InternalMed_Harrison

InternalMed_Harrison. Low-Molecular-Weight Heparin Consisting of smaller fragments of heparin, LMWH is prepared from unfractionated heparin by controlled enzymatic or chemical depolymerization. The mean molecular weight of LMWH is about 5000, one-third the mean molecular weight of unfractionated heparin. LMWH has advantages over heparin (Table 143-5) and has replaced heparin for most indications. mecHanism of action Like heparin, LMWH exerts its anticoagulant activity by activating antithrombin. With a mean molecular weight of 5000, which corresponds to about 17 saccharide units, at least half of the pentasaccharide-containing chains of LMWH are too short to bridge thrombin to antithrombin (Fig. 143-5). However, these chains retain the capacity to accelerate factor Xa inhibition by antithrombin because this activity is largely the result of the conformational changes in antithrombin evoked by pentasaccharide binding. Consequently, LMWH catalyzes factor Xa inhibition by antithrombin more than


InternalMed_Harrison

InternalMed_Harrison. Predictable anticoagulant response Coagulation monitoring is unnecessary in most patients Lower risk of heparin-induced throm-Safer than heparin for shortor longbocytopenia term administration Lower risk of osteoporosis Safer than heparin for extended administration Abbreviation: LMWH, low-molecular-weight heparin. thrombin inhibition. Depending on their unique molecular weight distributions, LMWH preparations have anti-factor Xa to anti-factor IIa ratios ranging from 2:1 to 4:1.


InternalMed_Harrison

InternalMed_Harrison. thrombin inhibition. Depending on their unique molecular weight distributions, LMWH preparations have anti-factor Xa to anti-factor IIa ratios ranging from 2:1 to 4:1. pHarmacology Although usually given SC, LMWH also can be administered IV if a rapid anticoagulant response is needed. LMWH has pharmacokinetic advantages over heparin. These advantages reflect the fact that shorter heparin chains bind less avidly to endothelial cells, macrophages, and heparin-binding plasma proteins. Reduced binding to endothelial cells and macrophages eliminates the rapid, dose-dependent, and saturable mechanism of clearance that is a characteristic of unfractionated heparin. Instead, the clearance of LMWH is dose-independent and its plasma half-life is longer. Based on measurement of anti-factor Xa levels, LMWH has a plasma half-life of ~4 h. LMWH is cleared almost exclusively by the kidneys, and the drug can accumulate in patients with renal insufficiency.


InternalMed_Harrison

InternalMed_Harrison. LMWH exhibits about 90% bioavailability after SC injection. Because LMWH binds less avidly to heparin-binding proteins in plasma than heparin, LMWH produces a more predictable dose response, and resistance to LMWH is rare. With a longer half-life and more predictable anticoagulant response, LMWH can be given SC once or twice daily without coagulation monitoring, even when the drug is given in treatment doses. These properties render LMWH more convenient than unfractionated heparin. Capitalizing on this feature, studies in patients with venous thromboembolism have shown that home treatment with LMWH is as effective and safe as in-hospital treatment with continuous IV infusions of heparin. Outpatient treatment with LMWH streamlines care, reduces health care costs, and increases patient satisfaction.


InternalMed_Harrison

InternalMed_Harrison. monitoring In the majority of patients, LMWH does not require coagulation monitoring. If monitoring is necessary, anti-factor Xa levels must be measured because most LMWH preparations have little effect on the aPTT. Therapeutic anti-factor Xa levels with LMWH range from 0.5 to 1.2 units/mL when measured 3–4 h after drug administration. When LMWH is given in prophylactic doses, peak anti-factor Xa levels of 0.2–0.5 units/mL are desirable.


InternalMed_Harrison

InternalMed_Harrison. Indications for LMWH monitoring include renal insufficiency and obesity. LMWH monitoring in patients with a creatinine clearance of ≤50 mL/min is advisable to ensure that there is no drug accumulation. Although weight-adjusted LMWH dosing appears to produce therapeutic anti-factor Xa levels in patients who are overweight, this approach has not been extensively evaluated in those with morbid obesity. It may also be advisable to monitor the anticoagulant activity of LMWH during pregnancy because dose requirements can change, particularly in the third trimester. Monitoring should also be considered in high-risk settings, such as in patients with mechanical heart valves who are given LMWH for prevention of valve thrombosis, and when LMWH is used in treatment doses in infants or children.


