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Year 4 > Haemotology > Flashcards

Haemotology Flashcards

1
Q

Blood film: hyposplenism

A
  • target cells
  • Howell-Jolly bodies
  • Pappenheimer bodies
  • siderotic granules
  • acanthocytes
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2
Q

Blood film:iron-deficiency anaemia

A
  • microcytic, hypochromic
  • target cells
  • ‘pencil’ poikilocytes
  • if combined with B12/folate deficiency a ‘dimorphic’ film occurs with mixed microcytic and macrocytic cells
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3
Q

Blood film:myelofibrosis

A

‘tear-drop’ poikilocytes

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4
Q

Blood film:intravascular haemolysis

A

schistocytes

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5
Q

Blood film: Megaloblastic anaemia

A

hypersegmented neutrophils

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6
Q

Target cells/ codocytes

A

Sickle-cell/thalassaemia
Iron-deficiency anaemia
Hyposplenism
Liver disease

due to increase in surface membrane area to volume ratio. either by increased membrane surface area or decreased intracellular haemoglobin

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7
Q

‘Tear-drop’ poikilocytes/ dacrocytes

A

Myelofibrosis

Due to compression of RBCs during release either from a fibrosed bone marrow or extramedullary haemopoiesis (RBCs produced outside the bone marrow e.g. Spleen)

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8
Q

Spherocytes

A

Hereditary spherocytosis
Autoimmune hemolytic anaemia

Rounded RBCs that have lost their biconcave shape due to membrane loss (usually in the spleen) and become spheres.
* This usually indicates active haemolysis.
* As a result of the shape, they cannot bend through capillaries as easily.

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9
Q

Basophilic stippling

A

Lead poisoning
Thalassaemia
Sideroblastic anaemia
Myelodysplasia

Describes the presence of small granular bodies (denatured RNA fragments) within the RBC cytoplasm due to disordered/accelerated erythropoiesis meaning RBCs with immature cytoplasm are released from the bone marrow.

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10
Q

Howell-Jolly bodies

A

Hyposplenism

Nuclear remnant found in RBCs, normally excluded before becoming reticulocytes and removed by the spleen

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11
Q

Heinz bodies

A

G6PD deficiency
Alpha-thalassaemia

Denatured Haemoglobin due to oxidative damage/unstable Hb.
* Normally removed by the spleen (becoming a bite/blister cell).
* Appears as “nose” or pale circle with specific staining.

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12
Q

Schistocytes (‘helmet cells’)

A

Intravascular haemolysis
Mechanical heart valve
Disseminated intravascular coagulation

Fragmented RBCs – caused by intravascular strands of fibrin or spleen dysfunction as the spleen removes RBCs from circulation.
* Small amounts can be seen in a normal individual.

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13
Q

‘Pencil’ poikilocytes

A

Iron deficency anaemia

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14
Q

Burr cells (echinocytes)

A

Uraemia
Pyruvate kinase deficiency

Describes cells with many (10-30) regular spicules.

a) Burr Cells:type of Echinocyte, found in patients with uraemia

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15
Q

Acanthocytes (spur cells)

A

Abetalipoproteinemia

These cells form from changes in the fats and proteins on red blood cells’ outer layers

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16
Q

Causes of iron deficiency

A
  • Blood loss (e.g. GI, menorrhagia )
  • Reduced absorption (e.g. small bowel disease (coeliac), hookworm infestation)
  • Increased demands (e.g. growth, pregnancy)
  • Reduced intake (e.g. vegans)
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17
Q

causes of microcytic anaemia

A

iron deficiency
thalassemia
sideroblastic anaemia
lead poisoning

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18
Q

presentation of anaemia

A

tiredness
dyspnea, esp on exertion
lethargy
pallor
exacerbation of ischemic conditions (angina, intermittent claudication)
palpitations

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19
Q

presentation of iron deficiency anaemia

A

anaemia presentation
- Pica
- restless legs syndrome
- Pallor
- Brittle nails and hair loss
- post cricoid webs→ plumber vinson syndrome
- Koilonychia (if severe): thinning, flattening, and then spooning of the nails
- glossitis
angular stomatitis

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20
Q

specific signs of lead poisoning

A
  • Blue gumline
  • Peripheral nerve lesions (causing wrist or foot drop)
  • Encephalopathy
  • Convulsions
  • Reduced consciousness
  • abdominal pain
  • N&V
  • constipation
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21
Q

Iron deficiency anaemia iron studies result

A

low serum iron
high TIBC
low transferrin saturation
low serum ferritin (raised ferritin does not necessarily rule out iron deficiency anaemia if the is co-occurring inflammation- high ferritin in anaemia of chronic disease)

Other: thrombocytosis. thrombocytopenia is severe, high RDW (anisocytosis), low MCHC & MCH, low Reticulocytes

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22
Q

anaemia of chronic disease iron study results

A

low TIBC
low serum iron
low transferrin saturation
high ferritin

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22
Q

anaemia of chronic disease iron study results

A

low TIBC
low serum iron
low transferrin saturation
high ferritin

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23
Q

lead poisoning blood film

A

basophilic stiplling
clover leaf morphology

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24
Q

when should you refer in anaemia

A
  • **2ww colorectal suspected cancer pathway referral
    • Anaemia (iron-deficiency), 60 and over
    • Anaemia (iron-deficiency, unexplained) with rectal bleeding in adults under 50
    • post-menopausal women with a haemoglobin level ≤10 dg/L and men with a haemoglobin level ≤11 dg/L should be referred to a gastroenterologist within 2 weeks.These are considered if no obvious cause of blood loss is identified
      • Upper GI endoscopy
      • Colonoscopy
      • Haematuria
  • Offer testing for occult blood in faeces (FIT)
    • Anaemia (iron-deficiency) without rectal bleeding in adults under 60
    • Anaemia (even in the absence of iron-deficiency) without rectal bleeding, 60 and over - Offer testing for occult blood in faeces (FIT)
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25
Q

treatment of iron deficiency anaemia, common side effects

A

underlying cause

  • oral iron supplements (ferris sulphate)
    • ( Absorption is enhanced by ascorbic acid (vitamin C) & meat, and inhibited by calcium, fibre, tea, coffee, and wine )
    • continue taking iron for 3 months after the iron deficiency has been corrected in order to replenish iron stores.
    • Common side effects of iron supplementation include nausea, abdominal pain, constipation, diarrhoea
      • Iron-rich diet: this includes dark-green leafy vegetables, meat, iron-fortified bread

-
2nd line if oral not working or intolerant :
- IV iron replacement
- red cell transfusion (esp, if cardiovascular compromise→ dyspnoea at rest, chest pain, or lightheadedness)

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26
Q

Lead poisoning treatment

A
  • Remove the source
  • various chelating agents are currently used:
    • dimercaptosuccinic acid (DMSA)
    • D-penicillamine
    • EDTA
    • dimercaprol
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27
Q

complications of anaemia

A

High-output cardiac failure

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28
Q

anaemia diagnostic values hb

A

<13.5 g/dL in men, <12 g/dL in women, and <11 g/dL in pregnant women

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29
Q

main points - Pathophys anaemia of chronic disease

A

Chronic disease precipitates the formation of inflammatory cytokines such as IL-1 and IL-6. High levels of IL-6 stimulates hepcidin release (from the liver) which is inhibitory in iron absorption as it decreases the activity of ferroportin.

Ferroportin is an iron export channel of the basolateral surface of gut (duodenal) enterocytes and the plasma membrane of reticuloendothelial cells (macrophages). Therefore, haemoglobin production decreases and anaemia of chronic disease precipitates. Also increased uptake of iron by macrophages

Anaemia is mainly due to decreased red blood cell production; may be aggravated by shortened red blood cell survival.

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30
Q

treatment of anaemia of CD

A

primarily treatment of the underlying disorder

if needed, adjunct with: red blood cell transfusion, erythropoises-stimulating agents (epoetin alfa or darbepoetin alfa SC), supplemental iron

  • RBC transfususion if severe (<80g/L) or life threatening anaemia (<65g/L), heart failure, significant pulmonary disease, or cerebral vascular disease.
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31
Q

what is sideroblastic anaemia

A

red cells fail to completely form haem, whose biosynthesis takes place partly in the mitochondrion.

This leads to deposits of iron in the mitochondria that form a ring around the nucleus called a ring sideroblast. It may be congenital or acquired.

hemosiderosis of the liver, heart and endocrine organs (similar to that seen in hereditary haemochromatosis).

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32
Q

features of sideroblastic a

A

microcytic anaemia refractory to intensive iron therapy, associated with an atypically high serum ferritin and iron.

