Hemolytic Anemia Decision Support

Interactive workup guide for hemolysis classification, triage, and differential diagnosis

FOR EDUCATIONAL USE ONLY

Version 0.1.0 - This tool is for educational purposes only and has not been evaluated by the FDA. It is not intended for clinical diagnosis or patient care. All clinical decisions should be made by qualified healthcare professionals.

Hemolytic Anemia Decision Wizard
1
Hemolysis
2
Urgent
3
Transfusion
4
DAT
5
Smear
6
Results
17% complete ←→ navigate steps
Step 1 of 6

Confirm Hemolysis

Select the hemolysis markers present in this patient.

Select markers to assess hemolysis likelihood
Step 2 of 6

Does the patient have findings requiring urgent attention?

Select any urgent features present.

Step 3 of 6

Did the patient receive a transfusion within the last 4 weeks?

Recent transfusion history is important for evaluating hemolytic transfusion reactions.

Step 4 of 6

What is the Direct Antiglobulin Test (DAT) result?

The DAT pattern determines immune vs. non-immune hemolysis pathway.

Anti-IgG:
Anti-C3:
Select DAT results to see interpretation
Type DAT Pattern Antibody Elution Timing Key Clinical Features Ref
Warm AIHA IgG+ ±C3 IgG (polyclonal) Panagglutinin (±Rh specificity) Chronic/relapsing Extravascular hemolysis; 95% DAT-positive; 15-30% VTE risk [1,2]
Cold Agglutinin Disease C3+ only IgM (monoclonal) Negative (IgM dissociates at 37°C) Chronic Intravascular hemolysis; high thermal amplitude; clonal B-cell disorder in adults [1]
PCH C3+ only (IgG+ in ~30%) Biphasic IgG (Donath-Landsteiner) Often negative (low-titer IgG may not be detected) Acute (post-viral in children) Intravascular hemolysis; binds at cold, lyses at warm; self-limited; NO RBC agglutination [1,7]
Mixed AIHA IgG+ C3+ IgG + IgM Panagglutinin Chronic/severe Both extra- and intravascular hemolysis; often refractory; poor splenectomy response [1]
Drug-Induced AIHA IgG+ ±C3 Variable (drug-dependent or independent) Variable (mechanism-dependent) Days to weeks after exposure Resolves with drug withdrawal; may require immunosuppression if drug-independent [1]
Acute Hemolytic Transfusion Reaction Positive (IgG or IgM + C3) Alloantibody (ABO/Rh incompatibility) Alloantibody-specific Minutes to hours Intravascular hemolysis; fever, hypotension, DIC; often clerical error; stop transfusion immediately [3,4]
Delayed Hemolytic Transfusion Reaction Positive (IgG ±C3) Alloantibody (anamnestic response) Alloantibody-specific 24h to 28 days post-transfusion Extravascular ± intravascular hemolysis; dark urine, jaundice, fever; 11% incidence in SCD; may cause hyperhemolysis [4,5,6]
References:
  1. Berentsen S, Barcellini W. Autoimmune Hemolytic Anemias. N Engl J Med. 2021;385(15):1407-1419.
  2. Brodsky RA. Warm Autoimmune Hemolytic Anemia. N Engl J Med. 2019;381(7):647-654.
  3. Jones DE, et al. Hematologic Emergencies: Recognition and Initial Management. Am Fam Physician. 2024;110(1):58-64.
  4. Panch SR, et al. Hemolytic Transfusion Reactions. N Engl J Med. 2019;381(2):150-162.
  5. Delaney M, et al. Transfusion Reactions: Prevention, Diagnosis, and Treatment. Lancet. 2016;388(10061):2825-2836.
  6. NHLBI. Evidence-Based Management of Sickle Cell Disease: Expert Panel Report, 2014.
Step 5 of 6

Peripheral Blood Smear Findings

Select the morphologic findings observed on peripheral smear.

Additional Clinical Features

Select any specialized test results that are already available:

Results

Differential Diagnosis

Based on your selections, here are the most likely diagnoses.

