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61

What is the ddx of myelofibrosis?

Leukoertyhroblastosis —> severe infection, inflammation or infiltrated BM BUT no poikilocytosis/weird platelets
BM fibrosis —> metastatic ca, Hodgkin lymphoma, hairy cell leukaemia, need morphology
CML —> but normal RBCs w/ marked leucocytosis
PCV - elevated haematocrit
ET —> platelet elevation dominant

62

What is the treatment of myelofibrosis?

Tx
Mild —> nothing
Anaemia —> transfusion +/- EPO
Splenic enlargement / pain / severe thrombocytopaenia /high transfusion requirement —> splenectomy
Bone pain / Pulm htn —> RTx
Curative:  Allo SCT
Hydroxurea or lenalidomide may help control anaemia
JAK2 inhibitors not on market yet

63

What is the prognosis in myelofibrosis?

Prognosis
Median survival - 5 years
End stage—> liver failure, bleeding from thrombocytopaenia, sometimes AML.

64

Name the microcytic anaemias

Iron deficiency 
Thalassemia
Anemia of chronic disease 
Lead toxicity

65

Name the macrocytic megaloblastic anaemias

Vitamin B12 deficiency 
Folate deficiency
DNA synthesis inhibitors

66

Name the Macrocytic Nonmegaloblastic anaemias

Myelodysplasia
Liver disease Reticulocytosis Hypothyroidism
Bone marrow failure state
(eg, aplastic anemia, marrow infiltrative disorder, etc.)

67

Name the normocytic anaemias

Kidney disease
Mild form of most acquired etiologies of anemia

68

Under what circumstances does reticulocytosis occur?

1.  acute blood loss, 
2.  recent replacement of a missing erythropoietic nutrient
3.  reduced red blood cell survival (ie, hemolysis)

69

What causes a severely microcytic anaemia?

Macrocytic?

A severely microcytic anemia (mean corpuscular volume [MCV <70 fL) is due either to iron deficiency or thalassemia, while a severely macrocytic anemia (MCV >125 fL) is almost always due to either megaloblastic anemia or to cold agglutinins in blood analyzed at room temperature. 

70

How and where is dietary iron absorbed and stored?

Why does free iron not circulate?

- RBCs, ferritin and hemosiderin are major storage pools
- 10% of dietary iron is absorbed
- Absorbed in stomach, duodenum, jejunum under acidic conditions
- 70% of iron is in RBCs
- minor daily losses from sloughing of epithelial cells or insignificant blood losses
- free iron can produce ROS —> tissue damage, promotion of bacteria (who need it for growth

71

Describe the mechanism of iron transport and what affects it.

Iron transport
- across intestinal lumen by ferroportin (it is exported from the basolateral surface of the enterocyte to the circulation)
- ferroportin also facilitates transport of iron in macrophages and then to apotransferrin (transferrin) in RBCs for haemoglobin synthesis
- Hepcidin (produced during iron loading and inflammation) promotes degradation of ferroportin by binding it —> decreased release into circulation, sequestration of iron into macrophages, and decreased circulating iron
- menstrual blood loss plays a major role in iron metabolism
Anaemia of chronic disease —> body iron stores not deficient but not available for RBC production due to hepcidin stimulation
Hepcidin suppression:  Fe deficiency, hypoxia, haemorrhagic or haemolytic anaemias —> release of stored iron and increased dietary absorption
In iron overload —> hepcidin deficiency

72

What is ferritin and what is it's role in assessing anaemia?

Ferritin
 - intracellular storage protein
 - <30 indicates iron deficiency
 - good marker of total body iron stores
 - low ferritin seen almost only in iron deficiency
 - do not reflect iron stores alone, normal-high levels does not exclude
 - elevated in inflammation, infection, malignancy (blood and solid), liver, kidney disease, high BMI, post-menopause
- serum iron is poor measure, is a negative acute phase reactant in acute inflammation
- level testing not currently available

73

What is transferrin and what is it's role in assessing anaemia?

Transferrin
- carrier protein for iron
- carries iron to transferrin receptor which endocytoses complex into cell which then releases iron for use or stores it
- liver synthesis apotransferrin so high levels in Fe+ defiency or high oestrogen states, low levels may be due to liver disease or inflame, it is also a negative acute phase reactant

74

What is the role of the soluble transferrin receptor in assessing anaemia?

Soluble transferrin receptor
- useful if presence of inflammation is obfuscating result (i.e. in inflammation)
- upregulated when iron needs are increased (i.e. deficiency, or PCV)
- not an acute phase reactant
- testing not currently rebateable

75

What is the transferrin saturation?  When is it useful?

Transferrin saturation
- calculated ratio between serum iron and TIBC - hence influenced by anything that affects serum iron
- elevation may be earliest indicator of hereditary haemochromatosis

76

What are the major causes of iron deficiency?

Chronic blood loss (most important)
- Esp GI
- Aspirin/anti-inflams even w/o structural lesion
- menorrhagia or uterine bleeding
- repeated blood donations
- chronic haemoglobinuria (uncommon): traumatic haemolysis (valve), or other intravascular haemolysis i.e. PNH.

Menorrhagia and Pregnancy
- iron deficient unless supplemented, diet alone doesn’t cut it

Decreased absorption
- coeliac disease, surgical stomach resection or jejunal bypass



77

What are the clinical findings of iron deficiency anaemia?

Clinical findings
Anaemia —> fatigue, tachycardia, palpitations, SOBOE
Severe:  skin and mucosal changes, smooth tongue, brittle nails, spooning (koilonychia) and cheilosis (inflamed corners of mouth)
Dysphagia due to oesophageal webs (Plummer-Vinson syndrome) in severe iron deficiency
Pica: often for foods not rich in iron

78

What are the lab findings in iron deficiency anaemia?

