Anaemia

Introduction

• Definition: Reduced concentration of RBC from individuals baseline level
• Erythrocyte lifespan 120 days on average
• Compensatory mechanisms depend on:
  • Rapidity of onset
  • Degree of anaemia
  • Underlying condition of patient
• Acute onset
  • Reduced intravascular volume results in peripheral vasoconstriction and central vasodilatation followed by systemic small vessel vasodilatation to increase blood flow to tissues
  • Results in decreased PVD, increased CO and tachycardia
  • RBC’s enhance ability to release O2 to tissues
• Chronic onset
  • Increase in plasma volume
  • Stimulation of erythropoiesis
  • New reticulocytes appear within 3-7 days

Normal values

Values

• MCV
  • Microcytosis – Iron, thalassaemia, chronic disease, lead poisoning
  • Macrocytosis – B12, folate, ethanol, liver disease, reticulocytosis
• Red cell distribution width
  • Measures variability of RBC population
  • May be increased in early deficiency anaemia (before even MCV changes)
  • Useful to differentiate deficiency anaemia (B12/folate/iron) from others
  • Differentiates iron deficiency anaemia (ncreased RCDW) from thalassaemia

Values

• MCHC
  • Low MCHC seen in iron deficiency, porphyria and haemolytic anaemia
• Ferritin
  • Most sensitive marker for iron deficiency
• Reticulocyte count
  • Decreased reticulocyte count = impaired production
  • Increased count = Accelerated production

Values

• Peripheral blood smear
  • Visualisation may diagnose sickle cell disease
  • Abnormal shapes may diagnose haemolytic disease e.g. schistocytes
  • WCC and platelet counts can add info for diagnosis
• Direct Coombs
  • Detects antibodies on RBC’s
  • Positive in autoimmune haemolytic anaemia, transfusion reactions and some drug-induced haemolytic anaemia
• Indirect Coombs
  • Detects antibodies to RBC in sera
  • Used in compatibility testing prior to transfusion

Classification

• Loss of red cells by haemorrhage – Acute GI bleeding
• Increased destruction – Sickle cell, haemolytic anaemia
• Reduced production – Nutritional deficiency(B12, folate, iron) or aplastic/myelodysplastic anaemia
• Dilutional – Rapid IV crystalloid

Hx and Ex

• Weakness, fatigue, lethargy, SOB, palpitations, orthostatic hypotension
• Tachycardia, pallor, systolic murmur, bounding pulse, widened pulse pressure
• Jaundice and hepatosplenomegaly – ? Haemolytic cause
• Skin ulcerations or peripheral neuropathy – Nutritional deficiency
• If acute onset:
  • Hypotension, resting and exertional dyspnoea, palpitations, diaphoresis, anxiety, severe weakness, ALOC, thirst
• Coronary artery blood flow not limited until Hb <50% of normal

Diagnosis

• MCV low
  • RDW high
    • Ferritin low = Iron deficiency
    • Ferritin normal = Anaemia of chronic disease, sideroblastic anaemia (hereditary or lead poisoning)
  • RDW normal
    • RBC count low = Anaemia of chronic disease, hypothyroidism, Vitamin C deficiency
    • RBC count normal or high = Thalassaemia

Diagnosis

• MCV normal
  • Reticulocyte count normal
    • RDW normal = Anaemia of chronic disease, chronic renal disease
    • RDW high = Iron, B12, folate deficiency
  • Reticulocyte count high
    • Coombs test positive = Autoimmune haemolytic anaemia
    • Coombs test negative = Enzymopathies (G6PD deficiency), Haemoglobinopathies (Sickle cell), Membranopathies (hereditary spherocytosis, microangiopathic haemolysis

Diagnosis

• MCV elevated
  • RDW high
    • Vitamin B12 or folate deficiency
  • RDW normal
    • Alcohol abuse, liver disease, hypothyroidism, drug-induced, myelodysplastic syndromes
• Drugs that can cause macrocytosis through folate alteration
  • Phenytoin, valproate, trimethoprim, sulfamethoxazole, metformin
  • Reverse transcriptase inhibitors (ARV)

