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blood coagulation Flashcards

1
Q

What is haemostasis?

A

Haemostasis is the body’s response to blood vessel injury and bleeding. The stopping of blood loss from damaged
vessels and protect against haemorrhage. A highly
complex, regulated process.

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2
Q

What mechanisms are involved in haemostasis following a wound?

A

The mechanisms involved include:
- Vasoconstriction
- Platelet adhesion to the exposed tissue
- Platelet activation to form a haemostatic plug
- Reinforcement of the plug by fibrin

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3
Q

What does the platelet plug consist of in haemostasis?

A

The platelet plug consists of:
- Platelet adhesion to the exposed tissue
- Platelet activation to form a haemostatic plug

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4
Q

What does blood coagulation (thrombus) involve in haemostasis?

A

Blood coagulation (thrombus) involves the reinforcement of the plug by fibrin.

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5
Q

What does haemostasis involve?

A

Haemostasis involves a coordinated effort between platelets and numerous blood clotting proteins (or factors).

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6
Q

What is the result of haemostasis?

A

Haemostasis results in the formation of a blood clot and subsequent stopping of the bleed.

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7
Q

What are the interactions critical to haemostasis?

A

Interactions between platelet activation and the coagulation cascade are critical to haemostasis.

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8
Q

Which mediator is critical in haemostasis?

A

Thrombin is a critical mediator in haemostasis.

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9
Q

What is thrombosis?

A

Thrombosis is the formation of a haemostatic plug within the vasculature in the absence of bleeding, also known as ‘haemostasis in the wrong place.’

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10
Q

What are the predisposing factors for thrombosis, as described by Virchow’s triad?

A

The predisposing factors for thrombosis include:
1. Injury to the vessel wall (e.g., rupture of an atherosclerotic plaque)
2. Altered blood flow (e.g., veins in legs during prolonged sitting, turbulence)
3. Increased coagulability of the blood (thrombophilia)

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11
Q

What is the role of antiplatelet agents in thrombosis treatment?

A

Antiplatelet agents inhibit platelet adhesion, activation, and aggregation, which helps to prevent thrombus formation.

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12
Q

Name some anticoagulants used to prevent thrombus formation.

A

Common anticoagulants include heparin, low-molecular-weight heparins (LMWHs), hirudin, and warfarin.

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13
Q

What is the function of fibrinolytic agents in managing thrombosis?

A

Fibrinolytic agents, such as anistreplase, alteplase, reteplase, streptokinase, and urokinase, activate plasminogen to plasmin, which breaks down fibrin in thrombi.

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14
Q

How does fibrin contribute to thrombus stability?

A

Fibrin forms the framework of the thrombus, trapping blood cells and providing structural integrity.

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15
Q

Describe the process of platelet plug formation in haemostasis.

A
  1. Adhesion: Platelets adhere to exposed collagen at the site of vessel injury.
  2. Activation: The adhered platelets become activated and release ADP and thromboxane A₂.
  3. Attraction of Additional Platelets: Released chemical messengers (ADP and thromboxane A₂) attract and activate more passing platelets.
  4. Aggregation: Newly activated platelets bind to the growing platelet plug, releasing additional aggregating chemicals to strengthen the plug.
  5. Inhibition Beyond Injury Site: Uninjured endothelium releases prostacyclin and nitric oxide to inhibit aggregation, ensuring the plug remains confined to the injury site.
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16
Q

How do antiplatelet agents work to reduce platelet aggregation and the risk of arterial thrombosis?

A
  1. Plaque Disruption leads to exposure of Collagen and vWF (von Willebrand factor), initiating platelet adhesion and secretion.
  2. Inhibition of COX-1:
    - Drug: Aspirin
    - Action: Blocks COX-1, reducing thromboxane A₂ (TXA₂) production, which inhibits platelet recruitment and activation.
  3. ADP Receptor Blockade:
    - Drugs: Ticlopidine, Clopidogrel, Prasugrel, Cangrelor, Ticagrelor
    - Action: Blocks ADP pathway, preventing platelet recruitment and activation.

GPIIb/IIIa Receptor Blockade:
- Drugs: Abciximab, Eptifibatide, Tirofiban
- Action: Prevents GPIIb/IIIa activation, reducing platelet aggregation.

