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Year 2 MCD 2 > Haematology > Flashcards

Haematology Flashcards

1
Q

Where are all blood cells originated from?

A

Bone marrow

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2
Q

Describe the lineage to progenitor cells

A

Haematfpoetic stem cells gives rise to Common myeloid progenitor and Common lymphoid progenitor.
Common myeloid progenitor gives rise to ‘Megakaryocytic Erythroid progenitor’ and ‘Granulocyte and Macrophage progenitor’ (myeloblast).

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3
Q

What cells are derived from the ‘Megakaryocyte and Erythroid progenitor’ cell?

A
  • Megakaryocyte –> platelets

- Erythroid –> erythrocytes

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4
Q

What cells are derived from the ‘Granulocyte and Macrophage progenitor’ cell?

A
  • Monocyte –> macrophage or dendritic cell

- Granulocyte progenitor –> neutrophil, basophil and eosinophil

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5
Q

What cells are derived from the common lymphoid progenitor cell?

A

T-cells, B-cells and Natural Killer cells

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6
Q

Describe the differentiation pathway to an erythrocyte

A

Haem stem cell –> common myeloid progenitor –> Mega/Eryth progenitor –> pro-erythroblast –> early erythroblast –> late erythroblast –> polychromatic erythrocyte –> erythrocyte

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7
Q

Describe the histological changes of the erythroid cell as it matures

A

With each stage of differentiation, the cell becomes smaller with the cytoplasm turning more pink (from purple) due to change from RNA to Hb.

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8
Q

What hormone is required for erythropoiesis?

A

Erythropoietin

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9
Q

Where is erythropoietin produced?

A

90% by the renal juxtabular interstitial cells

10% are produced by hepatocytes

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10
Q

How long does an erythrocyte survive for?

A

120 days

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11
Q

From where are erythrocytes removed from the circulation?

A

The spleen (phagocytic destruction)

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12
Q

What cytokines (include specific ones) control the process of leukopoiesis?

A

Interleukins such as colony stimulating factors. Specific ones include G-CSF, M-CSF and GM-CSF.
[G stands for granulocyte, M stands for macrophage]

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13
Q

Describe the pathway from a myeloblast to a granulocyte

A

Myeloblast –> promyelocyte –> myelocyte –> band cell –> granulocyte

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14
Q

How long does a neutrophil survive in circulation?

A

7-10h

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15
Q

What cells are platelets derived from?

A

Megakaryocytes

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16
Q

How long to platelets survive in circulation for?

A

10 days

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17
Q

What term is used to describe when RBCs show variation in size (more than normal)?

A

Anisocytosis

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18
Q

What term is used to describe when RBCs show variation in shape (more than normal)

A

Poikilocytosis

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19
Q

What term is used to describe when RBCs are smaller than usual?

A

Microcytosis

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20
Q

What term is used to describe when RBCs are larger than usual?

A

Macrocytosis

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21
Q

What are the types of macrocytes?

A
  • Round macrocytes
  • Oval macrocytes
  • Polychromic macrocytes
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22
Q

Define:

  • Anisocytosis
  • Poikilocytosis
  • Microcytosis
  • Macrocytosis
A

Anisocytosis is when RBCs show variation in size
Poikilocytosis is when RBCs show variation in shape
Micro/macrocytosis is when RBCs are smaller/larger than usual

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23
Q

What are the three broad categories for types of anaemia?

A

Microcytic, macrocytic and normocytic

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24
Q

Define:

  • normochromic
  • hypochromia
  • hyperchromia
  • polychromasia
A

Normochromic: normal staining erythrocytes.
Hypochromic: erythrocytes have a larger area of central pallor than normal
Hyperchromic: eyrthrocytes lack a central pallor
Polychromasia: increase blue tinge to the cytoplasm of eyrthrocyte

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25
Q

What percentage diameter of the erythrocyte is pale?

A

1/3

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26
Q

What causes a RBC to be hypochromic?

A
  • Lower Hb content
  • Hypochromic and microcytosis often go together
  • Thalassaemia major is a disease that shows very hypochromic cells
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27
Q

What causes a RBC to be hyperchromic?

A
  • spherocytes

- irregular contracted cells

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28
Q

What causes cells to be polychromastic?

A

Reticulocytes are polychromastic. Reticulocytes are young erythrocytes.

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29
Q

What are reticulocytes?

A

Reticulocytes are young erythrocytes.

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30
Q

What are the different types of poikilocytes?

A
  • Shperocytes
  • Irregularly contracted cells
  • Eliptocytes
  • Sickle cells
  • Fragments/schistocytes
  • Rouleaux
  • Agglutinates
  • Target cells
  • Howell-Jolly Bodies
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31
Q

How are spherocytes formed?

A

Loss of cell membrane without equivalent loss of cytoplasm.

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32
Q

How are Irregularly contracted cells formed?

A

Oxidant damage to the cell membrane

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33
Q

What causes the formation of eliptocytes?

A
  • hereditary eliptocytosis

- iron deficiency

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34
Q

How are sickle-cells formed?

A

Polymerisation fo haemoglobin S present in high concentrations

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35
Q

How are fragments/schistocytes formed?

A

Small pieces of RBC due to external forces applied to the cell

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36
Q

What causes the formation of rouleaux?

A

Alterations in plasma proteins

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37
Q

What causes the formation of Target cells?

A

Accumulation of Hb in the central concave region. Occurs in obstructive jaundice, liver disease, haemoglobinopathies, and hyposlenism.

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38
Q

What causes the formation of Howell-Jolly body?

A

This is where there is a nuclear remnant in a red cell. The commonest cause is a lack of splenic function

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39
Q

What is meant by the suffixes -penia, -philia and -cytosis

A

Penia: too few
Philia: too many (only for eosinophilia and neutrophilia)
Cytosis: too many

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40
Q

Define left-shift

A

An increase in non-segmented neutrophils or neutrophil precursors in the blood. Indicative of a response to an infection.

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41
Q

Define toxic granulation

A

Heavy granulation of neutrophils as a result of infection, inflammation and tissue necrosis

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42
Q

Define hypersegmented nuclei

A

Increase in average number of neutrophil lobes or segments.

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43
Q

What causes hypersegmented nuclei?

A

Lack of vitamin B12 or folic acid.

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44
Q

What are significant features of a bleeding history?