Megaloblastic anaemia

• MCV >112fL usually due to B12 or folate deficiency
• B12 usually due to malabsorption vs. folate deficiency usually nutritional
• Tetrahydrofolate is a precursor in DNA synthesis and, in turn, its formation from methylated precursor is B12 dependent
• Nitrous oxide therapy can cause an acute megaloblastic anaemia and pancytopaenia

Megaloblastic anaemia

• Pernicious anaemia
  • Autoimmune anti-gastric parietal cell/anti-intrinsic factor impaired absorption at terminal ileum
  • Present with achlorhydria, mucosal atrophy (painful smooth tongue) +- vitiligo/thyroid disease/Addison’s
  • Subacute combined degeneration of spinal cord due to demyelination of posterior and lateral columns presents as peripheral neuropathy and abnormal gait
  • Treatment of B12 deficiency with folate alone can accelerate the onset of this
  • Investigative workup includes B12 and red cell folate levels, autoantibodies to parietal cells/intrinsic factor, marrow aspirate and Schilling’s test of B12 absorption all by Haematology so liaise with them

Reduced red cell production

• Aplastic anaemia
  • Pancytopaenias secondary to failure of pluripotent myeloid stem cells
  • 50% idiopathic
  • Improtant causes are non-A, non-B hepatitis, Fanconi’s anaemia (inherited), irrdiation and drugs including antimetabolites/alkylating hemotherapeutics, chloramphenacol, chlorpromazine and streptomycin
  • Have conspicous absence of splenomegaly and reticulocyte response
  • Plt <20 and neutrophils <500/mL = severe disease
• Pure red cell aplasia (can be a complication of haemolytic states where a viral insult leading to aplastic crisis)

Reduced red cell production

• Myelodysplastic syndromes
  • Abnormal clone of stem cells lead to disordered and dsyfunctional pancytopaenia
  • Seen in elderly people and 1/3 progress to AML
• Metastatic cancer invasion of bone marrow
• Anaemia of chronic renal failure

Anaemia of chronic disease

• Chronic infective, malignant or connective tissue disorders get mild-to-moderate normochromic normocytic anaemia with no evidence of bleeding or response to haematinic therapy and no haemolysis
• Due to reticuloendothelial overactivity in chronic inflammation and defects in iron metabolism due to inflammatory mediators
• Importance lies in recognition and searching for underlying disease
• Iron studies rule out iron deficiency anaemia

Treatment

• Iron deficiency
  • Treat cause
  • Elemental iron 200-300mg/day
• B12 deficiency
  • Cyanocobalamin 1000mcg IM per week for 8 weeks then every month after
  • PO 2000mcg per day may be as effective (need to consider if malabsorption is causative however)
• Folate deficiency
  • Folate 1mg per day PO
• Sideroblastic anaemia
  • Evaluate for alcoholism, lead exposure

Hereditary haemolytic anaemias

• May result from defect in Hb production, RBC metabolism or RBC membrane
• If increased number of abnormal RBC are produced, haemolytic activity is increased
• Inherited haemoglobin disorder
  • Abnormal Hb structure e.g. sickle cell
  • Disorders of abnormal Hb production e.g. thalassaemias

Hb variants

Sickle cell disease

• Mostly in African Equatorial descent + Mediterranean, Indian and Middle Eastern
• 4.5% of world population are carriers of sickle cell gene
• Pathophysiology
  • Adenine to thymine substitution results in valine substitution for glutamic acid in beta-globin chain
  • In deoxygenated conditions, valine becomes buried in hydrophobic pocket on adjacent chain, deforming the RBC and producing sickled appearance
  • Autosomal recessive trait
  • Distorted sickle red cells result in premature RBC destruction (life span 20 days vs. 120) and increases viscosity of blood, leading to microvasculature obstruction
  • Overall chronic haemolysis with episodic vascular occlusion

Sickle cell disease

• Sickle cell trait
  • Heterozygous with one gene for normal beta-chain and one gene for mutant beta-chain
  • Normal life span and usually asymptomatic
  • Complications may arise during severe tissue hypoxia, acidosis, dehydration or hypothermia
  • Definite associations: Renal medullary carcinoma, haematuria, renal papillary necrosis, hyposthenuria, splenic infarcts, exercise-related deaths
  • Probable associations: VTE, pregnancy complications, complicated hyphaema
  • Possible associations: Retinopathy, acute chest syndrome, asymptomatic bacteriuria