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17
Q

What enzyme releases arachidonic acid (AA) from membrane phospholipids?

A

Phospholipase A2 releases arachidonic acid from membrane phospholipids.

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18
Q

What can arachidonic acid (AA) be converted into?

A

Arachidonic acid can be catalytically converted into biologically active metabolites known as eicosanoids.

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19
Q

What are the three major pathways for eicosanoid production from arachidonic acid?

A

The three major pathways are:
1. Cyclooxygenase pathway
2. Lipoxygenase pathway
3. Epoxygenase pathway

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20
Q

What enzyme catalyzes the conversion of arachidonate to endoperoxides (PGG₂ and PGH₂)?

A

Cyclooxygenase (COX) catalyzes this conversion.

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21
Q

What are the two main products derived from endoperoxides (PGG₂, PGH₂) in platelet function?

A

The two main products are PGI₂ (prostacyclin) and TXA₂ (thromboxane A₂).

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22
Q

What is the function of PGI₂ (prostacyclin) in platelet aggregation?

A

PGI₂ inhibits platelet aggregation.

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23
Q

What is the role of TXA₂ (thromboxane A₂) in platelet function?

A

TXA₂ promotes platelet aggregation.

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24
Q

How does aspirin affect cyclooxygenase (COX) in platelets?

A

Aspirin irreversibly acetylates COX-1, preventing the formation of endoperoxides (PGG₂, PGH₂), thus reducing thromboxane A₂ (TXA₂) production for the platelet’s lifespan.

