Haemolysis and Acquired Haemolytic Anaemia Flashcards
What are the three main functions of the spleen
- Controls rred cell integrity
- Immune Function
- Storage Function
Control Red Cell Integrity
Pitting
Culling
Grooming
Pitting
Removes inclusions such as RNA, siderotic granules etc.
Culling
Trap rigid red cells
Remove abnormal / senescent red cells
Hypoxic environment
Grooming
Removes excess lipids from reticulocytes
Immune Function
Filtration of antigens
Macrophages and dendritic cells
Presentation to T- and B-cells
NB! Encapsulated organisms
Storage
Platelets:
About 30% of platelets stored in normal spleen
Can increase to >90% in enlarged spleen
Red blood cells:
236.5 ml (~ one cup) of red blood cells
Released in cases of hypovolemia
E.g. trauma or massive blood loss
White blood cells:
Up to a quarter of lymphocytes
Also neutrophils etc.
Hyposplenism
Can be as a result of surgery or could be functional
Hyposplenism:
Causes
Splenectomy
Sickle cell disease
Gluten-induced enteropathy
Inflammatory bowel disease
Splenic artery thrombosis
Hyposplenism:
Risks
Infections:
-Encapsulated organisms:
Especially Pneumococcus, Haemophillus and
Meningococcus
Vaccinations NB!
Prophylactic antibiotics
Thrombosis:
Consider prophylaxis
Hyposplenism:
Features
Raised platelet count or white cell count:
-Usually temporary, but may be persistent
Peripheral smear:
-Acanthocytes, Howell-Jollly bodies, Pappenheimer
bodies, target cells, etc.
Normal Red Cell Destruction
Mean lifespan of 120 days
– Red cells have no nucleus
– Metabolism gradually deteriorates
– Cells become non-viable
Cam be removed either Extravascularly/Intravascularly
-Removed extravascularly by the macrophages of the
reticuloendothelial (RE) system, spleen, bone marrow, liver
-Intravascular haemolysis:
Little or no part in normal red cell destruction
Haemolysis:
Heamolytic Anaemia
Increased rate of red cell destruction / decreased red cell lifespan
Erythropoietic reserves:
– Potential to expand 6-8 times normal production
Haemolysis if red cell lifespan < 100 days
– Anaemia only occurs when red cell lifespan is less than 30days
Usually compensated initially due to ↑ erythropoietin
– Therefore anaemia may be mild
Haemolytic Anaemia in Adults
Anaemia as a result of increased rate of RBC destruction
Causes of Intravascular Haemolysis
Mismatched blood transfusions (usually ABO)
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
Microangiopathic haemolytic anaemia
– (Red cell fragmentation syndromes)
Autoimmune haemolytic anaemia (Some)
Drugs, toxins and infections (Some)
Paroxysmal nocturnal haemoglobinuria (PNH)
March haemoglobinuria
Unstable haemoglobins
Diagnosis of Haemolytic Anaemia
Specific clinical presentation due to increased red cell
destruction and associated increase in erythropoiesis.
Can be acute or chronic
No symptoms are specific for the diagnosis of haemolytic anaemia
Recognition of haemolysis is NOT DIFFICULT in the
classical patient
Clinical Presentation
Rapid onset of pallor (anaemia)
Jaundice
History of pigmented
(bilirubin) gallstones
Splenomegaly
Increased Red Cell Destruction:
Clinical/Laboratory Features and Mechanism
Pallor of mucous membranes:
↓ Haemoglobin
Jaundice:
↑ Unconjugated serum bilirubin
Dark urine:
(Especially if left to stand) ↑ Urobilinogen
Pigment gallstones:
↑ Bilirubin in bile
Splenomegaly:
↑ Red cell destruction
Absence of plasma haptoglobins:
Removed through hemoglobin/haptoglobin complexes
Increased Red Cell Production:
Clinical/Laboratory Features and Mechanisms
Reticulocytosis:
Erythroid precursors in peripheral blood
Folate deficiency:
Increased consumption by high red cell turnover
Bone deformities:
Erythroid hyperplasia of bone marrow lead to expansion
Investigations for Heamolysis
Evidence of haemolysis – 3 components
- Red cell damage/loss:
- FBC
- Peripheral smear
- Haemosiderinuria - Biochemistry
- Blood
- Urine - Increased red cell production
- Reticulocyte count
- Peripheral smear
- Bone marrow
Red Cell Damage/Loss
FBC-Full Blood Count
Haemoglobin, haematocrit, other indices:
-Normochromic, normocytic anaemia (May be macrocytic)
Other cell-lines involved:
- May have reactive leucocytosis/thrombocytosis
