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NMSK (Lectures) > Haemostasis > Flashcards

Haemostasis Flashcards

1
Q

Outline the structure of platelets

A

Also known as thrombocytes
Very small
No nucleus
Lifespan ~10 days
Stored in spleen

Membrane-bound fragments of cytoplasm from megakaryocytes
-Surface glycoproteins (GPs)
-Phosphatidyl serine (PS)
-Rich in microfilaments and microtubules - allows contraction

Organelles
-Alpha granules (a)
- Dense granules/bodies (d)
- g and l granules

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2
Q

Outline the importance of alpha granules in platelets

A

Growth factors
-Insulin-like growth factor
-Platelet-derived growth factor
-Transforming growth factor beta (TGFb)

von Willebrand factor

P-selectin, thrombospondin, fibronectin

Platelet factor 4 (heparin-binding chemokine)

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3
Q

List other granules found in platelets and outline their importance

A

δ (delta or dense granules)
-contain ADP or ATP
-calcium
-serotonin

γ (gamma granules)
-similar to lysosomes
-contain hydrolytic enzymes

λ (lambda granules)
-contents involved in clot resorption

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4
Q

Outline the function of platelets

A

Primary:
Initial response to endothelial damage
Local vasoconstriction
Formation of the platelet plug

Secondary:
Strengthening and reinforcement of the platelet plug
Formation of a stable fibrin clot

Tertiary
Removal of fibrin by fibrinolysis
Restore vessel patency (i.e. open / unblocked)

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5
Q

Discuss the process of Thrombopoiesis

A

Stem cells respond to Thrombopoietin (TPO) which is a growth factor that is produced primarily in liver (and kidney).

The stem cells differentiate into the megakaryocyte precursor cell, which then differentiates into the megakaryocyte.

Megakaryocytes undergo endomitosis until growth limit is reached and the cell membrane begins to bud off to form the thrombocytes

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6
Q

Describe how thrombopoiesis is regulated

A

Regulated by a negative feed back system where growth factor thrombopoietin binds to TPO receptors on both the megakaryocytes and platelets; if these are in high concentrations in the blood plasma then the level of TPO is kept low, reducing the maturation of CFU-Meg and thrombocyte production.

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7
Q

Describe the basic mechanism of blood clotting

A
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8
Q

Define haemostasis?

A

Stopping the flow of blood

Balancing between hypercoagulability (thrombosis) and bleeding (haemorrhagic diathesis)

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9
Q

List the steps involved in primary haemostasis

A

Initial (transient) response which influences vasoconstriction to reduced blood flow

Platelet adhesion

Platelet activation

Platelet aggregration

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10
Q

Describe the initial transient primary response

A

Damage to blood vessel endothelium
-Local neural reflexes (pain receptors)
-Muscle contraction (direct mechanical impact on smooth muscle cells)

Platelet activation
-thromboxane A produced
-serotonin released (δ granules)

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11
Q

Describe the primary response of platelet adhesion

A

Platelets bind to von Willebrand factor on exposed sub-endothelium via GPIb-IX-V receptor

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12
Q

Describe the primary response of platelet activation

A

-Platelets change shape
-GPIIb/IIIa receptor activation which binds collagen
-Release of agonists
a, b granule contents
ADP
serotonin
platelet activating factor
thromboxane A2

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13
Q

Describe the primary response of platelet aggregation

A

Primarily mediated by fibrinogen binding to GPIIb/IIIa on adjacent platelets

Enhanced by generation of thrombin (link with secondary haemostasis)

Leads to formation of the platelet plug

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14
Q

Explain the process of haemostasis in the healthy animal

A

Healthy endothelial cells & platelets repel each other (negatively charged)

Healthy endothelial cells produce prostacyclin (prostaglandin 2, PGl2)
-inhibits platelet activation
-effective vasodilator

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15
Q

Provide an overview of secondary haemostasis

A

Strengthening and reinforcement of the platelet plug
Involves coagulation factors (e.g. factor VIII)
Formation of a stable fibrin clot

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16
Q

Describe the coagulation cascade

A

Initiation (extrinsic pathway)
-Injury exposes TF-bearing cell to flowing blood
-small amount of FIXa and thrombin generated

Amplification
-Thrombin activates platelets (exposing PS)
-vWF released (tethers plts to site of injury by binding to GPIb/FIX receptor on one hand and sub-endothelial collagen on the other)
-Leads to activation of FXI, FVIII, FV

Propagation
-Factors assemble on the activated platelet to form intrinsic tenase (FIXa, FVIIIa and Ca2+)
-Results in FXa generation on the platelet surface
-Prothrombinase complex (FXa, FVa, Ca2+) forms and results in a burst of thrombin generation directly on the platelet (stabilisation)

17
Q

Explain and interpret laboratory tests with regards to haemostasis

A
18
Q

Describe the coagulation cascade

A

Initiation (extrinsic pathway)
-Injury exposes TF-bearing cell to flowing blood
-small amount of FIXa and thrombin generated

Amplification
-Thrombin activates platelets (exposing PS)
-vWF released (tethers plts to site of injury by binding to GPIb/FIX receptor on one hand and sub-endothelial collagen on the other)
-Leads to activation of FXI, FVIII, FV