Sickle cell disease

• ED Presentations of sickle cell disease
  • Stroke
  • Retinopathy
  • Acute chest syndrome
  • Pulmonary HTN
  • Acute splenic sequestration crisis
  • Splenic abscess
  • Hypersplenism
  • Hepatic sequestration
  • Cholelithiasis

Sickle cell disease

• ED presentations continued…
  • Acute mesenteric ischaemia
  • Priapism
  • Bone pain
  • Sickle cell nephropathy
  • Renal failure
  • AVN of femoral head
  • Osteomyleitis
  • Leg ulcers

Sickle cell disease

• Vaso-occlusive pain crises
  • Initiating event may be unknown but consider cold, exertion, infection, dehydration, altitude
  • Diffuse bone, muscle, viscera and soft tissue ischaemic pain
  • Initial Rx is aggressive analgesia and hydration
    • May require analgesia for hours to days and NSAID’s provide additive effect
    • May have absolute or relative hypovolaemia due to their disease (deficient renal concentrating ability) or crisis e.g. vomiting, anorexia, fever)
  • Recommended to generate patient management plans with those who present frequently
  • Supplemental oxygen is only beneficial if hypoxic

Sickle cell disease

• Bone pain
  • Common during painful crisis and usually back and extremity pain
  • Diffuse pain with no physical findings
  • Redness, warmth or swelling suggest alternative diagnosis
  • Localised hip pain only with painful ambulation suggests AVN of femoral head
  • Bone scan or MRI can help distinguish infection from infarction
  • In young children, early presentation is dactylitis or hand-foot syndrome
    • Infarction of red marrow in small bones of hand/feet with periosteal inflammation
    • Fever and painful swelling of hands, feet, or both, +- redness/warmth
    • As child grows, red marrow replaced by fatty tissue making this less common

Sickle cell disease

• Vaso-occlusive painful crises
  • FBC and reticulocyte count
    • Assess degree of anaemia and ensure marrow still producing red cells (i.e. not completely infarcted)
    • Low-grade temperature is common but WCC >20 with increased number of bands is not typical for isolated sickle cell disease so consider infection
  • LFT
    • Mild elevations in bilirubin and LDH are common due to chronic baseline haemolysis
  • CXR if chest symptoms

Sickle cell disease

• Vaso-occlusive crisis management
  • Bed rest, warmth, calm, relaxing environment
  • Distractions
  • Oral fluids (3L per day)
  • IV fluids to correct hypovolaemia
  • Encourage deep breathing, incentive spirometry
  • Consider antibiotics if febrile as at risk of functional asplenia
    • If WCC >20 and increased bands, this is also suggestive of infection

Sickle cell disease

• Vaso-occlusive crises
  • Admission if:
    • Acute chest syndrome suspected
    • Sepsis, osteomyelitis or serious infection suspected
    • WCC >30
    • Plt <100
    • Pain not under control

Sickle cell disease

• Discharge criteria after painful crises
  • Pain under control with oral agents
  • Tolerating oral food/fluid/medications
  • Home care instructions
  • Follow-up with LMO
  • When to return instructions

Sickle cell disease

• Painful crises
  • Transfusion reserved for:
    • Aplastic crisis
    • Pregnancy
    • Stroke
    • Respiratory failure
    • Generaly surgery
    • Priapism

Sickle cell disease

• Painful crises
  • Hydroxyurea
    • Most successful agent to date in reducing frequency and severity of painful crises
    • Blocks synthesis of DNA and impairs cell division
    • Increases HbF production to prevent sickling
    • Indicated for adults who present with 3 or more vaso-occlusive crises per year
    • Daily PenV prophylactic use reduces incidence of infection and reduces mortality in children but not adults