InternalMed_Harrison

InternalMed_Harrison. dosing The doses of LMWH recommended for prophylaxis or treatment vary depending on the LMWH preparation. For prophylaxis, once-daily SC doses of 4000–5000 units are often used, whereas doses of 2500–3000 units are given when the drug is administered twice daily. For treatment of venous thromboembolism, a dose of 150–200 units/kg is given if the drug is administered once daily. If a twice-daily regimen is used, a dose of 100 units/kg is given. In patients with unstable angina, LMWH is given SC on a twice-daily basis at a dose of 100–120 units/kg. side effects The major complication of LMWH is bleeding. Meta-analyses suggest that the risk of major bleeding is lower with LMWH than with unfractionated heparin. HIT and osteoporosis are less common with LMWH than with unfractionated heparin.


InternalMed_Harrison

InternalMed_Harrison. bleeding Like the situation with heparin, bleeding with LMWH is more common in patients receiving concomitant therapy with anti-platelet or fibrinolytic drugs. Recent surgery, trauma, or underlying hemostatic defects also increase the risk of bleeding with LMWH. Although protamine sulfate can be used as an antidote for LMWH, protamine sulfate incompletely neutralizes the anticoagulant activity of LMWH because it only binds the longer chains of LMWH. Because longer chains are responsible for catalysis of thrombin inhibition by antithrombin, protamine sulfate completely reverses the anti-factor IIa activity of LMWH. In contrast, protamine sulfate only partially reverses the anti-factor Xa activity of LMWH because the shorter pentasaccharide-containing chains of LMWH do not bind to protamine sulfate. Consequently, patients at high risk for bleeding may be more safely treated with continuous IV unfractionated heparin than with SC LMWH.


InternalMed_Harrison

InternalMed_Harrison. thrombocytopenia The risk of HIT is about fivefold lower with LMWH than with heparin. LMWH binds less avidly to platelets and causes less PF4 release. Furthermore, with lower affinity for PF4 than heparin, LMWH is less likely to induce the conformational changes in PF4 that trigger the formation of HIT antibodies. LMWH should not be used to treat HIT patients because most HIT antibodies exhibit cross-reactivity with LMWH. This in vitro cross-reactivity is not simply a laboratory phenomenon because there are case reports of thrombosis when HIT patients were switched from heparin to LMWH. osteoporosis Because the risk of osteoporosis is lower with LMWH than with heparin, LMWH is the better choice for extended treatment.


InternalMed_Harrison

InternalMed_Harrison. osteoporosis Because the risk of osteoporosis is lower with LMWH than with heparin, LMWH is the better choice for extended treatment. Fondaparinux A synthetic analogue of the antithrombin-binding pentasaccharide sequence, fondaparinux differs from LMWH in several ways (Table 143-6). Fondaparinux is licensed for thromboprophylaxis in general medical or surgical patients and in high-risk orthopedic patients and as an alternative to heparin or LMWH for initial treatment of patients with established venous thromboembolism. Although widely used in Europe, as an alternative to heparin or LMWH in patients with acute coronary syndromes, fondaparinux is not licensed for this indication in the United States.


InternalMed_Harrison

InternalMed_Harrison. mecHanism of action As a synthetic analogue of the antithrombinbinding pentasaccharide sequence found in heparin and LMWH, fondaparinux has a molecular weight of 1728. Fondaparinux binds only to antithrombin (Fig. 143-5) and is too short to bridge thrombin to antithrombin. Consequently, fondaparinux catalyzes factor Xa inhibition by antithrombin and does not enhance the rate of thrombin inhibition. pHarmacology Fondaparinux exhibits complete bioavailability after 753 SC injection. With no binding to endothelial cells or plasma proteins, the clearance of fondaparinux is dose independent and its plasma half-life is 17 h. The drug is given SC once daily. Because fondaparinux is cleared unchanged via the kidneys, it is contraindicated in patients with a creatinine clearance <30 mL/min and should be used with caution in those with a creatinine clearance <50 mL/min.


InternalMed_Harrison

InternalMed_Harrison. Fondaparinux produces a predictable anticoagulant response after administration in fixed doses because it does not bind to plasma proteins. The drug is given at a dose of 2.5 mg once daily for prevention of venous thromboembolism. For initial treatment of established venous thromboembolism, fondaparinux is given at a dose of 7.5 mg once daily. The dose can be reduced to 5 mg once daily for those weighing <50 kg and increased to 10 mg for those >100 kg. When given in these doses, fondaparinux is as effective as heparin or LMWH for initial treatment of patients with DVT or PE and produces similar rates of bleeding.


