When Red Cells Misbehave: The Curious World of Polyagglutination

Most of the time, our red cells are polite. They keep their surface antigens tucked away, only showing the parts of themselves that matter for ABO, Rh, and the usual cast of characters. But sometimes, hidden pieces of the red cell membrane — cryptantigens — are suddenly exposed. When that happens, nearly every adult’s serum will react. The result is polyagglutination: the striking, messy agglutination of a patient’s red cells with most sera, even when ABO-compatible.

It’s rare, it’s fascinating, and it can cause real confusion at the bench. Let’s walk through it.

The Culprit: Cryptantigens

Cryptantigens are usually masked by glycosylation or membrane structure. When they become exposed — through infection, clonal mutation, or inherited defects — they look like foreign antigens to the naturally occurring antibodies present in most adults.

A key laboratory note:

• T family (T, Th, Tk, Tx) antigens are recognized by Arachis hypogea (peanut) lectin.

• Tn antigen is different — it is not recognized by peanut lectin, but is picked up by Helix pomatia (snail) lectin.

  
  

Acquired Causes

T Activation

• Mechanism: Bacterial neuraminidase (from Clostridium perfringens, Streptococcus pneumoniae, and others) strips sialic acid from the red cell surface.

• Exposed antigens: T, Th, Tk, Tx.

• Clinical associations: Seen in sepsis, aHUS, and necrotizing enterocolitis.

• Key point: This form is acquired and transient.

• Lab detection: Arachis hypogea (peanut) lectin.

• Management: Avoid plasma (full of anti-T antibodies), and if transfusion is necessary, use washed RBCs or platelets.

  
  

Tn Polyagglutination

• Mechanism: Acquired somatic mutation in a hematopoietic stem cell → defective glycosylation.

• Exposed antigen: Tn antigen, distinct from the T family.

• Nature: Acquired, clonal, persistent. Sometimes shows mixed-field reactions.

• Lab detection: Helix pomatia (snail) lectin, not peanut lectin.

• Associations: May signal clonal hematopoiesis or preleukemic states.

  
  

Inherited Causes

HEMPAS (Congenital Dyserythropoietic Anemia II)

• Mechanism: Inherited SEC23B mutation → defective Golgi trafficking and incomplete glycosylation.

• Effect: Cryptantigens are exposed and react with about one-third of adult sera.

• Clinical picture: Chronic hemolytic anemia, multinucleated erythroblasts in marrow, positive acidified serum test.

  
  

Hyde Park Polyagglutination

• Mechanism: Inherited abnormal synthesis of Band 3 protein, described in individuals with Hemoglobin Hyde Park.

• Effect: Membrane structural changes expose cryptantigens.

• Detection: Confirmed with Sophora japonica lectin.

• Rarity: Extremely uncommon, familial.

  
  

Quick Reference Table

Type	Cause	Exposed Antigen	Nature	Detection	Notes
T Activation	Bacterial neuraminidase (infection)	T, Th, Tk, Tx	Acquired, transient	Arachis hypogea (peanut) lectin	Sepsis, aHUS, NEC; avoid plasma; wash RBCs/plt
Tn Polyagglutination	Somatic stem cell mutation	Tn antigen	Acquired, clonal	Helix pomatia (snail) lectin	Marrow disorders, preleukemia
HEMPAS (CDA II)	Inherited SEC23B mutation	Cryptantigens	Inherited, persistent	Acid serum test; ~1/3 sera positive	Dyserythropoietic anemia
Hyde Park	Inherited abnormal Band 3 synthesis (Hb Hyde Park)	Cryptantigen	Inherited, persistent	Sophora japonica lectin	Very rare familial condition

Why It Matters

Polyagglutination can be a diagnostic trap — suddenly, every crossmatch looks incompatible. Recognizing the pattern, reaching for lectins, and knowing which forms are acquired (T, Tn) and which are inherited (HEMPAS, Hyde Park) can help the blood banker avoid unnecessary delays, and in some cases, guide clinicians toward underlying conditions.