Unit 5: Drugs Used in the Treatment of Blood Disorders

What is hemostasis?

A process that keeps the blood fluid and clot-free in normal vessels and also forms a localized plug in injured vessels

What happens when a blood vessel is injured?

They induce the formation of a blood clot to prevent blood loss and allow healing (clot must stay localized to prevent widespread clotting within intact vessels)

What is the goal of normal hemostasis?

Preventing prolonged hemorrhage and spontaneous thrombosis

What are the four stages of hemostasis?

1) Vascular spasm or localized vasoconstriction is the first response to injury; the damaged vessel immediately constricts to restrict/reduce blood flow to the area to limit blood loss - this response occurs as a result of secretion of endothelium-derived vasoconstrictors such as endothelin; sympathetic and local factors (thromboxane) are also released which initiates the myogenic properties in the vessel wall and induces smooth muscle contraction

2) Immediately following vasoconstriction, primary hemostasis occurs which involves platelet activation to form the initial plug; platelets adhere to exposed collagen of the damaged endothelium and also to each other; the platelet plug releases chemical mediators which are responsible for recruiting more platelets, promoting vasoconstriction and initiating the coagulation cascade - the goal of the remaining stages is to form a stable permanent plug

3) Secondary hemostasis involves sequential conversion of inactivate proteins to catalytically active protease; the activated endothelium and nearby cells express a membrane-bound procoagulant factor called tissue factor, which complexes with coagulation factor VII to initiate the coagulation cascade - the result is the activation of thrombin which is a critical enzyme in the cascade; thrombin converts soluble fibrinogen to an insoluble fibrin polymer that forms the matrix of the clot

4) Fibrinolysis which involves clot dissolution; this is needed for wound healing and restoration of vessel flow - the process of fibrinolysis involves proteolytic actions of plasmin bound to clot

What are hemorrhagic diseases?

They’re characterized by excess bleeding and may be caused by several factors that regulate hemostasis

What are the different causes of hemorrhagic diseases?

1) Platelet deficiencies including thrombocytopenia and von Willebrand disease (genetic defect of the platelets) will result in improper clot formation, leading to prolonged bleeding after injury

2) Clotting factor deficiencies involving a single factor (e.g. factor VIII or IX, resulting in hemophilia) or multiple factors (caused by vitamin K deficiency)

3) Fibrinolytic hyperactivity

What is thrombocytopenia?

A decrease in platelet production

What treatments are available for hemorrhagic disease?

Vitamin K, antifibrinolytic agents, blood products (replacement factors), and many others

What are the two natural forms of vitamin K?

Vitamin K1, known as phytonadione (found in foods such as green leafy vegetables) and vitamin K2, known as menaquinone (found in intestinal bacteria)

How does vitamin K help through post-translational modification?

It serves as a cofactor for the biological factors II, VII, IX, and X

How is vitamin K1 administered?

Oral, parenteral, and intravenous - if given intravenously, it must be given slowly to avoid possible anaphylaxis

What does vitamin K require for intestinal absorption?

It’s fat soluble and therefore it requires bile salts

What is vitamin K used to treat?

Anticoagulant toxicity, vitamin K deficiency, and hemorrhagic disease in newborns

How do antifibrinolytics / fibrinolytic inhibitors?

Since fibrinolysis occurs when plasmin lyses fibrin and fibrinogen, antifibrinolytics work as agonists on the lysine binding site on plasmin, blocking its ability to bind to fibrin

What is aminocaproic acid?

A synthetic agent that’s similar to lysine and therefore binds and blocks the lysine binding site

How does aminocaproic acid block the lysine binding site?

It competitively inhibits the action of plasmin on fibrin

What does incomplete lysis lead to?

Thrombi formation, which can be dangerous

What are fibrinolytic inhibitors effective in the treatment of?

Bleeding disorder such as bleeding from fibrinolytic therapy or as adjunct therapy for hemophiliacs

What are blood products (plasma fractions)?

Deficiencies in plasma coagulation factors that can cause bleeding and will spontaneously occur when factors are 5-10% less than normal levels

What are some examples of plasma coagulation factor deficiencies?

Factor VIII deficiency resulting in hemophilia A (classic hemophilia) and factor IX deficiency resulting in hemophilia B (Christmas disease)

How are plasma coagulation factor deficiencies treated?

Plasma factors can be isolated from blood (fractionation) and concentrated so that they can be administered to the patient

What is desmopressin acetate?

An antidiuretic and transiently increases factor VIII activity in mild hemophilia or von Willebrand’s disease

How is desmopressin acetate administered?

An injectable form or a nasal spray if high doses are needed

What is protamine sulfate?

