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Haematology Flashcards

1
Q

Regarding RCs, define the following:

  • Normocytic
  • Microcytic
  • Macrocytic
A
  • Normocytic = RCs of normal sixe
  • Microcytic = small RCs
  • Macrocytic = large RCs
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2
Q

Regarding RCs, define the following:

  • Normochromia
  • Hypochromia
  • Hyperchromia
A
  • Normochromia = RCs that have 1/3 of diameter that is pale

This is normal as the biconcave disc of RCs has less Hb therefore is paler

  • Hypochromia = RCs that have a larger area of central pallor than normal

Low Hb content = flatter cells therefore more of it is pale

  • Hyperchromia = RCs that lack central palor

Abnormal shaped RCs therefore there is no colour difference

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3
Q

Define: Reticulocytosis

A
  • Too many reticulocytes
  • Detected using a stain in which living red cells are expose to methylene blue which precipitates as a network (aka reticulum)
  • Allows the number of reticulocytes to be counted
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4
Q

Sickle cells

A
  • Red cells that are sickle or cresent shaped
  • Result from polymerisation of haemoglobin S when present in a high concentration
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5
Q

Regarding RCs, define the following:

  • Rouleaux
  • Agglutinates
  • Howell-Jolly body
A
  • Rouleaux = Neat stacks of red cells that resemble a pile of coins. Result from alterations in plasma proteins
  • Agglutinates = Irregular clumps of red cells. Result from antibody on the surface of the red cells
  • Howell-Jolly body = A nuclear remnant in a red cell. Commonest cause is lack of splenic function
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6
Q

Regarding WCs, define:

  • Leucocytosis
  • Leucopenia
  • Lymphocytosis
  • Lymphopenia
  • Neutrophilia
  • Neutropenia
  • Eosinophilia
A
  • Leucocytosis = too many WCs
  • Leucopenia = too few WCs
  • Lymphocytosis = too many lymphocytes
  • Lymphopenia = too few lymphocytes
  • Neutrophilia = too many neutrophils
  • Neutropenia = too few neutrophils
  • Eosinophilia = too many eosinophils
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7
Q

Regarding platelets, define:

  • Thrombocytosis
  • Thrombocytopaenia
A
  • Thrombocytosis = too many platelets
  • Thrombocytopaenia = too few platelets
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8
Q

Define - gaussian and non-gaussian distribution

A
  • If data have a Gaussian distribution the mean plus and minus 2 standard deviations gives a 95% range.
  • If data has a non-Gaussian distribution then mathematical transformation of the data is required before analysis.
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9
Q

Where do blood cells originate from?

A

Blood cells of all types (red cells, granulocytes, monocytes and platelets) originate in the bone marrow (however RBCs and WBCs are produced in two separate lineages)

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10
Q

From what kind of cells do all blood cells origiate from?

A

They are ultimately derived from pluripotent haemopoietic stem cells

The pluripotent stem cells gives rise to lymphoid stem cells and multipotent myeloid stem cells/precursors, from which red cells, granulocytes, monocytes and platelets are derived

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11
Q

What controls the production of RCs?

A

Red cells are produced under the influence of erythropoietin

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12
Q

Where is EPO synthesised and under what circumstances?

A

EPO is mainly synthesised in the kidney under reduced O2 supply

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13
Q

Name all the cells from which RCs (known as eyrthrocytes) originate

What is this process called?

A

Synthesis and matruation of RCs = erythropoesis

All RCs (erythrocytes) originate from multipotent myeloid stem cells which give rise to pro-erythroblasts. These then give rise to erthyroblasts then erythrocytes.

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14
Q

What is the average life span of a healthy RC?

A

The erythrocyte survives about 120 days in the blood stream

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15
Q

List the various functions of RCs

A
  • The main function of red cells is oxygen transport by haemoglobin
  • Other functions of haemoglobin include:
    • Transport of carbon dioxide and of nitric oxide.
    • Haemoglobin also acts as a _buffer _
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16
Q

Where are WCs produced and what controls their synthesis?

A

WCs (eg: granulocytes and monocytes) synthesis occurs in the bone marrow under the influence of various cytokines

Examples of cytokines includes - interleukins and colony stimulating factors

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17
Q

Name the cell types invovled in the synthesis of WCs

A

The multipotent haemopoietic stem cell can also give rise to a myeloblast, which in turn can give rise to granulocytes and monocytes

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18
Q

How do monocytes matrue? What cell types do they mature into?