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33
Q

sideroblastic A: causes

A

Congenital cause: delta-aminolevulinate synthase-2 deficiency

Acquired causes

  • myelodysplasia
  • alcohol
  • lead
  • anti-TB medications - isoniazid
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34
Q

sideroblastic A: Ix & Tx

A
  • full blood count
    • hypochromic microcytic anaemia (more so in congenital)
  • iron studies
    • high ferritin
    • high iron
    • high transferrin saturation
  • blood film
    • basophilic stippling of red blood cells
  • bone marrow
    • Prussian blue staining will show ringed sideroblasts
  • supportive
  • treat any underlying cause
  • pyridoxine may help
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35
Q

causes of B12 deficiency

A

Reduced absorption (e.g. post-gastrectomy, pernicious anaemia, terminal ileal resection or disease)

  • Reduced intake (vegans)
  • Abnormal metabolism (congenital transcobalamin II deficiency)
  • Gastric causes – pernicious anaemia, chronic severe atrophic gastritis
  • Pancreatic – any cause of pancreatic insufficiency
  • Small bowel bacterial overgrowth (since bacteria utilize vitamin B12), terminal ileal resection, severe terminal ileal disease (i.e. Crohn’s disease)
  • Tuberculosis
  • Metformin therapy
  • Zollinger-Ellison syndrome
  • Drugs- colchicine, metformin, PPIs, H2 antagonists, anticonvulsants
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36
Q

pernicious anaemia

A
  • Pernicious anaemiais an autoimmune condition involving gastritis, atrophy of all layers of the body and fundus of the stomach and loss of normal gastric glands, parietal and chief cells
  • eads to alack of intrinsic factor

It commonly occurs in patients >40 years with a background of auto-immune thyroid disease, vitiligo, T1DM and Addison’s disease. In addition, patients have a 3x increased risk of gastric cancer.

Dietary insufficiency, malabsorption and excessive utilisation of vitamin B12 can also precipitate megaloblastic anaemia.

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37
Q

Causes ofFolate Deficiency:

A
  • Reduced intake (alcoholics, elderly, anorexia)
  • Increased demand (pregnancy, lactation, malignancy, chronic inflammation)
  • Reduced absorption
  • Jejunal disease (e.g. coeliac disease)
  • Drugs (e.g. phenytoin)
  • Methotrexate (dihydrofolate reductase inhibitor)
  • Hydroxyurea
  • Azathioprine
  • Zidovudine
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38
Q

Non-Megaloblastic (normoblastic) causes of megaloblastic anaemia

A
  • Alcohol excess
  • Liver disease
  • Myelodysplasia
  • Multiple myeloma
  • Hypothyroidism
  • Haemolysis (shift to immature red cell form - reticulocytosis)
  • Drugs (e.g. tyrosine kinase inhibitor, cytotoxic)
  • pregnancy
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39
Q

blood film in megaloblastic anaemia

A
  • Megaloblasts
  • Hypersegmented neutrophil nuclei
  • basophilic cytoplasm
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40
Q

Management Plan of megaloblastic anaemia

A
  • VB12 deficiency**Symptomatic
    • IM / SC cyanocobalamin or IM hydroxocobalamin first line. Then lifelong oral or parenteral.
    • IF NEEDED : Can adjunct with blood transfusion w diuretic , oral folic acid
    Asymptomatic
    • dietary supplementation + multivitamines
  • Pernicious Anaemia
    • IM hydroxycobalamin for life
  • Folate Deficiency
    • Oral folic acid + treatment of the underlying condition
    • If B12 deficiency is present, it must be treated before the folic acid deficiency
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41
Q

causes of normocytic anaemia

A
  • Causes:
  • Decreased production of normal-sized blood cells : Hypoproliferative (reticulocyte count <2%)
    • aplastic anaemia
    • anaemia of chronic disease
    • chronic kidney disease
  • Increased production of HbS
    • sickle cell disease
  • Increased destruction of red blood cells (e.g. haemolysis, post-haemorrhagic anaemia): Hyperproliferative (reticulocyte count >2%)
    • haemolytic anaemia
    • acute blood loss
  • Uncompensated increase in plasma volume
    • pregnancy, fluid overload
  • Vitamin B2 deficiency
  • Vitamin B6 deficiency
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42
Q

hereditary causes of haemolytic anaemia

A
  • Membrane Defects
    • Hereditary spherocytosis
    • Elliptocytosis
    • Paroxysmal nocturnal haemoglobinuria
  • Metabolic Defects
    • G6PD deficiency
    • Pyruvate kinase deficiency
  • Haemoglobinopathies
    • Sickle cell disease
    • Thalassemia
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43
Q

acquired causes of haemolytic anaemia

A
  • Autoimmune
    • Antibodies attach to erythrocytes causing intravascular and extravascular haemolysis
  • Isoimmune
    • Transfusion reaction
    • Haemolytic disease of the newborn
  • Drugs
    • Penicillin
    • Quinine
    • NOTE: this is caused by the formation of a drug-antibody-erythrocyte complex
  • Trauma
    • Microangiopathic haemolytic anaemia (caused by RBC fragmentation in abnormal microcirculation)
      • E.g. haemolytic uraemic syndrome, DIC, malignant hypertension
    • prosthetic heart valves
  • Infection
    • Malaria
    • Sepsis
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44
Q

AIHA causes

A

Autoimmune haemolytic anaemia (AIHA)

It is most commonly idiopathic but may be secondary to a lymphoproliferative disorder, infection or drugs.

warm:
- idiopathic
- autoimmune disease: e.g.systemic lupus erythematosus*
- Lymphoproliferative neoplasms
- lymphoma
- chronic lymphocytic leukaemia
- drugs: e.g. methyldopa

Causes of cold AIHA

  • neoplasia: e.g. lymphoma
  • infections: e.g. mycoplasma, EBV
    • Post-infectious haemolytic- occurring 2-3 weeks after
  • Idiopathic
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45
Q

warm AIHA features

A

Warm is the most common type of AIHA.

  • usuallyIgG
  • haemolysis at body temperature
  • haemolysis tends to occur in extravascular sites, for example the spleen.

causes
- idiopathic
- autoimmune disease: e.g.systemic lupus erythematosus*
- Lymphoproliferative neoplasms
- lymphoma
- chronic lymphocytic leukaemia
- drugs: e.g. methyldopa

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46
Q

cold AIHA features

A

The antibody in cold AIHA

  • usuallyIgM
  • haemolysis best at 4 deg C.
  • Haemolysis is mediated by complement
  • more commonly intravascular.

Features may include symptoms of Raynaud’s and acrocynaosis. Patients respond less well to steroids

Causes of cold AIHA

  • neoplasia: e.g. lymphoma
  • infections: e.g. mycoplasma, EBV
    • Post-infectious haemolytic- occurring 2-3 weeks after
  • Idiopathic
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47
Q

classification of haemolytic anaemia

A

AIHA: warm & cold
intravascular & extravascular
autoimmune (Coombs positive) and non-autoimmune (Coombs negative) haemolytic anaemia.

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48
Q

intravascular causes of haemolytic anaemia

A
  • intravascular haemolysis occurs in the blood stream, resulting in release of cellular contents (in particular haemoglobin) into the circulation.
  • This excess of haemoglobin is dealt with in many ways: combines with haptoglobin, combines with albumin (methaemalbuminaemia), loss in the urine (haemoglobinuria), and stored in tubular epithelial cells as haemosiderin and shed into the urine (hemosiderinuria).
  • Intrinsic cellular injury (e.g. glucose-6-phosphate deficiency - G6PD)
  • Intravascular complement mediated lysis (some autoimmune haemolytic anaemias
  • Paroxysmal nocturnal haemoglobinuria and acute transfusion reactions)
  • Mechanical injury (Microangiopathic haemolytic anaemia and cardiac valves)
  • Autoimmune haemolytic anaemia
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49
Q

extravascular causes of haemolytic anaemia

A

Extravascular haemolysis occurs in the reticuloendothelial system (the spleen and liver) and is therefore not associated with dramatic release of free haemoglobin into the circulation. Splenomegaly and hepatomegaly are typical.

Causes of Extravascular haemolytic anaemia

Causes include:

Abnormal red blood cells (sickle cell anaemia and hereditary spherocytosis)

Normal cells marked by antibodies for splenic phagocytosis.

