Drugs for Coagulation disorders

There are a number of different categories of drugs which modify the coagulation process: I. Anticoagulants II. Antiplatelet agents III. Thrombolytics

I. Anticoagulants A. The coagulation cascade The coagulation cascade begins when injured cells release thromboplastin.

Thromboplastin converts the clotting factor prothrombin to thrombin.

Thrombin then converts the plasma protein fibrinogen to long strands of fibrin and activates several clotting factors (V, VIII, XIII, and protein C)

The fibrin strands form an insoluble web

B. Types of anticoagulants The mechanism of action of anticoagulant medications involves either the inactivation of various existing coagulation factors, or

preventing the synthesis of coagulation factors (the vitamin K antagonists)

Anticoagulant medications do NOT dissolve clots.

1. heparins a. standard heparin b. low molecular weight (LMW) heparins

Heparins are indicated for the treatment of: deep vein thrombosis (DVT) prophylaxis and treatment of venous thrombi, alone prophylaxis and treatment of venous thrombi in conjunction with pulmonary emboli

Heparins are NOT direct thrombin inhibitors.

Instead, heparins prevent thrombin formation by binding to clotting factors in the circulation.

These clotting factors then bind to and inactivate thrombin, the major enzyme in the clotting pathway.

The main commercial sources of standard heparin are the lungs and intestines of cattle (bovine) and pigs (porcine).

LMW heparins are derived from porcine heparin.

They are smaller in size as they only contain the anticoagulant fraction of heparin, and not the additional saccharide chains that standard heparin has.

a. Standard heparin Standard heparin has an immediate onset of action if administered IV, it peaks within 5-10 minutes, and its duration is 2-6 hours.

Standard heparin has an onset of action of 20 minute – 1 hour if administered SC, it peaks within 2 hours, and its duration is hours.

Standard heparin IV administration: bolus of 10,000 – 12,000 units followed by 5,000-10,000 units every 4-6 hours

Standard heparin SC administration: bolus of 10,000 – 12,000 units followed by 15,000-20,000 units every 12 hours

b. Low molecular weight (LMW) heparins LMW heparins are ONLY administered SC, have a rapid onset of action, generally peak within 3-6 hours, and have a duration of hours depending on the agent. Specific LMW heparins include:

i. dalteparin (Fragmin): Indicated for prophylaxis of Deep Vein Thrombosis (DVT) in patients undergoing abdominal surgery or hip replacement surgery.

ii. enoxaprin (Lovenox): Indicated for prophylaxis of DVT in patients undergoing abdominal, hip, or knee surgery.

iii. fondaparinux (Arixtra): Indicated for both the treatment of and prophylaxis of DVT and pulmonary embolism (PE).

iv. tinzaparin (Innohep): Indicated for both the treatment of and prophylaxis of DVT.

LMW heparins have certain advantages over standard heparin: 90% bioavailability (standard heparin has 30%)

LMW heparin can be dosed based on body size without coagulation test monitoring (if patient has normal kidney function)

Adverse effects of heparins: hemorrhage anemia in elderly with Lovenox, due to decreased clearance fever hair loss thrombocytopenia (↓ in no. of platelets)

Black box warning for LMW heparin use in patients concurrently receiving epidural or spinal anesthesia as it increases the risk for epidural or spinal hematomas

2. thrombin inhibitors Unlike the heparins, these drugs bind directly to thrombin. They are all administered IV.

a. argatroban (Argatroban) indicated for patients with, or at risk for thrombocytopenia who are undergoing percutaneous coronary intervention (PCI).

b. bivalirudin (Angiomax): used, along with aspirin, in patients with unstable angina who undergo PCI. This treatment is intended to reduce the risk of acute ischemic complications

c. lepirudin (Refludan): derives from the natural product hirudin, found in leech saliva.

Leeches have been used for bloodletting since the times of the ancient Greeks.

3. anticoagulants which prevent the synthesis of coagulation factors This category of anticoagulant is significantly different from the heparins in that it can be administered orally.