Sickle cell disease

• Acute chest syndrome
  • New infiltrate on CXR + one of:
    • Fever >38.5
    • Cough
    • Wheeze
    • Tachypnoea
    • Chest pain
  • Most common in 2-4yo
  • Usually only occurs once but can be recurrent resulting in chronic lung disease
  • Mostly precipitated by intercurrent respiratory tract infection, fat embolism or rib infarction
  • Other causes: VTE, in-situ thrombosis, lung sequestration, following aggressive IV fluid resuscitation for painful crises or atelectasis following opioid analgesia

Sickle cell disease

• Acute chest syndrome
  • Infectious agents identified in 50% of cases
  • Mostly Chlamydia pneumoniae and Mycoplasma
  • Previously S. pneumoniae was thought to be mostly responsible but is rare now due to immunisation and prophylactic penicillin use
  • Leads to regional hypoxia, acidosis and lung injury, with VQ mismatch, further hypoxia, increased deoxygenation of HbS, vaso-occlusion and pulmonary infarction with further deterioration
  • Radiographic changes often lag behind clinical features (extent of hypoxia may not correlate with normal CXR)
  • Treatment
    • Oxygen, analgesics, hydration (1.5x maintenance), antibiotics for all for CAP, bronchodilators and exchange transfusion
    • Hypotonic fluids may be preferable to generate intracellular osmotic swelling and reduction in MCHC to prevent further sickling

Sickle cell disease

• Acute chest syndrome
  • Exchange transfusions believed to be lifesaving to reduce concentration of sickled Hb while maintaining normal blood viscosity and minimal iron gain
    • Usually reserved for severe crises, PaO2 <60mmHg
    • Aim is to reduce HbS to <30%
    • Indicated if:
      • Severe on admission and past history of venilation (may prevent intubaiton)
      • Deterioration despite medical management (may prevent ICU)
      • Patient already intubated
      • Suspected or confirmed fat or bone marrow embolism

Sickle cell disease

• Acute chest crisis
  • Hydroxyurea reduces occurrence by increasing HbF, inhibiting sickle polymerisation, increasing deformability of Hb and reducing adhesion of sickle cells to vascular endothelium
  • Nitric oxide
    • Pulmonary vasodilation, improved VQ matching, reduces adhesion of RBC’s and leukocytes to the endothelium by inhibiting VCAM-1

Sickle cell disease

• Abdominal crises
  • Typically patient will state it feels like previous episodes
  • If unsure, repeated examination is key
  • Should not be peritonitic if simple crisis
  • DDx
    • Hepatic infarction may produce jaundice and abdominal pain and difficulty differentiating from hepatitis or cholecystitis
    • Biliary disease is very common due to haemolysis
    • Intrahepatic cholestasis can occur without gallstones

Sickle cell disease

• Genitourinary system
  • Kidney vaso-occlusive events are common but usually asymptomatic
  • Infarction of renal medulla may cause flank pain, renal colic
  • Papillary necrosis can cause micro- or macroscopic haematuria but RBC casts are uncommon
  • Treatment is monitoring, IV fluids and ensuring anaemia does not worsen
  • Priapism occurs in 30% of males with SCD. Treatment is IV hydration, pain control and transfusion. Early urology involvement is key
  • Urinalysis recommended as UTI far more common

Sickle cell disease

• Splenic infarction
  • Microinfarctions culminate in non-functional asplenism
  • Children with SCD who are asplenic
    • 14% at 6mo
    • 94% by age 5
  • At risk of SBI from encapsulated organisms so need immunisations, prophylactic penicillin and parental education
    • S. pneumoniae, Hib, N. meningitidis, E. coli, Salmonella, Klebsiella, GBS
  • Risk of overwhelming sepsis decreases with age but remain predisposed to infection

Sickle cell disease

• Splenic sequestration
  • Mostly in children
  • Sudden enlargement in spleen with acute drop in Hb due to sequestration of majority of blood volume in spleen itself
  • Present in shock with abdominal fullness +- LUQ pain
  • Platelets can also be sequestered
  • Get high reticulocyte count as not due to marrow failure (unlike aplastic crisis)
  • Treatment – IV fluids, RBC transfusion or exchange transfusion
  • Ix for precipitating infection
  • Rarely splenectomy is required
  • Recurrence is common

Sickle cell disease

• Haemolytic anaemia
  • Baseline Hb 60-90 usually due to chronic haemolysis
  • Baseline reticulocyte count 5-15%
  • With infection, haemolytic process may upregulate causing drop in Hb

