Drugs affecting haemostasis

Question 1

What is hemostasis?

Answer 1

Hemostasis is the arrest of blood loss from a

damaged vessel and is essential to life.

Question 2

What happens when there is a wound in a blood vessel?

Answer 2

 Vasoconstriction
 Adhesion and activation of platelets
 Formation of fibrin

Question 3

What is thrombosis?

Answer 3

is the pathological formation of a ‘haemostatic’ plug within
the vasculature in the absence of bleeding (‘haemostasis in the
wrong place’).

Question 4

What are the predisposing factors (Virchow’s triad) of thrombosis?

Answer 4

 Injury to the vessel wall – e.g. an atheromatous plaque ruptures or becomes
eroded;

 Altered blood flow – e.g. in the left atrium of the heart during atrial fibrillation;

 Abnormal coagulability of the blood – as occurs, for example, in the later
stages of pregnancy or during treatment with certain oral contraceptives

Question 5

What are the different types of thrombosis?

Answer 5

1) arterial thrombus
2) venous thrombus
3) thrombus in the heart

Question 6

What is an arterial thrombus?

Answer 6

“white thrombus” consisting mainly of platelets in a fibrin

mesh – associated with atherosclerosis

Question 7

What is a venous thrombus?

Answer 7

“red thrombus” consists of a small white head (platelet
component) and a large jelly-like red tail (fibrin component); usually
associated with stasis of blood;

thrombus can break away from its attachment
and float through the circulation, forming an embolus; venous emboli usually lodge in the lungs

Question 8

What is a thrombus in the heart?

Answer 8

thrombus that embolizes from the left heart usually

lodges in an artery in the brain or other organs

Question 9

What is the coagulation cascade?

Answer 9

The coagulation cascade refers to the series of steps that occur during the formation of a blood clot after injury by activating a cascade of proteins called clotting factors.

There are three pathways: intrinsic, extrinsic, and common.

Question 10

What happens in the coagulation cascade?

Answer 10

The components (called
factors) are present in blood as inactive precursors of
proteolytic enzymes and cofactors.

 Activation of a small amount of
one factor catalyzes the
formation of larger amounts of the next factor.

The main event is the
conversion by thrombin
of soluble fibrinogen to
insoluble strands of fibrin,
the last step in a complex
enzyme cascade.

Question 11

What are the stages of the coagulation cascade?

Answer 11

The mechanism of hemostasis can divide into four stages.
1) Constriction of the blood vessel.

2) Formation of a temporary “platelet plug.”
3) Activation of the coagulation cascade.
4) Formation of “fibrin plug” or the final clot.

Question 12

What is involved in the anticoagulation system?

Answer 12

Antithrombin ІІІ
 ↓ ІІа, Ха

Protein С (Vitamin K-dependent factor)
– Proteolysis of factors Va and VIIIa

Protein S
 Co-factor of protein С

Question 13

What are the drugs that affect hemostasis?

Answer 13

Drugs affect haemostasis and thrombosis
in three distinct ways, by influencing:

1) Blood coagulation (fibrin formation) –
Anticoagulants

2) Fibrin removal (fibrinolysis) – Fibrinolytics
3) Platelet function – Antiplatelet drugs

Question 14

What are some examples of anticoagulants?

Answer 14

Vitamin K antagonists

Heparin and similar drugs
 Heparin
 Low-molecular-weight heparins (LMWHs)
 Synthetic pentasaccharides

Direct thrombin inhibitors

Direct inhibitors of factor Xa

Question 15

What are examples of vitamin k antagonists and what is their PK?

Answer 15

Drugs: Warfarin, Acenocoumarol

PK:
 Complete and rapid oral absorption with
excellent bioavailability
 Highly and loosely bound to plasma proteins
(> 95%)
 Metabolized in the liver
 Long t1/2 - 40 h

Question 16

What is the mechanism of action of vitamin k antagonists?

