Anticlotting Drugs

The Big Heart Disease Lie

Cardiovascular Disease Causes and Possible Treatments

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Various drugs are used clinically to prevent or reverse clotting, and a brief description of their actions serves as a review of key clotting mechanisms. One of the most common uses of these drugs is in the prevention and treatment of myocardial infarction (heart attack), which, as described in Section F, is often the result of damage to endothelial cells. Such damage not only triggers clotting but interferes with the normal anti-clotting functions of endothelial cells. For example, atherosclerosis interferes with the ability of endothelial cells to secrete nitric oxide.

TABLE 14-16 Anticlotting Roles of Endothelial Cells



Normally provide an intact barrier between the blood and subendothelial connective tissue

Platelet aggregation and the formation of tissue factor-factor Vila complexes are not triggered

Synthesize and release PGI2 and nitric oxide

These inhibit platelet activation and aggregation

Secrete tissue factor pathway inhibitor

Inhibits the ability of tissue factor-factor Vila complexes to generate factor Xa

Bind thrombin (via thrombomodulin), which then activates protein C

Active protein C inactivates clotting factors Villa and Va

Display heparin molecules on the surfaces of their plasma membranes

Heparin binds antithrombin Ill, and this molecule then inactivates thrombin and several other clotting factors

Secrete tissue plasminogen activator

Tissue plasminogen activator catalyzes the formation of plasmin, which dissolves clots

PART THREE Coordinated Body Functions

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

PART THREE Coordinated Body Functions

Aspirin inhibits the cyclooxygenase enzyme in the eicosanoid pathways that generate prostaglandins and thromboxanes (Chapter 7). Since thromboxane A2, produced by the platelets, is important for platelet aggregation, aspirin reduces both platelet aggregation and the ensuing coagulation. Importantly, low doses of aspirin cause a steady-state decrease in platelet cyclooxygenase activity but not endothelial-cell cyclooxygenase, and so the formation of prostacyclin—the prostaglandin that opposes platelet aggregation—is not impaired. [The reason for this difference between the responses of platelet and endothelial-cell cy-clooxygenase (COX) to drugs is as follows: Platelets, once formed and released from megakaryocytes, have lost their ability to synthesize proteins, so that when their COX is blocked—the effect on any given COX molecule is irreversible—thromboxane A2 synthesis is gone for that platelet's lifetime. In contrast, the en-dothelial cells produce new COX molecules to replace the ones blocked by the drug.] Aspirin is highly effective at preventing heart attacks. In addition, the administration of aspirin following a heart attack significantly reduces the incidence of sudden death and a recurrent heart attack.

A variety of new drugs that interfere with platelet function by mechanisms different from those of aspirin also have great promise in the treatment or prevention of heart attacks. In particular, certain drugs block the binding of fibrinogen to platelets and thus interfere with platelet aggregation.

Drugs that interfere with the action of vitamin K, which is required for synthesis of clotting factors by the liver, are collectively termed oral anticoagulants.

Heparin, the naturally occurring endothelial-cell cofactor for antithrombin III, can also be administered as a drug, which then binds to endothelial cells. In addition to its role in facilitating the action of an-tithrombin III, heparin also inhibits platelet function.

In contrast to aspirin, the fibrinogen blockers, the oral anticoagulants, and heparin, all of which prevent clotting, the fifth type of drug—plasminogen activators— dissolves a clot after it is formed. Use of such drugs is termed thrombolytic therapy. Intravenous administration of recombinant t-PA or a proteolytic drug called streptokinase within three hours after myocardial infarction significantly reduces myocardial damage and mortality. Recombinant t-PA has also been effective in reducing brain damage following a stroke caused by blood-vessel occlusion.


I. The initial response to blood-vessel damage is vasoconstriction and the sticking together of the opposed endothelial surfaces.

II. The next events are formation of a platelet plug followed by blood coagulation (clotting).

Formation of a Platelet Plug

I. Platelets adhere to exposed collagen in a damaged vessel and release the contents of their secretory vesicles.

a. These substances help cause platelet activation and aggregation.

b. This process is also enhanced by von Willebrand factor, secreted by the endothelial cells, and by thromboxane A2 produced by the platelets.

c. Fibrinogen forms the bridges between aggregating platelets.

d. Contractile elements in the platelets compress and strengthen the plug.

II. The platelet plug does not spread along normal endothelium because the latter secretes prostacyclin and nitric oxide, both of which inhibit platelet aggregation.

Blood Coagulation: Clot Formation

I. Blood is transformed into a solid gel when, at the site of vessel damage, plasma fibrinogen is converted into fibrin molecules, which bind to each other to form a mesh.

II. This reaction is catalyzed by the enzyme thrombin, which also activates factor XIII, a plasma protein that stabilizes the fibrin meshwork.

III. The formation of thrombin from the plasma protein prothrombin is the end result of a cascade of reactions in which an inactive plasma protein is activated and then enzymatically activates the next protein in the series.

a. Thrombin exerts a positive-feedback stimulation of the cascade by activating platelets and several clotting factors.

b. Activated platelets, which display platelet factor and binding sites for several activated plasma factors, are essential for the cascade.

IV. In the body, the cascade usually begins via the extrinsic clotting pathway when tissue factor forms a complex with factor VIIa. This complex activates factor X, which then catalyzes the conversion of small amounts of prothrombin to thrombin. This thrombin then recruits the intrinsic pathway by activating factor XI and factor VIII, as well as platelets, and this pathway generates large amounts of thrombin.