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50
Q

presentation of haemolytic anaemia

A

symptoms

  • Jaundice
  • Haematuria
  • Anaemia symptoms → fatigue, dyspnea
  • orthostatic hypotension

Presentation - signs

  • Pallor
  • Jaundice
  • Hepatosplenomegaly
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51
Q

blood & urine results in haemolytic anaemia

A
  • Low Hb
  • High reticulocytes
  • High MCV, can be normal too
  • High unconjugated (direct) bilirubin
  • Low haptoglobin (a protein that binds to free Hb released by red blood cells)
  • high LDH
  • U&Es, haemoglobinurea
  • Folate
  • High urobilinogen
  • Haemoglobinuria
  • Haemosiderinuria
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52
Q

blood film in haemolytic anaemia

A
  • Leucoerythroblastic picture
    • Macrocytosis
    • Nucleated erythrocytes or reticulocytes
    • Polychromasia
    • May identify specific abnormal cells such as:
      • Spherocytes
      • Elliptocytes
      • Sickle cells
      • Schistocytes
      • Malarial parasites
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53
Q

special tests in haemolytic anaemia

A
  • Direct Coombs’ Test (important for differentiating immune from non-immune aetiologies)
    • Tests for autoimmune haemolytic anaemia
    • Identifies erythrocytes coated with antibodies
  • Osmotic fragility test or Spectrin mutation analysis
    • Identifies membrane abnormalities
  • Ham’s Test
    • Lysis of erythrocytes in acidified serum in paroxysmal nocturnal haemoglobinuria
  • Hb Electrophoresis or Enzyme Assays
    • To exclude other causes
  • Bone Marrow Biopsy(rarely performed)
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54
Q

management of AIHA

A

underlying cause

warm AIHA

  • treatment of any underlying disorder
  • steroids (+/- rituximab)are generally used first-line

Other

  • plasmapheresis
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55
Q

what is hereditary sperocytosis & pathophys

A
  • most common hereditary haemolytic anaemia
  • autosomal dominant defect of red blood cell cytoskeleton- cell membrane protein
  • Abnormal sections of membrane are removed by the spleen, resulting in a reduced surface area to volume ratio and causing spherical distortion of cells (seen as spherocytes on blood film)
  • as more membrane is removed, the cells haemolyse (extravascular haemolysis) and are removed from circulation in the spleen.
  • red blood cell survival reduced as destroyed by the spleen
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56
Q

RFs & epidemiology of hereditary spherocytosis

A

family history of anaemia, jaundice, splenectomy, or known HS; also Northern European ancestry.

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57
Q

presentation of of hereditary spherocytosis

A

presents with neonatal or childhood onset jaundice/anaemia, and splenomegaly.

  • failure to thrive
  • jaundice,gallstones
  • splenomegaly
  • anaemia, pallor
  • aplastic crisis precipitated by parvovirus infection
  • degree of haemolysis variable
  • MCHC elevated
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58
Q

Ix: hereditary spherocytosis

A
  • the osmotic fragility test was previously the recommend investigation of choice. However, it is now deemed unreliable and is no longer recommended
  • ‘patients with a family history of HS, typical clinical features and laboratory investigations (spherocytes, raised mean corpuscular haemoglobin concentration [MCHC], increase in reticulocytes) do not require any additional tests
  • blood smear: spherocytes present, also may be pincer cells
  • elevated unconjugated bilirubin
  • LFTs normal
  • if the diagnosis is equivocal the BJH recommend theEMA bindingtest and the cryohaemolysis/ acidified glycerol lysis test test
  • for atypical presentations electrophoresis analysis of erythrocyte membranes is the method of choice
  • negative direct anti-globulin test (DAT) and an elevated reticulocyte count.
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59
Q

Tx: hereditary spherocytosis

A

depends on the severity of the haemolysis and degree of anaemia, but is generally supportive for most patients.

  • acute haemolytic crisis:
    • treatment is generally supportive
    • transfusion if necessary
    • folate replacement
  • longer term treatment:
    • if severe: splenectomy
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60
Q

what is Paroxysmal nocturnal haemoglobinuria (PNH)

A

disorder leading to haemolysis (mainly intravascular) of haematological cells and thrombophilia

rare acquired stem cell disorder of unknown aetiology

It is thought to be caused by increased sensitivity of cell membranes to complement (see below) due to a lack of glycoprotein glycosyl-phosphatidylinositol (GPI).

  • GPI can be thought of as an anchor which attaches surface proteins to the cell membrane
  • complement-regulating surface proteins, e.g. decay-accelerating factor (DAF), are not properly bound to the cell membrane due a lack of GPI
  • thrombosis is thought to be caused by a lack of CD59 on platelet membranes predisposing to platelet aggregation

may be associated with other stem cell defects and increased risk of thrombosis (via an effect on complement mediated platelet aggregation)

associated with relative or absolute marrow hypoplasia- aplastic anaemia

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61
Q

features of Paroxysmal nocturnal haemoglobinuria (PNH)

A
  • haemolytic anaemia
  • red blood cells, white blood cells, platelets or stem cells may be affected therefore pancytopaenia may be present
  • haemoglobinuria: classically dark-coloured urine in the morning (although has been shown to occur throughout the day)
  • thrombosis e.g. Budd-Chiari syndrome
  • aplastic anaemia may develop in some patients

Patients are more prone to venous thrombosis

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62
Q

investigation of Paroxysmal nocturnal haemoglobinuria (PNH)

A
  • flow cytometry of blood to detect low levels of CD59 and CD55has now replaced Ham’s test as the gold standard investigation in PNH
  • Ham’s test: acid-induced haemolysis (normal red cells would not)
  • urine dip m microscopy → haemaglobinurea, haemosiderinurea
  • FBC → anaemia, cytopenia
  • increased reticulocytes, LDH, unconjugated bilirubin (indicates haemolysis)
  • D dimer increased → indicates thrombosis
63
Q

management of Paroxysmal nocturnal haemoglobinuria (PNH)

A
  • eculizumab, a monoclonal antibody directed against terminal protein C5, is currently being trialled and is showing promise in reducing intravascular haemolysis
  • lifetime anticoagulation: enoxaparin
  • blood product replacement→ RBC transfusion if Hb<8.5g/dL
  • thrombolysis if thrombosis
  • epoetin alfa if underlying aplastic anaemia or kidney damage
  • stem cell transplantation
64
Q

what is Glucose-6-phosphate dehydrogenase (G6PD) deficiency

A

commonest red blood cell enzyme defect.

inherited in an X-linked recessive fashion.

Affected people lack the ability to tolerate biochemical oxidative stress, and red cell haemolysis is the most important clinical consequence.

↓ G6PD → ↓ reduced NADPH → ↓ reduced glutathione → increased red cell susceptibility to oxidative stress

65
Q

G6PD epidemiology & RFs

A

male sex; family history of G6PD deficiency; African, Mediterranean, or Asian origin; recent exposure to drugs or broad beans; and recent infection.

common among populations originating from parts of the world where malaria is or was common: that is, sub-Saharan Africa, Asia, the Mediterranean region, and the Middle East.

66
Q

trigger of G6PD

A

Many drugs can precipitate a crisis as well as infections and broad (fava) beans

  • Intercurrent illness or infection (often forgotten)
  • Fava/ broad beans: the disease was historically known as favism
  • Henna
  • Medications

Some drugs causing haemolysis

  • anti-malarials: primaquine
  • ciprofloxacin
  • sulph- group drugs: sulphonamides, sulphasalazine, sulfonylureas
  • nitrofurantoin
  • dapsone
  • NSAIDs/Aspirin

Some drugs thought to be safe

  • penicillins
  • cephalosporins
  • macrolides
  • tetracyclines
  • trimethoprim
67
Q

features of G6PD

A

Almost all patients are completely asymptomatic.

may present in the neonatal period with jaundice, or later in life with episodic intravascular haemolysis following exposure to oxidative stressors.

  • neonatal jaundice is often seen
  • intravascular haemolysis
  • gallstones are common
  • splenomegaly may be present

jaundice, pallor, dark urine

68
Q

Ix of G6PD

A

Blood smear

  • Heinz bodieson blood films.Bite and blister suggest oxidate stress as a cause of haemolysis

Diagnosis is made by using a G6PD enzyme assay

  • levels should be checked around3 months after an acute episode of hemolysis, RBCs with the most severely reduced G6PD activity will have hemolysed → reduced G6PD activity → not be measured in the assay → false negative results

Initial Ix→ anaemia, increased reticulocytes, haemoglobin urea, increased unconjugated (direct) billirubin & LDH, low haptoglobin

69
Q

management of G6PD

A

avoidance of precipitants, and some patients may rarely require transfusions.

acute severe haemolysis: folic acid, blood transfusion, phototherapy if high indirect hyperbillirubinaemia, exchange transfusion

70
Q

Acute intermittent porphyria pathophysiology

A
  • a rare autosomal dominant condition caused by a defect in porphobilinogen deaminase, an enzyme involved in the biosynthesis of haem.
  • results in the toxic accumulation of delta aminolaevulinic acid and porphobilinogen
71
Q

Acute intermittent porphyria RFs and epidemiology

A

AIP is more common in females (5:1)

20-40-year-olds

family history of acute porphyria, female gender, nutritional alterations (e.g., fasting, dieting), intercurrent illness, and exposure to drugs or hormones known to provoke attacks of AIP.