A

Monocytes migrate to tissues where they develop into macrophages and other specialized cells that have a phagocytic and scavenging function

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19
Q

What other type of WCs arises from myeloblasts?

A

A myeloblast can also give rise to eosinophil granulocytes and basophil granulocytes

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20
Q

What are the main functins of basphils and eosinophils?

A
  • Eosinophils = defence against parasitic infection
  • Basophils = allergic responses
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21
Q

What protein contrls the production of platelets?

A

The production of platelets is under the influence of thrombopoietin

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22
Q

What precursor cells are involved in platelet production?

A

The multipotent haemopoietic stem cell can also give rise to megakaryocytes and then platelets

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23
Q

What is the average lifespan of platelets?

A

Platelets survive about 10 days in the circulation

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24
Q

What is the major role of platelets?

A

Platelets have a role in primary haemostasis
Platelets contribute phospholipid, which promotes blood coagulation

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25
Q

What type of stem cell gives rise to T and B cells

A

The lymphoid stem cell gives rise to T cells, B cells and natural killer cells

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26
Q

What are the 4 caveats for normal reference ranges?

A
  • A value within the normal range may be abnormal for that individual
  • A value outside the normal range may be normal for that individual
  • Reference ranges for healthy and sick individuals usually overlap
  • Some haematological variables are dependent on the precise instrument or methodology used
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27
Q

What are the normal ranges (for men and women) for the following counts:

  • WBC
  • RBC
  • Hb
  • MCV (mean cell volume)
  • Platelets
A
  • WBC
    • Male = 3.6-9.2 x 109/l
    • Female = 3.5-10.8 x 109/l
  • RBC
    • Male = 4.25-5.77 x 1012/l
    • Female = 3.82-4.98 x 1012/l
  • Hb
    • Male = 13.5-16.9 g/dl
    • Female = 11.5-14.8 g/dl
  • MCV
    • 84-99 fl
  • Platelet Count
    • Male = 143-332 x 109/l
    • Female = 169-358 x 109/l
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28
Q

Define Polycythaemia

A

Polycythaemia is the opposite of anaemia - i.e. increased levels (number) of RCs causing high Hb levels

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29
Q

List the 4 types (mechanisms) of polycythaemia, giving an example for each

A
  • Physiological - found in newborn babies
  • Appropriate EPO secretion - alitutude
  • Inappropriate EPO secretion - EPO abuse (i.e. drug use in athletes)
  • Intrinsic BM disease - polycythaemia vera
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30
Q

Define Anaemia

A

Anaemia = a reduction in the concentration of Hb in circulating blood below what is normal in a healthy individual of that gender and age (this is important as Hb levels vary according to F/M and age)

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31
Q

What are the 4 major mechanisms of anaemia?

A
  • Reduced production of RBC/Hb in BM
  • Loss of blood from the body
  • Reduced survival of RBCs in circulation (haemolysis)
  • Pooling of RBC in a large spleen
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32
Q

Define: MCH & MCHC (in relation to anaemia)

A

MCH - absolute amount of Hb in an individual RBC

MCHC - concentration of Hb in a red cell (this is related to the shape of the cell)

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33
Q

Anaemia is calssed on the basis of RC size - define the following:

  • Microcytic
  • Normocytic
  • Macrocytic
A

Microcytic

  • RC = small (known as microcytes)
  • Cells are also hypochromic - appear pale
  • Common causes inc. iron deficiency, ACD & thalassaemia

Normocytic

  • RC = normal
  • Common causes inc. blood loss, failure to produce RC, GI problems, pooling of cells in spleen

Macrocytic

  • RC = large
  • Cells are also normochromic - appear normal
  • Common causes inc. lack of Vit. B12 or folic acid (megaloblastic anaemia), liver disease, ethanol toxicity
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34
Q

Define haemolytic anaemia

A

Haemolytic anaemia is anaemia caused by shorted RC life span - it can be inherited or acquired and is due to either an intrinsic (inherent problem with the RC) or extrinsic (external factors acting on the RC) RC problem

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35
Q

What are the consequences of haemolysis?

