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IHO Week 6 > Biochemistry of Coagulation > Flashcards

Biochemistry of Coagulation Flashcards

1
Q

What is the mechanism of action for aspirin?

A

Irreversibly inhibits COX (cyclooxygenase) by acetylation of a specific serine moiety. Aspirin is about 170x more potent in inhibiting COX-1 than COX-2. Aspirin appears to inhibit COX through two pathways. It does NOT inhibit peroxidase activity of COX and does NOT suppress leukotriene synthesis by lipoxygenase pathways.

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2
Q

What does aspirin do to platelets?

A

Aspirin irreversibly inhibits platelets. It keeps them from forming a primary hemostatic plug that can lead to a blood clot.

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3
Q

What drug class does aspirin belong to?

A

NSAID

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4
Q

What is the simplified mechanism of action for aspirin?

A

It irreversibly acetylates COX. COX1 is irreversibly inactivated in the platelet. Platelet cannot make more cyclooxygenase, so effect of aspirin lasts lifetime of the platelet (8-10 days).

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5
Q

What side effects are associated with aspirin?

A
  • GI side effects: Gastric or Intestinal ulceration
  • Prolongation of gestation
  • Renal function
  • Analgesic abuse
  • Nephropathy (daily large doses: fluid retention, nitrogen retentionHyperkalemia, anuria (no urine), renal insufficiency)
  • Hepatic function
  • Increased bleeding time (reduced platelet aggregation)
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6
Q

What happens with aspirin hypersensitivity?

A

Can happen with almost all NSAIDS. (3-10% of asthmatics)

  • Occurs in predisposed individuals
  • Symptoms are: rhinitis, urticaria, asthma, laryngeal edema
  • Aspirin hypersensitive people should NOT be given COX2 inhibitors
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7
Q

What are the proposed mechanisms of aspirin hypersensitivity?

A

(1) COX blocked which switches AA favoring to lipoxygenase pathway. This causes increased leukotriene production and symptoms of hypersensitivity
(2) COX1 inhibited, causes less PGE(2), which doesn’t block 5-lipoxygenase, allowing for synthesis of leukotrienes.

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8
Q

Who should you NOT use aspirin with?

A

KIDS

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9
Q

What is Reye syndrome?

A

Seen after giving aspirin to kids. Encephalopathy and fatty liver following viral infection in kids due to irreversible inhibition of COX.

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10
Q

What do platelets do in primary hemostasis?

A

Adhere to exposed collagen in areas of injury, release the content of their granules, and aggregate

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11
Q

What does vWF mediate?

A

The adhesion of platelets to the collagen exposed on endothelial cell surfaces. [von Willebrand factor, Gp1b-BpIX, GpV and GpVI]

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12
Q

Where does GpVI bind?

A

Directly to exposed collagen

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13
Q

What does vWF act as a bridge between?

A

A specific glycoprotein complex on the surface of platelets (GPIb-GPIX-GPV) and collagen fibrils

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14
Q

What is vWF?

A

Complex multimeric glycoprotein that is produced by and stored in the alpha-granules of platelets and synthesized by megakaryocytes and found associated with subendothelial connective tissue.

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15
Q

What does vWF bind?

A
  • Binds to sub-endothelial collagen at sites of injury
  • Binds to glycoprotein IB on the platelet surface
  • Binds to and stabilizes coagulation factor VIII
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16
Q

What does a deficiency in vWF function lead to?

A

vWD (disease)

  • Type I (quantitative - don’t make enough vWF)
  • Type II (make odd/non-functional vWF - numerous subtypes)
  • Type III (don’t make any vWF)
  • Patients with vWD can have reduced levels of factor VIII
  • Gp 1B deficiency causes Bernard Soulier syndrome
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17
Q

What is vWF very involved in?

A

Clotting and platelets

18
Q

When is VonWillebrand’s Disease a problem?

A

Usually isn’t a big problem unless they’re pregnant. Can also be involved in heavy menses.

19
Q

What does Heparin do?