A
  • Epistaxis that won’t stop by 10 minutes
  • Cutaneous haemorrhage or bruising with no trauma
  • Prolonged bleeding from trivial wounds
  • Spontaneous GI bleeding leading to anaemia
  • Menorrhagia requiring treatment or leading to anaemia
  • Heavy, prolonged bleeding after surgery
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45
Q

Define primary haemostasis

A

Formation of an unstable platelet plug

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46
Q

What are the different types of disorders of primary haemostasis?

A

1) Thrombocytopenia
2) Impaired function of platelets due to absence glycoproteins or storage granules
3) Von Willebrand Disease
4) Vessel wall issues

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47
Q

What can cause thrombocytopenia?

A
  • Bone marrow failure due to leukaemia or B12 deficiency
  • Accelerated clearance of platelets due to Autoimmune Thrombocytopenia (also known as immune thrombocytic purport) or DIC (Disseminated Intravascular Coagulation)
  • Pooling and destruction in an enlarged spleen
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48
Q

What causes impaired function of platelets due to absence of glycoproteins or storage granules?

A
  • Glanzmann’s thromasthenis (low GpIIb/IIIa)
  • Bernard Soulier syndrome (GpIb defect)
  • Storage Pool disease (ADP granules not released)
  • Acquired due to drugs (NSAIDs, clopidogre;)
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49
Q

What are the functions of vWF?

A
  • Binds collagen and captures platelets

- Stabilises FVIII

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50
Q

What are the types of vWF disease?

A

Type 1: not making enough
Type 2: faulty molecule
Type 3: not making any

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51
Q

What vessel wall issues can cause problems with primary haemostasis?

A
  • Inherited: Hereditary Haemorragic Telangiectasia, and Ehlers-Danlos syndrome
  • Acquired: scurvy, steroid therapy, ageing, vasculitis
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52
Q

What is the name of the condition characterised by abnormal bleeding due to age-related vessel wall dysfunction?

A

Senile Purpura

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53
Q

Describe the typical pattern of bleeding for disorders of primary haemostasis

A
  • Immediate
  • Prolonged
  • Epistaxes
  • Gum bleeding
  • Menorrhagia
  • Easy bruising
  • Petechiae (small red/purple spots) and purpura (rash of purple spots)
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54
Q

Define secondary haemostasis

A

The stabilisation of the platelet plug with fibrin

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55
Q

What are the general types of disorders of secondary haemostasis?

A

1) Deficiency of coagulation factors

2) Increased consumption of factors

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56
Q

What are the hereditary causes of coagulation factor deficiencies?

A
  • Haemophilia A (FVIII) and B (FIX)
  • Prothrombin deficiency is lethal and not compatible with life
  • Factor XI and XII deficiencies are not that bad as the intrinsic pathway isn’t that important
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57
Q

What are the acquired causes of coagulation factor deficiencies?

A
  • Liver disease (as most factors synthesised in liver)
  • Dilution (transfusions no longer contain plasma and this clotting factors)
  • Anticoagulation drugs like Warfarin
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58
Q

Describe the condition that causes increased consumption of coagulation factors

A

DIC (Disseminated Intravascular Coagulation) is an acquired condition where there is generalised activation of coagulation due to over-expression of tissue factor CAUSED by cancer or sepsis.

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59
Q

Describe the typical pattern of bleeding for disorders of secondary haemostasis

A
  • Superficial cuts do not bleed (due to functioning platelet plug)
  • Bruising is common
  • Epistaxis is rare
  • Spontaneous bleeding into muscles and joints (haemarthrosis is a hallmark of haemophilia)
  • Bleeding after trauma is delayed but not prolonged
  • Frequently restart bleeding after stopping
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60
Q

What bleeding pattern can be used to differentiate disorders of primary and secondary haemostasis?

A
  • Superficial cuts do not bleed in secondary (due to functioning platelet plug), but do bleed in primary
  • Hemarthrosis is a hallmark of haemophilia
  • Bleeding after trauma is delayed not prolonged in secondary; but prolonged not delayed in primary
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61
Q

What clotting tests can be done in investigating abnormal bleeding, and what are they testing

A
  • Activated Partial Thromboplastin Time (APTT) initiates coagulation through intrinsic and common pathway
  • Prothrombin Time (PT) initiates coagulation through extrinsic and common pathways
  • Thrombin clotting time (TCT) shows abnormalities in fibrinogen –> fibrin conversion
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62
Q

What tests can be done to investigate disorders of primary haemostasis?

A
  • Platelet count
  • asseys vWF
  • bleeding time
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63
Q

What tests can be done to investigate disorders of secondary haemostasis?

A
  • screening tests such as PT, APTT, full blood count
  • Factor assays
  • Tests for inhibitors
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64
Q

What bleeding disorders are not detected by routine clotting tests?

A
  • mild factor deficiency may still present with normal APTT
  • vonWillebrand disease (unless FVIII is also low)
  • FXIII deficiency
  • Platelet disorders
  • Excess fibrinolysis
  • Vessel wall disorders
  • Metabolic disorders
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65
Q

Describe the genetic nature of haemophillia

A
  • Sex linked (X chromosome) so affects males

- Severity in females varies with X-inactivation

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66
Q

How is autoimmune thrombocytopenia treated?

A

Steroids or Splenectomy

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67
Q

How can coagulation factors be replaced?

A
  • Plasma transfusion for ALL coat factors and anticoags
  • Cryoprecipitate for deficiencies of fibrinogen, vWF, FXIII (fibrin stabilising factor)
  • Factor concentrates for specific deficiencies
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68
Q

What factor (mild) deficiencies can desmopressin be used to treat?

A
  • vWF and Factor VIII
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69
Q

Outline the process of haemostasis

A
  1. Vessel constriction
  2. Formation of an unstable platelet plug (platelet adhesion and aggregation)
  3. Stabilisation of the platelet plug with fibrin (blood coagulation)
  4. Dissolution of the clot and vessel repair (fibrinolysis)
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70
Q

With regards to haemostasis, what is the function of the endothelium?

A
  • Maintain a barrier between the lumen and the subendothelial structures (which would cause coagulation)
  • Synthesise PGIs, thrombomodulin, vWF and plasminogen factors
  • provide a non-adhesive surface for platelets
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71
Q

How many nuclei does a megakaryocyte have?

A

16

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72
Q

How many platelets does each megakaryocytic produce?

A

4000 platelets

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73
Q

What is the half-life of a platelet?

