Hematology

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Chapter 16 Hematology

Heparins

Description

Heparin belongs to a family of endogenous substances known as glycosaminoglycans (GAGs). Heparin and its synthetic derivatives are anticoagulants.

Prototype and Common Drugs

image Prototype: heparin (also known as unfractionated heparin [UFH])
image Others: low–molecular-weight heparin (LMWH)

image Dalteparin, enoxaparin, nadroparin, tinzaparin

Pentasaccharides

image Prototype: Fondaparinux

Heparinoids

image Prototype: Danaparoid

MOA (Mechanism of Action)

image The coagulation (clotting) system is composed of many proteins. Most of these proteins are procoagulants, which means they contribute to clotting. Some proteins are anticoagulants that serve to keep the coagulation system in balance.
image When a protein is activated, its name is followed by a small letter a. Each activated protein serves as an enzyme for the next protein downstream in the cascade (Figure 16-1).
image Heparins interfere with the coagulation cascade by amplifying the anticoagulant effect of antithrombin III.
image Antithrombin III, a natural plasma protease inhibitor, is an anticoagulant, and it inhibits thrombin (IIa) and factor Xa.
image To inhibit factor Xa, heparins must bind only antithrombin III.
image To inhibit factor IIa, heparins must bind to both antithrombin III and factor IIa (dual binding not shown Figure 16-1).
image LMWHs are typically too small to bind both antithrombin III and factor IIa. Therefore their anticoagulant effects are exerted largely through factor Xa, with minimal effects on factor IIa.
image

Figure 16-1

Pharmacokinetics

Unfractionated Heparin

image Very complex pharmacokinetics exist because there is a large range in molecular weight of the molecules
image The dose-response curve is difficult to predict, so the dose must be individualized in every patient, with frequent measurements (i.e., activated partial thromboplastin time [aPTT]) made to guide titration.
image UFH binds to a variety of plasma proteins, reducing its bioavailability at low concentrations.

image Levels of these heparin-binding proteins can vary significantly, requiring the use of very high doses in some patients.

image UFH exhibits saturation kinetics, meaning that the elimination half-life (t1/2) increases with increasing dose.
image UFH is administered via the intravenous (IV) or subcutaneous (SC) routes.

image UFH acts immediately after IV administration, and effects last a few hours. Infusion is required to maintain continuous anticoagulation.
image Onset occurs in 60 minutes when UFH is given subcutaneously.

Low–Molecular-Weight Heparin

image LMWH has a more predictable dose-response curve than UFH because there is a smaller range of molecular weights.
image aPTT is not used to measure LMWH activity, but sometimes factor Xa levels can be measured (not commonly performed).
image LMWH is administered via the subcutaneous route. Compared to UFH, LMWH has:

image A longer half-life than heparin
image More predictable pharmacokinetic profile

• Less protein binding
• First-order kinetics

Indications

image Treatment and prevention of inappropriate thrombosis

image Venous thrombosis (and pulmonary embolism [PE]) caused by:

• Stasis (prolonged inactivity: airplane, surgery)
• Endothelial damage (common in orthopedic surgery)
• Hypercoagulable states (the balance of thrombogenesis and thrombolysis inappropriately favors thrombogenesis)

image Arterial thrombosis (less common than venous)

image Initial management of:

image Unstable angina or acute myocardial infarction (MI)
image Coronary angioplasty or stent placement
image Cardiac surgery requiring cardiopulmonary bypass (the bypass tubing activates the clotting cascade because it is a foreign surface)

image Disseminated intravascular coagulation (DIC)

Contraindications

image Previous heparin-induced thrombocytopenia syndrome (HITS) (see Side Effects)
image Coagulopathies: hemophilia, thrombocytopenia (low platelet count)
image Active bleeding: intracranial hemorrhage, gastrointestinal (GI) ulcers, certain cancers

Side Effects

image HITS

image Antibodies against platelet factor 4 are produced and bind to platelets.
image Platelets get activated and sticky, and this causes:

• Thromboses (multiple)
• Platelet consumption resulting in thrombocytopenia
• Bleeding as a result of thrombocytopenia

image Hemorrhage can be reversed with protamine (see later).
image Osteoporosis occurs with long-term therapy; the cause is unknown.
image Hyperkalemia: Although not a common occurrence, heparin can cause increased serum potassium; it is more likely to occur in patients with diabetes or renal disease. In this regard the action of heparin is similar to that of spironolactone, which is an aldosterone blocker classified as a K-sparing diuretic.
image Fever: Rarely, heparin can cause a drug fever.