A

Haemolysis (the destruction of RCs) has various potential clinical consequences:

  • Anaemia
  • Erythroid hyperplasia
  • Increased folate demand
  • Increased viral susceptibility (esp. B19)
  • Increased propensity to gallstones
  • Increased risk of iron overload
  • Increased risk of developing osteoporosis
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36
Q

List the common inherited & acquired abnormalities found in haemolytic anaemia

A

Inherited - due to abnormalities in the:

  • Cell membrane
  • Haemoglobin
  • Enzymes in the red cell

Acquired - due to extrinsic factors affecting the RC:

  • Micro-organisms (infectious anaemia)
  • Chemicals or drugs (iatrogenic)
  • Autoimmune haemolytic anaemia (AIHA)
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37
Q

Haemolytic anaemia can also be described as “intravascular” or “extravascular” - define these and give an example of each

A

Intravascular = within the circulation

  • Autoimmune Anaemia

Extravascular = removal or descruction of RC by RE system (reticuloendothelial)

  • Haemoglobinuria
  • Idiopathic
  • Infection (malaria)
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38
Q

List the various diagnosis points of haemolytic anaemias

A
  • Unexplained anaemia, normochromic and normocytic/macrocytic
  • Morphologically abnormal red cells:
    • Spherocytes in hereditary spherocytosis and AIHA
    • Heinz bodies in G6PD deficiency (clumps of denatured Hb due to oxidant damage)
  • Increased red cell breakdown
    • Jaundice, raised bilirubin
  • Increase bone marrow activity
    • Raised reticulocytes (immature RBC)
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39
Q

List the clinical features of haemolytic anaemia

A
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40
Q

Name a haemolytic anaemia due to:

  • Issues in Hb
  • Membrane defects
  • Autoimmune destruction
  • Infection
A
  • Sickle Cell
  • Hereditary Spherocytosis
  • Autoimmune Hereditary Anaemia
  • Malaria
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41
Q

Define the key clinical features of - Hereditary Spherocytosis

A
  • Most common inherited haemolytic anaemia
  • Due to a vertical disruption in the RC membrane
    • Disrupted interactions between the cytoskeleton and bilayer
  • ​Causes a change in RC appearance - mechanical abnormality resulting in osmotic changes
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42
Q

Define the key clinical features of - Hereditary Elliptocytosis

A
  • Due to a horizontal disruption in the RC membrane
    • Defects in the cytoskeleton
  • ​Causes a change in RC appearance - mechanical abnormality resulting in osmotic changes
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43
Q

Define the key clinical features of - G6PD Deficiency

A
  • This is an example of anaemia caused by disrupted metabolic pathways (in RCs)
  • Inherited - X-linked
  • Clinical Features (can be asymptomatic):
    • Neonatal jaundice
    • Acute haemolysis
    • Chronic haemolytic anaemia
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44
Q

Define the key clinical features of - Pyruvate Kinase Deficiency

A
  • Another example of disrupted metabolic pathways
  • Most common metabolic defect
  • Pathophysiology - ATP depletion –> loss of ions –> dehydrated RCs –> death of RCs
  • Clinical Features (often asymptomatic):
    • Haemolytic anaemia
    • Neonatal jaundice
    • Splenomegaly
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45
Q

Outline normal iron absorption & homeostasis

A
  • Iron is essential for haem-containing molecules
  • Role - hold onto oxygen
  • RDA - 20 mg (most is recycled)
  • Major (normal) losses of iron - menstruation & desquamated cells (skin & gut)
  • Dietary Sources - red meat, green vegetables etc.
  • Only Fe2+ (ferrous iron) can be absorbed (most dietary sources are ferric - Fe3+)
  • Abs of iron is affected by diet, intestinal acids and any iron deficiencies
  • Abs of iron depends on specific proteins
    • Ferroprotein = TM protein in duodenum that transports iron
    • Hepcidin = inhibitor of ferroprotein
    • Ferritin = storage protein of iron (within cells)
    • Transferrin = ferritin binding protein
  • Iron within the body is divided into pools
    • Metabolic pool (Hb & myoglobin)
    • Storage pool (ferritin)
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46
Q

Outline the role of transferrin

A
  • Transferrin = glycoprotein, ferrtin BP
  • Role = hold iron in the circulation (via ferritin)
  • Required for the internalisation of iron into cells
  • Clinical significance = can be used as a measure of [Fe]
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47
Q

What type of anaemia is iron deficiency anaemia?

A

Microcytic hypochromic anaemia

(NB: IDA = iron defcicency anaemia, most common cause of anaemia globally)

48
Q

What are the common causes of iron deficiency?

A
  • **Bleeding ** eg menstrual or GI
  • Increased use eg growth, pregnancy
  • Dietary deficiency eg vegetarian
  • Malabsorption eg coeliac
49
Q

Outline the (general) signs & symptoms of anaemia due to iron deficiency

A

IDA is often asymptomatic - if present, symptoms are very non-specific:

  • Fatigue
  • Faintness
  • Breathlessness
  • Pale mucosal membranes
  • Tachycardia
  • Koilonychias (spoon-shaped nails - specific to signficant IDA)
50
Q

What investigations are performed to confirm iron deficiency anaemia?