InternalMed_Harrison

InternalMed_Harrison. Fondaparinux is used at a dose of 2.5 mg once daily in patients with acute coronary syndromes. When this prophylactic dose of fondaparinux was compared with treatment doses of enoxaparin in patients with non-ST-segment elevation acute coronary syndrome, there was no difference in the rate of cardiovascular death, MI, or stroke at 9 days. However, the rate of major bleeding was 50% lower with fondaparinux than with enoxaparin, a difference that likely reflects the fact that the dose of fondaparinux was lower than that of enoxaparin. In acute coronary syndrome patients who require percutaneous coronary intervention, there is a risk of catheter thrombosis with fondaparinux unless adjunctive heparin is given.


InternalMed_Harrison

InternalMed_Harrison. side effects Fondaparinux does not cause HIT because it does not bind to PF4. In contrast to LMWH, there is no cross-reactivity of fondaparinux with HIT antibodies. Consequently, fondaparinux appears to be effective for treatment of HIT patients, although large clinical trials supporting its use are lacking. The major side effect of fondaparinux is bleeding. There is no antidote for fondaparinux. Protamine sulfate has no effect on the anticoagulant activity of fondaparinux because it fails to bind to the drug. Recombinant activated factor VII reverses the anticoagulant effects of fondaparinux in volunteers, but it is unknown whether this agent controls fondaparinux-induced bleeding.


InternalMed_Harrison

InternalMed_Harrison. Parenteral Direct Thrombin Inhibitors Direct thrombin inhibitors bind directly to thrombin and block its interaction with its substrates. Approved parenteral direct thrombin inhibitors include recombinant hirudins (lepirudin and desirudin), argatroban, and bivalirudin (Table 143-7). Lepirudin and argatroban are licensed for treatment of patients with HIT, desirudin is licensed for thromboprophylaxis after elective hip arthroplasty, and bivalirudin is approved as an alternative to heparin in patients undergoing percutaneous coronary intervention, including those with HIT. lepirudin and desirudin Recombinant forms of hirudin, lepirudin, and desirudin are bivalent direct thrombin inhibitors that interact with the active site and exosite 1, the substrate-binding site on thrombin. For rapid anticoagulation, lepirudin is given by continuous IV infusion, but the drug can be given SC. Lepirudin has a plasma half-life of 60 min after IV infusion and is cleared by the kidneys. Consequently,


InternalMed_Harrison

InternalMed_Harrison. TABLE 143-7 COMPArIsON Of THE PrOPErTIEs Of LEPIruDIN, BIVALIruDIN, AND ArgATrOBAN


InternalMed_Harrison

InternalMed_Harrison. Antiplatelet, Anticoagulant, and Fibrinolytic Drugs 754 lepirudin accumulates in patients with renal insufficiency. For thromboprophylaxis, desirudin is given SC twice daily in fixed doses; the half-life of desirudin is 2–3 h after SC injection. A high proportion of lepirudin-treated patients develop antibodies against the drug; antibody formation is rare with SC desirudin. Although lepirudin-directed antibodies rarely cause problems, in a small subset of patients, they can delay lepirudin clearance and enhance its anticoagulant activity. Serious bleeding has been reported in some of these patients. Lepirudin is usually monitored using the aPTT, and the dose is adjusted to maintain an aPTT that is 1.5–2.5 times the control. The aPTT is not an ideal test for monitoring lepirudin therapy because the clotting time plateaus with higher drug concentrations. Although the clotting time with ecarin, a snake venom that converts prothrombin to meizothrombin, provides a better index of lepirudin


InternalMed_Harrison

InternalMed_Harrison. the clotting time plateaus with higher drug concentrations. Although the clotting time with ecarin, a snake venom that converts prothrombin to meizothrombin, provides a better index of lepirudin dose than the aPTT, the ecarin clotting time has yet to be standardized. When used for thromboprophylaxis, desirudin does not require monitoring.