A

10 days

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74
Q

Describe the features of the platelet ultrastructure

A
  • No nucleus
  • Open canalicular systems (to increase surface area)
  • Dense granules (store ADP vital for haemostasis)
  • Alpha granules (storage granules for proteins)
  • Surface glycoproteins and receptors on phospholipid membrane
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75
Q

List the important receptors on platelets

A
  • Protease activated receptor (for thrombin)
  • P2Y(12) receptors (allows ADP to bind)
  • GpIIb/IIIa receptors (for vWF and fibrinogen)
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76
Q

What molecules can activate platelets?

A
  • Collagen (can be directly, or through vWF)
  • Thrombin
  • ADP
  • Thromboxane A2
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77
Q

How does vWF facilitate platelet adhesion to the vessel wall?

A 
Exposed collagen (on damaged endothelium) binds to circulating vWF.
Rheological shear forces unwinds vWF exposing the Gp1b
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78
Q

What is the functions of Thrombin?

A
  • Convert fibrinogen to fibrin
  • Activate platelets
  • Activate FVIII
  • Positive feedback for itself through FVa
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79
Q

Explain the process of platelet activation

A

Activation of receptor –> Increase in Ca2+ concentration. This causes exocytosis of ADP from the dense granules. This activates P2Y(12) receptor on the planets leading to expression of GPIIb/IIIa receptor and generation of thromboxane A2. The activated platelet spreads and flattens.

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80
Q

How do platelets aggregate?

A

Activated platelets express GpIIb/IIIa which bind to fibrinogen. Platelets can find to the same fibrinogen, forming a clot.

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81
Q

Describe the synthesis of Prostaglandin H2

A

Phospholipase converts membrane phospholipids to Arachidonic Acid, which then is converted to PGH2 by COX1/COX2 enzymes

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82
Q

What do the COX enzymes produce?

A

Converts AA –> PGH2

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83
Q

What important molecules are derived from PGH2 (and how?)

A
  • Prostacyclin (PGI2) by prostacyclin synthase in ENDOTHELIAL CELLS
  • Thromboxane A2 by thromboxane syntheses in platelets
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84
Q

What prostaglandins balance platelet activation and inhibition?

A
  • Prostacyclin (PGI2) is a potent inhibitor of platelet function
  • Thromboxane A2 (as well as PGH2 and PGG2) are potent inducers of platelet aggregation.
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85
Q

What are the potential targets for anti platelet drugs?

A
  • ADP receptor (P2Y) antagonists
  • COX-1 antagonist
  • GPIIb/IIIa antagonist
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86
Q

What type of anti-platelet drugs are:

  • Clopridogrel
  • Abciximab
  • Aspirin
A
  • ADP receptor (P2Y) antagonists
  • GPIIb/IIIa antagonist
  • COX-1 antagonist
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87
Q

What tests can we perform for platelets?

A
  1. Platelet count
  2. Bleeding time
  3. Platelet aggregation test
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88
Q

Where are the clotting factors synthesised?

A
  • Liver (most coagulation proteins)
  • Endothelial cells produce vWF
  • Megakaryocytes (factor V stored in alpha granules, and vWF)
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89
Q

Describe the extrinsic (and common) pathway of blood coagulation

A

TF + FVII –> TF-FVIIa. This activates FXa and FIXa.
FXa produces converts a small amount ProT to Thrombin. This then activates FVIIIa and FVa..

FVIIIa + FIXa produces more FXa.

FXa + FVa converts more of ProT to Thrombin.

Thrombin can now convert Fibrinogen to Fibrin.

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90
Q

What is the role of Vitamin K in blood coagulation?

A

It carboxylises the glutamate residues in factors II, VII, IX, X. This allows them to bind to platelet phospholipids.

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91
Q

How is plasmin activated?

A

Plasminogen is converted to Plasmin by plasmin activating factors such as tissue plasminogen activator (tPA)

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92
Q

How does plasmin dissolve a clot?

A

By digesting fibrin

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93
Q

What coagulation factors does antithrombin deactivate?

A
  • Thrombin
  • FXIIa and FXIa
  • FIXa
  • FXa
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94
Q

How does Protein C deactivate the coagulation cascade?

A

Thrombomoduilin on endothelial cells binds to thrombin which then binds to Protein C.

Activated protein C, along with protein S breaks down FVa and FVIIIa

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95
Q

What is the pathophysiology of Factor Va leiden?

A

Factor Va is not easily inactivated by Protein C leading to increased risk of thrombosis.

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96
Q

How does Warfarin work?

A

It is a vitamin K antagonist - preventing glutamate carboxylation of Factors II, VII, IX and X.

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97
Q

How does Heparin work?

A

It accelerates action of antithrombin, thus accelerating the inhibition of FXIa, IXa and Xa.

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98
Q

What is the difference between LMW and HMW Heparin?

A
  • High Molecular Weight is a charged polysaccharide which binds to antithrombin, accelerating FXa break down as well as binding to Thrombin (FIIa) to deactivate it
  • Low Molecular Weight only deactivates FXa
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99
Q

What is a reference range?

A

95% ranges of the data provided by the population.

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100
Q

Why may a health-related range be more meaningful than a 95% range?

A

Data from the 95% range includes data from patients with a subsequent high risk of developing disease. For example, the upper 20% of cholesterol concentration range have a risk if developing coronary artery disease.

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101
Q

Why aren’t all results outside the normal range necessarily abnormal, and not all inside the range normal?

A
  • Individual differences between people mean that someone’s normal may fall outside the reference range
  • Someone may have a reduced cell count that is significantly abnormal for them (previously with higher cell count), but may still fall within the reference range.
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102
Q

Define anaemia

A

Anaemia is the reduction the amount of haemoglobin in a given volume of blood

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103
Q

What does the PCV show?

A

The proportion of a column of centrifuged blood occupied by red cells. (Same as Hct)

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104
Q

What are the mechanisms (not causes) of anaemia?

A
  • Reduced production of RBC/Hb in bone marrow
  • Loss of blood from body
  • Reduced survival of RBC in circulation
  • Pooling of RBC in an enlarged spleen
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105
Q

What are the causes of reduced haemoglobin production?

A
  • haem: iron deficiency, anaemia of chronic disease, lead poisoning, sideroblastic anaemia
  • globin: Alpha and Beta thalassaemia
106
Q

What are the mechanisms and thus causes of microcytic anaemia?