Propagation
-Factors assemble on the activated platelet to form intrinsic tenase (FIXa, FVIIIa and Ca2+)
-Results in FXa generation on the platelet surface
-Prothrombinase complex (FXa, FVa, Ca2+) forms and results in a burst of thrombin generation directly on the platelet (stabilisation)

19
Q

List the inhibitors of the coagulation cascade and outline their inhibition process

A

Antithrombin - main inhibitor of thrombin. Binds and inactivates TF Ixa, Xa, Xia & XIIIa. The enzymatic activity of AT is enhanced by heparin

TFP1 - polypeptide produced by endothelial cells. Natural inhibitor of extrinsic pathway by inhibing TF-VIIa complex. Protein S enhances the interaction of TF Xa in the presence of calcium and phospholipids

Protein C- Inhibits propagation phase of coagulation pathway. Activated by thrombin to form activated protein C, inhibiting TF V & VIII

20
Q

Outline the process of tertiary haemostasis

A

Fibrin clot removal
-Tissue plasminogen activator (tPA) activates -plasminogen to form plasmin

-Breaks down fibrin fibres to fibrinogen degradation products (FDPs)

-Smallest = D-dimers

-FDPs act as anticoagulants by interfering with platelet aggregation and fibrin polymerisation

21
Q

How is haemostasis assessed

A

Thrombocytopenia
abnormally low platelet count
Decreased production
Increased destruction / consumption

Thrombocytopathy
Abnormal platelet function
e.g. von Willebrand’s disease

Vascular defects

22
Q

Outline the normal reference values for a dog undergoing haemostasis

A

Reference: 150–400 x109/L (dogs)
<100 : thrombocytopenia

50    :    haemorrhage may be induced
 
<30    :    spontaneous haemorrhage
23
Q

Lists the tests used to measure primary haemostasis

A

Buccal mucosal bleeding time (BMBT)
Simplate device
Platelet Count

24
Q

Describe the Buccal mucosal bleeding time (BMBT)
test

A

Time taken for bleeding to stop after making a small incision

A quick test to perform in practice

Requires practice and does not determine cause of abnormality

Healthy dog:	1.7 – 4.2 min
Healthy cat:	1.0 – 2.4 min

This time may be prolonged if disorder of primary haemostasis

25
Q

Describe how the Simplate device is used

A

A device used to measure buccal mucosal bleeding time

It is applied around the dog muzzle and two prongs puncture the mucosa. A stopwatch is then used to calculate the time for haemostasis. Dogs aren’t typically anaesthetised but cats are

26
Q

Describe how platelet counting can be done

A

EDTA sample

Counts should be performed as soon as possible to avoid clumping

Three methods can be used:
1. Haemocytometer

  1. Automated cell count
    More accurate BUT cannot see what is happening
    (e.g. cat platelets tend to clump; CKCS dogs have larger platelets) therefore must check on a smear
  2. Blood smear
    Estimated count from a blood smear
    = No. x 15 x 109/L
    healthy dog/cat >10 platelets / 100x oil immersion field

Check for clumping in feathered region
(pseudo-thrombocytopenia)

27
Q

Lists the tests used to measure secondary haemostasis

A

‘Group’ coagulation tests
Coumarin toxicity (rat poisoning)
Activated coagulation time
Thromboelastography (TEG) / ROTEM

28
Q

Describe the ‘Group’ coagulation tests

A

Measure the different coagulation factors

Prothrombin time (PT) or OSPT1
-add thromboplastin (@ TF) and Ca2+ ions to activate the extrinsic pathway

Activated partial thromboplastin time (aPTT)
-add reagent to activate the intrinsic system (surface activator & phospholipid) and Ca2+ ions – note no thromboplastin
-Time to clot formation prolonged by alterations of factors (<30% normal)

Thrombin clot time
-assesses the ability of added thrombin to convert fibrinogen g fibrin

29
Q

Describe how Coumarin toxicity (rat poisoning) affects coagulation

A

Vitamin K triggers carboxylase which is key in the activation of factors, warfarin which is found in rat poison blocks the action of vitamin K, leading to a reduction of tissue factors. It can take up to 1-2 to start to have an effect and TF VII affected first

30
Q

Describe how Activated coagulation time is measured

A

2ml blood in ACT tube containing contact activator
Warm (37°C)
Check for clot formation every 5–10 seconds
Record time that clot forms
Check reference range for the tube type

31
Q

Describe how Thromboelastography (TEG) / ROTEM is used

A

Measure process of blood clotting. Machines stir blood when coagulation is added the paddle will slow

32
Q

Describe the latex agglutination test (FDPs/D-dimers) and how it measures tertiary haemostasis

A

Measuring D dimers. Antibodies detect d dimers in the wells, if d dimer is present a speckly effect occurs

33
Q

Outline other specialist tests that can be used in haemostasis

A

-Platelet function tests
aggregometry, adhesion assays, flow cytometry (expression of surface molecules)

-vWF assays
ELISA for vWF antigen
vWf-dependent platelet aggregation to measure function
Protein immunoelectrophoresis to measure vWf multimer distribution

-Fibrinogen concentration

-Antithrombin concentration

NMSK (Lectures) (63 decks)

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