Sickle cell disease

• Aplastic crisis
  • If production of RBC’s declines significantly, unable to compensate for chronic haemolysis and get acute drop in Hb with reticulocytopaenia
  • Most commonly due to infection (parvovirus B19)
  • Folate deficiency and marrow necrosis are also seen
  • Mostly in children
  • Reticulocyte count <0.5% usually
  • Usually marrow begins producing RBC’s again within 1 week and is self-limiting
  • May require transfusion in the interim

Sickle cell disease

• Neurological presentations
  • Stroke (ischaemic and haemorrhagic) and SAH
  • Risk of stroke in children is 200x
  • 10% of patients have stroke before age 20
  • Haemorrhagic strokes and SAH usually in third decade of life
  • Cerebral aneurysms are also more common in SCD
  • Acute stroke is treated with simple or exchange transfusion
  • 70-90% recurrence in children who suffer a stroke
  • Chronic transfusion therapy indicated to prevent recurrent stroke after first one

Sickle cell disease

• Infections
  • Any unexplained fever >38 requires acute evaluation for source and consideration of empirical broad-spectrum antibiotics
  • Children should receive daily PenV and receive all immunisations
• Cardiac
  • Cardiomegaly correlates with degree of anaemia
  • Microinfarcts and haemosiderin deposits from haemolysis also occur
• Dermatological
  • Chronic poorly healing leg ulcers near malleoli are common in older patients

Thalassaemia

• Hallmark is microcytic, hypochromic, haemolytic anaemia
• Common in Mediterranean, Middle Eastern, African and SE Asian
• Beta-thalassaemias
  • Diminished production of beta-chains leading to alpha-chain tetramer formation in immature RBC’s
  • Precipitation of alpha tetramers damages developing erythroid precursors leading to early cell death
  • Cells that are produced have reduced Hb and are thus hypochromic with target cell appearance on film
  • Beta-thalassaemia major (Cooley’s anaemia – heterozygote) and minor (homozygote)

Thalassaemia

• Alpha-thalassaemias
  • Beta-tetramers form HbH leading to more stable cells so get effective erythropoiesis but increased destruction of red cells 
  • Silent alpha thalassaemia (1/4 non-functioning alpha chain gene)
  • Alpha-thalassaemai trait (2/4 non-functioning)
  • HbH disease (3/4 non-functioning)
  • HbBart’s disease (4/4 non-functioning) incompatible with life
• There are variants in severity depending on non-functional/dysfunctional globin chain production

Thalassaemia

• Tissue hypoxia due to anaemia results in increased erythropoiesis, enlargement of haematopoietic organs (liver/spleen) and bone marrow enlargement leading to osteopaenia
• Alpha-thalassaemia trait
  • No clinical symptoms but will have microcytic hypochromic RBC
• HbH disease
  • Presents in neonatal period as severe microcytic hypochromic anaemia
  • May not require regular transfusions but under oxidative stress get precipitation of unstable HbH and enhanced haemolysis
  • Need to avoid drugs that cause oxidative stress
    • Sulfonamides, primaquine/chloroquine, nitrofurantoin, ciprofloxacin, norfloxacin, chloramphenicol, naphthalene, Vitamin K, methylene blue

Thalassaemia

• Beta-thalassaemia minor
  • Mild microcytic anaemia
  • Splenomegaly is uncommon
  • Basophilic stippling on film
  • HbA2 4-6% confirms diagnosis
  • Usually no clinical manifestations

Thalassaemia

• Beta-thalassaemia major (Cooley anaemia)
  • Newborns okay due to HbF
  • During 6-12 month period, HbF is replaced by HbA with subsequent hepatosplenomegaly, jaundice, osteoporosis and increased susceptibility to infection
  • Anaemia is severe and requires lifelong transfusions
  • Iron overload is the subsequent issue leading to cardiac, hepatic and endocrine haemochromatosis
  • RBC show low MCV wth hypochromia with increased RDW and nucleated cells