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25
Why does aspirin act as an effective antiplatelet drug despite reducing both TXA₂ and PGI₂?
Aspirin’s inhibition of TXA₂ in platelets is irreversible (no nucleus to make new COX-1), while PGI₂ synthesis in endothelial cells is reversible (nucleus allows COX re-synthesis), leading to prolonged reduction in clotting without a long-term effect on PGI₂.
26
What is the effect of a single low dose of aspirin on clotting time, and why?
A single low dose of aspirin doubles clotting time for about a week, which is the lifespan of platelets, due to the permanent inactivation of COX-1 in platelets.
27
How does low dosing of aspirin reduce side effects?
Low dosing minimizes gastrointestinal side effects associated with blocking prostaglandins (PGs), which are protective in the gastrointestinal tract.
28
What is the role of COX-1 in platelet activation?
When platelets become activated, COX-1 generates thromboxane A₂ (TXA₂), which promotes further platelet aggregation.
29
How does TXA₂ enhance platelet aggregation?
TXA₂ binds to TP receptors on platelets, increasing the expression of GPIIb/IIIa on platelet cell membranes, which is crucial for platelet aggregation.
30
What is the mechanism of action (MOA) of aspirin as an antiplatelet drug?
Aspirin permanently inhibits TXA₂ production in platelets, thereby chronically reducing platelet aggregation.
31
What are the protective functions of PGI₂, PGE₂, and PGF₂α in the gastrointestinal tract?
PGI₂ prevents gastric secretion, while PGE₂ and PGF₂α increase the production of protective mucus in the stomach and small intestine.
32
How does aspirin affect gastrointestinal health?
Aspirin inhibits the production of PGI₂, PGE₂, and PGF₂α, leading to reduced protective mucus and gastric secretion, which can result in epigastric distress, ulceration, and hemorrhage.
33
What are common and rare side effects of low-dose aspirin as an antiplatelet drug?
Common side effect: Increased bleeding time. Rare side effects: GI irritation, hemorrhage, and ulcers, mitigated by low dosing frequency and enteric coatings.
34
What triggers platelet activation?
Platelet activation is triggered by interactions with exposed collagen, thrombin (IIa), and von Willebrand factor (vWF), leading to binding to receptors on the platelet surface.
35
What is the role of COX-1 in platelet activation?
COX-1 in platelets produces thromboxane A2 (TXA₂), which promotes platelet aggregation.
36
How do ADP and P2Y₁/P2Y₁₂ receptors contribute to platelet activation?
ADP binds to P2Y₁/P2Y₁₂ receptors on platelets, enhancing aggregation by increasing GPIIb/IIIa receptor expression for fibrinogen binding.
37
What role does GPIIb/IIIa play in platelet activation?
GPIIb/IIIa receptors bind fibrinogen, linking platelets together and facilitating aggregation.
38
How does PGI₂ regulate platelet activation?
PGI₂ (prostacyclin) from endothelial cells inhibits platelet aggregation, providing a balance to prevent excessive clotting.
39
What is the role of ADP in platelet aggregation?
ADP induces platelet aggregation by activating P2Y₁₂ receptors on platelets.
40
How do thienopyridines inhibit platelet aggregation?
Thienopyridines irreversibly inhibit P2Y₁₂ receptors, which blocks ADP-induced platelet aggregation.
41
How is clopidogrel activated in the body?
Clopidogrel is a prodrug that is well absorbed orally and converted to its active metabolite by CYP enzymes, including CYP2C19, in the liver.
42
What factors may reduce the effectiveness of clopidogrel?
Variant alleles or CYP2C19 inhibitors can decrease the effectiveness of clopidogrel due to alterations in CYP2C19 enzyme activity.
43
For what conditions is clopidogrel commonly used?
Clopidogrel is used for the prevention of ischemic events in patients with symptomatic atherosclerosis and can be used in combination with aspirin.
44
What are common adverse effects of clopidogrel?
Common adverse effects include diarrhea, GI ulcer, and an increased risk of bleeding.
45
What is the mechanism of action for GP IIb/IIIa inhibitors like abciximab and tirofiban?
GP IIb/IIIa inhibitors prevent fibrinogen crosslinking of platelets, thus inhibiting platelet aggregation.
46
What role does the GP IIb/IIIa receptor play in platelet aggregation?
The GP IIb/IIIa receptor, when activated, binds to fibrinogen, which crosslinks platelets and promotes aggregation.
47
How do GP IIb/IIIa inhibitors affect platelet function?
GP IIb/IIIa inhibitors block the fibrinogen binding sites on activated platelets, preventing platelet aggregation.
48
What is thrombin’s primary function in hemostasis?
Thrombin stimulates the conversion of fibrinogen to fibrin, which is essential for clot formation.
49
How does thrombin contribute to clot stability?
Thrombin activates Factor XIII, which stabilizes the fibrin meshwork of the clot.
50
What role does thrombin play in platelet aggregation?
Thrombin enhances platelet aggregation, which helps to strengthen the developing blood clot.
51
How does thrombin use positive feedback to amplify clotting?
Thrombin enhances the activation of more prothrombin into thrombin, increasing its own production through positive feedback.
52
What is Platelet Factor 3 (PF3) and how does it interact with thrombin?
Aggregated platelets secrete PF3, which stimulates additional clotting cascade activation, resulting in more thrombin production.
53
What is the role of thrombin in blood coagulation?
Thrombin (factor IIa) cleaves fibrinogen into fibrin, converting it from a soluble to an insoluble form, which is essential for clot formation.
54
How does thrombin contribute to clot stability beyond converting fibrinogen?