InternalMed_Harrison

InternalMed_Harrison. argatroban A univalent inhibitor that targets the active site of thrombin, argatroban is metabolized in the liver. Consequently, this drug must be used with caution in patients with hepatic insufficiency. Argatroban is not cleared via the kidneys, so this drug is safer than lepirudin for HIT patients with renal insufficiency. Argatroban is administered by continuous IV infusion and has a plasma half-life of ~45 min. The aPTT is used to monitor its anticoagulant effect, and the dose is adjusted to achieve an aPTT 1.5–3 times the baseline value, but not to exceed 100 s. Argatroban also prolongs the international normalized ratio (INR), a feature that can complicate the transitioning of patients to warfarin. This problem can be circumvented by using the levels of factor X to monitor warfarin in place of the INR. Alternatively, argatroban can be stopped for 2–3 h before INR determination.


InternalMed_Harrison

InternalMed_Harrison. bivalirudin A synthetic 20-amino-acid analogue of hirudin, bivalirudin is a divalent thrombin inhibitor. Thus, the N-terminus of bivalirudin interacts with the active site of thrombin, whereas its C-terminus binds to exosite 1. Bivalirudin has a plasma half-life of 25 min, the shortest half-life of all the parenteral direct thrombin inhibitors. Bivalirudin is degraded by peptidases and is partially excreted via the kidneys. When given in high doses in the cardiac catheterization laboratory, the anticoagulant activity of bivalirudin is monitored using the activated clotting time. With lower doses, its activity can be assessed using the aPTT. Bivalirudin is licensed as an alternative to heparin in patients undergoing percutaneous coronary intervention. Bivalirudin also has been used successfully in HIT patients who require percutaneous coronary intervention or cardiac bypass surgery.


InternalMed_Harrison

InternalMed_Harrison. Current oral anticoagulant practice dates back almost 60 years to when the vitamin K antagonists were discovered as a result of investigations into the cause of hemorrhagic disease in cattle. Characterized by a decrease in prothrombin levels, this disorder is caused by ingestion of hay containing spoiled sweet clover. Hydroxycoumarin, which was isolated from bacterial contaminants in the hay, interferes with vitamin K metabolism, thereby causing a syndrome similar to vitamin K deficiency. Discovery of this compound provided the impetus for development of other vitamin K antagonists, including warfarin. For many years, the vitamin K antagonists were the only available oral anticoagulants. This situation changed with the introduction of new oral anticoagulants, including dabigatran, which targets thrombin, and rivaroxaban, apixaban, and edoxaban, which target factor Xa.


InternalMed_Harrison

InternalMed_Harrison. Warfarin A water-soluble vitamin K antagonist initially developed as a rodenticide, warfarin is the coumarin derivative most often prescribed in North America. Like other vitamin K antagonists, warfarin interferes with the synthesis of the vitamin K–dependent clotting proteins, which include prothrombin (factor II) and factors VII, IX, and X. The synthesis of the vitamin K–dependent anticoagulant proteins, proteins C and S, is also reduced by vitamin K antagonists.


InternalMed_Harrison

InternalMed_Harrison. mecHanism of action All of the vitamin K–dependent clotting factors possess glutamic acid residues at their N termini. A posttranslational modification adds a carboxyl group to the γ-carbon of these residues to generate γ-carboxyglutamic acid. This modification is essential for expression of the activity of these clotting factors because it permits their calcium-dependent binding to negatively charged phospholipid surfaces. The γ-carboxylation process is catalyzed by a vitamin K– dependent carboxylase. Thus, vitamin K from the diet is reduced to vitamin K hydroquinone by vitamin K reductase (Fig. 143-6). Vitamin K hydroquinone serves as a cofactor for the carboxylase enzyme, which in the presence of carbon dioxide replaces the hydrogen on the γ-carbon of glutamic acid residues with a carboxyl group. During this process, vitamin K hydroquinone is oxidized to vitamin K epoxide, which is then reduced to vitamin K by vitamin K epoxide reductase.


InternalMed_Harrison

InternalMed_Harrison. Warfarin inhibits vitamin K epoxide reductase (VKOR), thereby blocking the γ-carboxylation process. This results in the synthesis of vitamin K–dependent clotting proteins that are only partially γ-carboxylated. Warfarin acts as an anticoagulant because these partially γ-carboxylated proteins have reduced or absent biologic activity. The onset of action of warfarin is delayed until the newly synthesized clotting factors with reduced activity gradually replace their fully active counterparts. The antithrombotic effect of warfarin depends on a reduction in the functional levels of factor X and prothrombin, clotting factors that have half-lives of 24 and 72 h, respectively. Because the antithrombotic effect of warfarin is delayed, patients with established thrombosis or at high risk for thrombosis require concomitant treatment with a rapidly acting parenteral anticoagulant, such as heparin, LMWH, or fondaparinux, for at least 5 days.