G6PD deficiency

• Most common enzymopathy
• Mostly African, Asian or Mediterranean
• X-linked inheritance so mostly men as women need two defective genes
  • However, expression of gene is variable so women with only one gene may still have some clinical signs
• Mostly asymptomatic with intermittent anaemia in the setting of oxidative stress
• Oxidation of sulfhydryl groups on Hb causes Hb to precipitate in RBC’s (Heinz bodies on blood smear) with subsequent extravascular haemolysis in spleen
  • Heinz bodies are denatured ferric (3+) Hb into multimers
  • Ferric Hb (methaemoglobinaemia) cannot be reduced back to O2-carrying Fe2+ in G6PD deficiency
• Also get oxidative damage to RBC membrane and subsequent intravascular haemolysis

G6PD deficiency

• Class I variants: Severe enzyme deficiency (<10% of normal) with chronic haemolytic anaemia
• Class II: G6PD Mediterranean with severe enzyme deficiency but only intermittent haemolysis
• Class III: moderate deficiency (10-60% of normal) with intermittent haemolysis usually in the setting of infection or drugs
• Class IV: No enzyme deficiency or symptoms
• Class V: Increased enzyme activity (no symptoms)
• Most common precipitants of haemolysis
  • Favism
  • Drugs (Sulfa drugs, primaquine, dapsone, amyl nitrate)
  • Infection
• Can present in neonatal period as neonatal jaundice

G6PD deficiency

• Treat infections aggressively and avoid known oxidants
• Should screen HIV patients for this due to common use of bactrim for prophylaxis
• Avoid fava beans
• Methylene blue therapy for methaemoglobinaemia can cause harm in G6PD deficiency so if Mediterranean reconsider plan

Hereditary spherocytosis

• Erythrocyte membrane defect
• Most common hereditary haemolytic anaemia in northern Europeans
• Autosomal dominant but 20% spontaneous mutation
• Spherocytes cannot pass through spleen resulting in extravascular haemolysis
• Main complications are aplastic crises, haemolytic crises, cholecystitis, cholelithiasis and neonatal jaundice
• Neonatal jaundice is seen in 30-50% of patients
• Mild disease are usually asymptomatic with intermittent haemolysis or aplastic crises in the setting of infection and minimal or no splenomegaly
• Moderate disease has mild-moderate anaemia, modest splenomegaly, periodic haemolysis with jaundice and increased pigmented gallstones
• Severe disease requires episodic blood transfusions, chronic jaundice and splenomegaly
• Peripheral blood smear shows spherocytes with low to normal MCV and increased MCHC

Acquired haemolytic anaemia

• Labs
  • Hb and Hct reduced
  • Reticulocyte count increased
  • Peripheral smear shows schistocytes (intravascular haemolysis) or spherocytes (extravascular haemolysis)
  • LDH increased released by RBC’s
  • K increased
  • Haptoglobin decreased (intravascular haemolysis)
  • Free Hb increased (intravascular haemolysis)
  • Haemoglobinuria
  • Total bilirubin increased
  • Unconjugated bilirubin increased (hepatic conjugation overwhelmed)
  • Urinary urobilinogen increased

Acquired haemolytic anaemia

• Immune-mediated haemolytic anaemia
  • Autoimmune haemolytic anaemia
    • Make antibodies against their own RBC’s
  • Alloimmune haemolytic anaemia
    • Requires exposure to allogeneic RBC’s with subsequent alloantibody formation
  • Drug-induced haemolytic anaemia

Drug-induced haemolytic anaemia

• Drug-induced immune
  • Beta-lactamase inhibitors, ceftriaxone, IVIG, NSAID, penicillin, piperacillin
• Drug-induced thrombotic microangiopathic
  • MDMA, clopidogrel, cocaine, ibuprofen, metronidazole, quetiapine, nitrofurantoin, simvastatin, tacrolimus, bactrim
• Drug-induced oxidative haemolysis
  • Dapsone, nitrofurantoin, primaquine, amyl nitrate, rifampicin, ribavirin

Autoimmune haemolytic anaemia

• Positive direct Coomb’s test (confirmatory test but not specific for autoimmune haemolytic anaemia)
• May have positive indirect Coomb’s if autoantibodies in sera also
• Haemolysis can be intra- or extravascular
• Primary (idiopathic) has no clear cause
• Secondary may be due to lymphoproliferative, autoimmune or infectious causes
• Divided into warm antibody, cold antibody and mixed-type