Thrombin activates factor XIII (fibrinoligase), which cross-links fibrin strands, stabilizing the clot.
55
What additional effects does thrombin have in the blood coagulation process?
Thrombin induces platelet aggregation and can affect vascular smooth muscle (VSM) tone.
56
What controls are in place to regulate the coagulation cascade?
Endogenous inhibitors, like antithrombin, inhibit critical clotting factors such as IXa, Xa, XIa, XIIa, and thrombin to prevent excessive clotting.
57
What are zymogens, and what is their significance in coagulation?
Zymogens are inactive enzymes present in the blood that become activated to initiate and amplify the coagulation cascade.
58
What is Hirudin?
Hirudin is one of the first anticoagulants and acts as a direct thrombin inhibitor.
59
How do Direct Thrombin Inhibitors (DTIs) differ from heparin and LMWH?
Direct thrombin inhibitors do not rely on endogenous anticoagulant systems, unlike heparin and LMWH.
60
What is Dabigatran?
Dabigatran is an orally-available direct thrombin inhibitor that reversibly inhibits both free and clot-bound thrombin, as well as thrombin-mediated platelet aggregation.
61
What is a notable benefit of Dabigatran over warfarin?
Dabigatran has a fixed dose that produces a predictable anticoagulant effect, making it a promising alternative to warfarin.
62
What is Rivaroxaban and its mechanism of action?
Rivaroxaban is an orally-available drug that inhibits factor Xa to reduce thrombin production, with similar usage indications as dabigatran.
63
What is Heparin?
Heparin is a family of large sulfated polysaccharides that is not absorbed from the gut due to its charge and high molecular weight, and is administered intravenously (IV) or subcutaneously (SC).
64
How does Heparin work as an anticoagulant?
Heparin indirectly inhibits thrombin by enhancing anti-thrombin (AT) mediated inactivation of factor Xa and thrombin, increasing AT's affinity for clotting factors.
65
Why is Heparin's inactivation of thrombin unique?
Inactivation of thrombin by heparin requires long polysaccharide chains that can complex with both AT and thrombin; these chains are absent in low molecular weight heparins (LMWH) like enoxaparin.
66
What is the main risk of Heparin and how can it be treated?
The main risk of heparin is hemorrhage, which can be treated with protamine sulfate, a compound that complexes with and inactivates heparin.
67
What are some adverse effects of Heparin?
Adverse effects of heparin include bruising, thrombosis, osteoporosis (long-term use), and hypersensitivity reactions.
68
What is the role of Vitamin K in blood coagulation?
Vitamin K is required for the synthesis of coagulation factors II, VII, IX, and X.
69
How is Vitamin K obtained?
Vitamin K is obtained from plants and produced by gut microflora; it is also routinely given at birth in Australia.
70
What is the function of Vitamin K in coagulation at the molecular level?
Vitamin K acts as a co-factor for the enzyme carboxylase, which is involved in activating coagulation factors.
71
What is the primary mechanism of action of Warfarin?
Warfarin competes with vitamin K for binding at vitamin K reductase (VKORC1), inhibiting the synthesis of key clotting factors.
72
How is Warfarin administered and absorbed?
Warfarin is orally active and rapidly absorbed.
73
Describe the pharmacokinetics of Warfarin regarding distribution and binding.
Warfarin has a small distribution volume and is strongly albumin-bound.
74
How long does it take for Warfarin to reach peak pharmacological effects?
Although it reaches peak blood concentration in a few hours, peak pharmacological effects take around 48 hours.
75
What genetic factors can affect a patient’s response to Warfarin?
Patient response to Warfarin varies due to polymorphisms in the VKORC1 gene and the CYP2C9 enzyme, which metabolizes Warfarin.
76
Why does Warfarin require frequent monitoring?
Warfarin has a low margin of safety, requiring dose individualization and regular monitoring.
77
What are some interaction risks associated with Warfarin?
Warfarin interacts with other albumin-bound drugs, antibiotics, and P450 enzyme inhibitors, affecting its efficacy and safety.
78
Can Warfarin cross the placenta?
Yes, Warfarin crosses the placenta, which is significant in pregnancy considerations.
79
What is the function of endogenous plasminogen activators?
They cleave plasminogen (bound to fibrin strands in a thrombus) to release plasmin, which digests fibrin, fibrinogen, ECM proteins, and some clotting factors.
80
Why is plasmin action localized to the clot?
Plasminogen activators are primarily effective on plasminogen bound to fibrin, and any escaping plasmin is inactivated by circulating plasmin inhibitors.
81
What is the clinical use of fibrinolytic drugs?
Fibrinolytic drugs are used to dissolve clots and reopen occluded arteries in patients with acute myocardial infarction (MI) within 12 hours of onset.
82
What is the origin of initial fibrinolytic drugs, and how have they evolved?
Initial drugs were derived from haemolytic streptococci; current versions use recombinant DNA technology.
83
What is Alteplase?
Alteplase is a recombinant tissue plasminogen activator (tPA) with greater activity on fibrin-bound plasminogen, increasing clot selectivity, and is non-antigenic.
84
How is Alteplase administered, and what are the major risks?
Alteplase is administered intravenously (IV), with major risks including bleeding (e.g., GI haemorrhage and haemorrhagic stroke).
85
What is Tenecteplase?
Tenecteplase is a modified version of tissue plasminogen activator (tPA) with similar properties to Alteplase.

Biom2402 (6 decks)

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