Complete the wizard to see results

Step 1 of 6
Path: Start
Live Probability Estimates
Clinical Context
Age:
Setting:
View evidence base & references
Selected Findings (updates as you progress)
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Differential Diagnoses

Select findings to see differential diagnosis probabilities.

Tip: Select findings in the Wizard tab to see live probability updates here.
Hemolytic Anemia Diagnostic Pathway

Click any node to view details and recommendations

flowchart TD START["Patient with Anemia
Evidence of hemolysis present"] Q_AGE{"Patient Age?"} Q_URGENT{"Urgent Features Present?
Hemodynamic instability,
schistocytes, AKI"} A_URGENT["URGENT: Hematology Consult
Evaluate for TMA/TTP"] Q_TRANSFUSION{"RBC Transfusion
Within 4 Weeks?"} A_TXRXN["Transfusion Reaction Workup
Continue hemolysis evaluation"] A_DAT["Perform DAT + Smear Review
Direct antiglobulin test"] Q_DAT{"DAT Result?"} Q_DAT_PATTERN{"DAT Pattern?
IgG vs C3"} A_WARM["Warm AIHA Workup
IgG ± C3 pattern"] A_COLD["Cold Antibody Workup
C3-only pattern"] Q_THROMBOCYTOPENIA{"Concurrent
Thrombocytopenia?"} A_EVANS["Evans Syndrome Evaluation
65% have underlying IEI
Consider immunology referral"] Q_PEDIATRIC_C3{"Pediatric with
C3-only DAT?"} A_PCH["PCH Evaluation
Donath-Landsteiner test
Post-viral etiology"] A_C3D_AIHA["Isolated C3d+ AIHA
>20% of childhood AIHA
Evaluate for IEI if refractory"] A_NONIMMUNE["Non-Immune Workup
TMA/DIC, PNH, inherited"] Q_SCHISTOCYTES{"Schistocytes
on Smear?"} A_TMA["TMA/MAHA Workup
ADAMTS13, TTP, HUS, DIC"] Q_DIARRHEA{"Recent
Diarrhea?"} A_STEC["STEC-HUS Likely
Shiga toxin testing
AVOID antibiotics"] A_AHUS["Consider aHUS
Complement studies
Genetic testing"] Q_FAMILY{"Lifelong Anemia
or Family History?"} A_INHERITED["Inherited Hemolysis
HS, G6PD, Hemoglobinopathy"] A_NGS["Consider NGS Panel
PKD, rare enzymopathies
Mitapivat if PKD confirmed"] A_OTHER["Other Non-Immune Causes
PNH, mechanical, infection"] END_IMMUNE(["Immune Hemolysis Pathway"]) END_TMA(["Microangiopathic Pathway"]) END_INHERITED(["Inherited Hemolysis Pathway"]) END_OTHER(["Other Non-Immune Pathway"]) START --> Q_AGE Q_AGE -->|Any| Q_URGENT Q_URGENT -->|Yes| A_URGENT Q_URGENT -->|No| Q_TRANSFUSION Q_TRANSFUSION -->|Yes| A_TXRXN Q_TRANSFUSION -->|No| A_DAT A_TXRXN --> A_DAT A_DAT --> Q_DAT Q_DAT -->|Positive| Q_DAT_PATTERN Q_DAT -->|Negative| A_NONIMMUNE Q_DAT_PATTERN -->|IgG ± C3| A_WARM Q_DAT_PATTERN -->|C3-only| A_COLD A_WARM --> Q_THROMBOCYTOPENIA Q_THROMBOCYTOPENIA -->|Yes| A_EVANS Q_THROMBOCYTOPENIA -->|No| END_IMMUNE A_EVANS --> END_IMMUNE A_COLD --> Q_PEDIATRIC_C3 Q_PEDIATRIC_C3 -->|Yes & Hemoglobinuria| A_PCH Q_PEDIATRIC_C3 -->|Yes & No hemoglobinuria| A_C3D_AIHA Q_PEDIATRIC_C3 -->|Adult| END_IMMUNE A_PCH --> END_IMMUNE A_C3D_AIHA --> END_IMMUNE A_NONIMMUNE --> Q_SCHISTOCYTES Q_SCHISTOCYTES -->|Yes| A_TMA Q_SCHISTOCYTES -->|No| Q_FAMILY A_TMA --> Q_DIARRHEA Q_DIARRHEA -->|Yes| A_STEC Q_DIARRHEA -->|No| A_AHUS A_STEC --> END_TMA A_AHUS --> END_TMA Q_FAMILY -->|Yes| A_INHERITED Q_FAMILY -->|No| A_OTHER A_INHERITED --> A_NGS A_NGS --> END_INHERITED A_OTHER --> END_OTHER classDef startNode fill:#007ac3,stroke:#005b92,color:#fff,stroke-width:2px classDef questionNode fill:#fff8e1,stroke:#f9a825,color:#333,stroke-width:2px classDef actionNode fill:#e3f2fd,stroke:#1976d2,color:#333,stroke-width:1px classDef urgentNode fill:#ffebee,stroke:#c62828,color:#333,stroke-width:2px classDef endNode fill:#e8f5e9,stroke:#388e3c,color:#333,stroke-width:2px classDef pediatricNode fill:#f3e5f5,stroke:#7b1fa2,color:#333,stroke-width:2px class START startNode class Q_AGE,Q_URGENT,Q_TRANSFUSION,Q_DAT,Q_DAT_PATTERN,Q_SCHISTOCYTES,Q_THROMBOCYTOPENIA,Q_PEDIATRIC_C3,Q_DIARRHEA,Q_FAMILY questionNode class A_DAT,A_TXRXN,A_WARM,A_COLD,A_NONIMMUNE,A_OTHER,A_INHERITED,A_NGS actionNode class A_URGENT,A_TMA,A_STEC,A_AHUS urgentNode class A_EVANS,A_PCH,A_C3D_AIHA pediatricNode class END_IMMUNE,END_TMA,END_INHERITED,END_OTHER endNode
Hemolytic Anemia Workup

