DRUGS USED IN DISORDERS OF COAGULATION CHAPTER SUMMARY

By: Melo L. Medecielo

Hemostasis is the controlled process that regulates blood flow, fixes damage to blood vessels,
and stops excessive bleeding or clotting. Problems in this process can occur due to various
factors like clotting issues, infections, cancer, or conditions such as atrial fibrillation. To manage
these issues, doctors often use anticoagulants, especially for conditions like atrial fibrillation,
which helps prevent complications like strokes. The decision to use oral anticoagulants depends
on specific risk factors. This chapter concentrates on medications that handle abnormal bleeding
and clotting issues.

Normally, the lining of blood vessels (vascular endothelium) has an anticoagulant role,
preventing blood cells from sticking and clotting. However, when a blood vessel gets injured,
these cells change their behavior and promote clotting. This injury exposes proteins under the
vessel lining, which triggers platelets to stick, become active, and release substances that cause
blood vessels to tighten. Platelets then gather and form a plug, while simultaneously, a series of
reactions in the blood lead to the formation of a stable clot (fibrin clot). Problems in this clotting
process can lead to different types of bleeding: surface bleeding if there are issues with platelets,
or deep tissue bleeding if there are problems with other clotting factors like in hemophilia A.
Platelets play a critical role in both stopping bleeding and causing clotting issues. Clots formed
in arteries, which are rich in platelets, can cause severe problems, while those in veins have more
fibrin and can lead to conditions like pulmonary embolism. The blood's clotting process involves
converting a soluble protein (fibrinogen) into an insoluble protein (fibrin) with the help of an
enzyme called thrombin. This process involves a sequence of reactions among clotting factors,
where each factor activates the next in line, ultimately leading to the formation of thrombin.
Thrombin then plays a crucial role by modifying fibrinogen, creating fibrin clots, activating more
clotting factors, and strengthening the clot. It also has some effects that prevent excessive
clotting. This entire response to injury is precisely controlled to ensure repair without causing
unwanted clotting under normal circumstances. After this clotting process, the blood vessels
undergo repair to regain their normal state.

The clotting process mainly starts with tissue factor (TF) and factor VIIa. Normally, tissue factor
isn't active inside blood vessels, but when there's damage, it interacts with factor VIIa, initiating
a sequence that activates other clotting factors and eventually forms a clot. This entire process
involves various factors, like calcium and specific molecules on cell surfaces. There are also
natural regulators in the body that control these clotting reactions. Problems in these regulators,
such as certain genetic mutations, can increase the risk of clotting in veins. After clot formation,
the body needs to dissolve these clots. This process, called fibrinolysis, involves the breakdown
of clots by a protein called plasmin, activated from plasminogen by tissue plasminogen activator
(t-PA). Plasmin and plasminogen specifically target the clot. However, when given at higher
doses for therapy, t-PA can lead to excessive clot breakdown and increased bleeding risk. There
are also other natural regulators in the body that control this clot breakdown. Certain conditions,
like disseminated intravascular coagulation (DIC), can cause abnormal clotting and breakdown,
leading to severe bleeding or clotting issues. Therapies targeting fibrinolysis can either increase
clot breakdown for treating clotting issues or reduce it to manage excessive bleeding.

The ideal drug for preventing clotting should stop abnormal clot formation, limit injury upon clot
breakdown, allow the body to respond normally to blood vessel injuries, and reduce bleeding
risk. Unfortunately, there's no perfect drug yet—all existing anticoagulants and drugs that
dissolve clots have an increased bleeding risk as their primary downside. Indirect thrombin
inhibitors like unfractionated heparin (UFH), low molecular-weight (LMW) heparin, and
fondaparinux work by enhancing the actions of natural anticoagulant proteins. They mostly
prevent factor Xa from causing clot formation and, to some extent, limit thrombin's actions.

Indirect Thrombin Inhibitors:

● Drug: Heparin
● MOA: Binds to antithrombin III, enhancing its ability to inhibit clotting factors, mainly
thrombin (Factor IIa) and Factor Xa.
● Uses: Prevents and treats blood clots in conditions like deep vein thrombosis (DVT),
pulmonary embolism, and during certain medical procedures.
● Toxicology: Potential side effects include bleeding, thrombocytopenia (low platelet
count), and osteoporosis with prolonged use.

