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Biom2402 > blood coagulation > Flashcards

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
Q

Why does aspirin act as an effective antiplatelet drug despite reducing both TXA₂ and PGI₂?

A

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.

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26
Q

What is the effect of a single low dose of aspirin on clotting time, and why?

A

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.

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27
Q

How does low dosing of aspirin reduce side effects?

A

Low dosing minimizes gastrointestinal side effects associated with blocking prostaglandins (PGs), which are protective in the gastrointestinal tract.

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28
Q

What is the role of COX-1 in platelet activation?

A

When platelets become activated, COX-1 generates thromboxane A₂ (TXA₂), which promotes further platelet aggregation.

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29
Q

How does TXA₂ enhance platelet aggregation?

A

TXA₂ binds to TP receptors on platelets, increasing the expression of GPIIb/IIIa on platelet cell membranes, which is crucial for platelet aggregation.

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30
Q

What is the mechanism of action (MOA) of aspirin as an antiplatelet drug?

A

Aspirin permanently inhibits TXA₂ production in platelets, thereby chronically reducing platelet aggregation.

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31
Q

What are the protective functions of PGI₂, PGE₂, and PGF₂α in the gastrointestinal tract?

A

PGI₂ prevents gastric secretion, while PGE₂ and PGF₂α increase the production of protective mucus in the stomach and small intestine.

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32
Q

How does aspirin affect gastrointestinal health?

A

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.

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33
Q

What are common and rare side effects of low-dose aspirin as an antiplatelet drug?

A

Common side effect: Increased bleeding time. Rare side effects: GI irritation, hemorrhage, and ulcers, mitigated by low dosing frequency and enteric coatings.

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34
Q

What triggers platelet activation?

A

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.

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35
Q

What is the role of COX-1 in platelet activation?

A

COX-1 in platelets produces thromboxane A2 (TXA₂), which promotes platelet aggregation.

36
Q

How do ADP and P2Y₁/P2Y₁₂ receptors contribute to platelet activation?

A

ADP binds to P2Y₁/P2Y₁₂ receptors on platelets, enhancing aggregation by increasing GPIIb/IIIa receptor expression for fibrinogen binding.

37
Q

What role does GPIIb/IIIa play in platelet activation?

A

GPIIb/IIIa receptors bind fibrinogen, linking platelets together and facilitating aggregation.

38
Q

How does PGI₂ regulate platelet activation?

A

PGI₂ (prostacyclin) from endothelial cells inhibits platelet aggregation, providing a balance to prevent excessive clotting.

39
Q

What is the role of ADP in platelet aggregation?

A

ADP induces platelet aggregation by activating P2Y₁₂ receptors on platelets.

40
Q

How do thienopyridines inhibit platelet aggregation?

A

Thienopyridines irreversibly inhibit P2Y₁₂ receptors, which blocks ADP-induced platelet aggregation.

41
Q

How is clopidogrel activated in the body?

A

Clopidogrel is a prodrug that is well absorbed orally and converted to its active metabolite by CYP enzymes, including CYP2C19, in the liver.

42
Q

What factors may reduce the effectiveness of clopidogrel?

A

Variant alleles or CYP2C19 inhibitors can decrease the effectiveness of clopidogrel due to alterations in CYP2C19 enzyme activity.

43
Q

For what conditions is clopidogrel commonly used?

A

Clopidogrel is used for the prevention of ischemic events in patients with symptomatic atherosclerosis and can be used in combination with aspirin.

44
Q

What are common adverse effects of clopidogrel?

A

Common adverse effects include diarrhea, GI ulcer, and an increased risk of bleeding.

45
Q

What is the mechanism of action for GP IIb/IIIa inhibitors like abciximab and tirofiban?

A

GP IIb/IIIa inhibitors prevent fibrinogen crosslinking of platelets, thus inhibiting platelet aggregation.

46
Q

What role does the GP IIb/IIIa receptor play in platelet aggregation?

A

The GP IIb/IIIa receptor, when activated, binds to fibrinogen, which crosslinks platelets and promotes aggregation.

47
Q

How do GP IIb/IIIa inhibitors affect platelet function?

A

GP IIb/IIIa inhibitors block the fibrinogen binding sites on activated platelets, preventing platelet aggregation.

48
Q

What is thrombin’s primary function in hemostasis?

A

Thrombin stimulates the conversion of fibrinogen to fibrin, which is essential for clot formation.

49
Q

How does thrombin contribute to clot stability?

A

Thrombin activates Factor XIII, which stabilizes the fibrin meshwork of the clot.

50
Q

What role does thrombin play in platelet aggregation?

A

Thrombin enhances platelet aggregation, which helps to strengthen the developing blood clot.

51
Q

How does thrombin use positive feedback to amplify clotting?

A

Thrombin enhances the activation of more prothrombin into thrombin, increasing its own production through positive feedback.

52
Q

What is Platelet Factor 3 (PF3) and how does it interact with thrombin?

A

Aggregated platelets secrete PF3, which stimulates additional clotting cascade activation, resulting in more thrombin production.

53
Q

What is the role of thrombin in blood coagulation?

A

Thrombin (factor IIa) cleaves fibrinogen into fibrin, converting it from a soluble to an insoluble form, which is essential for clot formation.

54
Q

How does thrombin contribute to clot stability beyond converting fibrinogen?