This pathway guides the systematic evaluation of patients with suspected hemolytic anemia, from initial triage through definitive diagnosis.

Key Principle: The DAT (Direct Antiglobulin Test) is the primary branch point separating immune from non-immune hemolysis. Always correlate with clinical context.
Key Guidelines
Node Types
Start Point
Decision Point
Action / Workup
Urgent Action
Pediatric/IEI Focus
Endpoint
Question
Node Title

Node description goes here.

Condition Types

Select a Condition

Choose a condition from the list to view detailed clinical information.

Specimen Handling for Cold-Related Tests

Cold Agglutinin Titer
Serum (Red Top) - CRITICAL
  • Pre-warm tube to 37°C before collection if possible
  • CRITICAL: Keep specimen at 37°C from draw until serum separated
  • Allow to clot at 37°C (use heated water bath or incubator)
  • Centrifuge at 37°C and separate serum within 1-2 hours
  • Refrigeration before separation causes false-negative results

Rationale: Cold agglutinins bind to RBCs during clotting if cooled, depleting antibody from serum

EDTA Plasma (Lavender/Pink Top) - Less Critical
  • Warm handling preferred but less critical than for serum
  • If specimen cooled: incubate at 37°C for 15 minutes before testing to dissociate autoabsorbed antibody
  • Some reference labs accept EDTA; verify with your laboratory

Rationale: No clotting period means faster separation; autoabsorbed antibody can be recovered by warming