- Evidence of underlying disease process
Peripheral smear:
- Spherocytes
- Red cell fragments if microangiopathic
Haemosiderinuria:
-Evidence of intravascular haemolysis
Biochemistry
Blood:
- Raised unconjugated bilirubin
- Raised lactate dehydrogenase (LDH)
- Low haptoglobin
- Low haemopexin
Urine:
- Haemoglobinuria
- Urobilinogenuria
Increased Red Cell Production
Reticulocyte count:
-Reticulocytosis
Peripheral smear:
-Polychromasia
Bone marrow:
-Erythroid hyperplasia
Immune Heamolytic Anaemia:
Types
Autoimmune Haemolytic Anaemia
Alloimmune Haemolytic Anaemia
Drug-Induced Immune Heamolytic Anaemia
Autoimmune Haemolytic Anaemia:
Types
Warm Autoimmune Haemolytic Anaemia
Cold Autoimmune Haemolytic Anaemia
Warm Autoimmune Haemolytic Anaemia
Red cell coated with immunoglobulin and/or complement:
– Usually IgG and C3, rarely IgA
Immunoglobulin recognized by Fc receptor on macrophages in reticuloendothelial (RE) system:
– Loss of membrane leads to spherocytes
– Shortened red cell lifespan
Clinical picture: – Any age, sex – Haemolytic anaemia – varying severity • Remit and relapse – Splenomegaly
Warm Autoimmune Haemolytic Anaemia:
Causes
- Idiopathic (70% of cases)
2.Secondary – Autoimmune diseases (SLE etc.) – Lymphoproliferative disorders: *Lymphoma *Chronic lymphocytic anaemia – Viral infections (EBV) – Drugs: Methyldopa etc.
Warm Autoimmune Haemolytic Anaemia:
Clinical Features
Pallor
Jaundice:
- Mild
- Fluctuating
Dark urine
+- Splenomegaly
Warm Autoimmune Haemolytic Anaemia:
Laboratory Findings
Full blood count
– Normocytic/macrocytic anaemia
– Leucocytosis
Peripheral smear
– Spherocytes, polychromasia, nucleated red cells
Features of EXTRAVASCULAR haemolysis
Direct Coombs (DAT) positive
– IgG and/or complement, IgA (rare)
– Antibodies detected at 37°C
Warm Autoimmune Haemolytic Anaemia:
Treatment
Remove/treat the underlying cause
Corticosteroids
Intravenous immunoglobulin (IVIG/Polygam®)
Splenectomy
Immmunosuppression
– If steroids and/ or splenectomy have failed
Folic acid is given in severe cases
Blood transfusion
– Least incompatible
– If the specificity of the autoantibody is known, use donor blood that lacks the relevant antigen(s)
Cold Autoimmune Haemolytic Anaemia
Antibody usually IgM and binds to red cells at 4°C
- Highly effective fixing complement
- INTRAVASCULAR AND EXTRAVASCULAR haemolysis
Antibody attaches to red cells in the peripheral circulation
– Blood temperature is cooled
– Antibody elute of cell at warmer parts and only
complement is usually detected
Cold Autoimmune Haemolytic Anaemia:
Clinical Features
Chronic haemolytic anaemia:
– Aggravated by cold
– Mild jaundice and splenomegaly may be present
Acrocyanosis (purplish skin discoloration)
– Tip of the nose, ears, fingers and toes
– Agglutination of red cells in small vessels
Cold Autoimmune Haemolytic Anaemia:
Laboratory Findings
Full blood count
– Normochromic/macrocytic anaemia
– Leucocytosis
Peripheral smear
– Haemagglutination
– Spherocytosis is less marked
DAT
– Complement (C3d) only on the red cell surface
High titre of “cold” autoantibodies to red cells
Cold Autoimmune Haemolytic Anaemia:
Treatment
Keep the patient WARM
– Warmed fluids
Treating the underlying cause
Splenectomy doesn’t help
– Unless massive splenomegaly
Medication
– Immunosuppression
Steroids are not helpful
Alloimmune Heamolytic Aneamia
Antibody produced when red cells of one individual reacts with red cell of another
Alloimmune Heamolytic Anaemia:
Causes
Transfusion of ABO-incompatible blood
Rh disease of the new-born
Allogeneic transplantation
Alloimmune Heamolytic Anaemia:
Laboratory Diagnosis
Full blood count and peripheral smear
– Anaemia
– Features of haemolysis-INTRA- AND/OR EXTRAVASCULAR
Direct antiglobulin test (Direct Coombs test)
– Positive
Antibody identification and quantification
Drug Induced Heamolytic Aneamia:
Mechanism
Drug-red cell membrane complex
Drug-protein-antibody complex
True autoimmune haemolytic anaemia (Rare)
Haemolytic anaemia disappears once drug is stopped
Drug-Red Cell Membrane Complex
Antibody directed against a drug-red cell membrane
complex
Only massive doses
Often antibiotics
– E.g. penicillin and ampicillin
Drug-protein-antibody complex
