Haematology Flashcards
1
Q
Regarding RCs, define the following:
- Normocytic
- Microcytic
- Macrocytic
A
- Normocytic = RCs of normal sixe
- Microcytic = small RCs
- Macrocytic = large RCs
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
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
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
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
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
7
Q
Regarding platelets, define:
- Thrombocytosis
- Thrombocytopaenia
A
- Thrombocytosis = too many platelets
- Thrombocytopaenia = too few platelets
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.
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)
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
11
Q
What controls the production of RCs?
A
Red cells are produced under the influence of erythropoietin
12
Q
Where is EPO synthesised and under what circumstances?
A
EPO is mainly synthesised in the kidney under reduced O2 supply
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.
14
Q
What is the average life span of a healthy RC?
A
The erythrocyte survives about 120 days in the blood stream
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 _
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
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
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
19
Q
What other type of WCs arises from myeloblasts?
A
A myeloblast can also give rise to eosinophil granulocytes and basophil granulocytes
20
Q
What are the main functins of basphils and eosinophils?
A
- Eosinophils = defence against parasitic infection
- Basophils = allergic responses
21
Q
What protein contrls the production of platelets?
A
The production of platelets is under the influence of thrombopoietin
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
23
Q
What is the average lifespan of platelets?
A
Platelets survive about 10 days in the circulation
24
Q
What is the major role of platelets?
A
Platelets have a role in primary haemostasis
Platelets contribute phospholipid, which promotes blood coagulation
25
What type of stem cell gives rise to T and B cells
The **lymphoid stem cell** gives rise to T cells, B cells and natural killer cells
26
What are the 4 caveats for normal reference ranges?
* 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
27
What are the normal ranges (for men and women) for the following counts:
* WBC
* RBC
* Hb
* MCV (mean cell volume)
* Platelets
* 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
28
Define Polycythaemia
Polycythaemia is the opposite of anaemia - i.e. increased levels (number) of RCs causing high Hb levels
29
List the 4 types (mechanisms) of polycythaemia, giving an example for each
* 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
30
Define Anaemia
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)
31
What are the 4 major mechanisms of anaemia?
* 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
32
Define: MCH & MCHC (in relation to anaemia)
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)
33
Anaemia is calssed on the basis of RC size - define the following:
* Microcytic
* Normocytic
* Macrocytic
**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
34
Define haemolytic anaemia
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
35
What are the consequences of haemolysis?
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
36
List the common inherited & acquired abnormalities found in haemolytic anaemia
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)
37
Haemolytic anaemia can also be described as "intravascular" or "extravascular" - define these and give an example of each
Intravascular = within the circulation
* Autoimmune Anaemia
Extravascular = removal or descruction of RC by RE system (reticuloendothelial)
* Haemoglobinuria
* Idiopathic
* Infection (malaria)
38
List the various diagnosis points of haemolytic anaemias
* 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)
39
List the clinical features of haemolytic anaemia
40
Name a haemolytic anaemia due to:
* Issues in Hb
* Membrane defects
* Autoimmune destruction
* Infection
* Sickle Cell
* Hereditary Spherocytosis
* Autoimmune Hereditary Anaemia
* Malaria
41
Define the key clinical features of - **Hereditary Spherocytosis**
* 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_
42
Define the key clinical features of - **Hereditary Elliptocytosis**
* 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_
43
Define the key clinical features of - **G6PD Deficiency**
* 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
44
Define the key clinical features of - **Pyruvate Kinase Deficiency**
* 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
45
Outline normal iron absorption & homeostasis
* 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)
46
Outline the role of transferrin
* 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]
47
What type of anaemia is iron deficiency anaemia?
Microcytic hypochromic anaemia
*(NB: IDA = iron defcicency anaemia, most common cause of anaemia globally)*
48
What are the common causes of iron deficiency?
* **Bleeding ** eg menstrual or GI
* **Increased use** eg growth, pregnancy
* **Dietary deficiency** eg vegetarian
* **Malabsorption** eg coeliac
49
Outline the (general) signs & symptoms of anaemia due to iron deficiency
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
What investigations are performed to confirm iron deficiency anaemia?
* 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
What are the main treatments of iron deficiency anaemia?
* Iron replacement (side effect = constipation)
* Oral iron
* Ferrous sulphate
52
What kind of anaemia is Anaemia of Chronic Disease (ACD)
Microcytic hypochromic anaemia
53
What co-morbidities is ACD associated with?
ACD is associatd with _chronic inflammation, infections & neoplastic conditions_
Unlike IDA, ACD is _not_ associated with bleeding or deficiencies
54
Outline the pathogenesis of ACD
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
What are the major differences between IDA and ACD?
In ACD there are raised BM Fe stores, raised ferritin and low transferrin
(in IDA, it is the reverse)
56
Outline the role of B12 & Folate
* 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
Outline the Abs. of B12 & Folate
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
What are the clinical consequences of B12 & Folate deficiency
* Anaemia
* Jaundice
* Glossitis
* Weight loss
* Sterility
59
What type of anaemia is anaemia of B12 and Folate deficiency
Macrocytic megaloblastic anaemia (associated with high MCV)
60
What is the cause of megaloblastic anaemia?