A generic drug that’s obtained from salmon sperm

What is protamine sulfate used to treat?

Heparin overdoses - it binds to heparin, neutralizing its anticoagulant effects

How is protamine sulfate administered?

This is given slowly through IV to avoid collapse of the vessels - high doses can produce anticoagulant effects, so the patient needs to be closely monitored

What is a thrombus?

The formation of a blood clot proper, there are two types that can form

What is a red thrombus?

A fibrin rich thrombus, containing a large number of RBCs, and typically occurring in venous vessels

What is a white thrombus?

A platelet rich thrombus that is usually found in arterial vessels

What is an embolus?

A detached travelling intravascular mass

What is a thromboembolism?

A blood clot that obstructs a blood vessel and later becomes dislodged and migrates in the body

What are prothrombic factors?

Factors released due to local vessel injury, circulatory stasis, or altered blood coagulability

What drug classes are used to treat thromboembolic disease?

Anticoagulants, antithrombotic drugs, and fibrinolytic drugs

What do ideal systemic anticoagulants do?

Prevents pathologic thrombosis, limits reperfusion injury, allows for a normal response to vascular injury, and limits bleeding

What is heparin (unfractionated)?

A mixture of sulfated mucopolysaccharides (or glycosaminoglycans) and is a widely used anticoagulant

What are glycosaminoglycans?

Long, unbranched polysaccharides

Where is heparin isolated from mast cells?

In bovine lung or porcine GI mucosa where it’s stored in secretory granules?

What does heparin do?

It enhances/accelerates (\~100 fold) the action of antithrombin III (AT-III) which forms a heparin-ATIII complex

What does AT-III do?

It inhibits activated clotting factors, especially (IIa) and factor (Xa), by means of irreversible binding

What is heparin used for?

Venous thrombosis, pulmonary embolism, unstable angina, atrial fibrillation, acute myocardial infarction, and various cardiovascular surgeries

What is the primary drug used in the initial treatment of thrombosis and thromboembolic disease?

Heparin

How fast is the onset of action of heparin?

Rapid, which is useful as an acute anticoagulant

What is generally taken concurrently with heparin?

An oral anticoagulant

Does heparin treat existing thrombus, or only prevent new thrombus?

Heparin only prevents new thrombus formation, and won’t lyse an existing thrombus

What are the adverse effects of heparin?

Increased bleeding tendencies and possible thrombocytopenia

What is the activated partial thromboplastin time (aPTT)?

A measure of anticoagulant effects that is used to monitor patients taking heparin

What is administered to neutralize heparin in overdose situations?

Protamine sulfate

What is enoxaparin?

A low molecular weight heparin that’s fractionated from standard unfractionated heparin

When is enoxaparin used?

Used more commonly than unfractionated heparin due to its advantages including fewer bleeding tendencies, less risk of thrombocytopenia, and improved pharmacokinetics

What is warfarin?

An oral anticoagulant (injectable formations are available) that antagonizes the actions of vitamin K to reduce clotting factors (II, VII, IX, and X)

What is warfarin used for?

It’s used as a chronic preventative anticoagulant therapy and dosing usually begins with heparin administration

How is warfarin monitored in patients?

Using the internalized normalized ratio (INR), which measures the patient’s prothrombin (PT) over the average PT for the lab

What is the main toxicity of warfarin and how is it treated?

Bleeding tendencies, which can be treated with vitamin K1 - serious bleeding requires fresh blood and plasma transfusion

Why can’t warfarin be used during pregnancy?

It crosses the placenta, instead use heparin as it doesn’t cross the placenta

What are the therapeutic targets of antithrombotic?

Various platelet activators

Where are platelet activators produced?

They can be agents outside the platelet that act on the platelet membrane (such as collagen or thrombin) while others are produced within the granules and act on the platelet membrane once they’re released (such as ADP, 5-HT, and TxA2)

What platelet activators are produced in the platelet and act within the platelet itself?

Cyclooxygenase, cAMP, cGMP, and calcium ions

What is the most commonly used anti-platelet drug?

Aspirin

How does aspirin reduce platelet aggregation and prevent TxA2 production in platelets?

It irreversibly binds and acetylates cyclooxygenase-1

Why do NSAIDs (other than aspirin) have a short duration of action as a cyclooxygenase inhibitor?

They inhibit cyclooxygenase-1, but isn’t irreversible

What does aspirin prevent?

Thrombus and re-thrombus formation, which can contribute to myocardial infarcts, stroke, and peripheral vascular disease

What are adverse effects of of aspirin?

GI ulceration, renal damage, and bleeding tendencies

How do clopidogrel and ticlopidine reduce platelet aggregation?

They act as P2Y12 (found on surface of platelets) receptor antagonists and prevent binding of ADP to receptors

What are prodrugs?