Important Notes

image To measure the effect of UFH, the aPTT test is used (compare this with prothrombin time [PT] or International Normalized Ratio [INR], which is used with warfarin). It is a measure of time to coagulation (in the laboratory) and is measured in seconds. The higher the number, the more strongly a patient is anticoagulated.
image Unlike UFH, LMWHs do not prolong the aPTT, and they also have a more predictable pharmacokinetic profile. These important differences make LMWH far more convenient for patients to use, with more stable administration and less rigorous monitoring.
image Heparins provide a safe and important alternative to teratogenic warfarin in pregnancy.
image For cases of heparin overdose, protamine sulfate is a strongly basic protein that forms a complex with heparin, acting as a chemical antagonist. LMWH does not have an antidote.
image Danaparoid works by the same mechanism as the heparins, but it is not structurally related to the heparins; it is therefore considered a heparinoid. Therefore it can be used in the management of patients with heparin-induced thrombocytopenia (HIT) too.
image Fondaparinux is synthetic and is based on the structure of the antithrombin binding region of heparin. The binding region of heparin is only 5 saccharide units and is the basis for the pentasaccharide structure of fondaparinux. Fondaparinux could be thought of as really low molecular weight heparin.

Evidence

LMWH versus UFH for Treatment of Venous Thromboembolism

image A 2005 Cochrane review (five studies, N = 1508 participants) found that LMWH may be more efficacious than UFH for the initial treatment of venous thromboembolism (VTE). This Cochrane review also found that LMWH was safer than heparin, with significantly fewer hemorrhagic adverse events.

LMWH versus Warfarin for Treatment of Venous Thromboembolism

image A 2001 Cochrane review (seven studies, N = 1137 participants), updated in 2003, compared warfarin with LMWH for long-term treatment of VTE. There was no difference in the risk of recurrent VTE between warfarin and LMWH. There was a lower risk of bleeding with LMWH (odds ratio [OR] 0.38), and no difference in mortality rates between these two interventions was found.

LMWH and Heparinoids versus UFH for Ischemic Stroke

image A 2008 Cochrane review (nine studies, N = 3137 patients) compared LMWH and heparinoids (danaparoid) with UFH in patients with acute, presumed or confirmed ischemic stroke. The odds of developing a deep vein thrombosis (DVT) were reduced with LMWH compared with UFH (OR 0.55); however, the incidence of key clinical outcomes such as PE, death, and hemorrhage (intracranial or extracranial) was too small to provide a reliable comparison.

FYI

image Heparin was discovered in 1916 by a medical student who was working on a summer research project. He was trying to extract procoagulant substances from various tissues and instead found a potent anticoagulant still used today.
image The name heparin reflects the fact that this substance was extracted from the liver (hepatic).
image Thrombo means blood clot. Cyto means cell. Thrombocytes (also known as platelets) are cells that contribute to blood clots. Penia means decreased. Thrombocytopenia means a low platelet count.

Direct Factor Xa Inhibitors

Description

Direct factor Xa inhibitors are agents that inhibit clotting by inhibiting a specific component of the coagulation cascade.

Prototype

image Prototype: rivaroxaban

MOA (Mechanism of Action)

image The coagulation system is composed of many proteins: most of these proteins are procoagulants, which means they contribute to clotting. Some proteins are anticoagulants, which serve to keep the coagulation system in balance.
image When a protein is activated, its name is given a small letter a at the end. Each activated protein serves as an enzyme for the next protein downstream in the cascade (Figure 16-2).
image Factor Xa converts prothrombin to thrombin (factor IIa). Thrombin is an enzyme that catalyzes the final step in the coagulation cascade, the conversion of fibrinogen to fibrin.
image Fibrin is a fibrous protein that forms a mesh, providing structural rigidity to a clot. The mesh is created by the cross-linking of fibrin, and this cross-linking step is facilitated by factor XIII.
image In addition to converting fibrinogen to fibrin, thrombin also activates factor XIII; thus thrombin not only catalyzes the creation of the key component of the clot, it also facilitates the provision of structural rigidity to the clot.
image Thrombin also activates factors V, VIII, and XI, therefore amplifying the coagulation cascade. In addition, thrombin activates platelets, leading to their aggregation.
image Direct factor Xa inhibitors directly inhibit the conversion of prothrombin to thrombin without using antithrombin III as an intermediary. The direct inhibition of thrombin formation results in an anticoagulant effect.
image

Figure 16-2

Pharmacokinetics

image Rivaroxaban, the first direct factor Xa inhibitor, is administered orally. It is rapidly absorbed, reaching peak plasma concentrations in 2 to 4 hours, and has an elimination half-life of 9 hours.
image One third of rivaroxaban is eliminated unchanged in the kidneys; therefore dose adjustments should be considered in renal impairment, and an alternative drug should be considered in patients with severe renal impairment.

