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Path - Haem > coagulation and haemostasis > Flashcards

coagulation and haemostasis Flashcards

1
Q

what is primary haemostasis?

A

Primary hemostasis occurs when platelets attach to a damaged or disrupted area of the endothelium. This adhesion allows the platelets to undergo a shape change and then aggregate together. Once adhered to each other a temporary platelet plug ‘primary haemostatic plug’ is created.

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2
Q

what is secondary haemostasis?

A

Secondary hemostasis is defined as the formation of insoluble, cross-linked fibrin by activated coagulation factors, specifically thrombin.

Fibrin stabilizes the primary platelet plug, particularly in larger blood vessels where the platelet plug is insufficient alone to stop hemorrhage.

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3
Q

which 3 mechanisms are involved in the formation of a stable haemostatiic plug?

A

Blood vessel constriction
Formation of platelet plug : platelet activation
Coagulation cascade: fibrin formation

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4
Q

what mechanisms does blood vessel injury trigger?

A 
Blood vessel constriction (via neural action)
Formation of platelet plug 
Coagulation cascade (via tissue factor)
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5
Q

what is the role of the endothelium?

A
  • Synthesis of PGI2, vWF, plasminogen activators (TPA), thrombomodulin
  • maintain barrier between blood and procoagulant subendothelial structures
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6
Q

what is the origin of platelets? properties?

A

from megakaryocytes

In the blood circulation, eeach megakaryocyte
produces ~4000 platelets.

Lifespan ~10 days, 1/3 stored in spleen

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7
Q

what is the structure of platelets - noteworthy stuff?

A

Surface glycoproteins:
GpIa, GpIb, GpIIb/IIIa

Dense granules:
ADP, ATP, Serotonin, Ca2+

a granules:
growth factors, fibrinogen, factor V, vWF

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8
Q

what is the mechanism of Platelet adhesion and aggregation? what factors are involved?

A

Platelet adhesion:
Tissue injury = platelets adhere to exposed subendothelial tissue via 2 WAYS:

  1. Via Gp1a (to collagen)
  2. Via Gp1b to vWF bound to collagen: more COMMON

Leads to Release of ADP & thromboxane

Platelet aggregation:
Platelets bind to fibrinogen (+ Ca2+) with the fibrinogen receptor aka Gp2b/3a.
This leads to activation cascade = more platelets join in

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9
Q

what are the biproducts in the metabolism of Arachidonic acid? what are their roles?

A

Arachidonic Acid is broken down by Cyclooxygenase enzymes and others forming:

Thromboxane A2 - Induces platelet aggregation

Prostacylin PGI2 - Inhibits platelet aggregation

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10
Q

what is the MOA of aspirin/ASA (Acetylsalicylic Acid) ?

MOA of NSAIDs?

A

Irreversibly blocks/inhibits the Cyclooxygenase 1 enzyme

preventing the formation of prostaglandin H2, and therefore thromboxane A2

NSAIDs - reversible effect

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11
Q

what does the term ‘tenase’ refer to?

A

the factors needed to activate factor 10.

they are slightly different in the ex/intrinsic pathways.

Intrinsic: Ca2+, FIXa, FVIIIa

Extrinisic: TF, Ca2+, FVIIa

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12
Q

what is the role of thrombin?

A

Cleaves Fibrinogen
Activates Platelets
Activates procofactors (FV and FVIII)
Activates zymogens (FVII, FXI and FXIII)

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13
Q

what is required to activate factor 2/prothrombin?

A

the prothrombinase complex:

Ca2+, FXa, FVa

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14
Q

what is the most important step in the coagulation cascade?

A

production of thrombin

as it catalyses the last step

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15
Q

what is the rate limiting step in fibrinogen formation?

A

production of FXa

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16
Q

what are the phases in the coagulatin cascade?

A

Initiation phase - small amounts of FXa production -> it binds to FVa

Amplification phase - 
The FXa/FVa complex converts small amounts of prothrombin into thrombin.
Thrombin generated activates F8,5,11
and platelets locally. 
Leads to platelet activation

Propagation phase -
F10a/5a converts prothrombin into thrombin creating a “thrombin burst”.
The “thrombin burst”leads to the formationof a stable fibrin clot.

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17
Q

what is the redvance of Prothrombinase
Components binding and the Relative Rate
of Prothrombin Activation?