Autoimmune haemolytic anaemia

• Warm antibody AIHA
  • Autoantibodies adhere most strongly at 37 degrees
  • 70-80% of cases
  • 50% idiopathic/50% secondary
  • Haemolysis usually extravascular
  • 70-80% are steroid responsive

Autoimmune haemolytic anaemia

• Cold antibody AIHA
  • Autoantibodies adhere most strongly at 0-4 degrees
  • Cold Agglutinin disease
    • Attacks precipitated by cold exposure with Raynaud, vascular phenomen, livedo reticularis
    • Rarely intravascular haemolysis and not steroid responsive
    • Mycoplasma pneumoniae and mononucleosis are two common causes
  • Paroxysmal cold haemoglobinuria
    • Usually secondary to URTI in children
    • Suffer intrasvascular haemolysis in cold weather
    • Usually not steroid responsive

Autoimmune haemolytic anaemia

• Mixed-type antibody AIHA
  • Usually chronic course with severe exacerbations
  • Usually steroid responsive
• Positive Direct Coomb’s
  • AIHA
  • Haemolytic transfusion reaction
  • Haemolytic disease of the newborn
  • Transplant
  • Drug-related haemolytic anaemia
  • IVIG therapy
  • Sickle cell/beta-thalassaemia, renal disease, multiple myeloma, Hodgkin disease, SLE, HIV

Alloimmune haemolytic anaemia

• In laboratory, alloantibodies in sera react specifically with allogeneic RBC’s that triggered their production, not the patients own
• E.g. haemolytic disease of the newborn due to maternal production of IgG to fetal Rh+ RBC’s
• Most adults who develop this have history of transfusion with subsequent transfusions causing alloantibody production, fever, chest, flank pain, tachypnoea, tachycardia, hypotension, haemoglobinuria
• Can be immediate (already high antibody titres) or delayed up to 3-7 days

Microangiopathic syndromes

• Anaemia results from RBC fragmentation when travelling through occluded arterioles and capillaries
• Thrombotic thrombocytopaenic purpura (TTP)
  • Classic pentad of: CNS abnormalities, renal pathology, fever, microangiopathic haemolytic anaemia and thrombocytopaenia
  • Diagnostic criteria now include all cases of microangiopathic haemolytic anaemia with thrombocytopaenia of unknown cause
    • Risk is inclusion of patients with malignant hypertension, sepsis, SLE and HELLP syndrome may be diagnosed as TTP (not treated with plasma exchange)
  • High mortality if remains untreated
  • Remission in >80% with plasma exchange

Microangiopathic syndromes

• TTP pathophysiology
  • ADAMTS-13 metalloprotease that cleaves vWF that has been unfolded by shear stress
  • Ordinarily, cleaving action of ADAMTS-13 prevents large multimers of vWF from forming
  • Insufficient ADAMTS-13 activity (due to autoantibodies or genetic mutation) leads to vWF multimer formation, leading to microthrombus formation
  • ADAMTS-13 activity <10% normal in TTP
  • Subsequent platelet aggregation leads to thrombocytopaenia and shearing of RBC’s as they cross microcirculation
  • Microthrombi (in kidneys and CNS predominantly) leads to tissue end-organ damage, stroke, seizure, focal neurological deficits, coma, AKI

Microangiopathic syndromes

• Labs
  • Severe anaemia, platelets <20, signs of intravascular haemolysis (reduced haptoglobin, raised LDH, schistocytes, raised LDH/K, increased free Hb, haemoglobinuria, raised unconjugated bilirubin), acute kidney injury
  • Normal coagulation studies as clots do not involve fibrin (this is how to distinguish from DIC)
• Typically require ADAMTS-13 activity <10% + another trigger e.g. infection, pregnancy, inflammation or medication use