Drug-protein-antibody complex
Deposition of complement
– E.g. quinidine, rifampicin
True autoimmune haemolytic anaemia (Rare)
True autoimmune haemolytic anaemia
Role of drug uncertain
-E.g. methyldopa
Infections
Causes haemolysis in a variety of ways:
- Precipitates an acute haemolytic crisis in G6PD deficiency
- Causes microangiopathic haemolytic anaemia
• E.g. meningococcal or pneumococcal septicaemia - Malaria causes haemolysis by extravascular destruction of parasitized red cells as well as by direct intravascular lysis
-Blackwater fever is an acute intravascular haemolysis
accompanied by acute renal failure caused by Falciparum malaria - Clostridium perfringens septicaemia can cause intravascular
haemolysis with marked microspherocytosis
Red Cell Fragmentation Syndromes:
Definition
Physical damage to red cells due to:
- Microangiopathic haemolytic anaemia (MAHA)
- Abnormal surfaces
- Mechanical trauma
Microangiopathic haemolytic anaemia (MAHA)
– Red cells passing through abnormally small vessels
• Caused by deposition of fibrin strands or platelet
aggregates
Abnormal Surfaces
Physical damage to red cells on abnormal surfaces
– e.g. artificial heart valves or arterial grafts
– Arteriovenous malformations
Mechanical Trauma
March haemoglobinuria
Microangiopathic Heamolytic Aneamia:
Clinical Presentation
Thrombotic microangiopathy
Pathological lesion on tissue biopsy
– Platelet-fibrin rich thrombus
Microangiopathic Heamolytic Anaemia:
Causes
1.Primary thrombotic microangiopathy (TMA) syndromes:
Thrombotic thrombocytopenic purpura (TTP)
Haemolytic Uremic Syndrome (HUS)
- Atypical HUS or Complement-mediated TMA
- Shiga toxin-mediated HUS (ST-HUS)
Drug-induced TMA
2.Systemic disorders that may present with MAHA and thrombocytopenia:
Disseminated intravascular coagulation (DIC)
Systemic infection (Sepsis) : May be bacterial, viral, rickettsial, or fungal
Systemic malignancy
Pregnancy-related syndromes HELLP syndrome, pre-eclampsia, etc.
Severe hypertension
Systemic rheumatic diseases: E.g. Vasculitis, antiphospholipid syndrome, etc.
Haematopoietic stem cell or organ transplants
Renal vascular disorders
Thrombotic Thrombocytopenic Purpura:
Types and Classification
Acquired TTP
– Severe ADAMTS13 deficiency (<10% ativity)
– Due to an ADAMTS13 antibody (autoimmune condition)
Hereditary TTP
– Inherited ADAMTS13 mutation
HIV associated TTP
– Exact pathogenesis uncertain
EMERGENCY REQUIRE URGENT TREATMENT AND REFERRAL
TTP:
Diagnosis Types
Clinically Suspicion
Laboratory Suspicion
Clinically Suspicion
MAHA
– Anaemia
– Fever
Platelet consumption
– Petechiae
Evidence of organ damage
– Neurological symptoms
– Cardiac symptoms
– Gastrointestinal symptoms
Laboratory Suspicion
MAHA
– Red cell fragments (Schistocytes)
– Raised LDH +++
Platelet consumption
– Thrombocytopenia-Usually very low
Evidence of organ damage
– Renal dysfunction
TTP
Pentad
video
TTP:
Treatment
IMPORTANT!
Consider TTP in all patients with MAHA and thrombocytopenia - Especially if no alternative
Check peripheral smear, consult haematologist
Urgent referral to haematologist if TTP is suspected
– Infusion with Fresh Frozen Plasma
– Plasma exchange needed
Immunosuppression
Other MAHA
Disseminated Intravascular Coagulopathy(DIC)
Pregnancy-Related Syndromes
Disseminated Intravascular Coagulopathy(DIC)
Fibrin-rich microthrombi
Consumption of coagulation factors
– Leads to bleeding
Occasional red cell fragments
Thrombocytopenia less prominent
Abnormal coagulation screen
Pregnancy-Related Syndromes
Patient pregnant
RED CELL FRAGMENTS on peripheral smear
HELLP syndrome
– Haemolysis
– Elevated Liver enzymes
– Low Platelets
Pre-eclampsia
– Neurological syndromes
– Proteinuria
– Hypertension
Chemical and Physical Agents
Drugs
Wilson’s Disease
Chemical Poisoning
Severe Burns
- Wilson’s disease
- Chemical poisoning
- Severe burns
Drugs
E.g. dapsone and Salazopyrin®
High doses causes oxidative intravascular haemolysis with Heinz body formation in normal subjects
Wilson’s Disease
Acute haemolytic anaemia
High levels of copper in the blood
Chemical Poisoning
E.g. with lead, chlorate or arsine
Severe Burns
Damage to red cells
Acanthocytosis or spherocytosis