A

Due to reduced haemoglobin synthesis:

  • haem: iron deficiency, anaemia of chronic disease, lead poisoning, sideroblastic anaemia
  • globin: Alpha and Beta thalassaemia
107
Q

What are the mechanisms and thus causes of normocytic anaemia?

A
  • Recent blood loss due to: bleeding peptic ulcers or oesophageal varices, trauma
  • Failure of production of red blood cells: early stages of iron deficiency or ACD, renal or bone marrow failure, bone marrow infiltration, aplastic anaemia
  • Pooling of red cells in spleen: hypersplenism
108
Q

What are the mechanisms behind macrocyte formation?

A
  • Megaloblastic erythropoiesis is where there is abnormal haemopoiesis causing a delay in the maturation of the nucleus while cytoplasm continues to mature and the cell continues to grow.
  • Premature release of cells from the bone marrow (release of reticulocytes)
109
Q

What are the common causes of macrocytic anaemia?

A
  • lack of vitamin B12 or folic acid
  • drugs that interfere with DNA synthesis
  • Liver disease and ethanol toxicity
  • Recent major blood loss (causing release of reticulocytes)
  • Haemolytic anaemia
110
Q

Defined haemolytic anaemia

A

Anaemia resulting from shortened survival of red cells in the circulation.

111
Q

Describe the categories of haemolytic anaemia based on where the RBCs are damaged/removed

A
  • Intravascular haemolysis occurs if there is very acute damage to the red cell
  • Extravascular haemolysis occurs due to defective red cells being removed by the spleen
112
Q

What are the signs of intravascular haemolysis compared to extravascular haemolysis?

A
  • Intravascular haemolysis is evident as haemoglobin and later haemosiderine is seen in the urine (brown urine). Also haemoglobin in plasma binds to haptoglobin and the complex is cleared by the liver (low serum haptoglobin)
  • Extravascular haemolysis leads to increased serum bilirubin, LDH as well as foecul and urinary bile pigments
113
Q

What are the causes of Inhertied haemolytic anaemia?

A
  • Hereditary spherocytosis
  • Sickle-cell anaemia
  • Pyruvate kinase deficiency
  • Glucose-6-phosphatase dehydrogenase deficiency
114
Q

What is the pathophysiology of hereditary spherocytosis?

A

Results from an inherited defect of the red cell membrane causing them to lose membrane in the spleen (without accompanied loss in cytoplasm) to become spherocytes.

Also RBC are removed prematurely in the spleen (extravascular heamolysis). Bone marrow responds by increasing output of red cells prematurely leading to polychromasia and reticulocytosis.

Haemolysis also leads to jaundice and pigment gallstones.

115
Q

What is the pathophysiology glucose-6-phosphate dehydrogenase deficiency, and how does it cause haemolytic anaemia?

A
  • Glucose-6-phosphate dehydrogenase is an important enzyme involved in the pentose pathway shunt. This protects the RBC from oxidant damage.
  • Infection or exposure to exogenous oxidants causes severe intervascular haemolysis producing irregularly contracted cells.
  • Haemoglobin is denatured and forms round inclusions known as Heinz bodies, which are removed by the speen.
116
Q

What are the causes of acquired haemolytic anaemia?

A
  • Autoimmune haemolytic anaemia
  • Microangiopathic haemolytic anaemias (include DIC, TTP HUS)
  • Drugs and chemicals damaging red cell membrane
  • Malaria
117
Q

What is the pathophysiology of Autoimmune haemolytic anaemia?

A
  • Antibodies or immune damage to erythrocyte membrane.
  • Macrophages remove part of the membrane leading to the formation of spherocytes
  • Spherocytes are removed in the spleen
118
Q

How is autoimmune haemolytic anaemia diagnosed?

A

Detecting spherocytes, reticulocytosis and immunoglobulin on RBC surface done by antibody test/ Coombs’ test.

119
Q

How is autoimmune haemolytic anaemia treated?

A

Splenectomy

Immunosuppressants

120
Q

What is the pathophysiology of micoangiopathic hameolytic anaemia?

A

Fibrin is deposited and damaged in endothelial cells in small vessels this traps red cells and tears them apart

121
Q

When should haemolytic anaemia be suspected?

A
  • otherwise unexplained anaemia that is normochronic and normocytic/macrocytic
  • evidence of spherocytes, eliptocytes and fragments
  • evidence of increased RBC breakdown (increased uncojugated serum bilirubin and LDH as liver cannot deal with quantity)
  • evidence of increased bone marrow activity
122
Q

Define polycytaemia

A

Refers specifically to many red cells in the circulation.

123
Q

What is pseudopolychythaemia?

A

Decrease in plasma volume distorting Hb, RBC, PCV/Hb figures.

124
Q

What are the types of polycythaemia?

A
  • Physiological - new born baby
  • Too much blood - blooding doping in athletes
  • Appropriate erythropoietin secretion - residence in high attitude places, hypoxia due to cyanotic heart disease or chronic lung disease
  • Inappropriate erythropoietin - erythropoietin abuse by athletes, erythropoietin secreted by renal cysts or tumours
  • Bone marrow disease such as a chronic myeloproliferative disorder
125
Q

What is the problem with polycythaemia, and how is it treated?

A

Polycythaemia leads to hyperviscous blood –> vascular obstruction

treated by blood letting and treating specific causes.

126
Q

What proteins have iron as an essential component?

A
  • ribonucleotide reductase
  • cyclo-oxygenase
  • succinate dehydrogenase
  • cytochrome a,b, and c
  • cytochrome P450
  • catalase
  • myoglobin
  • haemoglobin
127
Q

Describe a haemoglobin molecule

A

A haem group sits in a pocket formed by a globin chain. There are four globins in a haemoglobin molecule, and therefore also four heam groups. A ham porphyrin can hold one iron ion.

128
Q

In what state can iron be held by a heam porphyrin group?

A

Ferrous (Fe2+)

129
Q

How much iron is needed a day to make RBCs?

A

20mg/day

130
Q

How much iron is needed to be consumed a day?

A

1mg/day for men

2mg/day for women

131
Q

How is most iron lost from the body?

A
  • desquamated cells of the skin and gut

- bleeding

132
Q

What components of the diet contains iron?

A

Vegetables, whole grains, chocolate, meat and fish.

133
Q

What forms does the iron from the diet come in? What is the relevance of this?