Answer 16

 Vitamin K is essential for the
formation of clotting factors
II, VII, IX, and X

 Mechanism of action of
vitamin K antagonists: inhibit
the γ-carboxylation of the
vitamin K dependent clotting
factors:
- II, VII, IX, X

 Other vitamin K-dependent

proteins:
- Protein C and protein S
- Osteocalcin in bone

Question 17

What is the PD of vitamin K antagonists?

Answer 17

PD:

 Effective only in vivo
 10-24 h delay in the action,

according to the
t1/2 of the factors: VІІ – 6 h, ІХ – 24 h, Х – 36
h, ІІ – 50 h)

Question 18

What is the clinical use of vitamin k antagonists?

Answer 18

 After heparin treatment of deep vein thrombosis and pulmonary embolism (by
overlapping in time with heparin for 3-5 days)

 For prevention of:
- Deep vein thrombosis
- Thrombosis in the heart in patients with atrial
fibrillation, prosthetic heart valves, etc.)

Question 19

What is the clinical use of vitamin k antagonists?

Answer 19

 After heparin treatment of deep vein thrombosis and pulmonary embolism (by
overlapping in time with heparin for 3-5 days)

 For prevention of:
- Deep vein thrombosis
- Thrombosis in the heart in patients with atrial
fibrillation, prosthetic heart valves, etc.)

Question 20

What are the adverse effects of vitamin k antagonists?

Answer 20

Adverse effects:
 Hemorrhages (antagonist – vitamin K)
 Teratogenic and fetotoxic (contraindicated
in pregnancy)
 Hepatotoxicity (rarely)
 Necrosis of soft tissues, e.g. breast (due to
venous thrombosis secondary of
depression of protein C synthesis; protein
C t1/2 – relatively short – 8 h)

Drug interactions: numerous and risky

Question 21

What is Heparin?

Answer 21

A family of
mucopolysaccharides (m.w.
from 5000 up to 30000)
 Pentasaccharide sequence (sulfated
glucosamine, glucuronic acid and iduronic acid)

Question 22

What is the mechanism of action of Heparin?

Answer 22

 Mechanism of action:

 Via a unique pentasaccharide
sequence it binds to and
activates АТ III changing its
conformation and increasing its
activity

 To inhibit factor IIa, it is
necessary for heparin to bind to the enzyme as well as to АТ III;
 To inhibit factor Xa, it is
necessary only for heparin to
bind to АТ III

Question 23

What is the PK of heparin?

Answer 23

PK:
 Orally inactive -> parenteral administration (IV, SC)
 Metabolism in liver and renal excretion (hepatic and renal failure
prolong the action)

Question 24

What are the clinical uses of heparin?

Answer 24

 Initial treatment of deep vein thrombosis and pulmonary
embolism

 Initial treatment of unstable angina and acute myocardial
infarction

 For prevention of deep vein thrombosis in patients at risk

 For prophylaxis of thrombosis in cardiovascular surgery

Question 25

What are the adverse effects of Heparin?