They need to be activated by the liver and cytochrome P450 metabolism

What do ADP inhibitors reduce or prevent?

The recurrence of strokes and myocardial infarcts in affected individuals - the agents are also considered fairly safe

What is glycoprotein IIb/IIa?

A platelet surface integrin receptor for fibrinogen and von Willebrand inhibitor

What activates glycoprotein IIb/IIa?

PLA2 (activated by TxA2) and platelet glycoprotein VI (GPVI; activated by collagen)

What does glycoprotein IIb/IIa do?

It binds and anchors platelets to each other via fibrinogen and to the exposed vessel matrix via von Willebrand factor

What can glycoprotein IIb/IIa be used as?

Antithrombotic drugs

What is abciximab?

A glycoprotein IIb/IIa receptor antagonist that acts as a platelet aggregation inhibitor

What is the major toxicity of abciximab?

Possible bleeding tendencies

How do fibrinolytic lyse thrombi?

It activates plasma from plasminogen

What are tissue plasminogen activators (t-PAs)?

Serine proteases that are involved in the breakdown of a clot - it binds fibrin and preferentially activates clot-bound plasminogen and limits activation of systemic plasmin

What is the half-life of t-PA?

It has a short half-life which necessitates delivery via constant infusion

What is t-PA used to treat?

Coronary thrombosis in acute myocardial infarction, deep venous thrombosis, stroke, and pulmonary embolism

What is the toxicity of t-PA?

Bleeding tendencies

What is hyperlipidemia?

It involves an increased amount of lipids and/or lipoproteins in the blood which are considered risk factors for cardiovascular disease such as atherosclerosis

What is atherosclerosis risk associated with?

Increased plasma lipoproteins such as low density lipoprotein (LDL), intermediate density lipoprotein (IDL), and very low density lipoprotein (VLDL), as well as decreased high density lipoprotein (HDL)

How does a decrease in plasma LDL effect atherosclerosis?

It decreases atherosclerosis

What diseases are caused by atherosclerosis?

Coronary artery disease, stroke, and peripheral artery disease

How do atherosclerosis lesions arise?

A variety of ways, including from an intimal cell mass (ICM)

What is the tunica intima?

The innermost layer of an artery or vein

What is the tunica intima composed of?

A layer of endothelial cells (endothelium) and is supported by an internal elastic membrane

What is below the tunica intima?

The tunica media

What is the tunica media composed of?

Several layers of smooth muscle cells and connective tissue

What happens when smooth muscle proliferation occurs in the layers of the vessel?

It can result in a cell mass; LDLs cross the endothelium and make their way into this mass where they can accumulate, macrophages then engulf the LDL and become activate, which produces ‘foam cells’ resulting in an early lesion

What stimulates further vascular smooth muscle proliferation?

Damage to the endothelium ensues, platelets adhere, and growth factors stimulate proliferation - this eventually results in fibrous plaque formation along with more lipid accumulation

What are statins?

Compounds that are structural analogs to 3-hydroxyl-3-methylglutaryl-coenzyme A (HMG-CoA)

What is HMG-CoA?

A liver enzyme responsible for producing cholesterol - therefore statins are used to lower cholesterol levels by inhibiting HMG-CoA

What are lovastatin (generic) and simvastatin?

Statins that are the most effective and best tolerated therapy for hyperlipidemias

How are lovastatin and simvastatin used?

They’re used as monotherapy due to their high efficacy, but can also be used in combination with other drug classes

What type of metabolism do statins have?

They have a high hepatic first-pass effect

What is the first-pass effect?

Concentration of a drug is drastically reduced before reaching system circulation

How do statins effect cholesterol levels?

They partially inhibit HMG-CoA which reduces cholesterol levels, but induces an increase in high affinity LDL receptors (predominantly in the liver), resulting in an increase in LDL clearance and a decrease in plasma LDLs

What are toxicities of statins?

An increase in liver enzymes and a risk of teratogenic effects (statins are contradicted in pregnancy)

What is one of the oldest drugs used to treat hyperlipidemias?

VLDL secretion inhibitors such as niacin

What is niacin (nicotinic acid)?

A hyperlipidemias pharmacological treatment that acts as a vitamin (B3) when it’s converted to nicotamide adenine dinucleotide (NAD)

What does unconverted niacin produce?

Lipid lowering effects which inhibit VLDL production and secretion - thus inhibiting LDL levels via effects in the liver

How does niacin effect lipoprotein lipase activity?

It increases lipoprotein lipase activity, resulting in increased clearance of VLDLs and is the best agent for raising HDLs

How is niacin formulated?

As both rapid-release and slow-release tablets