A
  • meat and fish provides haem iron (already in haem group)
  • ferrous iron (Fe2+)
  • most come as ferric iron (Fe3+)

Only haem and ferrous iron are absorbed NOT ferric.

134
Q

How does orange juice and tea affect iron absorption?

A
  • Orange juice reduces the ferric ions to ferrous, allowing more consumed iron to be absorbed
  • Tea does the opposite.
135
Q

What factors increase iron absorption from the diet?

A
  • acid pH such as orange juice
  • ascorbic acid
  • digestive enzymes
  • diet composition (ferrous rather than ferric)
  • iron deficiency, anaemic/hypoxic or pregnancy can also increase absorption.
136
Q

What is the total amount of iron in an adult?

A

3-5g

137
Q

What are the amounts of iron each iron pool contains?

A
  • Metabolic pool in haemoglobin (2500mg) and myoglobin (500mg)
  • Storage pool in ferritin and haemosiderin (upto 1000mg)
  • Transit pool (transferrin-bound) (upto 3mg)
138
Q

What is Hephaestin?

A

A transmembrane peroxidase converting cytosolic Fe2+ into Fe3+ to bind to transferrin

139
Q

How is iron transported in the blood?

A

Transferrin can bind to Fe3+ iron, and moves iron in the blood.

140
Q

What is measured by the Total Iron Binding Capacity?

A

How saturated transferrin is with iron.

141
Q

How does the iron absorbed by the enterocyte leave into the blood?

A

It must exit through a protein called feroportin. Then must be converted to ferric ion to be transported by transferrin.

142
Q

What is Hepcidin?

A

A protein transcribed by a iron sensitive gene which blocks ferroportin. When iron levels are high, more hepcidin is made, and less iron is output from the enterocyte.

143
Q

How is iron stored in the enterocyte?

A

In ferritin molecules (essentially a bin) storing 4000 ferric ions.

144
Q

What is Anaemia of Chronic Disease?

A

Anaemia associated with chronic inflammation, infections or neoplastic conditions with no bleeding, infiltration of bone marrow nor iron/B12/folate deficiency.

145
Q

What types of anaemia can be caused by anaemia of chronic disease?

A
  • normocytic

- microcytic hypochromic anaemia

146
Q

What are the laboratory signs of being ill (in the context of ACD)?

A
  • Raised ESR
  • Raised C-reactive Protein
  • Acute phase (increase in ferritin, FVIII, fibrinogen and immunoglobulins)
147
Q

What conditions are associated with ACD?

A
  • Chronic infections (TB/HIV etc)
  • Chronic inflammation (RhA, SLE)
  • Malignancy
  • Miscellaneous (e.g cardiac failure)
148
Q

What are the signs of ACD?

A
  • Tiredness
  • Pallor
  • Breathlessness on exercise
  • Tachycardia
149
Q

What is the pathophysiology of ACD?

A

Cytokines such as TNF-a and interleukins blocking IRON UTILISATION:

  • Stops erythropoietin increasing
  • Stop iron flowing out of cells
  • Increase production of ferritin
  • Shorter life span of RBC and reduction in Hb levels
150
Q

What are the causes of iron deficiency?

A
  • Bleeding
  • Increased use (e.g growth or pregnancy)
  • Dietary deficiency
  • Malabsorption (e.g coeliac disease)
151
Q

What are the signs of iron deficiency?

A

Clinical features include:

  • pallor
  • fatigue
  • light-headedness
  • weakness
152
Q

When is an endoscopy done when a patient is iron deficient?

A

If the patient is above 40 years or post-menopausal

153
Q

What laboratory parameters indicate iron deficiency?

A
  1. Low MCV (also for thalassaemia and ACD)
  2. Serum iron low (ACD also causes this)
  3. Ferritin is low in iron deficiency (high in ACD)
  4. Transferrin is high in iron deficiency (low in ACD)
  5. Transferrin saturation is low in iron deficiency
154
Q

What lab parameters differentiate ACD from iron deficiency?

A
  1. Ferritin is low in iron deficiency, but high in ACD (however if iron deficient AND ACD this can be normal)
  2. Transferrin is high in iron deficiency, but low in ACD
155
Q

What’s Rhea’s favourite laboratory parameter?

A

Rhea

156
Q

What is the difference between malignant and normal haematopoiesis?

A

Normal is shown by polyclonal, healthy and reactive cells seen from the normal and reactive bone marrow.

Malignant haematopoiesis is shown by abnormal and clonal cells, caused by leukaemia (lymphoid or myeloid), myelodisplasia, or myeloproliferative disorders.

157
Q

How does IL-2 influence haematopoiesis?

A

Drives the Haematopoietic stem cell to go down the lymphoid differentiation pathway

158
Q

How can leukocytosis due to malignant (primary) or reactive (secondary) causes be differentiated through looking at a blood film?

A
  • Reactive will produce more MATURE leukocytes

- Malignant will produce more mature and IMMATURE blood cells

159
Q

Why are the number of neutrophils counted in the FBC not indicative of the total number of neutrophils in the body?

A
  • They normally reside in the bone marrow and tissues as well as the blood
  • 50% are marginated (attached to the epithelial cells of blood vessels)
160
Q

How quickly can neutrophilia develop?

A
  • minutes when due to demarginalisation
  • hours due to early release from bone marrow
  • days if due to increased production
161
Q

What are the primary and secondary causes of neutrophilia?

A

Primary:
- Malignant neutrophilia due to myeloproliferative disorders and CML

Secondary:

  • Infection (mainly bacterial)
  • Tissue inflammation and necrosis
  • Physiological stress (adrenaline causes demarginalisation)
  • neoplasia may produce cytokines
162
Q

What are the primary and secondary causes of eosinophilia?

A

Primary:
- Malignant Chronic Eosinophilic Leukaemia

Secondary:

  • Parasitic infection such as schistomiasis
  • Allergic disease such as eczema, RA, pulmonary eosinophilia
  • Neoplasms (reactive to Hodgkin’s or non-Hodgkin’s T-cell Lymphoma releasing IL-5
  • Hypereosinophilic syndrome
163
Q

What can cause monocytosis?

A

Certain chronic bacterial infections that don’t produce a neutrophil response (such as tuberculosis, brucellosis and typhoid).

Viral causes include CMV and Varicella Zoster

Can also be seen in sarcoidosis and Chronic Myelomonocytic Leukaemia

164
Q

What chronic bacterial infections don’t produce a neutrophil response?

