 sent."

Key Points to Cover on Rounds

MAHA + severe thrombocytopenia + neuro symptoms + renal impairment -TTP until proven otherwise. PLASMIC 7 (high probability). ADAMTS13 sent -don't wait for result. Treatment initiated emergently: (1) PLEX (plasmapheresis) -first session today, (2) methylprednisolone 1g IV daily × 3 days, (3) caplacizumab 11 mg IV then SQ daily HERCULES, 2019. Platelets NOT transfused (contraindicated -fuels thrombosis). Hgb 7.8 → transfuse pRBCs (safe, not platelets). Plan: daily PLEX until plt >150 × 2 days, ADAMTS13 pending.

Monitoring

Platelet count daily -primary response marker. Goal: > 150K × 2 consecutive days before stopping/tapering PLEX. If platelets plateau or drop during taper → resume daily PLEX.
LDH daily -should trend down with effective treatment. Persistent elevation despite rising platelets → consider ongoing hemolysis or alternate diagnosis.
Schistocytes -should decrease on serial peripheral smears. Request daily smear during active treatment.
ADAMTS13 activity -send at diagnosis. Recheck after PLEX completion. Monitor for relapse (ADAMTS13 < 10% even in remission = high relapse risk → consider preemptive rituximab).
ADAMTS13 inhibitor level (Bethesda assay) -quantifies antibody titer. Helps differentiate immune TTP from congenital TTP.
Cr + UA -renal function. Improving Cr supports treatment response.
Neuro exam -focal deficits, confusion, seizures. Fluctuating neuro symptoms are classic for TTP. Should improve with PLEX.
Haptoglobin + indirect bilirubin -hemolysis resolution markers. Haptoglobin should recover as hemolysis resolves.
Bleeding assessment -especially while on caplacizumab (mucocutaneous bleeding risk). Check for gum bleeding, epistaxis, GI bleed.
Long-term follow-up -ADAMTS13 levels q3-6 months for 2+ years. Relapse rate ~30-50% in immune TTP. Preemptive rituximab if ADAMTS13 drops < 10%.

⚡ Summary

Summary

Suspect When

MAHA (schistocytes) + severe thrombocytopenia + end-organ damage (neuro, renal). Do NOT wait for ADAMTS13 -start treatment.

PLASMIC Score

6-7 = high probability of ADAMTS13 < 10% → start PLEX tonight. Don't delay for confirmatory testing.

Treatment

Triple therapy: (1) PLEX daily until plt > 150 × 2 days, (2) steroids (methylpred 1g IV × 3 days), (3) caplacizumab HERCULES, 2019.

Do NOT Transfuse Plt

Contraindicated -platelets fuel the thrombotic process. Analogy: adding fuel to fire. Transfuse RBCs only if needed.

Differentiate from HUS

TTP: neuro-predominant (confusion, seizures, focal deficits). HUS: renal-predominant (AKI, oliguria). Both have MAHA + thrombocytopenia.

Relapse

ADAMTS13 monitoring after recovery. Relapse risk ~30-50% for autoimmune TTP. Rituximab for relapsing or refractory disease.

📄 One Pager

Hematology · One Pager

TTP -Thrombotic Thrombocytopenic Purpura

MAHA + severe thrombocytopenia → start PLEX tonight. Don't wait for ADAMTS13. Don't transfuse platelets. Caplacizumab + steroids + PLEX = triple therapy.

🧪 Suspect When

MAHA (schistocytes on smear) + severe thrombocytopenia (< 30K) ± neuro symptoms ± renal impairment ± fever. PLASMIC score 6-7 = high probability → start PLEX.

🚨 Treatment -Triple Therapy

(1) PLEX daily (until plt > 150 × 2 days). (2) Methylprednisolone 1g IV × 3d. (3) Caplacizumab 11 mg IV then SQ daily HERCULES, 2019. Don't wait for ADAMTS13 result.

⚠️ Critical Rules

Do NOT transfuse platelets (fuels thrombosis -adding fuel to fire). DO transfuse pRBCs if needed (Hgb support is safe). TTP vs HUS: TTP = neuro-predominant, HUS = renal-predominant.

💊 Key Drugs

PLEXDaily until plt > 150 × 2d

Methylprednisolone1g IV daily × 3d

Caplacizumab11 mg IV then SQ daily

Rituximab375 mg/m² (refractory/relapsing)

⚠️ Pitfalls

Platelet transfusion (fuels microthrombosis)
Waiting for ADAMTS13 before starting PLEX
Not starting caplacizumab (reduces mortality)
Confusing with DIC (DIC has low fibrinogen, TTP has normal fibrinogen)