Lab findings
Initially iron deficiency w/o anaemia followed by anaemia and normal MCV, then hypo chromic microcytic anaemia
Ferritin <30 (or <15 is v specific but not sensitive)
Ferritin is an acute phase reactant so unreliable in response to inflammation - not ruled out if normal or elevated
Transferrin elevates to compensate leading to transferrin saturations of less than <15% (Serum iron : TIBC) however this ratio will be low in anaemia of inflammation too 
Anisocytosis (size) & poikilocytosis (shape) in more severe disease, followed by severe hypochromia, target cells, or pencil/cigar-shaped cells.

79

What is the differential diagnosis of iron deficiency anaemia?  How do you exclude them?

DDx
Anaemia of chronic disease (normal or increased iron stores in BM macrophages, normal or elevated ferritin, serum iron and transferrin saturation is low, TIBC and transferrin n/low
Thalassaemiea - greater degree of microcytosis for level of anaemia with normal or elevated RBC count (unlike every other cause of anaemia).  Similar smear to severe iron deficiency

80

What is the treatment of iron deficiency anaemia?

Treatment
Identify cause
Ferrous sulcate, go slower and lower for compliance
Should be halfway toward normal within 3 weeks, full return to baseline after 2 months, continue for 3-6 months to replenish iron stores
Failure mostly due to non compliance, sometimes poor absorption due to stomach achlohydria - give ascorbic acid
Other: incorrect dx, ongoing GI blood loss

Parenteral iron
Indications:  Intolerance to oral, refractory to oral, GI disease (usually inflammatory)
New formulation is iron oxide coated in a carbohydrate
Iron deficit = % iron deficit x normal RBC volume
I.e. if the Hb is 75% of normal then it’s 0.25 x 27ml/kg (normal RBC volume) = 337.5 grams
The dose is then iron deficit + 1 gram = 1.4gm

81

A 65-year-old woman, established on haemodialysis for nine months, is maintained on erythropoietin 4,000 units twice a week intravenously. Previously her haemoglobin (Hb) had remained steady in the range of 105 – 115 gm/L. She now presents with a Hb of 89 gm/L on routine testing. There have been no changes to her erythropoietin dose or other medications. 
Her mean corpuscular volume (MCV) is 84 fL [78-98], 
her serum iron is 13 μmol/l [13-35], iron saturation is 18% [15-46], 
serum ferritin is 630 μg/l [20-300] and her reticulocyte count is 30 x 109/L [12-100]. 

Which of the following is the most likely cause for her erythropoietin resistance?

A. Inflammation.

B. Pure red cell aplasia. 

C. Vitamin B12 deficiency.

D. Iron deficiency. 

E. Hyperparathyroidism.

A. Inflammation.

B. Pure red cell aplasia.  – reticulocyte count normal

C. Vitamin B12 deficiency. – not macrocytic

D. Iron deficiency. – not microcytic, ferritin up so can’t say

E. Hyperparathyroidism. – not significant

82

What are the essential features of the anaemia of chronic disease?

Essentials
- mild-mod normocytic or microcytic anaemia
- normal-increased ferritin
- normal-reduced transferrin
- underlying chronic disease

83

What are the mechanisms of the anaemia of chronic disease?

Mechanism
- EPO resistance
- inflammatory cytokines diminishing RBC production
- in the elderly:  decreased EPO production due to reduced nephron mass and low level chronic inflammation.  Normal serum iron
- low serum iron in inflammatory states

84

What are the lab findings in the anaemia of chronic disease?

Lab findings
- HCT rarely below 60% of baseline (except in renal failure)
- normal or mildly reduced MCV
- minimally changed reticulocyte count
- low serum iron
- low serum transferrin
- normal to elevated serum ferreting (if <30, coexistent iron deficiency)
- in organ failure and elderly: normal iron studies
- if ferritin super elevated —> soluble transferrin receptor (high = iron deficiency
- BMBx - absent iron staining, sequestration of iron in marrow macrophages but very rarely done.
- ultimate test:  Hb response to oral iron in setting of inflammation if iron deficiency is suspected.

85

What are the indications for EPO therapy?

EPO indicated in:
 - Hb <10 & anaemia due to RA, IBD, Hep-C, Zidovudine in HIV, myelosuppresive chemo w/ solid malignancy and palliative intent, CKD with GFR <60.
 - Aim for Hb 100-120, risk of VTE and ATE

86

What is the significance of marked erythroid hyperplasia in the bone marrow?

A sign of ineffective erythropoiesis (expansion of the erythroid compartment of the bone marrow that does not result in the adequate production of reticulocytes in the peripheral blood).

87

In a transfusion-dependent patient with idiopathic acquired sideroblastic anaemia, the most appropriate treatment for prevention of transfusional iron overload is: 
 
A. vitamin C. 
 
B. phlebotomy. 
 
C. desferrioxamine. 
 
D. ethylene-diamine tetra-acetic acid (EDTA). 
 
E. pyridoxine. 

C

88

Aside from being an anticoagulant for blood samples, what else is EDTA used for?

Lead poisoning chelation

89

What are the diagnostic essentials for sideroblastic anaemia?

Diagnostic essentials
- ringed sideroblasts in the BM
- elevated serum Fe+ and transferrin saturation

90

What is the mechanism and causes of sideroblastic anaemia?

Mechanism
Reduced ability to synthesise or incorporate heme into protophyrin IX —> accumulation of iron in RBC precursor mitochondria

Causes
- subtype of MDS most commonly
- chronic alcholism
- lead poisoning
- drugs: isoniazid, chloramphenicol
- chronic infection/inflamattion
- inherited: x-linked