A

tuberculosis, brucellosis and typhoid

165
Q

What can mature lymphocytosis point to?

A
  • Chronic lymphocytic leukaemia
  • Reaction to infection
  • Autoimmune/inflammatory disease
  • Sarcoidosis or neoplasia
166
Q

What can immature lymphocytosis point to?

A

Acute lymphoblastic leukaemia’s

167
Q

How can lymphocytosis be investigated?

A
  • Morphology: for example smear cells may be seen with any condition with high lymphocyte count
  • Immunophenotyping by light chain restriction. This can distinguish between a monoclonal (either kappa or lambda) or polyclonal (mixture) response
  • Gene rearrangement: monoclonal response will have daughter cells with identical configuration.
168
Q

How much is a blood donor allowed to donate?

A

1 pint every 4 months

169
Q

What is the shelf-life of blood?

A

5 weeks

170
Q

What is the difference between A,B, and O antigens?

A

A has N-acteyl galactosamine to the common glycoprotein and frutose stem
B adds galactose to the stem
O is just the fructose stem

171
Q

What are the inheritence patterns of the ABO blood group?

A

A and B are co-dominant

O is recessive

172
Q

What antibodies are present in ABO blood group plasma?

A

A has anti-B
B has anti-A
O has anti-A and anti-B
AB has no antibodies

173
Q

What are the most common blood groups?

A

O (47%), followed by A (42%), followed by B followed by AB

174
Q

After ABO, which blood group is the most important?

A

Rh (with RhD being the most important antigen)

175
Q

Describe the distribution of RhD in the population

A

85% of people are RhD+

15% of people are RhD-

176
Q

Why is the Rh blood group less important than the ABO blood group?

A

RhD- patients don’t have pre-made antibodies and will only make RhD antibodies after exposure to antigen.
ABO patients have pre-made anti-A/B antibodies

Also anti-RhD antibodies are IgG and don’t activate complement well (unlike IgM for ABO)

177
Q

Why shouldn’t we give RhD+ blood to RhD- patients?

A
  • They may have been sensitised –> haemolytic transfusion reaction –> anaemia/high plasma Hb can lead to kidney failure
  • If RhD- mother with antibodies is pregnant with a RhD+ foetus –> Haemolytic Disease of the Newborn –> death
178
Q

Why is it important to check the patient’s antibodies before a transfusion (even if blood type is known)?

A

They might have had a previous exposure to other blood antigens. 8% of patients transfused have antibodies for Kell, Duffy, Kidd antigens (other side-men blood groups).

179
Q

How much blood is in 1 unit of blood?

A

1 pint

180
Q

In what ‘package’ are RBCs transfused to patients?

A

As packed cells (plasma removed)

181
Q

At what temperature can RBCs be stored?

A

4 degrees C

182
Q

Why are only rare blood groups RBCs frozen to extend shelf-life?

A

There is poor recovery on thawing - losing 1/4 of cells.

183
Q

How much plasma is in 1 unit?

A

300ml

184
Q

How long can plasma be stored for? And at what temperature?

A

Stored at -30 degrees C with a shelf life of 2 years

185
Q

What precautions must be taken while storing/thawing plasma with regards to the coagulation factors?

A

Frozen within 6h to preserve coagulation factors

Administer ASAP after thawing or coagulation factors degenerate.

186
Q

What is the standard dose of Fresh Frozen Plasma?

A

12-15ml per Kg. A patient usually requires 3 units

187
Q

Why must blood groups also been known when transfusing plasma?

A

Because plasma may (if not AB) contain anti-A/B antibodies.

188
Q

What are the indications for Fresh Frozen Plasma?

A
  • if bleeding actively and have abnormal coagulation test results
  • Reversal for warfarin (e.g for urgent surgery)
189
Q

What does cryoprecipitate contain? (and how is it formed?)

A
  • contains FVIII and Fibrinogen and vWF

- Separated from FFP thawed overnight - it is the 3% that failed to redissolve

190
Q

How many donors are needed for a standard dose of cryoprecipitate?

A

10

191
Q

When is cryoprecipitate indicated?

A
  • massive bleeding with low fibrinogen

- hypofibrinogenaemia

192
Q

How many donors are needed for 1 pool of platelets

A

4 donors

193
Q

How are platelets stored, and for how long?

A

22 degrees C for 5 days

194
Q

Why do we need to know blood groups for platelet transfusions?

A

Platelets have low levels of ABO antigens

They can cause RhD sensitisation due to red cell contamination.

195
Q

What are the indications for platelet use?

A
  • Prophylaxis due to thrombocytopenia
  • Bone marrow failure
  • Massive bleeding
  • If very low platelets and needs surgery
  • If for cardiac bypass and patient on anti-platelet drugs
196
Q

What are the fractionated products taken from blood and why?

A
  • Factor VIII and IX for haemophilia A and B respectively as well as VIII for vWD
  • Immunoglobulins for administrations against specific antigens such as rabies and tetanus
  • Albumin - used in severe liver and kidney conditions
197
Q

What infections are blood designated for transfusion tested for?

A

HIV, Hep C and B, Syphillis, HTLV, CMV

198
Q

What are haematinics?

A

Molecules required for normal erythropoiesis such as Iron, Vitamin B12 and Folate

199
Q

Why are eyrthrocytes particularly sensitive to B12 and folate deficiency?

A

Vitamin B12 and folate are essential for DNA synthesis. RBCs are particularly sensitive due to their high turnover rate - requiring those molecules all the time

200
Q

What are the other uses of Vitamin B12 and Folate (apart from DNA synthesis)?

A

Vitamin B12 is important in the integrity of the nervous system
Folate in important in homocysteine METABOLISM

201
Q

How exactly is vitamin B12 and folate used in DNA synthesis?

A

It is used in the formation of dTMP (deoxythymidine) from dUMP (deoxyuridine mono phosphate).

Vitamin B12 acts as a cofactor for methione sythetase, which converts homocystein to methionine, producing methyl groups needed to methylate dUMP to dTMP

202
Q

What are the clinical features of Vitamin B12 deficiency?

A
  • Anaemia: weak, tired, short of breath
  • Jaundice due to do erythrocyte breakdown
  • Glossitis and angular cheilosis
  • Weight loss and change in bowel habbits
  • Sterility (affects turnover in spermatogenesis)
203
Q

What type of anaemia is a result of Vitamin B12 deficiency?