Donath-Landsteiner Test
  • CRITICAL: Warm-separated serum required
  • Keep blood at 37°C continuously from collection
  • Separate serum at 37°C in pre-warmed centrifuge
  • Do NOT refrigerate before separation
  • Coordinate with transfusion medicine/immunohematology laboratory before collection
  • Often requires referral to specialized laboratory
Cryoglobulin Test
  • CRITICAL: Maintain specimen at ~37°C from draw through serum separation
  • Use pre-warmed tubes and transport container
  • Separate serum at 37°C (heated centrifuge or water bath)
  • FALSE NEGATIVES are common if temperature drops before separation
  • Coordinate with lab for special collection protocol
  • Separated serum is incubated at 4°C for 72 hours to 7 days
General Note: For all cold-related testing, early communication with the laboratory is essential to ensure proper specimen handling and timely processing.
Collection Tube Types Quick Reference
Tube Color Additive Specimen Type Key Points
Red None (clot activator optional) Serum
  • Requires clotting time (30-60 min)
  • Standard for cold agglutinin titer at most labs
  • SST (gel separator) NOT acceptable for cold tests
Lavender EDTA (K2 or K3) Whole blood / Plasma
  • Anticoagulant prevents clotting
  • Immediate mixing required
  • Some labs accept for cold agglutinin testing
  • Cooled specimens can be recovered by warming to 37°C
Pink EDTA (K2) Whole blood / Plasma
  • Essentially same as lavender
  • Often designated for blood bank use
  • EDTA preserves RBC antigens well
Gold/SST Clot activator + gel separator Serum
  • NOT acceptable for cold agglutinin testing
  • Gel barrier may trap cold-reactive antibodies
Why does tube type matter for cold antibody testing?
Cold agglutinins (IgM antibodies) bind to RBCs when the temperature drops below body temperature.
  • Serum (red top): During the clotting period, if the specimen cools, cold agglutinins bind to RBCs and are removed when serum is separated, giving falsely low/negative results.
  • EDTA (lavender/pink): No clotting period allows faster separation. Even if antibodies bind, they can often be recovered by warming the specimen to 37°C for 15 minutes before testing.
Important: Drug association does not prove causality. Many drugs cause DAT positivity without clinically significant hemolysis. This list includes drugs reported in association with AIHA or positive DAT; clinical significance varies.

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PLASMIC Score Calculator TTP Probability

Score to estimate probability of ADAMTS13 deficiency in suspected TMA.

Score: 0/6
Select criteria
Check applicable criteria above
Note: PLASMIC score is a screening tool. ADAMTS13 activity testing remains the gold standard for TTP diagnosis.
ISTH DIC Score Overt DIC

Scoring system for diagnosis of overt disseminated intravascular coagulation.

Parameter 0 1 2 3
Platelet count >100 50-100 <50 —
D-dimer/FDP Normal — Moderate ↑ Strong ↑
PT prolongation <3s 3-6s >6s —
Fibrinogen >1.0 <1.0 — —
Score ≥5
Overt DIC
Score <5
Not overt, repeat in 1-2 days
Prerequisite: Underlying disorder known to be associated with DIC must be present to apply score.
Peripheral Smear Morphology Library
Schistocytes
TMA, DIC, mechanical
Spherocytes
AIHA, HS, burns
Bite/Blister Cells
G6PD deficiency
Target Cells
Hemoglobinopathy, liver dz
Sickle Cells
Sickle cell disease
RBC Agglutination
Cold agglutinins
Polychromasia
Reticulocytosis
Intracellular Parasites
Malaria, babesiosis
Recommended Order Sets
Initial Hemolysis Workup
  • CBC with differential & indices
  • Reticulocyte count
  • Peripheral blood smear review
  • LDH, haptoglobin, total & indirect bilirubin
  • Urinalysis with microscopy
  • Direct antiglobulin test (DAT)
MAHA/TMA Workup
  • BMP/creatinine (trend)
  • PT/INR, aPTT, fibrinogen, D-dimer
  • ADAMTS13 activity ± inhibitor
  • Peripheral smear review (schistocyte %)
  • If diarrhea: Stool Shiga toxin/STEC
  • If aHUS suspected: Complement studies
DAT-Positive Workup
  • Monospecific DAT (IgG, C3)
  • Review transfusion hx (past 3 months)
  • Review medication list
  • Cold agglutinin titer (if C3-only/cold sx)
  • Consider: ANA, lymphoma workup
DAT-Negative Workup
  • Peripheral smear focus on morphology
  • PNH flow cytometry (if intravascular)
  • If lifelong/family hx: G6PD assay, EMA binding, Hb electrophoresis
  • Evaluate mechanical causes (echo if valve/device)