V. Vitamin K is required by the liver for normal production of prothrombin and other clotting factors.

Anticlotting Systems

I. Clotting is limited by three events: (1) Tissue factor pathway inhibitor inhibits the tissue factor-factor VIIa complex; (2) protein C, activated by thrombin, inactivates factors VIIIa and Va; and (3) antithrombin III inactivates thrombin and several other clotting factors.

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition



II. Clots are dissolved by the fibrinolytic system.

a. A plasma proenzyme, plasminogen, is activated by plasminogen activators to plasmin, which digests fibrin.

b. Tissue plasminogen activator is secreted by endothelial cells and is activated by fibrin in a clot.



platelet factor (PF)

von Willebrand factor

intrinsic pathway


extrinsic pathway

platelet activation

tissue factor

platelet aggregation

vitamin K

platelet plug

tissue factor pathway

thromboxane A2

inhibitor (TFPI)

prostacyclin (PGI2)


nitric oxide

protein C

blood coagulation

antithrombin III




fibrinolytic system






plasminogen activators


tissue plasminogen activator




Describe the sequence of events leading to platelet activation and aggregation, and the formation of a platelet plug. What helps keep this process localized? Diagram the clotting pathway beginning with prothrombin.

What is the role of platelets in clotting? List all the procoagulant effects of thrombin. How is the clotting cascade initiated? How does the extrinsic pathway recruit the intrinsic pathway? Describe the roles of the liver and vitamin K in clotting.

List three ways in which clotting is limited. Diagram the fibrinolytic system.

How does fibrin help initiate the fibrinolytic system?


iron deficiency hemochromatosis anemia iron-deficiency anemia hemorrhage sickle-cell anemia polycythemia ectopic pacemakers

AV conduction disorders pacemaker atrial fibrillation heart murmurs stenosis insufficiency echocardiography cardiac angiography elephantiasis edema hypotension shock hypovolemic shock low-resistance shock cardiogenic shock hypertension renal hypertension primary hypertension left ventricular hypertrophy stroke diuretics beta-adrenergic receptor blockers calcium-channel blockers angiotensin-converting enzyme (ACE) inhibitors heart failure diastolic dysfunction systolic dysfunction pulmonary edema cardiac inotropic drugs digitalis vasodilator drugs coronary artery disease ischemia myocardial infarction heart attack angina pectoris ventricular fibrillation cardiopulmonary resuscitation (CPR)

defibrillation atherosclerosis coronary thrombosis vitamin E folacin homocysteine nitroglycerin coronary balloon angioplasty coronary stents coronary bypass transient ischemic attacks

(TIAs) embolus embolism hematoma hemophilia hypercoagulability aspirin oral anticoagulants thrombolytic therapy recombinant t-PA streptokinase


(Answers are given in Appendix A.)

1. A person is found to have a hematocrit of 35 percent. Can you conclude from this that there is a decreased volume of erythrocytes in the blood?

2. Which would cause a greater increase in resistance to flow, a doubling of blood viscosity or a halving of tube radius?

3. If all plasma-membrane calcium channels in contractile cardiac-muscle cells were blocked with a drug, what would happen to the muscle's action potentials and contraction?

4. A person with a heart rate of 40 has no P waves but normal QRS complexes on the ECG. What is the explanation?

5. A person has a left ventricular systolic pressure of 180 mmHg and an aortic systolic pressure of 110 mmHg. What is the explanation?

6. A person has a left atrial pressure of 20 mmHg and a left ventricular pressure of 5 mmHg during ventricular filling. What is the explanation?

7. A patient is taking a drug that blocks beta-adrenergic receptors. What changes in cardiac function will the drug cause?

8. What is the mean arterial pressure in a person whose systolic and diastolic pressures are, respectively, 160 and 100 mmHg?

9. A person is given a drug that doubles the blood flow to her kidneys but does not change the mean arterial pressure. What must the drug be doing?

10. A blood vessel removed from an experimental animal dilates when exposed to acetylcholine. After the endothelium is scraped from the lumen of the vessel, it no longer dilates in response to this mediator. Explain.

PART THREE Coordinated Body Functions

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

PART THREE Coordinated Body Functions

A person is accumulating edema throughout the body. Average capillary pressure is 25 mmHg, and lymphatic function is normal. What is the most likely cause of the edema?

A person's cardiac output is 7 L/min and mean arterial pressure is 140 mmHg. What is the person's total peripheral resistance?

The following data are obtained for an experimental animal before and after a drug. Before: Heart rate = 80 beats/min, and stroke volume = 80 ml/beat.

After: Heart rate = 100 beats/min, and stroke volume = 64 ml/beat. Total peripheral resistance remains unchanged. What has the drug done to mean arterial pressure?

When the nerves from all the arterial baroreceptors are cut in an experimental animal, what happens to mean arterial pressure?

What happens to the hematocrit within several hours after a hemorrhage?

Vander et al.: Human Physiology: The Mechanism of Body

Vander et al.: Human Physiology: The Mechanism of Body

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  • Osman
    Which causes greater increase in resistance to a doubling of blood viscosity?
    8 years ago
  • emmi paavolainen
    What is bodys anti clotting mechanism?
    8 years ago
  • Mantissa Fairbairn
    Do endothelial cells secrete heparin?
    7 years ago

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