72
Q

features of Acute intermittent porphyria

A

The classical presentation is a combination ofabdominal, neurological and psychiatric symptoms:

  • abdominal: abdominal pain, vomiting
  • neurological: motor neuropathy
  • psychiatric: e.g. depression
  • hypertension and tachycardia common
  • urine turns deep red on standing
73
Q

diagnosis of Acute intermittent porphyria

A
  • classicallyurine turns deep red on standing
  • raised urinary porphobilinogen(elevated between attacks and to a greater extent during acute attacks)
  • assay of red cells for porphobilinogen deaminase
  • raised serum levels of delta aminolaevulinic acid and porphobilinogen
74
Q

management of Acute intermittent porphyria

A
  • avoiding triggers
  • acute attacks
    • IV haematin/haem arginate
    • IV glucose should be used if haematin/haem arginate is not immediately available
75
Q

Thalassemia causes and pathophysiology

A
  • Autosomal recessive
  • Result in animbalance of globin chain production and deposition in erythroblasts and erythrocytes
  • This leads to:
    • Ineffective erythropoiesis
    • Haemolysis
    • Anaemia
    • Extramedullary haematopoiesis
76
Q

types of thalassemia

A
  • ALPHA THALASSEMIA- reduction in alpha-globin chain synthesis.
  • There are 2alpha-globin genes & 4 alleles for these on the chromosome.
    • 4 gene deletion= Haemoglobin Barts Hydrops Fetalis (intrauterine death)
    • 3 gene deletion= Haemoglobin H –> microcytic hypochromic anaemia and splenomegaly
    • 1 or 2 gene deletion= microcytic hypochromic red cells,NO ANAEMIA
  • BETA THALASSEMIA
    • Beta Thalassemia Major(homozygous beta thalassemia) –> little or no beta-chain synthesis. * chromosome 11
  • problem w beta globulin gene
    • Beta Thalassemia Intermedia- mild defect in beta-chain synthesis leads to:
      • Microcytic anaemia
    • Beta Thalassemia Trait(heterozygous carrier state)
      • ASYMPTOMATIC
      • Mild microcytic anaemia
      • Increased red cell count
77
Q

epidemiology and RFs of thalassemia

A

Mutations in the beta-globin gene cluster occur at high frequencies (>1%) in regions including the Mediterranean, Middle East, northern Africa, India, and almost all of Southeast Asia

FHx

  • WORLDWIDE
  • Most common in theMEDITERRANEANand areas of theMiddle-East
78
Q

presentation of Beta Thalassemia Major

A
  • Anaemia
  • Presenting at3-6 months
    • This is when the change from HbF to HbA takes place
    • Failure to thrive
    • Prone to infection
  • Pallor
  • Malaise
  • Dyspnoea
  • Mild jaundice
  • Frontal bossing
  • lethargy, abdo distension, failure to gain weight, pallor, spinal changes
  • Thalassaemia facies - chipmunk (facial features caused by marrow hyperplasia), large hear, misaligned teeth
  • Hepatosplenomegaly (due to erythrocyte pooling and extramedullary haematopoiesis)
  • Patients withbeta-thalassemia intermediamay also have these signs
79
Q

presentation of Beta Thalassemia Major

A
  • Anaemia
  • Presenting at3-6 months
    • This is when the change from HbF to HbA takes place
    • Failure to thrive
    • Prone to infection
  • Pallor
  • Malaise
  • Dyspnoea
  • Mild jaundice
  • Frontal bossing
  • lethargy, abdo distension, failure to gain weight, pallor, spinal changes
  • Thalassaemia facies - chipmunk (facial features caused by marrow hyperplasia), large hear, misaligned teeth
  • Hepatosplenomegaly (due to erythrocyte pooling and extramedullary haematopoiesis)
  • Patients withbeta-thalassemia intermediamay also have these signs
80
Q

Alpha or Beta Thalassemia Trait presentation

A
  • May be ASYMPTOMATIC
  • Detected during routine blood tests or due to family history
  • Beta-thalassaemia trait is an autosomal recessive condition characterised by a mild hypochromic, microcytic anaemia. It is usually asymptomatic
81
Q

Ix of Thalassemia

A
  • FBC
    • Low Hb
    • Low MCV (microcytic anaemia)
    • Low MCH
    • microcytic anaemia, normal to elevated leukocyte and platelet counts from generalised haematopoietic hyperactivity, all decreasing as the spleen enlarges
  • LFT- elevated total and unconjugated bilirubin, elevated LDH
  • Blood Film
    • Hypochromic microcytic anaemia
    • Target cells
    • tear drops
    • Nucleated red cells
    • High reticulocyte count
  • Hb Electrophoresis
    • Absent or reduced HbA
    • High HbF & HBA2
  • Bone Marrow
    • Hypercellular
    • Erythroid hyperplasia
  • Genetic Testing(rarely used)
  • Skull X-Ray
    • ‘Hair on end’ appearance in beta thalassemia major
      • This is caused by expansion of marrow into the cortex
      • widening of the diploeic space, facial deformity
82
Q

management of beta thalassemia major

A
  • repeated transfusion
    • this leads to iron overload → organ failure
    • iron chelation therapyis therefore important (e.g. desferrioxamine)
  • consider splenectomy
83
Q

What is sickle cell anaemia

A
  • DEFINITION:a chronic condition with sickling of red blood cells caused by inheritance ofhaemoglobin S(HbS)
    • Sickle Cell Anaemia= Homozygous HbS
    • Sickle Cell Trait= Carrier of one copy of HbS
    • Sickle Cell Disease= includes compound heterozygosity for HbS and:
      • HbC (abnormal haemoglobin in which glutamic acid is replaced by lysine at the 6th position in the beta-globin chain) -> formation of abnormalhaemoglobin S
      • Beta-thalassemia
  • These sickled red cells are prone to:
    • Sequestration and destruction (reduced red cell survival ~ 20 days)
    • Occlusion of small blood vessels causing hypoxia, which leads to further sickling and occlusion
    • clotting of the microcirculation, precipitating a vaso-occlusive crisis leading to ischaemia of vitals organs, and pain.
84
Q

factors that precipitate sickling in SC anaemia

A
  • Infection
  • Dehydration
  • Hypoxia
  • Acidosis
85
Q

sickle cell anaemia epidemiology

A
  • Rarely presents before 4-6 months (because HbF can compensate for the defect in adult haemoglobin)
  • Common in central/ west Africa, Caribbean, Middle-East and other areas with a high prevalence of malaria
  • Around 10% of UK Afro-Caribbean’s are carriers of HbS (i.e. heterozygous). Such people are only symptomatic if severely hypoxic.
86
Q

sickle cell anaemia presentation

A

Symptoms in homozygotes don’t tend to develop until 4-6 months when the abnormal HbSS molecules take over from fetal haemoglobin.

  • Signs ofanaemia

A number of types of crises are recognised:
- thrombotic, ‘painful crises’ - vso-oclusive
- sequestration
- acute chest syndrome
- aplastic
- haemolytic
- bone pain

87
Q

thrombotic, ‘painful crises’ - vso-oclusive : SCA

A
  • precipitated byinfection, dehydration, deoxygenation
  • painful vaso-occlusive crises should bediagnosed clinically- there isn’t one test that can confirm them although tests may be done to exclude other complications
  • infarcts occur in various organs including the bones (e.g. avascular necrosis of hip, hand-foot syndrome in children, lungs, spleen and brain
  • Autosplenectomy (splenic atrophy or infarction)
    • ickle cells commonly sequester in the spleen and undergo phagocytosis by the reticular endothelial system leading to extravascular haemolysis- splenic congestion
    • Leads to increased risk of infections withencapsulated organisms(e.g. pneumococcus, meningococcus)
  • Abdominal Pain
  • Bones
    • Painful crises affect small bones of the hands and feet causingdactylitisin CHILDREN
  • Painful crises mainly affect the ribs, spine, pelvis and long bones in ADULTS
  • Myalgia and Arthralgia
  • CNS
    • Fits and strokes
  • Retina
    • Visual loss (proliferative retinopathy)
  • Bone- joint or muscle tenderness or swelling (due to avascular necrosis)
  • Short digits- due to infarction in small bones of the hands
  • Retina- cotton wool spots due to retinal ischaemia
88
Q