Answer 25

```  Bleeding Antagonist – Protamine sulfate - 1 mg за 100 U To avoid bleeding – Laboratory monitoring: activated partial trhromboplastin time (aPPT = 1,5-2,5 х) ```  Thrombosis: paradoxically associated with heparin-induced thrombocytopenia (HIT)  Osteoporosis (mechanism unknown) - with long-term (6 months or more) treatment with heparin  Hypersensitivity reactions  Alopecia

Question 26

What are low molecular weight heparins?

Answer 26

Drugs:  Enoxaparin  Nadroparin  Molecular weight – 4000 to 15000

Question 27

What is the mechanism of action of low molecular weight heparins?

Answer 27

Mechanism of action:  Predominantly anti-Ха activity through binding to AT III

Question 28

What is the PK of LMW heparins?

Answer 28

PK:  SC administration  Longer t1/2  Renal excretion

Question 29

What are the adverse effects of LMW heparins?

Answer 29

Adverse effects:  Bleeding (lower risk?)  Thrombocytopenia (less frequent)

Question 30

What are the clinical uses and advantages of LMW heparins?

Answer 30

Clinical use:  Initial treatment of deep vein thrombosis and pulmonary embolism  Initial treatment of unstable angina and acute myocardial infarction  For prevention of deep vein thrombosis in patients at risk  For prophylaxis of thrombosis in cardiovascular surgery Advantages  Predictable and controllable effect  Allow outpatients treatment and self-application

Question 31

What are synthetic pentasaccharides?

Answer 31

Synthetic pentasaccharides |  Drugs: Fondaparinux

Question 32

What is the mechanism of action of synthetic pentasaccharides?

Answer 32

Mechanism of action |  High affinity to АТІІІ  anti-Ха activity

Question 33

What are the PK, advantages, and clinical uses of synthetic pentasaccharides?

Answer 33

PK: SC administration; long t1/2; renal excretion Advantages:  Do not cause thrombocytopenia Clinical use:  For prevention of deep vein thrombosis in orthopedic surgery

Question 34

What are direct thrombin inhibitors? What is their clinical use?

Answer 34

Dabigatran etexilate  Oral application Clinical use:  For prevention of deep vein thrombosis in orthopedic surgery  For prevention of acute coronary syndrome and stroke in patients with atrial fibrillation  Treatment of deep vein thrombosis antagonist: Idarucizumab – monoclonal antibody fragment attaching firmly to dabigatran, and forming a complex in the blood

Question 35

What are direct inhibitors of factor Xa? What is their clinical use?

Answer 35

Rivaroxaban, Apixaban  Oral application Clinical use:  For prevention of deep vein thrombosis in orthopedic surgery  For prevention of stroke and systemic embolism in patients with atrial fibrillation  Treatment of deep vein thrombosis Antagonist:  Andexanet alfa – anticoagulants attach to andexanet alfa are no longer available to block factor Xa

Question 36

What is fibrinolysis?

Answer 36

What do you mean by fibrinolysis? Fibrinolysis is a normal body process. It prevents blood clots that occur naturally from growing and causing problems. Primary fibrinolysis refers to the normal breakdown of clots. Secondary fibrinolysis is the breakdown of blood clots due to a medical disorder, medicine, or other cause

Question 37

What is fibrinolytics?

Answer 37

A fibrinolytic cascade is initiated concomitantly with the coagulation cascade, resulting in the formation within the coagulum of plasmin, which digests fibrin.  Various agents promote the formation of plasmin:  Streptokinase  Tissue plasminogen activators (tPAs):  Alteplase  Reteplase  All are given IV: by infusion (Alteplase) or bolus (Reteplase)

Question 38

What is the PD of fibrinolytics?

Answer 38

Mechanism of action: convert plasminogen deposited on fibrin strands to plasmin. Reopen the occluded blood vessel and provide reperfusion  directly – tPAs  indirectly (streptokinase) – by binding to plasminogen activators

Question 39

What are the unwanted effects and contraindications of fibrinolytics?

Answer 39

 Bleeding from GIT and stroke.  Allergic reactions and hypotension (streptokinase) ``` Contraindications:  Active internal bleeding  Hemorrhagic cerebrovascular disease  Bleeding diathesis  Pregnancy  Metastatic cancer  Invasive procedures and recent trauma ```