Indications

image Postsurgical VTE prophylaxis
image As an alternative to heparins in patients with severe HIT

Contraindications

image Active bleeding
image Pregnancy
image Patients at increased risk of bleeding: clotting disorders, history of recent hemorrhagic stroke

Side Effects

image Bleeding: As with all anticoagulants, bleeding is the major side effect.

Important Notes

image There are no monitoring requirements for rivaroxaban. This and the fact that it is an orally administered agent suggest that drugs in its class, and perhaps the direct thrombin inhibitors, will supplant warfarin as the drugs of choice among oral anticoagulants.

Advanced

Drug Interactions

image CYP450 3A4 enzymes are involved in the metabolism of rivaroxaban; thus the potential exists for pharmacokinetic drug interactions with inhibitors or inducers of this isozyme. Rivaroxaban is also a P-glycoprotein (Pgp) substrate, and therefore its levels could also be affected by inhibitors or inducers of Pgp.

Evidence

Postsurgical Venous Thromboembolism Prophylaxis

image The RECORD trials were a series of double-blind randomized controlled trials that compared rivaroxaban with enoxaparin for the prophylactic treatment of VTE after total hip replacement (RECORD-1 and RECORD-2) or total knee replacement (RECORD-3 and RECORD-4). The trials were all relatively large, randomizing 2509 to 4541 patients between the two treatment groups. Rivaroxaban-treated patients had fewer events of VTE and all-cause deaths compared with enoxaparin in each of the four studies. The risk of bleeding was slightly higher with rivaroxaban than with enoxaparin.

FYI

image For a quick summary of the difference between two of the newer oral anticoagulants—direct factor Xa and direct thrombin inhibitors. Direct factor Xa inhibitors inhibit the formation of thrombin, whereas direct thrombin inhibitors allow thrombin to be formed but interfere with the actions of thrombin.

Direct Thrombin Inhibitors

Description

Direct thrombin inhibitors reduce clotting by inhibiting a specific component of the coagulation cascade.

Prototype and Common Drugs

Parenteral

image Prototype: hirudin (lepirudin)
image Others: bivalirudin, desirudin

Oral

image Prototype: argatroban
image Others: dabigatran, ximelagatran

MOA (Mechanism of Action)

image The coagulation (clotting) system is a multistep cascade that eventually leads to the formation of fibrin and development of a clot.
image Thrombin (factor IIa) is an enzyme that catalyzes the final step in the coagulation cascade, the conversion of fibrinogen to fibrin (Figure 16-3).
image Fibrin is a fibrous protein that forms a mesh, providing structural rigidity to a clot. The mesh is created by the cross-linking of fibrin, and this cross-linking step is facilitated by factor XIII.
image In addition to converting fibrinogen to fibrin, thrombin also activates factor XIII; thus thrombin not only catalyzes the creation of the key component of the clot, it also facilitates the provision of structural rigidity to the clot.
image Thrombin also activates factors V, VIII, and XI, therefore amplifying the coagulation cascade. Thrombin also has antiplatelet effects.
image Thrombin has an active site as well as two other sites, referred to as exosite 1, which binds fibrin, and exosite 2, which binds heparin.
image Direct thrombin inhibitors all bind to thrombin directly at its active site. The bivalent inhibitors (-irudins) also bind at exosite 1 (hence the term “bivalent”, indicating two binding sites), while the univalent inhibitors only bind at the active site.
image The univalent thrombin inhibitors (e.g., argatroban and dabigatran) and bivalirudin all bind reversibly, whereas the other bivalent inhibitors bind thrombin irreversibly.
image The net result of this binding is that the effects of thrombin are inhibited. The inhibition of thrombin results in an anticoagulant effect.
image

Figure 16-3

Pharmacokinetics

image Argatroban has a short half-life and is typically administered by infusion.
image Hirudin is administered by either IV or SC injection, with elimination half-life of 60 minutes and 120 minutes, respectively. It is cleared by the kidneys.
image Bivalirudin is administered intravenously and has rapid onset and offset, with a half-life of about 25 minutes. It is primarily eliminated by proteolysis, although about 20% of elimination is renal.