A

Macrocytic Megaloblastic Anaemia

204
Q

What MCV value indicates macrocytes?

A

Greater than 100 fl

205
Q

What are the causes of Macrocytic Megaloblastic anaemia?

A
  • Vitamin B12/folate deficiency resulting in oval macrophages
  • Liver disease or alcohol toxicity resulting in round macrocytes
  • Hypothyroidism
  • Haematological disorders
  • Drugs that interfere with DNA synthesis
206
Q

Describe erythrocyte maturation that results in megaloblastic macrocytes

A

In megaloblastic anaemia there is asynchronous maturation of the nucleus and cytoplasm in the erythroid series.
The level of nuclear chromatin is immature for the degree of haemoglobinisation of the cytoplasm.

207
Q

What haematological abnormalities results from a delay in DNA synthesis?

A
  • Increased size of red cell precursors
  • Delay in nuclear maturation
  • Increased bone marrow activity due to dysplastic haematopoiesis
  • Phagocytosis of dysplastic red cell precursors
  • Giant metamyelocytes and hypersegmented neutrophils
208
Q

Where is folate usually found naturally?

A

In leafy vegetables (although destroyed by cooking)

209
Q

What situations in life require extra folate?

A
  • Pregnancy and lactation
  • Adolescence
  • Premature babies
  • Malignancy
  • Eyrthroderma
  • Haemolytic anaemia
210
Q

Where is folate absorbed?

A

Duodenum and jejunum

211
Q

What are the consequences of folate deficiency?

A
  • Megaloblastic anaemia
  • Neural tube defects
  • Increased risk of venous thromboemboli
  • High homocysteine levels
212
Q

Why are high homocysteine levels dangerous?

A

Mildly light can cause CVD and aterial and venous thrombosis

Very high levels are associated with atherosclerosis and premature vascular disease

213
Q

How is Vitamin B12 absorbed?

A

Absorbed in the small intestine by two methods:

  • slowly and inefficiently in duodenum (1%)
  • combined with intrinsic factor in stomach. B12-IF binds to ileal cells
214
Q

What are the causes of Vitamin B12 deficiency?

A
  • Diet (rare unless vegan or people with abnormal flora or tapeworms)
  • Autoimmune (Pernicious anaemia is the lack of Intrinsic Factor)
  • Surgery such as gastrectomy, gastric bypass
  • Inflammatory conditions such as Chron’s disease
215
Q

What are the signs of a Vitamin B12 deficiency?

A
  • Paraesthesia
  • Muscle weakness
  • Difficulty walking
  • Visual impairment
  • Psychiatric disturbance
  • Absent reflexes
216
Q

What are the consequences of B12 deficiency

A
  • Macrocytic megaloblastic anaemia

- Neurological problems due to demyelination

217
Q

How can a B12 deficiency be diagnosed?

A
  • FBC and film
  • Assay for anti-IF antibodies
  • Plasma homocysteine levels
  • Schilling test
218
Q

What is the DNA/Amino Acid difference between normal and sickle cell haemoglobin?

A

A point mutation at codon 6 of the beta globin gene. Normal glutamic acid (polar, soluble) is replaced by Valine (non-polar, insoluble).

219
Q

What gives sickle-cell its shape?

A

Deoxyhaemoglobin S is insoluble allowing it to polymerise forming fibres called tactoids, which distorts and sickles the cell

220
Q

What is the order of red cell changes that are seen in sickle cell?

A
  1. Distortion of the biconcave shape into crescent shaped cells. Polymerisation of deoxyglobin S is initially reversible when HbS becomes oxygenated. This becomes irreversible over time
  2. Dehydration due to loss of water as a consequence of membrane damage
  3. Increased aherance to vascular endothelium
221
Q

What is the difference between Sickle Cell Anaemia and Sickle Cell Disease?

A
  • Sickle Cell Anaemia refers to people with two BetaS genes (no normal Beta gene)
  • Sickle Cell Disease covers all conditions that lead to formation of sickle cells
222
Q

What phenotypes can be formed with combinations of BetaS (sickle beta globulin)

A
  • Sickle cell: BetaS BetaS
  • Sicke cell/haemoglobin C disease: BetaS BetaC
  • Sickle trait: BetaS BetaA
    (- Normal: BetaA BetaA)
223
Q

How is normal adult Hb noted?

A

HbA

224
Q

Why isn’t HbF (Foetal Hb) affected by fault sickle beta globulin (BetaS)?

A

HbF doesn’t have a beta globulin

225
Q

What are the four main features of Sickle Cell Anaemia?

A
  1. Anaemia
  2. Gall Stones
  3. Vaso-occlusion
  4. Aplastic Crisis
226
Q

Why do Sickle Cell Anaemia patients experience anaemia?

A
  • shortened red cell lifespan

- reduced erythropoietic drive as HbS is a low affinity haemoglobin

227
Q

Why do Sickle Cell Anaemia patients experience gall stones?

A
  • increased bilirubin concentration as a result of increased haemolysis
  • by 25 years, gallstones are prevalent in 50% of patients
  • co-inheritence of Gilbert’s syndrome further increases risk
228
Q

Why do Sickle Cell Anaemia patients experience aplastic crises?

A

Due to reticulocytopenia (RBC production stopped for a few days)
- may be a result of Parvovirus B19 infection which destroys RBC precursors for up to a week
Normally this has little impact on Hb levels, but in conditions with shortened red cell life spans, it can cause Hb to crash

229
Q

Why do Sickle Cell Anaemia patients experience vaso-occlusions?

A

Sickle cells are rigid which can slow and stop the flow of blood through microvasculature

230
Q

What are the sequelae of vaso-occlusions in SCA patients?

A
  • Tissue infarction causes damage and necrosis
  • Spleen can become enlarged acting as a resrevoir for blood supply - leading to drop in Hb and hypovolumic shock
  • Skin ulceration - typically around ankles
  • Lungs: acute chest syndrome, pulmonary hypertension
  • Haematouria, renal failure, priapism
231
Q

What are the early (after HbF disappears) manifestations of sickle cell anaemia?

A
  • Dactylitis (inflammation of entire digit due to one infarction)
  • Splenic sequestration
  • Pneumococcal infection
232
Q

What can trigger a painful crisis in SCA?