Question 40

What are the clinical uses of fibrinolytic drugs?

Answer 40

The main use is:  Acute myocardial infarction, within 6-12 hrs of onset ``` Other uses:  Acute thrombotic stroke within 3 hrs of onset (tPAs)  Deep vein thrombosis, acute pulmonary embolism, acute arterial thromboembolism ```

Question 41

What happens to platelets when they are activated?

Answer 41

Adhesion following vascular damage  Secretion of the granule contents (including platelet agonists, such as ADP and 5-hydroxytryptamine)  Biosynthesis of labile mediators such as platelet-activating factor and thromboxane A2 (TXA2) ```  Aggregation, which is promoted by various agonists, including collagen, thrombin, ADP, 5-hydroxytryptamine and TXA2, acting on specific receptors on the platelet surface; activation by agonists lead to expression of GPIIb/IIIa receptors that bind fibrinogen, which links adjacent platelets to form aggregates ```

Question 42

What are antiplatelet drugs?

Answer 42

 Inhibitors of СОХ-1 in platelets: Acetylsalicylic acid (ASА, Aspirin)  Adenosine (P2Y) receptor antagonists:  Clopidogrel  Prasugrel (introduced recently)  Ticagrelor (introduced recently)  Phosphodiesterase inhibitors: Dipiridamol  Antagonists of GPІІb/ІІІа receptors  Abciximab (monoclonal ab)  Cyclic oligopeptides: Tirofiban, Eptitibatide  Stable analogs of PgІ2  Iloprost  Epoprostenol

Question 43

What is acetylsalicylic acid? How does it work as an antiplatelet drug?

Answer 43

Aspirin inhibits COX1 by irreversible acetylation of a serine residue in its active site which results in:  At lower doses – reduction of TxA2 synthesis in platelets  At higher doses – reduction of PgI2 synthesis in the endothelium  Endothelial cells can synthesize new enzyme, whereas the anucleate platelets can not and synthesis does not recover until new platelets are formed (7-10 days).  The balance between TxA2 and PgI2 is thus shifted to PgI2 which inhibits platelet aggregation The effect of aspirin on platelet aggregation is rapid  The recommended dose is: a daily dose of ~ 100 mg

Question 44

What are the adverse effects and possible drug interactions of aspirin?

Answer 44

Adverse effects:  Bleeding from GIT  Increased incidence of hemorrhagic stroke Drug interactions  Synergy with other antiplatelet drugs (clopidogrel, dipiridamol) and fibrinolyitics or anticoagulants.  Caution with warfarin

Question 45

What are the clinical uses of aspirin?

Answer 45

Clinical use: for the treatment and prevention of arterial thrombosis  Acute myocardial infarction  High risk of myocardial infarction, including a history of myocardial infarction, angina, or intermittent claudication  Unstable coronary syndromes  Primary and secondary prophylaxis of angina pectoris  Following coronary artery bypass grafting  Following coronary artery angioplasty and stenting (clopidogrel or abciximab in addition to aspirin)  Transient cerebral ischaemic attack ('ministrokes') or thrombotic stroke, to prevent a recurrence  Atrial fibrillation, if oral anticoagulation is contraindicated

Question 46

What are inhibitors of P2Y12 receptors? What is the mechanism of action?

Answer 46

Mechanism of action  Antagonists of adenosine (P2Y) receptors of platelets; thereby they inhibit platelet responses to ADP.  Drugs: Clopidogrel , Prasugrel, Ticagrelor, Ticlopidine  Clopidogrel is a prodrug and is converted into its active sulfhydryl metabolite by CYP enzymes in the liver including CYP2C19. Slow onset of effect (3-5 days). Patients with variant alleles of CYP2C19 (poor metabolisers) are at increased risk of therapeutic failure. There is a potential for interaction with other drugs, such as omeprazole, that are metabolised by CYP2C19 and current labelling recommends against use with proton pump inhibitors for this reason.  Prasugrel (prodrug; effective in most individuals, faster onset of the effect compared to Clopidogrel)  Ticagrelor (not a prodrug; allosteric antagonist; superior to Clopidogrel)  Ticlopidine – rarely used because of adverse effects (neutropenia and thrombocytopenia)