sequestration SCA

A
  • sickling within organs such as the spleen or lungs causes pooling of blood with worsening of the anaemia
  • associated with anincreased reticulocyte count
    • NOTE: sequestration crises occur due to pooling of red cells in various organs (mainly thespleen)
    • Liver –> exacerbation of anaemia
    • Lungs –> acute chest syndrome
      • Breathlessness
      • Cough
      • Pain
      • Fever
    • Corpora cavernosa
      • Persistent painful erection (priapism)
      • Impotence
    • Organomegaly
      • The spleen isENLARGEDin early disease
      • Later on, the spleen will reduce in size due tosplenic atrophy
    • Priapism
89
Q

acute chest syndrome SCA

A
  • vaso-occlusion within the pulmonary microvasculature → infarction in the lung parenchyma
  • dyspnoea, chest pain, pulmonary infiltrates on chest x-ray, low pO2
  • management
    • pain relief
    • respiratory support e.g. oxygen therapy
    • antibiotics: infection may precipitate acute chest syndrome and the clinical findings (respiratory symptoms with pulmonary infiltrates) can be difficult to distinguish from pneumonia
    • transfusion: improves oxygenation
  • the most common cause of death after childhood
90
Q

aplastic & haemolytic SCA

A
  • aplastic
    • caused by infection with parvovirus
    • sudden fall in haemoglobin
    • bone marrow suppression causes areduced reticulocyte count
  • haemolytic
    • rare
    • fall in haemoglobin due an increased rate of

haemolysis
- screening
- Sickle cell anaemia in the UK is typically diagnosed postnatally (national screening programme), but otherwise presents with progressive anaemia in early life as levels of foetal haemoglobin (which contains no beta-globin component) fall.

91
Q

Investigations SC anaemia

A
  • Bloods
    • FBC
      • Low Hb
      • Reticulocytes:
        • HIGH - in haemolytic crises
        • LOW - in aplastic crises
    • U&Es
    • microcytic anaemia with variable degrees of haemolysis (reticulocytosis and unconjugated hyperbilirubinemia may be noted).
  • Blood Film
    • Sickle cells
  • Anisocytosis (variation in size of red cells)
  • reticulocytes with polychromasia
  • Features ofHyposplenism:
    • Target cells
    • Howell-Jolly bodies
    • nucleated red blood cells
  • Sickle Solubility Test
    • Dithionate is added to the blood
    • In sickle cell disease you getincreased turbidity
  • Haemoglobin Electrophoresis - Definitive diagnosis +/- genetic testing.
    • Shows HbS
    • Absence of HbA (if homozygous HbS)
    • High HbF
  • Hip X-Ray
    • Femoral headis a common site of avascular necrosis
  • MRI or CT Head
    • If there are neurological complications
92
Q

management thrombotic, ‘painful crises’ - vso-oclusive : SCA

A
  • Oxygen
  • IV Fluids
  • Strong analgesia (IV opiates)
  • consider Antibiotics if infection evidence
  • blood transfusion
  • exchange transfusion: e.g. if neurological complications
  • Folic Acid
    • If severe haemolysis or in pregnancy
  • Red Cell Transfusion
    • For SEVERE anaemia
    • Repeated transfusions (with iron chelators) may be required in patients suffering from repeated crises
    • indications include: severe or symptomatic anaemia, pregnancy, pre-operative
    • do not rapidly reduce the percentage of Hb S containing cells
  • exchange transfusion
    • indications include: acute vaso-occlusive crisis (stroke, acute chest syndrome, multiorgan failure, splenic sequestration crisis
    • rapidly reduce the percentage of Hb S containing cells
93
Q

management Acute chest syndrome SCA

A
  • pain relief
  • respiratory support e.g. oxygen therapy
  • antibiotics: infection may precipitate acute chest syndrome and the clinical findings (respiratory symptoms with pulmonary infiltrates) can be difficult to distinguish from pneumonia
  • transfusion in some patients: improves oxygenation
94
Q

Longer-term management of SC anaemia

A
  • hydroxyurea/ Hydroxycarbamide
    • increases the HbF levels and is used in the prophylactic management of sickle cell anaemia to prevent painful episodes
    • n patients aged ≥2 years with sickle cell anaemia.
  • pneumococcal polysaccharide vaccine every 5 years
  • antibiotic prophylaxis with penicillin in children under 5 years of age,
  • nutritional counselling, and prompt treatment when infections do occur.
  • in some patients: repeated blood transfusions:to maintain HbS below 30%.
  • Infection Prophylaxis
    • Penicillin V
    • Regular vaccinations (particularly against capsulated bacteria e.g. pneumococcus)
  • Advice
    • Avoid precipitating factors, good hygiene and nutrition, genetic counselling, prenatal screening
  • Surgical
    • Bone marrow transplantation
    • Joint replacement in cases with avascular necrosis
95
Q

Mortality in sickle cell A

A
  • Mortality is usually the result of:
    • Pulmonaryorneurological complicationsin ADULTS
    • Infectionin CHILDREN
96
Q

RFs of ALL

A

children less than 5 years of age, age in late 30s or mid-80s; history of malignancy; treatment with chemotherapy; exposure to radiation; smoking; genetic disorders (such as Klinefelter’s syndrome or trisomy 21); and family history of ALL.

97
Q

What happens in ALL

A
  • Lymphoblasts undergo malignancy transformation and proliferation
  • This leads to thereplacement of normal marrow elements, leading tobone marrow failureand infiltration into other tissues
98
Q

presentation of ALL

A
  • Bone Marrow Failure:
    • Anaemia (fatigue, dyspnoea)
    • Bleeding (spontaneous bruising, bleeding gums, menorrhagia)
      • Pallor. ecchymoses, Bruising, petechiae
    • Opportunistic infections
      • common infections: involve chest, mouth, perianal, skin. bacterial septicaemia, zoster, CMV, measles, candidiasis, pneumocystis pneumonia
  • Organ Infiltration:
    • Lymphadenopathy (superficial, mediastinal or orchidomegaly)
    • Hepatosplenomegaly- due to infiltration of leukaemic lymphoblasts
    • Tender bones, bone pain- pressure from leukaemic-cell infiltration in the medullary cavity and periosteum.
    • Meningeal involvement (headache, visual disturbances, nausea) - CNS involvement common
      • Cranial nerve palsies,
      • meningism & nuchal regidity
      • Retinal haemorrhage, Papilloedema on fundoscopy, Leukaemic infiltration of the anterior chamber of the eye
    • painless unilateral enlargement. - Testicular infiltration
    • renal enlargement
    • Mediastinal compression
99
Q

ALL bloods

A
  • Bloods
    • FBC - leukocytosis and blast cells on blood film and bone marrow analysis., low platelets and low RBCs with low reticulocyte count
      • despite leukocytosis, they have neutropenia so prone to infection
    • U& E →
      • High uric acid- reflects extent of tumor burden
      • high phosphorous - ineffective leukopoiesis/ tumor lysis
      • high calcium - (bony infiltration/ ectopic release of PTH)
      • hyperkaliemia - extensive leukemic cell lysis
    • renal function - important baseline Ix: urea may be normal or elevated if there is renal dysfunction
    • High LDH - important baseline Ix: may be elevated if there is increased cell turnover
    • Clotting screen
      • Prothrombin time, partial thromboplastin time,and levels of fibrinogen and D-dimers should be measured in any patient with bleeding or petechiae
100
Q

ALL Ix and Dx

A

blood - - eukocytosis and blast cells on blood film and bone marrow analysis., low platelets and low RBCs with low reticulocyte count
- despite leukocytosis, they have neutropenia so prone to infection

  • Blood Film
    • Abundant lymphoblasts - not sufficient to diagnose ALL
  • Bone Marrow Aspirate or Trephine Biopsy
    • morphology, cytochemical stains, immunophenotyping (using flow cytometry), chromosome (cytogenetic) analysis, fluorescence in situ hybridisation, polymerase chain reaction for t(9;22), and other molecular studies performed
    • Hypercellular with > 20% lymphoblasts
  • Immunophenotyping(using flow cytometry)(on bone marrow, or peripheral blood if cell count is raised)
    • using antibodies to recognise cell surface antigens
    • is used to identify markers on leukaemic lymphoblasts.
    • Normally, leukaemic cells exhibit markers of one cell type.
101
Q

ALL Tx

A

upportive

  • transfusions, IV fluids, allopurinol (for TLS), insert a SC port system or Hickman lone for IV access

Infection

  • neutropenia so infections are dangerous.
  • Immediate IV antibiotics
  • neutropenic regime: prophylactic antivirals, antifungals, and antibiotics

Chemotherapy (complex, multi-drug, multi-phasic, can take years)

  • remission induction: vincristine, corticosteroid (prednisolone/ dexamethasone), cyclophosphomide & anthracycline (doxorubicin/-rubacin)
    • treat CNS involvement with intrathecal therapy (e.g. methotrexate) or CNS irradiation
  • consolidation : high-medium-dose therapy in blocks over several weeks
  • CNS prophylaxis: intrathecal (or high dose IV) methotrexate
  • Maintainance : prolonged chemotherapy: mercaptopurine (daily), methotrexate (weekly), and vincristine+ prednisolone (monthly) for 2 year.