Indication

image Postsurgical VTE prophylaxis

Bivalirudin

image Severe heparin-induced thrombocytopenia (HIT)

Contraindications

image Patients who are at high risk of bleeding, such as those with the following conditions:

image Uncontrolled active bleeding
image Major bleeding (coagulopathy) disorders
image Acute gastric or duodenal ulcer
image Recent (<6 months) stroke

Side Effects

image Bleeding: As with all anticoagulants, bleeding is the major side effect.

Important Notes

image All of the agents in this class are approved for prophylaxis of DVT and VTE after orthopedic surgery. Patients undergoing knee or hip replacement surgeries, in particular, are at high risk for developing a DVT or VTE. The risk is so high that these patients receive prophylactic anticoagulants for several days postsurgery.
image The theoretical advantage of direct over indirect thrombin inhibitors such as LMWHs is that the direct inhibitors inactivate fibrin-bound thrombin, in addition to the thrombin in the fluid phase. This may lead to a greater inhibition of the thrombus. Direct thrombin inhibitors may also provide more predictable anticoagulation, as they are not bound to plasma proteins (unlike heparin) and are not neutralized by platelet factor 4 (a protein secreted by platelets) and other factors generated at the site of vascular injury.
image The anticoagulation of bivalirudin can be monitored using aPTT.
image Warfarin has been the prototypical oral anticoagulant for decades, but with its narrow margin of safety, significant potential for drug-drug and drug-food interactions, and significant variability in response among patients, there is much anticipation that new oral anticoagulants will soon be able to replace it. The direct thrombin inhibitors, which lack any of these limitations associated with warfarin, are one of the classes that might replace warfarin.

FYI

image The -irudins are based on the anticoagulant activity of leeches. Leeches secrete hirudin, and that facilitates their ability to draw blood from their victim. The recombinant form of hirudin, lepirudin, is used clinically.
image Ximelagatran, the first direct thrombin inhibitor, was withdrawn from the market because of concerns over hepatotoxicity.

Vitamin K Antagonists

Description

Vitamin K antagonists are a family of naturally derived anticoagulants, which are also known as coumarins.

Prototype

image Prototype: warfarin

MOA (Mechanism of Action)

image Vitamin K is key cofactor in the hepatic activation of four coagulation factors. The four vitamin K-dependent clotting factors are II, VII, IX, and X (Figure 16-4).
image To act as a cofactor, vitamin K must be in its reduced form, vitamin K hydroxyquinone. The enzyme vitamin K epoxide reductase (VKOR) converts vitamin K to its reduced form.
image Warfarin inhibits the enzyme VKOR. Blocking formation of the reduced form of vitamin K inhibits the activation of these four clotting factors.
image These clotting factors vary in their half-lives (6 to 50 hours), with factor II having the longest half-life and factor VII having the shortest. This delays the onset of action of warfarin, as one must wait until these clotting factors have been mostly depleted before the full anticoagulant effects have been achieved.
image

Figure 16-4

Pharmacokinetics

image Warfarin is an orally administered anticoagulant.
image Warfarin requires 2 to 3 days of treatment before anticoagulation takes effect. This is because warfarin prevents vitamin K–dependant protein synthesis, and before anticoagulation occurs the plasma proteins must be cleared from the plasma, which takes about 48 hours.
image Drug-drug and drug-food interactions are frequent with this agent.

image Pharmacodynamic: competitive antagonism with vitamin K

• Foods containing vitamin K will oppose warfarin.

image Pharmacokinetic: enzyme induction or inhibition

• Warfarin may also inhibit or induce metabolism of other drugs.

Indications

image Long-term (home) anticoagulation. Note that heparin would be used first for many of these conditions in the hospital and that warfarin would replace heparin on discharge.
image The most common indications include the following:

image PE or DVT treatment
image Atrial fibrillation
image Prevention of thrombus for mechanical heart valves
image Chronic hypercoagulable states

Contraindications

image Pregnancy: Warfarin is teratogenic and can also cause fetal bleeding.
image Recent events that predispose to bleeding include the following:

image Surgery
image Stroke

image Platelet disorders (If you have dysfunctional clotting cells and dysfunctional clotting proteins, there really is not much left to form a clot if you should need it.)

Side Effect

image Hemorrhage

image Minor: Small cuts, nosebleeds, easy bruising, hematuria (blood in urine), and bleeding gums may occur.
image Major: Intracranial bleeding is often catastrophic.