A

Infection, exertion, dehydration, hypoxia, psychological stress

233
Q

What is the median age of survival for Sickle cell anaemia pateints?

A

48 yrs for women

42 years for men

234
Q

What are the general management strategies for sickle cell anaemia?

A
  • Folic acid to compensate for shortened RBC life span
  • Penicillin - prophylactically to prevent infections caused by hypersplenism
  • Vaccination to protect agaist pneumococcal, haemophillus and menigococeal infections
  • Monitor spleen size for sequestration by looking for Howell-Jolly bodies
  • Blood transfusion for acute anaemic events
  • Pregnancy Care
235
Q

How is a painful crisis in sickle cell anaemia treated?

A
  • Opioids
  • Hydration
  • Warmth
  • Give oxygen if hypoxic
  • Important to exclude infection as an explanation for symptoms
236
Q

What are the more intensive strategies for sickle cell management?

A
  • Exchange transfusion if a patient is a risk of a stroke or acute chest syndrome
  • Haematopoietic stem cell transplantation in severe cases in children (
237
Q

What are the laboratory features of Sickle Cell Anaemia?

A
  • Low Hb (typically 6-8 g/dl)
  • High reticulocyte count
  • Sickle cells
  • Boat cells
  • Target cells and Howell-Jolly bodies
238
Q

What is a sickle-solubility test?

A

A test that mimics HbS polymerisation. A reducing agent is added to a blood sample.

If present, the solution turns turbid and opaque.

Tests for the presence of HbS not sickle cell anaemia (as can also be sickle cell trait)

239
Q

What is the definitive test for sickle cell anaemia?

A

Haemoglobin electrophoresis with solubility test

240
Q

Describe the composition of HbA

A

2 alpha chains and 2 beta chains

241
Q

Describe the composition of HbA2

A

2 alpha chains and 2 delta chains

242
Q

Describe the composition of HbF

A

2 alpha chains and 2 gamma chains

243
Q

When would HbA2 increase proportionally?

A

If someone had a reduction in beta chains

244
Q

Describe the two conformations of Haemoglobin

A

Tight and Relaxed
In the tight conformation,, 2,3-BPG forms bonds to stabilise deoxyhaemoglobin, making it harder to pick up oxygen.
As more oxygen binds, the 2,3-BPG bonds break and the haemoglobin molecule changes conformation into a relaxed form, which has greater affinity for oxygen.

245
Q

Describe the differences in the affinity of Deoxy and Oxyhaemoglobin (and the purpose of this difference)

A

Deoxyhaemoglobin has a LOW AFFINITY for oxygen so it only takes up oxygen when saturation is high (in lungs) and not in metabolically active tissues where O2 tension is low.

Oxyhaemoglobin has a HIGH AFFINITY for oxygen so it doesn’t release oxygen easily. It only gives up oxygen in tissues where there is low O2 pressure.

246
Q

Describe the oxygen dissociation curve

A

Its X-axis has the Partial Pressure of O2, while its Y-axis has HbO2%.

It has a sigmoid shape reflecting low affinity when O2 pressure is low, and high affinity when O2 pressure is high.

247
Q

In what direction does the O2 dissociation curve shift in the presence of deoxyhaemoglobin stabilising molecules?

A

To the right

248
Q

What factors stabilise deoxyhaemoglobin?

A
  • H+ ions
  • Co2 (Bohr Shift)
  • 2,3-DPG
249
Q

Compared to the HbA oxygen dissociation curve where does the HbF curve lie?

A

To the left

250
Q

How many alpha globulin genes do we have?

A

2 (so 4 alleles)

251
Q

Describe the transient embryonic haemoglobin molecules

A
  • Very early embryonic haemoglobin uses Epsilon and Zeta globin chains. Both die to nothing at around 3 months
  • Embryonic Alpha-type globin and later Alpha globin is made from 3 months to the rest of the life
  • Beta globin is only made from 4-5 months postnatally.
252
Q

What gene clusters contain globin genes

A
  • Alpha cluster on chromosome 16 contains 2 alpha globin and a zeta globin gene.
  • Beta cluster on chromosome 11 containa a beta globin, delta globin, gamma globin, and epsilon gene
253
Q

How many variants of normal haemoglobin are there

A

6
- Always two globins from alpha cluster and two from beta cluster.

3 transient embryonic haemoglobin, foetal, HbA and HbA2

254
Q

Define thalassaemia

A

Thalassaemas are disorders in which there is reduced production of one of the two types of globin chains leading to an imbalance globin chain synthesis

255
Q

What percentage of the world carries thalassaemia genes?

A

5%

256
Q

How are alpha and beta globins usually defected in thalassaemia?

A

alpha is usually defected by deletion of gene

beta is usually through point mutation

257
Q

What are the types of alpha thalassaemia?

A

Alpha+ thalassaemia is when 1 loci fails to function - causes mild anaemia
Alpha0 thalassaemia is when 2 loci on the same chromosome are dysfunctional causing mild anaemia
HaemoglobinH is when 3 loci are affected causing significant anaemia and in need of lifelong blood transfusion
Haemoglobin Barts is when all 4 loci are affected, causing death in utero

258
Q

Why is it important to identify people with Alpha0 thalassaemia?

A

Because if they have children with another Alpha0 person, their offspring could have Haemoglobin Barts and die in utero

259
Q

What are the types of beta thalassaemia?

A
  • Thalassaemia trait/minor is when a person is heterozygous for the beta-thalassaemia gene.
  • Thalassaemia major is when both beta chains are affected
260
Q

What are the sequelae of thalassaemia major?

A

In the absence of beta chains, alpha chains accumulate and form tetramers which precipitate in the bone marrow. Cells which do mature enters the circulation containing ineffective Beta-chains and are removed by the spleen which subsequently enlarges. Bone marrow in skull and legs also enlarge to produce RBC.

261
Q

What accounts for the short life-expectancy of a patient with thalassaemia major?

A

They need to have lifelong blood transfusions. Blood contains 200mg of iron in each unit, which accumulates in the patient’s:
liver –> cirrhosis
heart –> cardiac failure
endocrine glands –> diabetes, hypogonadism, hypothyroidism

262
Q

What are the problems with Stem Cell transplants for patients with thalassaemia major?

A

Needs to be from HLA-identical sibling, and the patient is less than 16 years.

The transplant is also associated with mortality, causes infertility and there is still a possibility of iron overload.

Year 2 MCD 2 (5 decks)

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