A

Thrombin activates factor XIII (fibrinoligase), which cross-links fibrin strands, stabilizing the clot.

55
Q

What additional effects does thrombin have in the blood coagulation process?

A

Thrombin induces platelet aggregation and can affect vascular smooth muscle (VSM) tone.

56
Q

What controls are in place to regulate the coagulation cascade?

A

Endogenous inhibitors, like antithrombin, inhibit critical clotting factors such as IXa, Xa, XIa, XIIa, and thrombin to prevent excessive clotting.

57
Q

What are zymogens, and what is their significance in coagulation?

A

Zymogens are inactive enzymes present in the blood that become activated to initiate and amplify the coagulation cascade.

58
Q

What is Hirudin?

A

Hirudin is one of the first anticoagulants and acts as a direct thrombin inhibitor.

59
Q

How do Direct Thrombin Inhibitors (DTIs) differ from heparin and LMWH?

A

Direct thrombin inhibitors do not rely on endogenous anticoagulant systems, unlike heparin and LMWH.

60
Q

What is Dabigatran?

A

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
Q

What is a notable benefit of Dabigatran over warfarin?

A

Dabigatran has a fixed dose that produces a predictable anticoagulant effect, making it a promising alternative to warfarin.

62
Q

What is Rivaroxaban and its mechanism of action?

A

Rivaroxaban is an orally-available drug that inhibits factor Xa to reduce thrombin production, with similar usage indications as dabigatran.

63
Q

What is Heparin?

A

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
Q

How does Heparin work as an anticoagulant?

A

Heparin indirectly inhibits thrombin by enhancing anti-thrombin (AT) mediated inactivation of factor Xa and thrombin, increasing AT’s affinity for clotting factors.

65
Q

Why is Heparin’s inactivation of thrombin unique?

A

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
Q

What is the main risk of Heparin and how can it be treated?

A

The main risk of heparin is hemorrhage, which can be treated with protamine sulfate, a compound that complexes with and inactivates heparin.

67
Q

What are some adverse effects of Heparin?

A

Adverse effects of heparin include bruising, thrombosis, osteoporosis (long-term use), and hypersensitivity reactions.

68
Q

What is the role of Vitamin K in blood coagulation?

A

Vitamin K is required for the synthesis of coagulation factors II, VII, IX, and X.

69
Q

How is Vitamin K obtained?

A

Vitamin K is obtained from plants and produced by gut microflora; it is also routinely given at birth in Australia.

70
Q

What is the function of Vitamin K in coagulation at the molecular level?

A

Vitamin K acts as a co-factor for the enzyme carboxylase, which is involved in activating coagulation factors.

71
Q

What is the primary mechanism of action of Warfarin?

A

Warfarin competes with vitamin K for binding at vitamin K reductase (VKORC1), inhibiting the synthesis of key clotting factors.

72
Q

How is Warfarin administered and absorbed?

A

Warfarin is orally active and rapidly absorbed.

73
Q

Describe the pharmacokinetics of Warfarin regarding distribution and binding.

A

Warfarin has a small distribution volume and is strongly albumin-bound.

74
Q

How long does it take for Warfarin to reach peak pharmacological effects?

A

Although it reaches peak blood concentration in a few hours, peak pharmacological effects take around 48 hours.

75
Q

What genetic factors can affect a patient’s response to Warfarin?

A

Patient response to Warfarin varies due to polymorphisms in the VKORC1 gene and the CYP2C9 enzyme, which metabolizes Warfarin.

76
Q

Why does Warfarin require frequent monitoring?

A

Warfarin has a low margin of safety, requiring dose individualization and regular monitoring.

77
Q

What are some interaction risks associated with Warfarin?

A

Warfarin interacts with other albumin-bound drugs, antibiotics, and P450 enzyme inhibitors, affecting its efficacy and safety.

78
Q

Can Warfarin cross the placenta?

A

Yes, Warfarin crosses the placenta, which is significant in pregnancy considerations.

79
Q

What is the function of endogenous plasminogen activators?

A

They cleave plasminogen (bound to fibrin strands in a thrombus) to release plasmin, which digests fibrin, fibrinogen, ECM proteins, and some clotting factors.

80
Q

Why is plasmin action localized to the clot?

A

Plasminogen activators are primarily effective on plasminogen bound to fibrin, and any escaping plasmin is inactivated by circulating plasmin inhibitors.

81
Q

What is the clinical use of fibrinolytic drugs?

A

Fibrinolytic drugs are used to dissolve clots and reopen occluded arteries in patients with acute myocardial infarction (MI) within 12 hours of onset.

82
Q

What is the origin of initial fibrinolytic drugs, and how have they evolved?

A

Initial drugs were derived from haemolytic streptococci; current versions use recombinant DNA technology.

83
Q

What is Alteplase?

A

Alteplase is a recombinant tissue plasminogen activator (tPA) with greater activity on fibrin-bound plasminogen, increasing clot selectivity, and is non-antigenic.

84
Q

How is Alteplase administered, and what are the major risks?

A

Alteplase is administered intravenously (IV), with major risks including bleeding (e.g., GI haemorrhage and haemorrhagic stroke).

85
Q

What is Tenecteplase?

A

Tenecteplase is a modified version of tissue plasminogen activator (tPA) with similar properties to Alteplase.

Biom2402 (6 decks)

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