Early Matched related allogenic stem cell marrow transplant

  • best option once in 1st remission
  • instead of Maintenace therapy
102
Q

worse prognostic factors in ALL

A

male adult , philadelphia chromosome or CNS signs, B-cell ALL,

103
Q

what is Acute promyelocytic leukaemia

A

Type of AML
- associated with t(15;17)
- fusion of PML and RAR-alpha genes
- presents younger than other types of AML (average = 25 years old)
- (hypergranular promyelocytes with bilobed nuclei and bundles of Auer rods),
- Auer rods(seen with myeloperoxidase stain)
- DIC or thrombocytopenia often at presentation
- good prognosis

104
Q

what is AML

A

malignancy ofprimitive myeloid lineage white blood cells(myeloblasts) with proliferation in the bone marrow and blood
- Myeloblasts undergo malignant transformation and proliferation
- This leads toreplacement of normal marrowandbone marrow failure
It may occur as a primary disease or following a secondary transformation of a myeloproliferative disorder.

remember Auer rods

105
Q

Associations and RFs of AML

A
  • long-term complication of chemotherapy (e.g for lymphoma)
  • previous myelodysplatic states, aplastic anaemia, paroxysmal nocturnal haemaglobinurea, CML, myeloprliferative disorders (PV, ET, myelofibrosis)
  • radiation exposure
  • benzene exposure
  • Down’s syndrom, kleinfelterse or other inherited genetic conditions

more common in adults

106
Q

presentation of AML

A
  • Symptoms ofBone Marrow Failure:
    • Anaemia (lethargy, dyspnoea)
    • Bleeding (due to thrombocytopaenia or DIC)
    • Opportunistic or recurrent infections
      • neutropenia: whilst white cell counts may be very high, functioning neutrophil levels may be low leading to frequent infections etc
  • Symptoms ofTissue Infiltration:
    • Gum swelling or bleeding
    • CNS involvement (headaches, nausea, diplopia)
    • hepatosplenomegaly
    • bone pain
    • Skin rashes
    • Deposit of leukaemic blasts in the eye, tongue and bone (RARE)
    DIC most common in acute promyelocytic leukaemia
107
Q

Ix AML

A
  • Bloods
    • FBC - low Hb, low platelets, variable WCC- usually high, neutropenia
    • High uric acid
    • High LDH
    • Clotting studies, fibrinogen and D-dimers (to check for DIC)
  • Blood Film
    • Myeloblasts (but may be few in the peripheral blood)
    • Presence of ≥20% blast cells in the peripheral blood confirms the diagnosis of AML
    • AML is characterised by myeloid blasts with Auer rods or Phi bodies.
    Since the above basic tests are not often clear, diagnosis depends on bone marrow biopsy, immunophenotyping, and molecular methods
  • Bone Marrow Aspirate or Biopsy
    • Hypercellular with > 20% blasts
    • differentiated from ALL, by presence of Auer rods
  • Immunophenotyping
    • Antibodies against surface antigens used to classify the lineage of the abnormal clones
  • Cytogenetics - guides treatment & prognosis
  • Immunocytochemistry
108
Q

Management of AML

A

upportive

  • walking exercises may relieve fatigue

Chemotherapy
- chemotherapy induction, consolidation, and maintenance regimens.
- intensive → so long periods of bone marrow suppression, neutropenia, thrombocytopenia
- daunorubicine and cytarabine (if RAS mutation, increased sensitivity to cytarabine) → 5 cycles in 1 weak blocks
- tretinoin and arsenic trioxide in APML
- intrathecal cytarabine if CNS involvement

Bone marrow transplant

  • Allogenic transplant
    • indicated if refractory or relapsing disease
    • from HLA matched doner
    • destroy leukaemic cells and immune system with cyclophosphamide & total body irradiation, the repopulate with donor cells infused IV.
109
Q

poor prognostic factors of AML

A
  • > 60 years
  • > 20% blasts after first course of chemo
  • cytogenetics: deletions of chromosome 5 or 7
110
Q

What is CLL

A

Chronic lymphocytic leukaemia (CLL) is caused by amonoclonal proliferation of well-differentiated lymphocytes which are almost always B-cells(99%). It is themost common form of leukaemia seen in adults.
Malignant cells may accumulate as a result of theirinability to undergo apoptosis

111
Q

RFs and associations CLL

A
  • The most common chromosomal changes include:
    • Trisomy 12
    • 11q and 13q deletions
  • RFs: 60 years, male sex, white ethnicity, and positive family history.
112
Q

CLL presentation

A
  • Asymptomatic- 40-50% of cases are diagnosed following routine blood tests
    • or SOB or fatigue
  • often none: may be picked up by an incidental finding of lymphocytosis
  • patients may present with non-tender lymphadenopathy, hepatosplenomegaly,
  • Features of marrow failure (infection, anaemia, and bleeding)or B symptoms (weight loss, night sweats, and fever). are less common than in the acute leukaemias.
  • lymphadenopathy more marked than chronic myeloid leukaemia
    • Non-tender lymphadenopathy
113
Q

Ix

A
  • Bloods
    • FBC
      • Lymphocytosis → required for diagnosis
      • low Hb and platelets
  • NOTE: In later disease, CLL may be associated withautoimmune phenomenasuch ashaemolytic anaemia(warm agglutinins) orthrombocytopaenia
  • Blood Film
  • Small lymphocytes with thin rims of cytoplasm
  • Smudge cells(also known as smear cells)
  • Cytogenetics- Flow cytometry of peripheral blood is then used to measure particular markers expressed by the malignant cells.

Bone marrow biopsy not often required

114
Q

Complications of CLL

A
  • hypogammaglobulinaemialeading to recurrent infections
  • warm autoimmune haemolytic anaemiain 10-15% of patients
  • transformation to high-grade lymphoma(Richter’s transformation)
115
Q

What is richters transformation

A

Ritcher’s transformation occurs when leukaemia cells enter the lymph node and change into a high-grade, fast-growing non-Hodgkin’s lymphoma.Patients often become unwell very suddenly.

Ritcher’s transformation is indicated by one of the following symptoms:

  • lymph node swelling
  • fever without infection
  • weight loss
  • night sweats
  • nausea
  • abdominal pain
116
Q

CLL Tx

A

conservative and observation

Only if symptomatic - chemotherapy

1st line: Fludarabine + rituximab + cyclophosphamide

117
Q

What is CML

A

malignant clonal disease characterised by proliferation of granulocyte precursors in the bone marrow and blood, distinguished from AML by its slower progression

myeloproliferative disorder

  • The Philadelphia chromosome results in the formation of theBCR-ABL fusion gene
  • The product of this gene enhances tyrosine kinase activity and drives cell replication
  • THREE phases of CML
    • Relativelystablechronic phase (4-6 yr duration)
    • Accelerated phase (3-9 months)
    • Acute leukaemia phase - blast transformation
118
Q

RFs of CML

A

RFS: middle age, male sex, and exposure to ionising radiation.

  • Incidenceincreaseswith age
  • Mean age of diagnosis: 40-60 yrs
  • 4 x more common in MALES
  • rare in children
119
Q

Presentation of CML

A
  • ASYMPTOMATIC in 40-50% of cases - diagnosed on routine blood count
  • B symptoms: weight loss, tiredness, fever, and sweating.
  • Chronic & insidious
  • Massive SPLENOMEGALY- most common physical finding (90% of cases)
120
Q

Ix CML

A
  • Bloods
    • FBC
      • High WCC
      • High basophils/neutrophils/eosinophils (myeloid cells)
      • Low Hb
      • High/normal/low platelets
      • High uric acid
      • High B12 and transcobalamin I
  • Blood Film
    • Immature granulocytes
  • Bone Marrow Aspirate or Biopsy
    • Hypercellular with raised myeloid-erythroid ratio
  • Cytogenetics
    • Show the Philadelphia chromosome
  • an increase in granulocytes at different stages of maturation +/- thrombocytosis
  • decreased leukocyte alkaline phosphatase
  • may undergo blast transformation (AML in 80%, ALL in 20%)
121
Q

Tx CML

A

CML is commonly treated with chemotherapy regimens.