A

Potentiates ability of antithrombin III to inhibit Factor Xa

20
Q

The inability of the body to control the circulating levels of active thrombin. . .

A

. . .would lead to dire consequences.

21
Q

The activation of thrombin is regulated by what four thrombin inhibitors?

A
  1. Antithrombin III
  2. Alpha2-macroglobulin
  3. Heparin Cofactor II
  4. Alpha1-antitrypsin
22
Q

What should you know about Antithrombin III?

A
  • Most important of the four thrombin inhibitors as it can also inhibit activities of factors IXa, Xa, XIa and XIIa, plasmin, and kallikrein
  • Activity is potentiated by HEPARIN (altered conformation can bind thrombin more readily); heparin sulfate is on the surface of vessel endothelial cells
23
Q

What should you know about Alpha1-antitrypsin?

A
  • Minor player in thrombin regulation
  • Primary serin protease inhibitor of human plasma
  • Deficiency leads to emphysema and liver dysfunction
24
Q

What things can cause blood clots?

A

Trauma, surgery, birth control, flying/long travel –> causes blood clots

25
Q

How do Heparins work?

A
  • Binds to and activates ATIII which leads to thrombin inactivation
  • ATIII also blocks the activity of factors VIIIa, IXa, Xa, XIa
26
Q

What can Heparin be administered as?

A

-HMW heparin
and
-Fractionated or LMW heparin (Lovanox)

27
Q

What is HMW Heparin?

A

Heterogenous mixture of glycosaminoglycans, with an average chain length of 45 monosaccharides with an average molecular weight of 15 kDa

28
Q

What is LMW Heparin?

A

(e.g. Enoxaparin) are fragments of HMW heparin, containing fewer than 18 monosaccarhides with an average of 4-5 kDa

29
Q

Why does the use and form of heparin for a patient require constant monitoring?

A

Because different individuals synthesize different levels of plasma proteins, the use and form of heparin as an anticoagulant requires constant monitoring of the patient to ensure that the correct dosage has been given

30
Q

What does Heparin bind to?

A

Plasma proteins and cell surfaces in addition to its prime target, ATIII.

31
Q

When is constant monitoring of Heparin not required?

A

LMW heparin has fewer nonspecific interactions than HMW heparin and its effects are easier to predict on patients, so you don’t need to constantly monitor.

32
Q

What is the trade name for Warfarin?

A

Coumadin

33
Q

What is Warfarin (Coumadin)?

A

Slow- and long- acting blood anticoagulant with a structure resembling that of vitamin k.

34
Q

How does Warfarin work?

A

Its structural similarity to vitamin k allows the compound to compete with vitamin k and prevent gamma-carboxylation of glutamate residues in factors II, VII, IX, X and proteins C and S
-The noncarboxylated blood clotting precursors increase in both the blood and plasma, but they are unable to promote blood coagulation because they cannot bind calcium and thus cannot bind to their phospholipid membrane sites of activation

35
Q

What is Warfarin commonly used in?

A

Rat poison

36
Q

What is the most commonly known vitamin k antagonist?

A

Warfarin!

37
Q

How does Warfarin act?

A

By blocking the vitamin k reductase enzymes used to regenerate active vitamin k

  • This results in reduced gamma-carboxylation of II, VII, IX and X
  • In the absence of gamma-carboxylation, the factors cannot bind calcium nor form the complexes necessary for the coagulation cascade to be initiated
38
Q

What else does Warfarin do?

A

Also blocks the activity of proteins S and C; this is a primary reason one needs to “bridge with heparin” (proteins C and S put the ‘brakes’ on coagulation)

39
Q

What do you need to do with unfractionated heparin?

A

Give a loading dose

40
Q

What happens initially when you give a patient coumadin?

A

It also inhibits factors C and S (they are breaks on coagulation - decrease ability to clot)
-SO, when you first put people on coumadin, you’re increasing the risk of clotting - initially you need to bridge this risk of clotting with another drug

IHO Week 6 (16 decks)

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