A

each component thatbinds leads to 10 fold increase in activation

when they all bind to lipid bilayer, there is 1000 fold increase.

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18
Q

what are the vit K dependent coagulation factors? made where?

A

F2,7,9,10

produced in the liver

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19
Q

how can a biliary tract issue lead to a coagulation defect?

A

vitamin k is fat soluble vitamin

needs bile

if bile duct obstruction -> can become vitamin k deficient

liver keeps on making the coagulation factors BUT they cant be activated (gamma carboxylation) due to lack of vit K

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20
Q

what are the different ways the body deals with blood clots?

A
  1. Fibrinolysis
  2. Antithrombins - heparin potentiates its effect
  3. Protein C/S - deactivate FVa, F8a - so those activating complexes dont form
  4. TFPI - tissue factor pathway inhibitor
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21
Q

describe the events in fibrinolysis?

A

the process is activated as soon a a clot forms

plasminogen is converted to Plasmin

Plasmin leads breakdown of Fibrin

activating enzymes of plasmin production = tPA, Urokinase
other stimulatory factors: Kallikrein, F11a, F12a

22
Q

list some factors that inhibit fibrinolysis?

A

inhibit plasmin:
a2 plasmin
a2 macroglobulin

inhibit fibrin degradation:
TAFI; thrombin activated fibrinolysis inhibitor

23
Q

how do antithrombins work?

A

they bind to proteoglycans on endothelial cells surface

stop thrombin generation

24
Q

what is the mechanism in FV Leiden?

A

this mutation confers resistance to activated protein C

meaning that activated protein C cannot degrade F5a/8a

high levels of F8 also has the same effect

25
Q

how does Tissue Factor pathway inhibitor work?

A

when tissue factor binds to F7 and converts it to 7a, TFPI steps in and inhibits straight away.

26
Q

characterise the defects implicated here

  1. Haematoma & Joint bleed
  2. wound / surgical bleeding
    Immediate -
    Delayed -
  3. Petechiae
A

Haematoma & Joint bleed - Coagulation

Wound / surgical bleeding –
Immediate - (Platelet)
Delayed - (Coagulation)

Petechiae: platelet

27
Q

characterise the defects implicated here

Ecchymoses (“bruises”)

Haemarthrosis / muscle bleeding

Bleeding after cuts & scratches

A

Ecchymoses (“bruises”):
Small, superficial - platelets
Large, deep - coagulation

Haemarthrosis / muscle bleeding:
Commonly coagulation defect

Bleeding after cuts & scratches:
platelet

28
Q

Where is the Site of bleeding for

platelet disorders

coagulation disorders

A

platelet disorders:
Skin
Mucous membranes
(epistaxis, gum,vaginal, GI tract)

coagulation disorders:
joints, muscles
Soft tissues

29
Q

list some disorders of platelets?

A

Decreased Number: Thrombocytopenia
Decreased Production
Decreased Survival – Immune (ITP)
Increased utilization – DIC

Defective Platelet function:
Acquired – Drugs – Aspirin, ESRF
Congenital – Eg. Thrombasthenia

30
Q

what is the MOA of clopidogrel?

A

Clopidogrel is a specifc, non-competive inhibitor of adenosine diphosphate- (ADP) induced platelet aggregation,

irreversibly inhibiting the binding of ADP to its platelet membrane receptors.

Ultimately it inhibits the activation of the GPIIb/IIIa receptor, its binding to fibrinogen and further platelet aggregation.

31
Q

What is the MOA of TXA2?

A

TXA2 activates the GPIIb/IIIa binding site on the platelet, allowing fibrinogen to bind.

32
Q

In general what is the Mode of Action of Antiplatelet Agents?

A

through various mechanisms - they inhibit platelet aggregation

33
Q

what is the MOA of an Idiopathic Immune Thrombocytopenic Purpura (auto-ITP)?

A

antiplatelet autoantibodies coat the platelet leading to macrophage mediated destruction of the platelet

34
Q

what are the features and epidemiology of Acute ITP?

A

Children 2-6

Preceding infection - Common
Platelet count at presentation - <20,000

Spontaneous resolution

35
Q

what are the features and epidemiology of chronic ITP?

A

adults
Preceding infection - rare
Platelet count at presentation - <30,000

spontaneous remission Uncommon

36
Q

what is thee Initial Treatment for ITP?