Warfarin & Other Coumarin Anticoagulants:

● Drug: Warfarin
○ MOA: Inhibits vitamin K-dependent clotting factors (Factors II, VII, IX, X) by
interfering with the recycling of vitamin K.
○ Uses: Long-term prevention and treatment of blood clots, stroke prevention in
atrial fibrillation, and management of thromboembolic events.
○ Toxicology: Has a narrow therapeutic window and interacts with various
medications and dietary vitamin K. Overdose can lead to bleeding complications.

Oral Direct Factor Xa Inhibitors:

● Drugs: Rivaroxaban, Apixaban, Edoxaban
○ MOA: Inhibit Factor Xa directly, disrupting the coagulation cascade.
○ Uses: Prevent or treat blood clots in conditions like atrial fibrillation, DVT, and
pulmonary embolism.
○ Toxicology: Can cause bleeding, particularly in patients with kidney problems or
those taking other anticoagulants.
Parenteral Direct Thrombin Inhibitors:
● Drugs: Hirudin, Bivalirudin
○ MOA: Bind to and inhibit thrombin directly, preventing clot formation.
○ Uses: Used during medical procedures like cardiac catheterization and in patients
with heparin-induced thrombocytopenia.
○ Toxicology: May cause bleeding and allergic reactions.

Oral Direct Thrombin Inhibitor:

● Drug: Dabigatran etexilate mesylate
○ MOA: Directly inhibits thrombin (Factor IIa).
○ Uses: Prevents and treats blood clots, particularly in atrial fibrillation and after hip
or knee replacement surgeries.
○ Toxicology: Can cause bleeding, and there's a risk of gastrointestinal side effects.

Fibrinolytic Drugs:
● Drugs: Streptokinase, Urokinase
○ MOA: Activate plasminogen, converting it to plasmin, which breaks down fibrin
clots.
○ Uses: Used in emergencies like heart attacks or severe blood clots.
○ Toxicology: Can cause bleeding, allergic reactions, and rarely, stroke or severe
bleeding in the brain.

Antiplatelet Agents:
● Drugs: Aspirin, Ticlopidine, Clopidogrel, Prasugrel
○ MOA: Act on platelets to prevent them from clumping together and forming
blood clots.
○ Uses: Prevent blood clots in conditions like heart disease, stroke prevention, and
after certain heart procedures.
○ Toxicology: Common side effect is bleeding, particularly gastrointestinal
bleeding. Ticlopidine and clopidogrel might cause rare but severe side effects like
low platelets and neutrophils.

Blockade of Platelet Glycoprotein IIb/IIIa Receptors:

● Drugs: Abciximab, Eptifibatide, Tirofiban
○ MOA: Inhibit platelet aggregation by blocking glycoprotein IIb/IIIa receptors on
platelets.
○ Uses: Used during angioplasty and in certain cases of acute coronary syndrome.
○ Toxicology: Can cause bleeding complications and, rarely, allergic reactions.
Additional Antiplatelet-Directed Drugs:
● Drugs: Dipyridamole, Cilostazol
○ MOA: Dipyridamole increases levels of certain substances that prevent platelets
from sticking together. Cilostazol inhibits phosphodiesterase, improving blood
flow.
○ Uses: Used in preventing blood clots, especially in conditions like stroke or after
heart procedures.
○ Toxicology: Side effects may include bleeding and gastrointestinal upset.

Drugs Used in Bleeding Disorders:

● Drug: Vitamin K
○ MOA: Required for the synthesis of clotting factors in the liver, particularly
factors II, VII, IX, and X.
○ Uses: Reversal agent for anticoagulants like warfarin in cases of excessive
bleeding.
○ Toxicology: Rarely, allergic reactions can occur.

Fibrinolytic Inhibitors:
● Drug: Aminocaproic Acid
○ MOA: Inhibits the activation of plasminogen, thereby slowing down the breakdown of
blood clots.
○ Uses: Used to prevent excessive bleeding or to reduce bleeding complications in
situations like surgeries or to treat certain bleeding disorders.
○ Toxicology: Side effects may include gastrointestinal disturbances, muscle weakness, and
in high doses, there's a risk of blood clotting.

Drugs Removed from Market for Lack of Efficacy or Safety:

● Drugs: Aprotinin, Activated Protein C
○ Aprotinin was used to reduce bleeding in cardiac surgery. However, it was withdrawn due
to safety concerns related to increased mortality, kidney damage, and cardiovascular
complications.
○ Activated Protein C (Drotrecogin alfa) was used to treat severe sepsis. However, it was
withdrawn from the market due to lack of efficacy in reducing mortality and concerns
about severe bleeding complications.