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Perth Haematology :: Dr Steven Ward

Haemolysis

 

Haemolysis = the excessive breakdown of red blood cells.

 

 

Assessing Haemolysis - Clinical

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Family History

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Past History: jaundice, gall stones; leg ulcers

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Recent History: jaundice, dark urine, pain, rigors, sweats, fever, transfusion, drugs, toxins/bites, burns

 

Assessing Haemolysis - Laboratory

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Inspection of urine:
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Urobilinogen = bilirubin turnover

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Bilirubinuria = conjugated hyperbilirubinaemia

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Blood = frank red, smoky = red cells

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dark muddy = oxidised Hb or myoglobin

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 Inspection of plasma
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red/brown = suspicious of blood

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Yellow  = bilirubin

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Blood Film: anaemia, polychromasia, spherocytes, bite cells, sickle cells, fragmented cells.

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Hyperbilirubinaemia: unconjugated (ddx Gilberts)

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Reticulocytosis

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Elevated LDH (LD1); other liver enzymes normal

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Absent Haptoglobin: but acute phase protein

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Plasma Hb: not very helpful

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Schumms Test: Methaemalbumin

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Haemosiderinuria: iron in urine; 1 week after acute HA or in chronic HA.

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Red Cell Survival Study: 51Cr labelled RBCs; also localise site of haemolysis.

 

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 What is the cause?
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Blood film

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Direct Coombs Test

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Other specific tests

 

 

 

 

 

Intravascular Haemolysis

Causes:

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Transfusion reaction (usually ABO incompatibility)

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G6PD defic with oxidant stress

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Red cell fragmentation syndromes

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Some AIHA

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Some drug and infection related HA

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PNH

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March haemoglobinuria

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Unstable Hb

 

Main lab features:

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Hb-aemia; Hb-uria

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 Haemosiderinuria

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Methaemalbuminaemia

 

General Management Concepts

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Problems related to acute intravascular haemolysis:
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Marked systemic reaction

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Activation of kinin-kininogen, complement, coagulation systems

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Shock; pre-renal or renal failure

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Abdominal, chest, back pain

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Maintain circulation, perfusion, urine output

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Consider DIC

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 Problems related to bilirubin load:
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Pigment gall stones

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Biliary sludge

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 Factors affecting the marrow response to anaemia
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Rate of onset; age; folic acid; infection; marrow failure

 

Membrane Defects: HS

Hereditary Spherocytosis

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Autosomal dominant; variable gene expression

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Vertical membrane protein defect Progressive loss of membrane spherocytosis haemolysis

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Spectrin most common defect

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Extravascular haemolysis spleen

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Often asymptomatic; neonatal jaundice; jaundice with infection; leg ulcers; poor exercise tolerance; biliary colic; splenomegaly

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Normocytic spherocytes; hyperchromatic (MCHC)

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Flow cytometry diagnostic test

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Osmotic Fragility: increased fragility

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Management:
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wide variability in clinical severity.

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Splenectomy: chronic anaemia; repeated haemolytic episodes; pigment gall stones; leg ulcers

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Folic acid

 

 Other Membrane defects

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Hereditary Elliptocytosis (HE)
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Horizontal membrane defect (spectrin or Protein 4.1)

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Usually clinically silent

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Autosomal Dominant

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 Hereditary Pyropoikilocytosis (HPP)
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Rare; homozygous HE or double heterozygous

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Severe haemolytic anaemia

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 South-East Asian Ovalocytosis (SEAO)
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Defect of Band 3

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Usually mild

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 Hereditary Acanthocytosis
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Autosomal recessive

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Malabsorption; retinitis pigmentosa; peripheral neuropathy

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Due to a-betalipoproteinaemia

 

 

Heinz Body Haemolytic Anaemia

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Oxidative stress on RBC Heinz Bodies haemolysis

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Heinz Bodies = degraded Hb.  

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Attach to rbc membrane rigid removal by spleen Bite cells, spherocytes

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Oxidation occurs by 3 methods:
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1: Aerobic glycolysis: Hexose-monophosphate shunt (G6PD)  
    or Glutathione

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2: Unstable Hb

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3: Drug/toxin oxidative effect on normal rbc
    (eg sulphasalazine, dapsone)

 

 

Enzyme Defects: G6PD Deficiency

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X-linked; female carriers have ~50%

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Resistance to Plasmodium falciparum malaria

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Mainly W Africa, Med, Middle East, SE Asia

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Mild (10-15% enzyme activity) in Africa to severe in Orientals and most severe in Mediterraneans

 

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Triggers to haemolysis in G6PD Deficiency
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Infection and other acute illness (eg DKA)

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Drugs: anti-malarial;sulphas; analgesics; anti-helminthics; vit K analogues; naphthalene; probenecid

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Fava beans

 

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Rapid development of intravascular haemolysis with Hb-uria

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In mild (African) often self-limiting due to new RBCs having adequate G6PD levels.