InternalMed_Harrison

InternalMed_Harrison. pHarmacology Warfarin is a racemic mixture of R and S isomers. Warfarin is rapidly and almost completely absorbed from the FIGURE 143-6 Mechanism of action of warfarin. A racemic mixture of Sand R-enantiomers, S-warfarin is most active. By blocking vitamin K epoxide reductase, warfarin inhibits the conversion of oxidized vitamin K into its reduced form. This inhibits vitamin K–dependent γ-carboxylation of factors II, VII, IX, and X because reduced vitamin K serves as a cofactor for a γ-glutamyl carboxylase that catalyzes the γ-carboxylation process, thereby converting prozymogens to zymogens capable of binding calcium and interacting with anionic phospholipid surfaces. S-warfarin is metabolized by CYP2C9. Common genetic polymorphisms in this enzyme can influence warfarin metabolism. Polymorphisms in the C1 subunit of vitamin K reductase (VKORC1) also can affect the susceptibility of the enzyme to warfarininduced inhibition, thereby influencing warfarin dosage requirements.


InternalMed_Harrison

InternalMed_Harrison. tion. Thromboplastins vary in their sensitivity to TABLE 143-8 frEquENCIEs Of CYP2C9gENOTYPEs AND VKORC1 HAPLOTYPEs IN DIffErENT POPuLATIONs AND THEIr EffECT ON wArfArIN DOsE rEquIrEMENTs monitoring Warfarin therapy is most often moni-755 tored using the prothrombin time, a test that is sensitive to reductions in the levels of prothrombin, Frequency, % factor VII, and factor X. The test is performed by adding thromboplastin, a reagent that contains tis- Compared with sue factor, phospholipid, and calcium, to citrated plasma and determining the time to clot forma gastrointestinal tract. Levels of warfarin in the blood peak about 90 min after drug administration. Racemic warfarin has a plasma half-life of 36–42 h, and more than 97% of circulating warfarin is bound to albumin. Only the small fraction of unbound warfarin is biologically active.


InternalMed_Harrison

InternalMed_Harrison. Warfarin accumulates in the liver where the two isomers are metabolized via distinct pathways. CYP2C9 mediates oxidative metabolism of the more active S isomer (Fig. 143-6). Two relatively common variants, CYP2C9*2 and CYP2C9*3, encode an enzyme with reduced activity. Patients with these variants require lower maintenance doses of warfarin. Approximately 25% of Caucasians have at least one variant allele of CYP2C9*2 or CYP2C9*3, whereas those variant alleles are less common in African Americans and Asians (Table 143-8). Heterozygosity for CYP2C9*2 or CYP2C9*3 decreases the warfarin dose requirement by 20–30% relative to that required in subjects with the wild-type CYP2C9*1/*1 alleles, whereas homozygosity for the CYP2C9*2 or CYP2C9*3 alleles reduces the warfarin dose requirement by 50–70%.


InternalMed_Harrison

InternalMed_Harrison. Consistent with their decreased warfarin dose requirement, subjects with at least one CYP2C9 variant allele are at increased risk for bleeding. Compared with individuals with no variant alleles, the relative risks for warfarin-associated bleeding in CYP2C9*2 or CYP2C9*3 carriers are 1.9 and 1.8, respectively.


InternalMed_Harrison

InternalMed_Harrison. Polymorphisms in VKORC1 also can influence the anticoagulant response to warfarin. Several genetic variations of VKORC1 are in strong linkage disequilibrium and have been designated as non-A haplotypes. VKORC1 variants are more prevalent than variants of CYP2C9. Asians have the highest prevalence of VKORC1 variants, followed by Caucasians and African Americans (Table 143-8). Polymorphisms in VKORC1 likely explain 30% of the variability in warfarin dose requirements. Compared with VKORC1 non-A/non-A homozygotes, the warfarin dose requirement decreases by 25 and 50% in A haplotype heterozygotes and homozygotes, respectively. These findings prompted the Food and Drug Administration to amend the prescribing information for warfarin to indicate that lower initiation doses should be considered for patients with CYP2C9 and VKORC1 genetic variants. In addition to genotype data, other pertinent patient information has been incorporated into warfarin dosing algorithms. Although such algorithms


InternalMed_Harrison

InternalMed_Harrison. for patients with CYP2C9 and VKORC1 genetic variants. In addition to genotype data, other pertinent patient information has been incorporated into warfarin dosing algorithms. Although such algorithms help predict suitable warfarin doses, it remains unclear whether better dose identification improves patient outcome in terms of reducing hemorrhagic complications or recurrent thrombotic events.