  • imatinib is now considered first-line treatment
    • inhibitor of the tyrosine kinaseassociated with the BCR-ABL defect
    • very high response rate in chronic phase CML
  • Allogeneic haematopoietic stem cell transplant (HSCT) and high-dose induction chemotherapy should be considered for those who have failed tyrosine kinase inhibitor (TKI) therapy.
122
Q

Prognosis CML

A

median survival is 5-6 years.

The ‘chronic phase’ of the disease may transform to an ‘accelerated’ or ‘blast’ phase in 5% to 10% of patients despite treatment with a tyrosine kinase inhibitor, the latter resulting in acute myeloid or acute lymphoblastic leukaemia (ALL).

no Philadelphia gene = worse prognosis

123
Q

Management of suspected haematological malignancy in young people

A

Any of the following features in a person aged 0-24 years should prompt a very urgent full blood count (within 48 hours) to investigate for leukaemia:

  • Pallor
  • Persistent fatigue
  • Unexplained fever
  • Unexplained persistent infections
  • Generalised lymphadenopathy
  • Persistent or unexplained bone pain
  • Unexplained bruising
  • Unexplained bleeding
124
Q

What is Hodgkin lymphoma

A

lymphomas are malignant neoplasms of lymphoid cells, originating in the lymph nodes or other lymphoid tissues.

uncommon haematological malignancy arising from mature B cells

Hodgkin’s lymphoma (15% of all lymphomas) is diagnosed histopathologically by the presence of Reed-Sternberg Cells (binucleate lymphocytes).

125
Q

RFs and causes of Hodgkins lymphoma

A
  • UNKNOWN
  • Likely to be an environmental trigger in a genetically susceptible individual
  • Epstein Barr Virus
  • positive family history
  • young adults from higher socio-economic class.

More common in MALES
young adults

126
Q

Presentation of hodgekins lymphoma

A
  • lymphadenopathy (75%) - painless, non-tender, asymmetrical
    • Non-tender firm rubbery lymphadenopathy(may be cervical, axillary or inguinal)
    • cervical or supraclavicular non-tender lymphadenopathy
  • B symptoms of Lymphoma
    • Fever > 38 degrees
      • If this is cyclical it is referred to asPel-Ebstein fever
    • Night sweats
    • Weight loss > 10% body weight in the past 6 months
  • alcohol pain in HL
  • normocytic anaemia, eosinophilia
  • symptoms caused by compression of surrounding structures e.g. shortness of breath or abdominal pain
  • LDH raised
  • systemic (25%): weight loss, pruritus, night sweats, fever (Pel-Ebstein)
  • Other symptoms
    • Pruritis
    • Cough
    • Dyspnoea
    • Signs of intrathoracic disease (e.g. pleural effusion, superior vena cava obstruction)
    • Splenomegaly (or sometimes, hepatosplenomegaly)
    • Skin excoriations
    • cachexia
127
Q

Ix of Hodgekin lymphoma

A
  • Bloods
    • FBC
      • Anaemia of chronic disease
      • Leucocytosis
        • Lymphopaenia inadvanced disease
      • High neutrophils
      • High eosinophils
    • High ESR and CRP
  • Lymph Node Biopsy- Reed sternburg cells, required for diagnosis
  • Imaging- CXR, CT, PET, - preferably PET-CT, essential to determine extent of disease.
128
Q

Ann Arbor Staging

A
  • Ann Arbor Staging
    • I = single lymph node region
    • II = 2+ lymph node regions on one side of thediaphragm
    • III = lymph node regions on both sides of the diaphragm
    • IV = extranodal involvement
    • A = absence of B symptoms
    • B = presence of B symptoms (worse prognosis)
    • E = localised extranodal extension
    • S = involvement of spleen
129
Q

Hodgekin lymphoma Tx

A
  • stage I or stage II Hodgkin lymphoma (HL) is chemotherapy plus radiotherapy.
  • Chemotherapy is the cornerstone of treatment for patients with stage III or stage IV HL.
130
Q

Prognosis of Hodgekin lymphoma

A

depends on type

5-year survival rate of <40% to >95% depending on the type of disease.

lymphocyte rich - best

lymphocyte depleted - worst

nodular sclerosing - good

mixed cellularity - good

‘B’ symptoms also imply a poor prognosis

  • weight loss > 10% in last 6 months
  • fever > 38ºC
  • night sweats
131
Q

what is non-H lymphoma

A

Non-Hodgkin’s lymphoma is an umbrella term for a group of malignancies affecting the lymphoid system.

  • Lymphoma is the malignant proliferation of lymphocytes which accumulate in lymph nodes or other organs. Lymphoma may be classified as either Hodgkin’s lymphoma (a specific type of lymphoma characterized by the presence of Reed-Sternberg cells) or non-Hodgkin’s lymphoma (every other type of lymphoma that is not Hodgkin’s lymphoma).
  • Non-Hodgkin’s lymphoma is the 6th most common cause of cancer in the UK.
  • It can range from stable, indolent disease to aggressive disease
  • Diffuse large B-cell lymphoma is the most common type of lymphoma.
132
Q

RFs of non-H lymphoma

A
  • Elderly
  • Caucasians
  • History of viral infection (specifically Epstein-Barr virus)
    • HIV, HBV, HCV
    viral infection and immunodeficiency.
    • Helicobacter pylori with gastric MALT (mucosa-associated lymphoma tissue).
    • Epstein Barr virus with Burkitt’s lymphoma and AIDS-related CNS lymphoma.
    • Hepatitis C virus with diffuse large B-cell lymphoma and splenic marginal zone lymphoma.
    • Human T cell lymphotropic virus type 1 with T-cell lymphoma.
    • Immunodeficiency states e.g. HIV/AIDS and post-organ transplant.
    • Autoimmune disorders e.g. Sjogren’s syndrome and coeliac disease.
  • Family history
  • Certain chemical agents (pesticides, solvents)
  • History of chemotherapy or radiotherapy
  • Immunodeficiency (transplant, HIV, diabetes mellitus)
  • Immunosuppressive agents
  • Autoimmune disease (SLE, Sjogren’s, coeliac disease)
133
Q

types of extranodal non-H lymphoma

A
  • gastric maltoma → H-pylori
  • Non-malt gastric lymphoma→ usually large B cell lymphoma
  • small bowl lymphoma - diarrhoea , vomittting, abode pain
  • skin = T cells in mycosis fungicides
  • Waldeyer’s ring lymphoma - may obstruct throat/ breathing
134
Q

Presentation of non-H lymphoma

A
  • Painless enlarging mass (in neck, axilla or groin)
  • Systemic Symptoms (occurs less frequently than in Hodkin’s- indicates disseminated disease ):
    • Constitutional/B symptoms (fever, weight loss, night sweats, lethargy)
    • Symptoms of hypercalcaemia
  • Symptoms related to organ involvement
    • Painless lymphadenopathy (non-tender, rubbery, asymmetrical)
      • In contrast to Hodgkin’s lymphoma, the lymphadenopathy is more likely to be symmetrical, at multiple sites, and spread discontinuously across nodal sites.
    • Extranodal Disease - gastric (dyspepsia, dysphagia, weight loss, abdominal pain), bone marrow (pancytopenia, bone pain), lungs, skin, central nervous system (nerve palsies)
      • Extranodal disease isMORE COMMONin NHL than in Hodgkin’s lymphoma, e.g. gastric MALToma
    • Testicular swelling

Signs

  • Signs of weight loss
  • Lymphadenopathy (typically in the cervical, axillary or inguinal region)
  • Palpable abdominal mass - hepatomegaly, splenomegaly, lymph nodes
  • Testicular mass
  • Fever
  • Skin rashes
    • Mycosis fungoides - looks like a fungal infection but is in fact acutaneous T-cell lymphoma)
  • Abdominal mass
  • Hepatosplenomegaly
  • Signs of bone marrow involvement:
    • Anaemia
    • Infections
    • Purpura
    • Pacytopenia
135
Q

differentiating between non-H and Hodgkin lymphoma

A

While differentiating Hodgkin’s lymphoma from non-Hodgkin’s lymphoma is done by biopsy certain elements of the clinical presentation can help point towards one rather than the other.