* 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)
61
What are the causes of B12 and/or folate deficiency?
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
What are the laboratory features of megaloblastic anaemias?
* Auto-Abx to IF
* Coeliac Abx
* Shilling Test (no longer used)
63
What are alternate causes of non-magalobasltic macrocytic anaemia anaemia?
* Liver disease
* Alcoholism
* Hypothyroidism
* Drugs (esp. immunosuppressants)
* Haematological disorders (eg: aplastic anaemia)
64
What is the genetic cause of sickle cell anaemia?
Sickle Cell is caused by a _single aa change_ in the **B-globin gene** (glutamic acid replaced by valine), Results in **HbSS**
65
What are the consequences of HbSS?
* 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
Describe the epidemiology of Sickle Cell
The sickle gene is most commonly distributed amongst the black population:
* 10% Afro Carribbean
* 25% African populations
67
What are the major effects of microvascular occlusion caused by sickle cell?
* Tissue Damage
* Necrosis
* Pain (sickle cell crisis)
68
Outline the major diagnostic features of Sickle Cell
* 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
Outline the major treatment approaches to Sickle Cell
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
Define Leukaemia
* **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
Define Lymphoma
* **Neoplastic transformations of normal mature B or T lymphocytes** which reside predominantly in the lymphoid tissues.
* Spill into blood
* More common than leukaemia
72
How are leukaemias classified?
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
Outline the differences between Acute & Chronic Leukaemias
_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
What the the origins of myeloid leukaemias & lymphoblastic leukaemias?
Myeloid = myeloid precursors (eg: granulocytes)
Lymphoblastic = lymphoid precursors (eg: lymphocytes)
75
How to you diagnose lymphoblastic or myeloid leukaemias?
Diagnosis made by **blood film** (morphology), **bone marrow aspirate** (immunophenotyping) and **cytogenetics**
76
Outline the major myeloid leukaemias
**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
Outline the major lymphoblastic leukaemias
**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
What are the two major types of lymphoma and how do you differentiate between them?
Hodgkin's & Non-Hodgkins
**_Reed-Sternberg Cells = Hodgkin's_**
79
Hodgkin's Lymphoma - outline:
* Epidemiology
* Investigations
* Clinical Features
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
Non-Hodgkin's Lymphoma - outline:
* Epidemiology
* Investigations
* Environmental Associatesion
* Clinical Features
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
Define Haemostasis
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
Outline the role of platelets
* 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
What is the first, non-specific response to vessel injury?
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
Outline Primary Haemostasis
* 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
What is the major role of Secondary Haemostasis
Secondary Haemostasis = Coagulation Pathway
Role = activation & stabilisation of platelet plug
86
Outline the Intrinsic Pathway
*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
Outline the Extrinsic Pathway
*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
Outline the Common Pathway
*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
Outline Tertiary Haemostasis
* 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
Outline the lab tests used to investigate haemostasis
**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
Outline the lab tests used to investigate coagulation
**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
Outline the general features of disorders of primary haemostasis
General Characteristics:
* Immediate bleeding
* Prolonged bleeding
* Nose bleeds & gums
* Easy bruising
93
What are the four potential mechanisms of primary haemostasis defects
1. Low platelet number
2. Impaired platelet function
3. Problems with vWF
4. Problems with vessel wall
94
Outline thrombocytopenia & how it can cause issues with primary homeostasis
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
Outline vWF deficiency
* von Willebrand deficiency (can also cause F VIII deficiency) = defect in platelet adhesion.
* Inherited condition, prolonged bleeding from cuts.
96
Give one example of an acquired and one example of an inherited problem within the vessel wall which can disrupt coagulation
* Inherited: **Ehlers-Danlos Syndrome**
* Acquired: **scurvy**, steroids, vasculitis
97
Outline the general features of disorders of secondary haemostasis
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
What are the two (overall) major causes of coagulation disorders?
**Deficiency of coagulation factor production**
(can either be acquired or inherited)
**Increased consumption of coagulation factors** (always acquired)
99
Outline Haemophilia
* 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
List the causes of acquired coagulation disorders
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
What are antiplatelet drugs? Name a few and the MOA
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
Outline the MOA of Warfarin
103
Outline the MOA of heparin
* 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
Outline the pattern of Hb synthesis & expression
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
What is the difference between Haemmoglobinopathies & Thallasemia?
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
Outline a-thalassaemia
* 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
Outline b-thalassaemia
* 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
Explain how the blood groups arise
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
Describe how the blood groups work
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
Explain the RH groups
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
What is the universal donor and why?
O negative - because there are no antigens (either to the blood groups or to RhD)
112
Outline HDN (haemolytic disease of the newborn)
* 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
Define "cross-matching" in terms of blood transfusions
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
What is the purpose of cross-matching?
* 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
What are the major components within whole blood?
* 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