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Between crises FBP is normal

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Enzyme assay

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During attack: Bite and Blister cells; Heinz bodies

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NB: Young RBC have higher enzyme level false N

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Treatment: Treat the cause; diuresis; transfuse

 

 

Enzyme Defects: PK Deficiency

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Pyruvate Kinase :: Glycolytic (Embden-Meyerhof) pathway

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Autosomal recessive

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Rigid RBC due to reduced ATP prduction

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Wide range of severity and Hb 40-100g/L

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O2-dissociation curve right shifted due to high 2,3-DPG milder symptoms

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Jaundice and gallstones common

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FBP: poikilocytes and prickle cells

 

 

Immune Haemolytic Anaemia

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Ab mediated attack on RBC membrane

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IgG or IgM Complement

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Usually extravascular destruction in spleen/liver

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Occasionally complete complement activation intravascular haemolysis

 

Types:

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Autoimmune
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Warm

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Cold

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Alloimmune

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Drug-induced

 

 

Warm AIHA

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Features of haemolysis

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Spherocytes on blood film

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Positive Direct Antiglobulin Test (DAT) = Coombs Test

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IgG, C3d, occ IgA, rarely IgM

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Management:
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Remove/treat the cause

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Steroids

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Splenectomy

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Immunosuppression: Azathioprine, cyclophosphamide, cyclosporin

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Folic acid

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IvIg

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Rituximab (anti-CD20 Ab, MabThera)

 

Cold AIHA

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Abs react in cold (<37C) in peripheral circulation

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Usually IgM Ab

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Severity varies:

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Ab titre; Thermal amplitude of Ab ; Affinity of Ab for RBC; Ability to bind Complement

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Agglutination of RBC in peripheral circulation is common; haemolysis is less common

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Ab almost always directed to I or i RBC Ag
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IM = i    Mycoplasma = I    NHL usually I

 

Paroxysmal Cold Haemoglobinuria (PCH)

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Rare syndrome of acute intravascular haemolysis afte cold exposure

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Donath-Landsteiner Ab: binds RBC in cold, causes lysis in warm (P)

 

 

Alloimmune Haemolytic Anaemia

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Occurs when pt receives RBCs expressing an Ag that pt has an Ab against in their plasma

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From transfusion or pregnancy

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HDN

 

Haemolytic Transfusion Reactions

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Immediate: pre-formed Ab present: ABO incompatibilty

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 Delayed: usually difficult to Dx Hb lower than expected

 

 

Fragmentation Haemolysis

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Physical damage to RBC
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Abnormal surface: cardiac valve, AVMs, burns

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MAHA: fibrin strands in microcirculation

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Damaged vessels: HUS/TTP, PET, meningoccal sepsis

 

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Fragmented RBCs

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Abnormal coags: DIC

 

  HUS / TTP

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Rare disorder

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 Microangiopathy
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Cerebral

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Gut

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Kidney

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Lung, liver

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Haemolysis

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Thrombocytopenia

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Severe haemostatic failure

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Management:
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Plasmapheresis
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Remove plasma with abnormal multimers of vWF

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Replace with FFP or cryo-poor FFP (no vWF)

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Treat underlying cause

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Steroids

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Splenectomy

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 NO platelet transfusions

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 Relapses and remits

 

PNH

Paroxysmal Nocturnal Haemoglobinuria

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Haemolytic anaemia

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Marrow failure (aplasia)

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Thrombophilia

 

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Due to non-malignant clonal expansion of haemopoietic stem cell(s) with somatic mutation of PIG-A gene.
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Defect in glycosyl phospatidyl inositol anchor

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Loss of Complement regulatory Proteins CD59, CD55

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Anaemia: complex
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Coombs negative HA

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Also marrow failure

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Worse with epsiodes of complement activation (infection, trauma, surgery, pregnancy)

 

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Management:
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Steroids

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Androgen

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Iron replacement

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Transfusion

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Splenectomy

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Folate

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Eculizumab: C5 inhibitor

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Stem cell transplant (Aplastic Anaemia)

 

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Thrombosis
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Major cause of morbidity and death

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Mechanism is unclear

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? Related to size of PNH clone
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Clone >50% = VTE risk of 44%

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Clone <50% = VTE risk of 5.8%

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? VTE prophylaxis debatable; ? Selective; Ethnic variation

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VTE usually venous. Heparin, warfarin

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Thrombolysis for Budd-Chiari

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Ongoing anticoagulation after VTE