Haemolytic Anaemias

Article Last Updated:13/02/2026

Haemolytic Anaemia Overview

Aetiology

The key split comes into whether the haemolytic anaemia is immune-mediated or non-immune mediated (clinically assessed by the direct Coombs test or DAT).

Immune-Mediated Haemolytic Anaemia (+ve Coombs)

Majority of cases: autoimmune haemolytic anaemia (AIHA), which are further sub-categorised as: ^[Ref]

Category	Diagnostic clues	Causes
Warm AIHA	IgG-mediated Splenomegaly is typical (due to extra-vascular haemolysis)	Antibodies binds to antigen at warm temperature (37°C) Primary (~50%) Secondary causes are mostly immunologic / lymphoproliferative disorders CLL SLE Common variable immunodeficiency
Cold AIHA	IgM-mediated and complement-dependent ↑ Cold agglutinin titre RBC clumping (agglutination) on blood film May cause Raynaud-like phenomena	Antibodies binds to antigen at cold temperature (0-4°C) Primary (cold agglutinin disease) Secondary causes are mostly infections Mycoplasma pneumoniae EBV infection CMV infection SARS-CoV-2 infection Lymphomas
Paroxysmal cold haemoglobinuria	IgG mediated Binds to antigen at cold temperature (<37°C), but activates complement pathway after rewarming to 37°C Almost exclusively as a rare, temporary, post-viral complication in children Acute-onset haemolytic anaemia Jaundice Fatigue, pallor Haemoglobinuria (cola-coloured urine)
Drug-induced	Typically warm, and IgG mediated	Historical causes: Methyldopa Penicillin Morden causes: Cephalosporins (e.g. ceftriaxone) Piperacillin NSAIDs

Less common: non-autoimmune immune haemolytic anaemia

Acute and delayed transfusion reactions
Haemolytic disease of the newborn

Non-Immune Haemolytic Anaemia (-ve Coombs)

Causes can be further sub-categorised as: ^[Ref1]^[Ref2]

Intrinsic	Membrane defect	Hereditary spherocytosis Hereditary elliptocytosis Paroxysmal nocturnal haemoglobinuria (this is DIFFERENT from paroxysmal cold haemoglobinuria)
	Enzyme defect	G6PD deficiency Pyruvate kinase deficiency
	Haemoglobinopathies	Thalassaemia Sickle cell disease
Extrinsic	Microangiopathic haemolytic anaemia (MAHA)	Thrombotic thrombocytopenic purpura (TTP) Haemolytic uraemic syndrome (HUS) Disseminated intravascular coagulation (DIC) HELLP syndrome
	Macroangiopathic haemolytic anaemia	Prosthetic (metallic) heart valves Severe valvular stenosis Dialysis
	Toxins / infection	Malaria Lead poisoning Toxins (e.g. snake venom) Severe burns

Work Up

1. Confirming Haemolysis

These findings would indicate haemolytic anaemia, but are non-specific to underlying causes: ^[Ref]

Normocytic normochromic anaemia
- Low Hb
- Normal mean corpuscular volume
- Normal mean corpuscular haemoglobin
Low haptoglobin
High reticulocyte
High unconjugated bilirubin
High LDH

Intravascular vs extravascular haemolysis (not as important):

Intravascular

Destruction of RBC within the blood vessels → release of haemoglobin directly into plasma →

Haemoglobinuria (dark urine)
Rapid depletion of haptoglobin
Marked increase in LDH levels

Extravascular

RBCs destroyed by macrophages in the spleen and liver →

Haemoglobinuria is absent
Haptoglobin mildly
Less pronounced increase in LDH levels

Main causes of extravascular haemolysis are:

Immune-mediated haemolytic anaemia causes
Intrinsic causes of non-immune haemolytic anaemia
- Membrane defect (e.g. hereditary spherocytosis)
- Haemoglobinopathies (e.g. thalassaemia, sickle cell disease)
- Enzyme defect (e.g. G6PD deficiency)

Other causes that are not listed, are mainly intravascular.

2. Investigating Underlying Cause

The direct Coombs test and blood film are the most useful initial investigations for identifying the cause of haemolytic anaemia.

Basic laboratory tests (e.g. FBC, U&E, LFTs, coagulation profile) should also be performed, with additional targeted tests outlined in the condition-specific sections below.