A
  • Full GI investigtion (i.e. endoscopy) on males and females >40 y.
  • Coeliac antibodies
  • Blood film: microcytic and hypochromic RBC
  • Anisocytosis (size) and poikilocytosis (shape) eg target cells and pencil cells
  • Blood counts (inc. ferritin, transferrin)
    • Ferritin is low in IDA but high in ACD (useful for DDx)
    • Transferrin is high in IDA but low in ACD (useful for DDx)
51
Q

What are the main treatments of iron deficiency anaemia?

A
  • Iron replacement (side effect = constipation)
    • Oral iron
    • Ferrous sulphate
52
Q

What kind of anaemia is Anaemia of Chronic Disease (ACD)

A

Microcytic hypochromic anaemia

53
Q

What co-morbidities is ACD associated with?

A

ACD is associatd with chronic inflammation, infections & neoplastic conditions

Unlike IDA, ACD is not associated with bleeding or deficiencies

54
Q

Outline the pathogenesis of ACD

A

ACD is related to cytokine production - these are released in response to chronci infection and prevent the Abs. of iron

ACD = block in iron abs and utilisation

55
Q

What are the major differences between IDA and ACD?

A

In ACD there are raised BM Fe stores, raised ferritin and low transferrin

(in IDA, it is the reverse)

56
Q

Outline the role of B12 & Folate

A
  • B12 & Folate are haemolytics (i.e. without them = anaemia) and required for DNA synthesis
  • B12 is also requried for the integrity of the NS
  • Folate is also required for homocysteine metabolism
57
Q

Outline the Abs. of B12 & Folate

A

B12 absorption

  • Not straightforward
  • Requires Intrinsic Factor (found in stomach)
  • Occurs in the ileum (therefore ilieal resection = B12 deficiency)

Folate absorption

  • More straightforward
  • Occurs directly in the digestive system
58
Q

What are the clinical consequences of B12 & Folate deficiency

A
  • Anaemia
  • Jaundice
  • Glossitis
  • Weight loss
  • Sterility
59
Q

What type of anaemia is anaemia of B12 and Folate deficiency

A

Macrocytic megaloblastic anaemia (associated with high MCV)

60
Q

What is the cause of megaloblastic anaemia?

A

<!--StartFragment-->

  • Megaloblastic anemia = cells can’t synthesise DNA Cause = B12 and/or folate deficiencies
  • Result = cells with normal cytoplasm but immature nuclei –> large cells (i.e. macrocytic)

<!--EndFragment-->

61
Q

What are the causes of B12 and/or folate deficiency?

A

Decreased Intake

  • Folate = low veg. diet (common cause)
  • B12 = rare (B12 is found in all animal products)

Decreased Absorption

  • Folate = rare (occurs in duodenum & jejunum directly)
  • B12 = complex abs due to intrinsic factor and location (common)

Increased Demand

  • Folate = physiological increases (eg: pregnancy, adolescence etc.) or pathological increase (eg: haemolytic anaemias, malignancy etc.)
  • B12 = rare (B12 stores are high and are sufficent)

Increased Loss

  • Folate = rare due to sufficient stores
  • B12 = rare due to sufficient stores
62
Q

What are the laboratory features of megaloblastic anaemias?

A
  • Auto-Abx to IF
  • Coeliac Abx
  • Shilling Test (no longer used)
63
Q

What are alternate causes of non-magalobasltic macrocytic anaemia anaemia?

A
  • Liver disease
  • Alcoholism
  • Hypothyroidism
  • Drugs (esp. immunosuppressants)
  • Haematological disorders (eg: aplastic anaemia)
64
Q

What is the genetic cause of sickle cell anaemia?

A

Sickle Cell is caused by a single aa change in the B-globin gene (glutamic acid replaced by valine), Results in HbSS

65
Q

What are the consequences of HbSS?

A
  • Alteration in B-globin gene = change in chain
  • Deoxy. Hb becomes LESS soluble
  • Hb polymerises within RC = distorts the RC shape
  • RC = sickle shaped in deoxygenated states
  • Cells become trapped in vessels = occlusion
66
Q

Describe the epidemiology of Sickle Cell

A

The sickle gene is most commonly distributed amongst the black population:

  • 10% Afro Carribbean
  • 25% African populations
67
Q

What are the major effects of microvascular occlusion caused by sickle cell?