Question 47

What are the clinical effects and clinical use of aspirin?

Answer 47

 Clinical effect – additive with aspirin  Clinical use: following coronary artery angioplasty and stenting (in addition to aspirin)

Question 48

What are PDA inhibitors?

Answer 48

Dipiridamol  increase in сАМР -> decreased aggregation  Synergism with ASA  Clinical use: in addition to aspirin in some patients with stroke or transient ischaemic attack

Question 49

What are other antiplatelet drugs?

Answer 49

 Antagonists of GPІІb/ІІІа receptors: Abciximab, Tirofiban, Eptitibatide  Short-term IV administration following coronary angioplasty (+ Heparin + ASA) Stable analogs of PgІ2:  Vasodilating and antiplatelet effects  Iloprost  IV infusion in severe peripheral arterial occlusive disease  Unwanted effects: headache, flushing, hypotension, tachycardia, arrhythmia, extrasystoles and anxiety  Epoprostenol  To prevent blood clotting during haemodialysis  To treat 'pulmonary arterial hypertension'

Question 50

What are the drugs used in bleeding? Mechanism of action and clinical use

Answer 50

Phytomenadione (Vitamin K) ``` Mechanism of action:  Co-factor in the posttranslational activation of factors ІІ, VІІ, ІХ, Х (γ-carboxylatiaon of glutamic acid residues)  Onset of the effect - after 6 hrs, full effect - after 24 hrs ``` ``` Clinical use:  In oral anticoagulants-induced bleeding  To prevent hemorrhagic disease in the newborn (due to hypoprothrombinemia)  As supplementation for patients receiving some cefalosporins (cefoperazone, etc.)  In vit. K deficiencies, e.g. sprue, lack of bile ```

Question 51

Inhibitors of fibrinolysis - what is the PD, indications, ADRs and contraindications of Para-aminomethylbenzoic acid?

Answer 51

 Applied IV or IM  PD: prevents the degradation of the blood clot (antifibrinolytic effect) ``` Indications:  In case of fibrinolytics overdose  Local bleeding due to increased fibrinolysis: uterine bleeding of unknown origin; bleeding after tonsillectomy, dental operations; local bleeding in urological and gynecological operations; in case of overdose with anticoagulants.  Massive fibrinolytic bleeding: in operations in the chest and abdomen; in prostate cancer; in leukemia; in obstetric practice ``` ``` ADR:  GIT: nausea, abdominal pain, vomiting  CNS: dizziness, very rarely seizures  CVS: arrhythmias and bradycardia; hypotension  Musculoskeletal system: myopathy, myoglobinuria ``` Contraindications:  Renal failure  Thrombosis and embolism

Question 52

What are the PK, PD, clinical use, ADRs, and contraindications of aminocaproic acid?

Answer 52

Аminocaproic acid ```  Synthetic inhibitor of fibrinolysis  PK:  Rapid oral absorption  Renal excretion  PD: Competitively inhibits the activation of plasmin ``` ``` Clinical use  Adjunctive therapy in haemophilia  Bleeding from fibrinolytic therapy  Prevention of re-bleeding of intracranial aneurysm  Bleeding after gastrointestinal surgery and prostatectomy  Bleeding in hemorrhagic cystitis (radiation-or drug-induced) ``` Adverse effects:  Intravascular thrombosis  Hypotension  GI discomfort ``` Contraindications:  Bleeding from the upper genitourinary system: kidney and uterus because of the danger of excessive blood clotting ```

Question 53

Explain Etamsylate - hemostatics for systemic use.

Answer 53

 Hemostatics for systemic use ``` Etamsylate  Affects the interaction of the endothelium with platelets  Suppresses capillary bleeding  Applied IV or orally:  In parenchymal hemorrhages in surgery  In dentistry  In ophthalmology ```

Question 54

Explain Terlipressin - hemostatic for systemic use.

Answer 54

```  Terlipressin  Analog of ADH (vasopressin)  Applied IV  To stop bleeding from esophageal varices before surgery in patients with liver cirrhosis ```

Question 55

Hemostatics containing gelatin, collagen, or thrombin? | gelaspon

Answer 55

```  Hemostatics for local use – containing gelatin, collagen or thrombin  Gelaspon  Sterile gelatin sponge  Absorbs blood and facilitates clotting  Completely absorbed  Use:  Haemorrhages in surgery of parenchymal organs  After tooth extraction  Capillary bleeding ```