Tests of haemolysis - haptoglobin

What it is

An alpha-2 glycoprotein made by the liver whose only job is to bind free plasma haemoglobin
*The most sensitive single marker of intravascular haemolysis*
A LOW haptoglobin is the abnormal result - it is consumed, not produced, by haemolysis
Normal range ~0.3-2.0 g/L (assay-dependent)
Part of the haemolysis quartet: haptoglobin low, LDH high, unconjugated bilirubin high, reticulocytes high

Congenital anhaptoglobinaemia - up to 1-4% of people of African ancestry, ~1 in 1,000 Europeans
- A permanently undetectable haptoglobin that has nothing to do with haemolysis
Three common phenotypes (Hp 1-1, 2-1, 2-2) with differing binding capacity and clearance
Haptoglobin is absent or very low in normal neonates until ~3-6 months

Red cell lysis -> free haemoglobin dimers in plasma
Haptoglobin binds haemoglobin with very high affinity -> Hb-Hp complex
-> complex bound by CD163 on macrophages and hepatocytes -> cleared within minutes
-> *consumption outstrips hepatic resynthesis (which takes days) -> serum haptoglobin falls to undetectable*

Free haemoglobin is toxic
- Scavenges nitric oxide -> vasoconstriction, pulmonary and systemic hypertension, priapism, dysphagia
- Filtered at the glomerulus -> tubular toxicity and AKI
- Iron loss and oxidative injury
Once haptoglobin is saturated: free haemoglobin -> haemoglobinuria; haem binds haemopexin and albumin (methaemalbumin); haemosiderin appears in shed tubular cells (haemosiderinuria, from ~1 week)

	Haptoglobin
Intravascular haemolysis (ABO reaction, PNH, TMA, mechanical valve, march haemoglobinuria)	Undetectable
Extravascular haemolysis (warm AIHA, hereditary spherocytosis, hypersplenism)	Low but often measurable - some haemoglobin still escapes into plasma

*Haptoglobin is a POSITIVE acute phase reactant* - inflammation, infection, malignancy, trauma, corticosteroids and oestrogen raise it
- -> a "normal" haptoglobin in an inflamed patient may represent significant haemolysis
*Haptoglobin is made in the liver - it is low in cirrhosis, hepatitis and any synthetic failure* without any haemolysis
- So is albumin - check it

Distinguishing haemolysis from ineffective erythropoiesis or blood loss in an anaemic patient
Confirming a haemolytic transfusion reaction
Monitoring PNH, mechanical valve haemolysis, TMA

Consider	Clue
Haemolysis	High LDH, high reticulocytes, high unconjugated bilirubin, abnormal film
Liver disease	Low albumin, abnormal LFTs, coagulopathy, splenomegaly
Congenital anhaptoglobinaemia	Persistently zero with no biochemical or clinical haemolysis, relevant ancestry
Neonate	Age <3-6 months
Massive transfusion, dilution	Context

Undetectable haptoglobin with a raised LDH is ~90% specific for haemolysis
Normal haptoglobin with a normal LDH makes haemolysis very unlikely (~90% sensitive to exclude)
*Never interpret it alone* - always with LDH, bilirubin, reticulocytes, film and DAT

FBE + film, reticulocytes, LDH, bilirubin (conjugated and unconjugated)
DAT
CRP and albumin - to interpret the haptoglobin itself
Urine for haemoglobinuria (dipstick positive for blood, no red cells on microscopy) and haemosiderinuria (chronic intravascular haemolysis)

Confirm haemolysis is real - LDH, bilirubin, reticulocytes
Classify it
- DAT positive -> autoimmune haemolysis -> look for CLL/lymphoma, SLE, drug, infection
- DAT negative with schistocytes -> TMA (TTP, HUS, DIC, mechanical valve, malignant hypertension) -> *this is the urgent branch*
- DAT negative without schistocytes -> hereditary (spherocytosis, G6PD, sickle, thalassaemia), PNH, infection (malaria, Clostridium perfringens, babesia), drug, burns, march haemoglobinuria
Free plasma haemoglobin and urinary haemosiderin confirm the intravascular component

*It does not indicate severity, and it does not guide treatment* - it is a diagnostic marker only
It is a poor monitoring test - it stays undetectable until haemolysis has essentially stopped, then recovers over days
- Use haemoglobin, reticulocytes and LDH to follow response
*Do not diagnose haemolysis on a low haptoglobin alone* - exclude liver disease and congenital absence

Intravascular haemolysis - PNH, ABO-incompatible transfusion, TTP/HUS/DIC, prosthetic and paravalvular leak haemolysis, march haemoglobinuria, severe burns, Clostridium perfringens sepsis, malaria (blackwater fever), snake envenomation
Extravascular haemolysis - AIHA, hereditary spherocytosis, G6PD deficiency, sickle cell disease, thalassaemia, hypersplenism
Liver disease (reduced synthesis)
Inflammation, infection and malignancy (acute phase rise masking haemolysis)
Congenital anhaptoglobinaemia
Ineffective erythropoiesis - megaloblastic anaemia and MDS also lower haptoglobin and raise LDH (intramedullary haemolysis - a classic trap for "haemolysis" in B12 deficiency)
Oestrogen therapy and corticosteroids (raise it)

Falls within hours of significant intravascular haemolysis
Recovers over 3-7 days once haemolysis stops - hepatic resynthesis is slow
In chronic haemolysis (PNH, mechanical valve, sickle cell) it stays persistently undetectable

*Send haptoglobin BEFORE transfusing* - transfused haptoglobin-replete plasma confounds the result
In a patient with both inflammation and suspected haemolysis, a normal haptoglobin does not exclude it - rely on LDH, reticulocytes, film and DAT
A persistently undetectable haptoglobin with a normal LDH, normal reticulocytes and normal film in a well patient is usually congenital anhaptoglobinaemia - no further investigation needed

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