Direct Coombs Test

The direct Coombs test (direct antiglobulin test) help differentiate between immune and non-immune mediated haemolysis ^[Ref]

+ve = immune-mediated haemolytic anaemia
-ve = non-immune haemolytic anaemia

See the aetiology section for specific causes of immune vs non-immune haemolytic anaemia

Blood Film

Key blood film findings and corresponding underlying cause: ^[Ref1]^[Ref2]

Underlying cause	Blood film findings
G6PD deficiency	Heinz bodies (denatured haemoglobin due to oxidative stress – appears as small dark round dots inside the RBCs) Bite cells (notched RBCs, due to splenic removal of Heinz bodies)
Microangiopathic haemolytic anaemia (MAHA)	Schistocytes (fragmented RBCs) Helmet cells (a form of schistocyte caused by partial RBC destruction)
Hereditary spherocytosis	Spherocytes (small, dense RBCs with no central pallor)
Sickle cell disease	Sickle cells (crescent-shaped RBCs)
Cold AIHA	RBC agglutination (clumping)

Cause-Specific Haemolytic Anaemia

Autoimmune Haemolytic Anaemia (AIHA)

Diagnosis

^[Ref]

+ve Direct Coombs test
Further subclassified into warm vs cold AIHA
- Warm AIHA = IgG mediated
- Cold AIHA = IgM mediated + ↑ cold agglutinin titre + RBC agglutination on blood film

Exception: paroxysmal cold haemoglobinuria is cold-related but IgG mediated (instead of IgM).

Various causes of AIHA are covered in the aetiology section above. Further tests depend on the working diagnosis, which is out of the scope of this article.

Management

^[Ref]

AIHA type	Management
Warm AIHA	1st line (for both primary and secondary forms): oral prednisolone Also treat underlying causes of warm AIHA (if any)
Cold AIHA	Do NOT treat cold AIHA with glucocorticoids Management depends on the form: Primary cold AIHA: supportive care (if minimal symptoms) and/or rituximab Secondary cold AIHA: treat underlying cause when possible (only established treatment) Paroxysmal cold haemoglobinuria: supportive care and avoidance of cold exposure (usually self-limiting)

AIHA type

Management

Warm AIHA

1st line (for both primary and secondary forms): oral prednisolone

Also treat underlying causes of warm AIHA (if any)

Cold AIHA

Do NOT treat cold AIHA with glucocorticoids

Management depends on the form:

Primary cold AIHA: supportive care (if minimal symptoms) and/or rituximab
Secondary cold AIHA: treat underlying cause when possible (only established treatment)
Paroxysmal cold haemoglobinuria: supportive care and avoidance of cold exposure (usually self-limiting)

Non-Immune Haemolytic Anaemia

Key supportive test: -ve direct Coombs test

Further investigations and management vary by underlying cause and are covered in separate articles. The table below summarises the key diagnostic clues and main management principles.

Underlying condition	Key diagnostic clues	Mainstay of management
Hereditary spherocytosis	Spherocytes on blood film ↑ Mean corpuscular haemoglobin concentration Splenomegaly	Folic acid Splenectomy if severe
Hereditary elliptocytosis	Elliptical RBCs on blood film	Usually none Splenectomy if severe
(this is DIFFERENT from paroxysmal cold haemoglobinuria)	This is DIFFERENT from paroxysmal cold haemoglobinuria! Haemoglobinuria in the morning (due to nocturnal haemolysis) Pancytopaenia Thrombosis (most common cause of death) (due to thromboplastin being released from RBC lysis) Flow cytometry (↓ CD55 and CD99)	Supportive care Anticoagulation for thrombosis prevention
G6PD deficiency	Heinz bodies and bite cells on blood film Episodic haemolysis after triggers	Avoid oxidant drugs / foods Supportive care
Pyruvate kinase deficiency	Chronic haemolysis Reticulocytosis Splenomegaly	Supportive care Splenectomy if severe
Sickle cell disease	Sickle cells on blood film Painful crises, haemolysis, infections Gold standard: haemoglobin electrophoresis (showing HbS)	Hydroxyurea Transfusions if needed
Thalassaemia	Depends on the type and severity
MAHA (TTP/HUS/DIC/HELLP)	Schistocytes on blood film Thrombocytopenia	Treat underlying cause Plasma exchange for TTP
Macroangiopathic haemolytic anaemia	Schistocytes on blood film History of stenotic valves / metallic valves / dialysis	Treat mechanical cause
Malaria	Parasites on blood film Fever Haemolysis	Antimalarial therapy
Lead poisoning	Basophilic stippling Abdominal pain Peripheral neuropathy	Chelation therapy
Severe burns/toxins	Haemolysis Exposure history	Supportive care Remove trigger

Share Your Feedback Below Cancel reply

You must be logged in to post a comment.