A

based on platelet count:

> 50,000 No sx Dont treat

20-50,000 Not bleeding Don’t treat
Bleeding Steroids + IVIG

<20,000 Not bleeding -Steroids
Bleeding - Steroids + IVIG +Hospitalization

37
Q

how do you differentiate a petechial rash from meningococcal rash?

A

petechial rash - non blanching

38
Q

what is the aetiology of haemophilia? rx?

A

Congenital deficiency -Factor 8 (A) or 9 (B)

Bleeding – Haematoma, joint etc. haemophilia A & B are indistinguishable.
the lower the % factors available the increase in spontaneity of bleeding

Gene on X chromosome.
(Carrier females, Males suffer)

Prolonged aPTT (intrinsic and common pathway) but normal PT (extrinsic and common pathway).

Clotting factor replacement-Life long.

39
Q

what is the aetiology and epidemiology of vWD?

A

Inheritance - autosomal dominant (apart from type 3)
An affected parents means 50% chance of kids being affected.

IF 2 parents affected, you can have hetero and homoxygous forms -> varying severity phenotypically

Females can be affected

factor 8 is low

40
Q

what are the types of vWD? most common? most severee?

A

Type 1 Partial quantitative deficiency

- most common 
- reduced number of vWF
- desmopressin effective

Type 2 Qualitative deficiency
- vWF present but reduced function

Type 3 Total quantitative deficiency

  • most severe
  • severely low vWF number
  • autosomal recessive
  • desmopressin INeffective
41
Q

how is vitamin k deficiency treated?

A

Vitamin K

Fresh frozen plasma

42
Q

which mechanisms are activated in DIC? what happens, and why is it an issue?

A

Activation of both coagulation and fibrinolysis triggered by a range of events eg sepsis

Systemic activation of coagulation -> deposition of fibrin in vessels -> thrombosis in small and medium vessels -> organ failure

Systemic activation of coagulation -> depletion of platelet and coagulation factors -> bleeding

43
Q

what will be the blood ivx results in DIC?

A

Increased/Prolonged:
aPTT
PT
TT

Fibrinogen Low

Presence of plasmin:
Increased FDP (fibrin degradation products)

Intravascular clot:
Increased Platelets
Schistocytes - as blocked vessel causes shredding

44
Q

how do we treat DIC?

A

Treat cause/underlying condition

Platelet transfusion

Fresh frozen plasma

Coagulation inhibitor concentrate:
APC concentrate (activated protein c)
45
Q

what is involved in the Management of Haemostatic Defects in Liver Disease?

A

Treatment for prolonged PT/PTT
Vitamin K 10 mg o.d x 3 days - usually ineffective

Fresh-frozen plasma infusion
25-30% of plasma volume (1200-1500 ml)
immediate but temporary effect

Treatment for low fibrinogen
Cryoprecipitate (1 unit/10kg body weight)

Treatment for DIC (Elevated D-dimer, low factor VIII, thrombocytopenia
Replacement therapy

46
Q

list some factors that can be used to inhibit initiation?

A

Tissue Factor Pathway Inhibitors:

TFPI, NAPc2

47
Q

list some factors that can be used to inhibit amplification?

A

Inhibitors of thrombin generation:

 Factor IXa Inhibitors:
	  IXa inhibitors, IXa antibody
	Protein C Activators:
    APC, thrombomodulin
	Factor Xa Inhibitors:
    fondaparinux, rivorxaban, abixaban etc
48
Q

list some factors that can be used to inhibit amplification?

A

Inhibitors of thrombin activity:

Thrombin Inhibitors:
Hirudin, bivalirudin, argatroban,
melagatran, dabigatran

49
Q

how do we manage Vitamin K deficiency due to warfarin overdose?

A

based on INR value

low INR - omit next warfarin does, monitor INR

medium INR- many need to give a dose of vitamin K

high INR - may need to lower dose/ stop warfarin
give vitamin k PO/IV
give FFP/PCC

50
Q

what would be the ivx finding in vWD?

A

Type 1:
Platelet count - normal
PT - normal
aPTT - prolonged

F8 activity low

Type 2A&B:
Low platelet - thrombocytopaenia

51
Q

how can vWD present?

A

Mennorhagia

Epistaxis

Gingival bleeding

Mucosal bleeding

Bleeding post surgeries

Type 2A: TTP

Type 3:
Spontaneous bleeding
bit like haemophilia a

52
Q

how is the number of vWF measured?

A

vWF antigen

Path - Haem (13 decks)

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