A
  • Tissue Damage
  • Necrosis
  • Pain (sickle cell crisis)
68
Q

Outline the major diagnostic features of Sickle Cell

A
  • Family history (this is important as it is inherited)
  • Symptom presenation is varied even within the same family (it is common for multiple children to be affected)
  • Lab Features
    • Blood film = low Hb, raised reticulocytes
    • Appearance = sickle-shaped RCs
  • Screening = new born blood spot (early detection = decreased mortality)
  • Definitive diagnosis requires a Hb electrophoresis test and a sickle solubility test
69
Q

Outline the major treatment approaches to Sickle Cell

A

General Measures

  • Folic acid to increase RC production
  • Vaccination & Penicilln to decrease risk of infection (increases mortality)
  • Spleen size monitoring to reduce chance of splenic complications

Acute Measures

  • Blood transufusions (this is usually life saving)

Managing Crises

  • Pain releif
  • Oxygen
  • Hydration
70
Q

Define Leukaemia

A
  • Malignant neoplasms of the haematopoietic stem cells, characterised by diffuse replacement of the bone marrow by neoplastic cells.
  • The leukaemic cells spill over into the blood
  • Cells may also infiltrate the liver, spleen and other tissues
  • Relatively rare, incidence 10 per 100,000/year
71
Q

Define Lymphoma

A
  • Neoplastic transformations of normal mature B or T lymphocytes which reside predominantly in the lymphoid tissues.
  • Spill into blood
  • More common than leukaemia
72
Q

How are leukaemias classified?

A

Leukaemias are classified by the lineage (i.e. myeloid or lymphoblastic), degree of maturity of the malignant clone, and speed of evolution of the disease (i.e. acute or chronic)

73
Q

Outline the differences between Acute & Chronic Leukaemias

A

Acute Leukaemias

  • Malignant cells are at a less mature stage - therefore increased presence of precursors
  • More aggressive types of leukaemia - present quickly and more seriously
  • Fatal if not treated
  • Presentation:
    • Anaemia, bleeding, infection (result of BM failure)
    • Bloods: ↑ WCC (but may be normal or low) and blast cells in blood film
    • Sometimes peripheral lymphadenopathy +hepatosplenomegaly

_Chronic Leukaemias _

  • Malignant cells are at a more mature stage
  • Slower natural history
  • Median survival if untreated: CML 3-4 years, CLL 10 years
  • Presentation (chronic have mild symptoms or asymptomatic)
    • Anaemia, tiredness, weight loss, fever
    • Splenomegaly
    • May have thrombocytopenia – bleeding and bruising
    • Bloods: ↑ WCC
74
Q

What the the origins of myeloid leukaemias & lymphoblastic leukaemias?

A

Myeloid = myeloid precursors (eg: granulocytes)

Lymphoblastic = lymphoid precursors (eg: lymphocytes)

75
Q

How to you diagnose lymphoblastic or myeloid leukaemias?

A

Diagnosis made by blood film (morphology), bone marrow aspirate (immunophenotyping) and cytogenetics

76
Q

Outline the major myeloid leukaemias

A

AML (acute myeloid leukaemia)

  • Leukaemia of middle age -50-60ys
  • Poor prognosis
  • Blood film – Auer rods
  • Treat with chemo

APML (a type of AML)

  • t(15;17) to give PML-RARa fusion protein.
  • Often presents with DIC
  • Treat: chemo + All-trans-retinoic acid

CML (chromic myeloid leukaemia)

  • Leukaemia of middle age - 40-60ys
  • ‘Philidelphia chromosome’ t(9;22) BCR-ABL fusion protein.
  • Chronic phase 3-4 years, usually followed by a blast transformation.
  • Treat with chemo + tyrosine kinase inhibitors (imatinib).
77
Q

Outline the major lymphoblastic leukaemias

A

ALL (acute lymphoblastic leukaemia)

  • Common in childhood
  • Can cause neurological symptoms
  • Good prognosis with treatment (chemo).
  • Blood film- lymphoblasts

CLL (chronic lymphoblastic leukaemia)

  • Common in elderly
  • Slow course = slow proliferation of B cells. Early
  • CLL is generally asymptomatic
    • ~30% don’t require treatment

NB: the differentiating difference between ALL & CLL is age

78
Q

What are the two major types of lymphoma and how do you differentiate between them?