TTP and pregnancy

• ADAMTS-13 activity levels decrease by up to 30% during pregnancy
• Hypercoagulable state of pregnancy + reduced ADAMTS-13 activity may lead to TTP in pregnancy
• TTP shares many features with pre-eclampsia, HELLP and acute fatty liver of pregnancy
• Symptoms of severe pre-eclampsia or HELLP before 24 weeks gestation should trigger consideration of TTP
• Liver enzyme abnormalities tend to be less severe in TTP vs. other diagnoses
• Failure to platelet count to respond to steroids also raises likelihood of TTP vs. HELLP
• Delivery will not alter the course of TTP
• If TTP is successfully treated with plasma exchange, pregnancy can continue to term

TTP

• PLASMIC Score for predicting ADAMTS13 activity
  • Plt <30
  • Haemolysis
  • No cancer hx
  • No transplant hx
  • MCV <90
  • Creatinine <177
  • INR <1.5
• Score
  • 0-4: Low risk (4.3%)
  • 5-6: Intermediate (56.8%)
  • 7: High risk (96.2%)

Treatment of TTP

• Plasma exchange via CVL
  • Replaces defective or insufficient ADAMTS-13 and removes defective ADAMTS-13, autoantibodies against ADAMTS-13 and large vWF multimers
  • FFP can be given if plasmapheresis not immediately available
  • Platelet transfusions should be avoided except for life-threatening bleeds as acutely worsened thrombosis can cause acute renal failure and death
  • Aspirin can exacerbate haemorrhagic complications in the setting of severe thrombocytopaenia but can be used if platelet counts are adequate in the setting of cardio- or cerebrovascular disease
  • Heparin is not beneficial

Haemolytic uraemic syndrome (HUS)

• Most common cause of preventable renal failure in children
• Microangiopathic haemolytic anaemia, acute renal impairment and thrombocytopaenia
• Typical
  • 1 week after infectious diarrhoea (often bloody and afebrile)
  • Due to Shiga toxin-producing E. coli 0157:H7
  • Less common causes are Shigella, Yersinia, Campylobacter and Salmonella
• Atypical
  • Older children and adults and can be due to above + Strep pneumoniae, EBV, bone marrow transplant, HIV, Influenza or chemotherapeutics
  • Can be difficult to distinguish from TTP as often have extrarenal involvement

HUS

• Pathophysiology
  • Shiga-toxin leads to microvascular injury (predominantly in kidneys), platelet aggregation and thrombus formation
  • Subsequent haemolytic anaemia worsens tissue ischaemia and necrosis
  • Microthrombi in pancreas can cause deficits in insulin secretion due to beta-cell loss

HUS

• Treatment
  • Supportive IV hydration therapy can prevent AKI
  • Opioid analgesia for abdominal/back pain
    RBC or platelet transfusion for significant anaemia or thrombocytopaenia if associated with active bleeding
  • May require dialysis
  • Antimotility drugs increase risk of HUS
  • Antibiotic treatment may increase risk of HUS

Macrovascular haemolysis

• Can arise due to prosthetic heart valves
  • Usually paravalvular leak in modern valves
• Also seen with intracardiac patch repairs, aortofemoral bypass, coarcatation of the aorta, severe aortic valve disease or ventricular assist devices and in ECMO/CPB/plasma exchange and haemodialysis
• Shistocytosis on film
• If ongoing and mild – iron + folate + B12 supplementation to promote healthy reticulocytosis

Other infections causing haemolysis

• Malaria
  • P. falciparum can cause blackwater fever with intravascular haemolysis
• Clostridium perfringens
  • Direct lysis of RBC’s via toxin production
• Leptospirosis
  • Toxins attack RBC’s directly leading to haemolysis
  • Severe form (Weil’s disease) presents with intravascular haemolysis, jaundice, nephropathy and haemorrhage

March haemoglobinuria

• Haemolysis due to mechanical trauma
• Transient haemoglobinuria after exercise
• Runners with heavy stride, soldiers, barefoot dancers
• Usually <1% of RBC’s are damaged so anaemia is not seen

Paroxysmal nocturnal haemoglobinuria

• Intrinsic red cell defect seen in context of acquired haemolytic anaemia
• Cells become prone to complement-mediated lysis
• Patients also have deficiencies in white cells and platelets and are prone to aplastic anaemia or leukaemia

Last Updated on October 2, 2020 by Andrew Crofton