This type of anticoagulant has a longer onset because of the time required to clear the normal clotting factors from the circulation before an effect can be observed.

The only drug in this class is warfarin sodium (Coumadin): 2-10 mg

Its onset of activity is about hours.

However, its duration of action is longer (2 to 10 days) even after drug administration has been discontinued.

Coumadin is indicated for the treatment of DVT and prevention of myocardial re- infarction

Adverse effects include: GI disturbances hypotension hair loss headache hemorrhage (most serious)

A black box warning indicates that there is an ↑ risk of hemorrhage in: patients over 65 patients with a history of GI bleeding INR > 4

INR (international normalized ratio) is a test used to monitor coagulation status.

People not on anticoagulants have an INR of 1 An INR of 2 – 3 is needed for a therapeutic effect with warfarin

II. Antiplatelet agents Antiplatelet agents exert an anticoagulant effect by interfering with various aspects of platelet function.

Antiplatelet agents are indicated for the treatment of : thrombocytopenia acute coronary syndrome prevention of myocardial re-infarction and reducing coronary events

The 2 subclasses of antiplatelet agents are: A. nonselective COX inhibitors B. adenosine diphosphate (ADP) receptor blockers

A. nonselective COX inhibitors Normally, the cyclooxygenase enzyme pathway in platelets results in the production of thromboxane A 2, a potent platelet aggregator.

Aspirin, in doses from 81 mg (baby aspirin) to 325 mg (adult analgesic dose) irreversibly blocks a step in this pathway, preventing the synthesis of thromboxane A 2.

Therefore, thromboxane will not be active until new platelets are formed.

B. ADP receptor blockers These drugs interfere with a receptor on the membrane of platelets, preventing them from aggregating.

Adenosine diphosphate (ADP) normally binds to these membrane receptors in platelets, resulting in the coagulation of the platelets.

The drugs in this class block the receptor so that ADP cannot bind.

All of the drugs in this class are administered orally.

1. ticlopidine (Ticlid): 250 mg, bid 2. clopidogrel (Plavix): 75 mg 3. cilostazol (Pletal): 100 mg, bid 4. prasugrel (Effient): 5 – 10 mg with food 5. anagrelide (Agrylin): 1.0 mg, bid

III. Thrombolytics Thrombolytics are enzymes used to dissolve blood clots.

They convert plasminogen to plasmin, which is then able to degrade the fibrin present in clots.

Their primary functions are: to break apart pulmonary emboli and coronary artery thromboses during acute MI.

They need to be administered as soon as possible once it has been established that a clot or infarct has occurred.

Other disorders for which they may be indicated are: DVT stroke occluded central venous access devices

For the treatment of acute MI: administer the drug within 1-6 hours of the onset of symptoms.

There is a longer window of opportunity for use of these drugs in treating a pulmonary embolism. Here the time for initiation of therapy may be up to a few days.

All drugs in this class are enzymes that must be administered IV.

A. streptokinase Streptokinase (Streptase, Kabbikinase): generally, 250,000 IU over 30 minutes, then 100,000 IU/hour for up to 72 hours Larger doses may be used in the treatment of MI

B. urokinase urokinase (Abbokinase): IV IU administered over several minutes to 12 hours

A symptomatic ulnar artery occlusion before and after urokinase infusion therapy.

C. thrombolytics produced via recombinant DNA alteplase (Activase, Cathflo), reteplase (Retavase) and tenecteplase (TNKase) are thrombolytic enzymes produced through recombinant DNA technology

alteplase: based on patient weight, not to exceed 100 mg. Generally, a 15 mg bolus, followed by 50 mg over next 30 minutes then 35 mg over the next 60 minutes

reteplase: 10 unit bolus over 2 minutes, wait 30 minutes, repeat

tenecteplase: a single bolus, over 5 seconds based on body weight, not to exceed 50 mg Generally used in conjunction with aspirin and heparin therapy

Adverse effects of the thrombolytics: hemorrhage rash/itching headache nausea bronchospasm cardiogenic shock or arrhythmias with the recombinants