A

Hodgkin’s & Non-Hodgkins

Reed-Sternberg Cells = Hodgkin’s

79
Q

Hodgkin’s Lymphoma - outline:

  • Epidemiology
  • Investigations
  • Clinical Features
A

Epidemiology

  • Rare (incidence 3 per 100,000)
  • Young adults
  • Previous infection with EBV (glandular fever)

Ix

  • Lymph node biopsy: Reed Sternberg cells (multinucleate malignant B cells ‘owl like’)
  • CXR: mediastinal widening from enlarged nodes

Clinical features

  • Painless lymph node enlargement, rubbery consistency
    • Alcohol-induced pain
  • Hepatosplenomegaly
  • Systemic ‘B’ symptoms: fever, drenching night sweats, weight loss
  • Fatigue, anorexia
80
Q

Non-Hodgkin’s Lymphoma - outline:

  • Epidemiology
  • Investigations
  • Environmental Associatesion
  • Clinical Features
A

Epidemiology & Investigations

  • Many types
  • These are malignant tumours of lymphoid tissue, that do not contain Reed-Sternberg cells
  • 70% of B cell origin, 30% of T cell origin

Environmental associations

  • Burkitt’s lymphoma: occurs in African children, jaw lymphadenopathy, assoc. with EBV infection
  • Gastric MALT lymphoma: assoc. with H. pylori infection

Clinical features:

  • Rare <40 years old
  • Lymphadenopathy
  • Systemic ‘B’ symptoms: fever, drenching night sweats, weight loss
81
Q

Define Haemostasis

A

The process which causes bleeding to stop - purpose is to keep blood within a damaged blood vessel.

Haemostasis is in balance with thrombisis (coagulation)

Abnormalities = bleeding disorders

82
Q

Outline the role of platelets

A
  • Platelets are anucleate cells involved in primary haemostasis
  • They major role is to form a plug which stops blood flow
  • They originate from the megakaryotyle lineage therefore present with dense granules (loaded with ADP to perform function)
  • Platelets ontain various graunules and surface GPs which help perform function
83
Q

What is the first, non-specific response to vessel injury?

A

Vessel Constriction

  • This is a local contractile response to injury
  • It is only sufficient to temporarily resitric blood loss (can be sufficient in minor injuries)
  • It is mediated by the vascular endothelium
84
Q

Outline Primary Haemostasis

A
  • Primary Haemostasis = first true step of haemostasis
  • Key Function = formation of platelet plug
  • Stimulus = disruption of vascular endothelum
    • BM exposed by injury
    • Exposure of collagen stimulates von Willebrand Factor
    • vWF binds to collagen and “captures” platelets (binding via surface GP)
    • Platelet binding stimulates ADP + Thromboxane synthsesis
  • Platelet plug is unstable - stabilisation requires platelet aggregation & adhesion
    • ​Platelets undergo a confirmation change on binding - enables binding of fibrinogen
    • Fibrinogen + Thrombin cause aggregation
85
Q

What is the major role of Secondary Haemostasis

A

Secondary Haemostasis = Coagulation Pathway

Role = activation & stabilisation of platelet plug

86
Q

Outline the Intrinsic Pathway

A

They key point is that each factor activates the next one in a coagulation cascade

  1. Factor XII –> XIIa
  2. Factor XI –> XIa
  3. Factor X –> Xa (requires co-factors = VIIIa + Ca)

This then becomes the common pathway

87
Q

Outline the Extrinsic Pathway

A

They key point is that each factor activates the next one in a coagulation cascade

  1. Vessel Damage = Tissue Factor release
  2. VII –> VIIa
  3. X –> Xa (Tisue Factor + VIIa + Ca)

This then becomes the common pathway

88
Q

Outline the Common Pathway

A

The common pathway starts at the Factor Xa stage which is activated by both the intrinsic and extrinsic pathways

  1. Prothrombin –> Thrombin (cofactors Va + Ca)
  2. Fibrinogen –> Fibrin
  3. XIII –> XIIIa
  4. Cross-linking of fibrin = formation of clot
89
Q

Outline Tertiary Haemostasis

A
  • Tertiary Haemostasis = **Fibrinolysis **
  • Purpose = removal of clot (clot dissolution & vessel repair)
  • Tissue Plasminogen Activator binds to the clot and activates plasminogen –> plasmin
  • Plasmin = proteolytic activator
    • Produces fibrin degradation products
    • Breaks down clot
90
Q

Outline the lab tests used to investigate haemostasis

A

Platelet Count

  • Monitors for thrombocytopoaenia
  • Major test for platelet function
  • Normal = 15-400 x10^9
  • Reduction = progressive bleeding