  • Lymphadenopathy in Hodgkin’s lymphoma can experience alcohol-induced pain in the node
  • ‘B’ symptoms typically occur earlier in Hodgkin’s lymphoma and later in non-Hodgkin’s lymphoma
  • Extra-nodal disease is much more common in non-Hodgkin’s lymphoma than in Hodgkin’s lymphoma
136
Q

Ix non-H lymphoma

A
  • Bloods
    • FBC
      • Anaemia
      • Neutropaenia
      • Thrombocytopaenia
        • FBC and blood film (patient may have a normocytic anaemia and can help rule out other haematological malignancy such as leukaemia)
    • High ESR and CRP- * ESR (useful as a prognostic indicator)
    • Calcium may be raised
    • HIV, HBV and HCV serology
        • HIV test (often performed as this is a risk factor for non-Hodgkin’s lymphoma)
    • LDH - if high = worse prognosis
    • LDH (a marker of cell turnover, useful as a prognostic indicator)
    • Other investigations can be ordered as the clinical picture indicates (LFT’s if liver metastasis suspected, PET CT or bone marrow biopsy to look for bone involvement, LP if neurological symptoms)
  • Blood Film
    • Lymphoma cells may be visible in some patients
    • the blood film typically reveals nucleated red cells and left shift (the presence of early white blood cell precursors) -
      • particularly in the high grade cancers. This occurs due to marrow involvement and increased marrow turnover. Blood film may also reveal circulating lymphoma cells (i.e. abnormal lymphocytes).
  • Lymph Node Biopsy- allows histopathological evaluation, immunophenotyping and cytogenetics
      • Excisional node biopsy is the diagnostic investigation of choice (certain subtypes will have a classical appearance on biopsy such as Burkitt’s lymphoma having a ‘starry sky’ appearance)
  • Bone Marrow Aspiration and Biopsy
  • Imaging- CXR, CT, PET, * CT chest, abdomen and pelvis (to assess staging)
    • Staging- Ann-Arbor
137
Q

Tx non-H lymphoma

A

depends on subtype

  • R-CHOP-21 (rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisolone given for 21 days) is the most commonly used chemotherapy regimen.
  • Management is dependent on the specific sub-type of non-Hodgkin’s lymphoma and will typically take the form of watchful waiting, chemotherapy or radiotherapy.
  • All patients will receive flu/pneumococcal vaccines
  • Patients with neutropenia may require antibiotic prophylaxis
138
Q

what is burkitts lymphoma, types, associations

A

high-grade B-cell neoplasm. There are two major forms:

  • endemic (African) form: typically involves maxilla or mandible
  • sporadic form: abdominal (e.g. ileo-caecal) tumours are the most common form. More common in patients with HIV

Burkitt’s lymphoma is associated with the c-myc gene translocation, usually t(8:14). The Epstein-Barr virus (EBV) is strongly implicated in the development of the African form of Burkitt’s lymphoma and to a lesser extent the sporadic form.

139
Q

microscopic findings of burkitts lymphoma

A

‘starry sky’ appearance: lymphocyte sheets interspersed with macrophages containing dead apoptotic tumour cells

140
Q

what is methaglobinaemia & features

A

haemoglobin which has beenoxidised from Fe2+ to Fe3+.

There is tissue hypoxia as Fe3+ cannot bind oxygen, and hence the oxidation dissociation curve is moved to the left

  • chocolate’ cyanosis
  • dyspnoea, anxiety, headache
  • severe: acidosis, arrhythmias, seizures, coma
  • normal pO2 but decreased oxygen saturation
141
Q

management of methaglobinaemia

A
  • NADH - methaemoglobinaemia reductase deficiency:ascorbic acid
  • IV methylthioninium chloride (methylene blue) if acquired
142
Q

causes of methaglobinaemia

A
  • haemoglobin chain variants: HbM, HbH
  • NADH methaemoglobin reductase deficiency

Acquired causes

  • drugs: sulphonamides,nitrates (including recreational nitrates e.g. amyl nitrite ‘poppers’),dapsone, sodium nitroprusside, primaquine
  • chemicals: aniline dyes
143
Q

causes of DIC

A
  • Infection- particularlyGRAM-NEGATIVEsepsis
  • Obstetric Complications
    • Missed miscarriage (when the foetus dies but the body doesn’t realise it and the placenta continues to release hormones)
    • Severe pre-eclampsia
    • Placental abruption (separation of the placenta from the wall of the uterus during pregnancy)
    • Amniotic emboli
    • hemolysis, elevated liver function tests, and low platelets (HELLP syndrome)
  • Malignancy
    • Solid tumours or haematological malignancies
    • Acute promyelocytic leukaemia - ACUTE DIC → Acute promyelocytic leukaemia (APL) is an uncommon subtype of acute myelogenous leukaemia that is associated with DIC.
    • Lung, breast and GI malignancy - CHRONIC DIC
  • Severe trauma or surgery
    • Multiple-organ failure
  • Others: haemolytic transfusion reaction, burns, severe liver disease, aortic aneurysms, haemangiomas
144
Q

presentation of DIC

A
  • The patients will tend to be severely unwell with symptoms of the underlying disease
  • fever, confusion, or coma.
  • Evidence of shock (hypotension, tachycardia)
  • Acute DIC
    • Petechiae, purpura, ecchymoses
    • Epistaxis
    • Mucosal bleeding
    • Overt haemorrhage
    • Signs of end organ damage
    • Respiratory distress
    • Oliguria due to renal failure
  • Chronic DIC
    • Signs of deep vein and arterial thrombosis or embolism
    • Superficial venous thrombosis
145
Q

Ix and Dx DIC

A
  • Bloods
    • FBC
      • Low platelets
      • Low Hb
      • High APTT/PT & bleeding time
      • Low fibrinogen
      • High fibrin degradation products
      • High D-dimers
  • Peripheral Blood Film
    • Schistocytes due to microangiopathic haemolytic anaemia

Diagnosis is based on presence of ≥1 known underlying conditions causing DIC plus abnormal global coagulation tests: decreased platelet count, increased prothrombin time, elevated fibrin-related marker (D-dimer/fibrin degradation products), and decreased fibrinogen level.

146
Q

Tx DIC

A

Aggressive treatment of the underlying disorder is indicated

A platelet transfusion should be considered when the platelet count is <20 x 10⁹/L (<20 x 10³/microlitre) or <50 x 10⁹/L (<50 x 10³/microlitre) with active bleeding.

Fresh frozen plasma (FFP) is the preferred agent for replacement of coagulation factors and coagulation inhibitors when significant bleeding is present or when fibrinogen levels are <2.94 micromol/L

147
Q

complications of DIC

A

life-threatening haemorrhage, acute renal failure, and gangrene and loss of digits.

148
Q

What is Thrombotic thrombocytopenic purpura

A
  • abnormally large and sticky multimers of von Willebrand’s factor cause platelets to clump within vessels
  • in TTP there is a deficiency of ADAMTS13(a metalloprotease enzyme) whichbreakdowns (‘cleaves’) large multimers of von Willebrand’s factor
  • overlaps with haemolytic uraemic syndrome (HUS)
149
Q

Presentation & epidemiology of TTP

A
  • rare, typically black adult females

Shares these symptoms w HUS

  • microangiopathic haemolytic anaemia
  • thrombocytopenia
  • renal failure

Also

  • fever
  • fluctuating neuro signs(microemboli)
150
Q

causes of TTP

A
  • post-infection e.g. urinary, gastrointestinal
  • pregnancy
  • drugs: ciclosporin, oral contraceptive pill, penicillin, clopidogrel, aciclovir
  • tumours
  • SLE
  • HIV
151
Q

What is HUS

A

Haemolytic uraemic syndrome is generally seen in young children and produces a triad of:

  • acute kidney injury
  • microangiopathic haemolytic anaemia
  • thrombocytopenia
152
Q

Causes of HUS

A

Most cases are secondary (termed ‘typical HUS’):

  • classically Shiga toxin-producing Escherichia coli (STEC) 0157:H7(‘verotoxigenic’, ‘enterohaemorrhagic’). This is the most common cause in children, accounting for over 90% of cases
  • pneumococcal infection
  • HIV
  • rare: systemic lupus erythematosus, drugs, cancer

Primary HUS (‘atypical’) is due to complement dysregulation.

153
Q

HUS Ix

A
  • full blood count: anaemia, thrombocytopaenia, fragmented blood film
  • U&E: acute kidney injury
  • stool culture
    • looking for evidence of STEC infection
    • PCR for Shiga toxins
154
Q

Management of HUS

A
  • treatment is supportive e.g. Fluids, blood transfusion and dialysis if required
  • there isno role for antibiotics, despite the preceding diarrhoeal illnessin many patients
  • the indications for plasma exchange in HUS are complicated. As a general rule plasma exchange is reserved for severe cases of HUS not associated with diarrhoea
  • eculizumab (a C5 inhibitor monoclonal antibody) has evidence of greater efficiency than plasma exchange alone in the treatment of adult atypical HUS
155
Q

treatment of idiopathic ITP

A

acute - plasma exchange
chronic - aspirin

Year 4 (3 decks)

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