Important Notes

image Warfarin therapy is monitored using the International Normalized Ratio (INR), which is a standardized form of the PT test. Because different laboratories use different reagents to test the PT, every laboratory generates a slightly different result, so the INR corrects for this discrepancy among laboratories.
image Patients must undergo regular blood tests to ensure that their INR levels remain “therapeutic,” which means being in the appropriate range for their problem. For example, DVT treatment requires that the INR be 2.0 to 2.5 but for mechanical valves, the INR should be 2.5 to 3.5.
image The anticoagulant effects of warfarin can be reversed by administration of vitamin K. The time required for vitamin K to work is dependent on the time the liver requires to generate more proteins (many hours).
image Fresh frozen plasma (plasma from another human) can be transfused to immediately replace clotting factors and is the fastest way to correct an overdose of warfarin.
image When warfarin is being administered, all vitamin K–dependent protein synthesis is inhibited. This includes the prothrombotic factors II, VII, IX, and X but also includes the antithrombotic factors protein C and protein S. Protein C and S are inhibited very early with warfarin, and thus there can be a short duration of time when only the natural anticoagulants are inhibited and a paradoxical, temporary hypercoagulable state can be induced with warfarin. Therefore it is important to coadminister heparin with warfarin until the patient’s anticoagulation levels (measured by INR) are in the desired range.

Advanced

image Warfarin is actually a racemic mixture of two enantiomers: R (weak) and S (potent). Each is eliminated by different metabolic pathways:

image S by 2C9
image R by 1A2 (major) as well as 2C19 and 3A4 (both minor)

Pharmacogenetics

image There is significant genetic variability in responses to warfarin owing to variants in 2C9 that metabolize the drug less efficiently and to variants in VKOR. See Chapter 6 for further details.

Evidence

Warfarin versus LMWH for Treatment of Venous Thromboembolism

image A 2001 Cochrane review (seven studies, N = 1137 participants), updated in 2003, compared warfarin with LMWHs for long-term treatment of VTE. There was no difference in the risk of recurrent VTE between warfarin and LMWH. There was a lower risk of bleeding with LMWH (OR 0.38), and no difference in mortality rates between these two interventions.

Warfarin versus Acetylsalicylic Acid for Atrial Fibrillation

image A 2007 Cochrane review (eight studies, N = 9598 participants) compared warfarin with acetylsalicylic acid (ASA) in atrial fibrillation patients who had not had a prior stroke or transient ischemic attack (TIA). Treatment with warfarin led to a lower risk of stroke (OR 0.68), ischemic stroke (OR 0.53), and systemic emboli (OR 0.48). The risk of intracranial hemorrhage was increased with warfarin (OR 1.98). All-cause mortality and vascular deaths were similar between groups, and disabling or fatal strokes and MI were almost reduced with oral anticoagulants, but this did not reach statistical significance.

FYI

image Coumarins were first isolated from spoiled sweet clover and were discovered when cattle consuming this feed began to develop hemorrhagic disease.
image You may hear warfarin referred to as “ rat poison,” as it is commonly used as a rodenticide. However, the dose that a rat receives is very high.

Salicylates

Description

Salicylates comprise a heterogeneous group of agents that are related by chemical structure and by their antiinflammatory effects.

Prototype and Common Drugs

Salicylates

image Prototype: acetylsalicylic acid
image Others: sodium salicylate, salsalate, sodium thiosalicylate, choline salicylate, magnesium salicylate
image Others (derivative): diflunisal

Aminosalicylates

image Prototype: 5-ASA
image Others: sulfasalazine, olsalazine, balsalazide, mesalamine

MOA (Mechanism of Action)

Salicylates

image Like nonsteroidal antiinflammatory drugs (NSAIDs), the salicylates work by inhibiting the actions of the cyclooxygenase (COX) enzyme (Figure 16-5).
image ASA works by irreversibly inhibiting COX-1, an enzyme that catalyzes the formation of cyclic endoperoxide, which in turn is then converted to the following:

image Thromboxane A2 (TXA2) in platelets

• TXA2 is a potent inducer of platelet aggregation and release.
• Inhibition of TXA2 leads to the antiplatelet effects of ASA (Figure 16-6).

image Prostaglandin E2 (PGE2) mediates fever, pain, inflammation, and mucous production.

• Inhibition of PGE2 formation therefore leads to many of the most well known effects of the salicylates, namely their antiinflammatory, analgesic, and antipyretic properties.

image PGI2 (prostacyclin) in endothelial cells

• PGI2 performs essentially the opposite role as TXA2 (see Figure 16-5).

image

Figure 16-5

image

Figure 16-6

Aminosalicylates

image Although the aminosalicylates are related to salicylates in chemical structure, inhibition of prostaglandin (PG) synthesis is believed to play only a minor role, if any, in their efficacy in inflammatory bowel disease.
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