Bleeding Time

  • Tests for haemostatis function of the platelets
  • Used in conjunction with count
  • Ensures platelet-vessel interactions are functioning

**Platelet Aggregation **

  • Measures any potential functional defects in platelets
91
Q

Outline the lab tests used to investigate coagulation

A

APTT

  • Active partial thromboplastin time
  • Test for XIIa (intrinsic pathway)
  • Measures clotting time
  • Used to screen for bleeding disorders
  • Used to monitor heparin therapy

PT

  • Prothrombin time
  • Test for tissue factor (extrinsic pathway)
  • Measures clotting time
  • Used to screen for bleeding disorders
  • Used to monitor warfarin therapy

TCT/TT

  • Thrombin clotting time
  • Test for firbinogen –> fibrin abnormalities
92
Q

Outline the general features of disorders of primary haemostasis

A

General Characteristics:

  • Immediate bleeding
  • Prolonged bleeding
  • Nose bleeds & gums
  • Easy bruising
93
Q

What are the four potential mechanisms of primary haemostasis defects

A
  1. Low platelet number
  2. Impaired platelet function
  3. Problems with vWF
  4. Problems with vessel wall
94
Q

Outline thrombocytopenia & how it can cause issues with primary homeostasis

A

Thrombocytopenia = issues with platelets. Can be caused by a variety of things

  • Decreased Production
    • BM failure, leukaemia
  • Accelerated Clearance
    • ​ITP (immune) - paediatric = viral association; adult = seen in autoimmune disorders (eg: common with SLE).
    • TTP (thrombotic) - widespread adhesion & aggregation of platelets = thrombosis. Caused by defiency in ADAMTS 13
    • DIC (disseminated intravascular coagulation) - very serious, overactivation of clotting cascade due to increased Tissue Factor. Large thrombus = vessel occlusion
  • Splenic Pooling
    • ​Splenomegaly
  • Decreased Function
    • vWF deficiency
95
Q

Outline vWF deficiency

A
  • von Willebrand deficiency (can also cause F VIII deficiency) = defect in platelet adhesion.
  • Inherited condition, prolonged bleeding from cuts.
96
Q

Give one example of an acquired and one example of an inherited problem within the vessel wall which can disrupt coagulation

A
  • Inherited: Ehlers-Danlos Syndrome
  • Acquired: scurvy, steroids, vasculitis
97
Q

Outline the general features of disorders of secondary haemostasis

A

Defects of secondary haemostasis = issues with stabilisation of plug with fibrin

General Characteristics

  • Superficial cuts don’t bleed
  • Onset of bleeding is delayed and deep, into muscles and joints (haemarthrosis).
98
Q

What are the two (overall) major causes of coagulation disorders?

A

Deficiency of coagulation factor production

(can either be acquired or inherited)

Increased consumption of coagulation factors (always acquired)

99
Q

Outline Haemophilia

A
  • Haemophilia is major hereditary coagulation disorder
  • It is a sex linked disorder
  • It can be split into A and B depending on which factor is disrupted
  • Haemophilia A
    • VIII deficiency
    • 1 in 5000 (more common)
    • Clinical features = a spectrum depending on level of F VIII
    • Characterised by spontaneous bleeding into muscles and joints, prolonged bleeding after injury or surgery.
    • Treatment = prophylactic IV infusions of recombinant F VIII
  • Haemophilia B
    • IX deficiency
    • 1 in 30,000 (rare)
    • Similar clinical features to A
    • Treatment = IV recombinant F IX
100
Q

List the causes of acquired coagulation disorders

A

Causing deficiencies in factor production

  • Liver disease = all factors produced in liver
  • Dilution = following a red cell transfusion, there is dilution of the factors compared to the blood levels
  • Iatrogenic = anticoagualtion drugs (warfarin, heparin)

Causing increased factor consumption

  • DIC (disseminated intravascular coagulation)
  • Autoimmunity
101
Q

What are antiplatelet drugs? Name a few and the MOA

A

Antiplatelet drugs are used in the treatment of CVD to reduce clotting

  • Aspirin = COX-I inhibitor = reduce platelet production
  • Clopidogrel = ADP receptor antagonist = reduce platelet function (prevents adhesion)
  • Abciximab = surface GP antagonsits = reduce platelet function (prevents adhesion)
102
Q

Outline the MOA of Warfarin

A
103
Q

Outline the MOA of heparin

A
  • Heparin is another anticoagulant
  • It is an immediate drug (eg: used for PE)
  • It is a potent activator of anti-thrombin
    • Anti-thrombin (physiological) has a rapid anticoagulation effect
104
Q

Outline the pattern of Hb synthesis & expression

A

Embryonic Hb

  • Gower 1
  • Gower 2
  • Portland

Foetal Hb

  • Hb F
  • Hb A

Adult Hb

  • Hb A (from foetal to adult)
  • Hb A2 (from infant to adult)
105
Q

What is the difference between Haemmoglobinopathies & Thallasemia?

A

Haemmoglobinopathies

  • Genetic globin chain disorder
  • Caused by the synthesis of structurally abnormal molecules (due to chain alterations)

Thallasemia

  • Genetic globin chain disorder
  • Caused by reduced synthesis of normal molecules
  • Essentially a type of anaemia
106
Q

Outline a-thalassaemia

A
  • a-thalassaemia is caused by a quantitative defect in Hb synthesis
  • It is caused by a mutation or deletion of alpha globin chains
    • Mutation = non-deletional thalassaemia = alpha+
    • Deletion = deletional thalassaemia = alpha0
  • A clinical syndrome is only caused if 3+ alpha genes are missing
107
Q

Outline b-thalassaemia

A
  • b-thalassaemia is an example of ineffective erythropoesis
  • It is caused by point mutations in the b-globin gene
  • Mutations in the b-chain cause malfunctioning
  • Lack of b-chains cause the a-chains to accumulate in the bone marrow causing ineffective erythropoesis
  • Requires lifelong blood transfusions (otherwise fatal)
  • BM transplatation can lead to cure
108
Q

Explain how the blood groups arise

A

The ABO blood groups are based on antigens

  • A and B are antigens on red cells
  • All cells have the H antigen
  • If no other antigens are added = O
  • If the A antigen is added = A
  • If the B antigen is added = B
  • If the A and B antigen are added = AB
109
Q

Describe how the blood groups work

A

Everyone has antibodies against all antigens, apart from their own (eg: O = no antigens, Ab to A and B). These antibodies are from birth and are IgM (therefore very potent)

110
Q

Explain the RH groups

A

RhD is the most important - blood groups are either RhD positive or RhD negative

This is encoded for by the RhD genes - D = antigen, d = no antigen

So - dd = no antigen = RhD negative, DD or Dd = antigen = RhD positive

However, you can make anti-D antigens is you are RhD negative (this is problematic for blood transufsions)

111
Q

What is the universal donor and why?

A

O negative - because there are no antigens (either to the blood groups or to RhD)

112
Q

Outline HDN (haemolytic disease of the newborn)

A
  • HDN occurs when the mother is RhD negative but has anti-D antibodies (eg: due to blood transfusions or a previous pregnancy being RhD positive).
  • If the foetus is RhD positive, the anti-D antibodies can cross the placenta - this leads to haemolysis of foetal red cells and if not corrected causes hydrops foetalis and/or death
113
Q

Define “cross-matching” in terms of blood transfusions

A

The Px blood will be sampled (plasma and cells) to determine the ABO groups. Cross matching involves the mixing of Px serum with donor red cells - if the correct blood group (and RhD) has been selected, there should be no reaction (i.e. no agglutination)

114
Q

What is the purpose of cross-matching?

A
  • ​Prevents deaths due to incorrect ABO transfusion
  • Prevents incorrect RhD (i.e. giving RhD- RhD+ blood)
  • Prevents rare blood groups getting the incorrect blood (other rare grups include RhC, RhE and even rarer - Duffy, Kidd etc.)
115
Q

What are the major components within whole blood?

A
  • Red Cells - major component of blood, each unit is from one donor, must be from the same blood group (crossmatched)
  • Platelets - given to BM failure Px and massive bleeding (trauma), must be of the same blood group (no crossmatching), each unit is from 4 donors
  • Plasma
    • FFP (fresh frozen plasma) - given for heavy bleeding (trauma, abnormal coags) and to reverse warfarin, each unit is from one donor, must be of the same blood group (no crossmatching)
    • Cyroprecipitate - like FFP but also contains fibrinogen + VIII, given for massive bleeding (trauma) and low fibrinogen, one unit is from 10 donors
    • Fractionated Products
      • Factors VIII + IX - for haemophilia
      • Immunoglobulins - for infection treatment (eg: anti-rabies)
      • Albumin - for burns and severe liver/kidney dysfunction

MCD (13 decks)

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