InternalMed_Harrison

InternalMed_Harrison. In addition to genetic factors, the anticoagulant effect of warfarin is influenced by diet, drugs, and various disease states. Fluctuations in dietary vitamin K intake affect the activity of warfarin. A wide variety of drugs can alter absorption, clearance, or metabolism of warfarin. Because of the variability in the anticoagulant response to warfarin, coagulation monitoring is essential to ensure that a therapeutic response is obtained.


InternalMed_Harrison

InternalMed_Harrison. reductions in the levels of the vitamin K–dependent22 clotting factors. Thus, less sensitive thromboplastins 34 will trigger the administration of higher doses of 43 warfarin to achieve a target prothrombin time. This is problematic because higher doses of warfarin increase the risk of bleeding.76 The INR was developed to circumvent many of the problems associated with the prothrombin time. To calculate the INR, the patient’s prothrombin time is 26 divided by the mean normal prothrombin time, and 50 this ratio is then multiplied by the international sensitivity index (ISI), which is an index of the sensitivity of the thromboplastin used for prothrombin time determination to reductions in the levels of the vitamin K–dependent clotting factors. Highly sensitive thromboplastins have an ISI of 1.0. Most current thromboplastins have ISI values that range from 1.0 to 1.4. Although the INR has helped to standardize anticoagulant practice, problems persist. The precision of INR determination


InternalMed_Harrison

InternalMed_Harrison. 1.0. Most current thromboplastins have ISI values that range from 1.0 to 1.4. Although the INR has helped to standardize anticoagulant practice, problems persist. The precision of INR determination varies depending on reagent-coagulometer combinations. This leads to variability in the INR results. Also complicating INR determination is unreliable reporting of the ISI by thromboplastin manufacturers. Furthermore, every laboratory must establish the mean normal prothrombin time with each new batch of thromboplastin reagent. To accomplish this, the prothrombin time must be measured in fresh plasma samples from at least 20 healthy volunteers using the same coagulometer that is used for patient samples. For most indications, warfarin is administered in doses that produce a target INR of 2.0–3.0. An exception is patients with mechanical heart valves, particularly those in the mitral position or older ball and cage valves in the aortic position, where a target INR of 2.5–3.5 is recommended.


InternalMed_Harrison

InternalMed_Harrison. An exception is patients with mechanical heart valves, particularly those in the mitral position or older ball and cage valves in the aortic position, where a target INR of 2.5–3.5 is recommended. Studies in atrial fibrillation demonstrate an increased risk of cardioembolic stroke when the INR falls to <1.7 and an increase in bleeding with INR values >4.5. These findings highlight the fact that vitamin K antagonists have a narrow therapeutic window. In support of this concept, a study in patients receiving long-term warfarin therapy for unprovoked venous thromboembolism demonstrated a higher rate of recurrent venous thromboembolism with a target INR of 1.5–1.9 compared with a target INR of 2.0–3.0.


InternalMed_Harrison

InternalMed_Harrison. dosing Warfarin is usually started at a dose of 5–10 mg. Lower doses are used for patients with CYP2C9 or VKORC1 polymorphisms, which affect the pharmacodynamics or pharmacokinetics of warfarin and render patients more sensitive to the drug. The dose is then titrated to achieve the desired target INR. Because of its delayed onset of action, patients with established thrombosis or those at high risk for thrombosis are given concomitant initial treatment with a rapidly acting parenteral anticoagulant, such as heparin, LMWH, or fondaparinux. Early prolongation of the INR reflects reduction in the functional levels of factor VII. Consequently, concomitant treatment with the parenteral anticoagulant should be continued until the INR has been therapeutic for at least 2 consecutive days. A minimum 5-day course of parenteral anticoagulation is recommended to ensure that the levels of factor Xa and prothrombin have been reduced into the therapeutic range with warfarin.


InternalMed_Harrison

InternalMed_Harrison. Because warfarin has a narrow therapeutic window, frequent coagulation monitoring is essential to ensure that a therapeutic anticoagulant response is maintained. Even patients with stable warfarin dose requirements should have their INR determined every 3–4 weeks. More frequent monitoring is necessary when new medications are introduced because so many drugs enhance or reduce the anticoagulant effects of warfarin.


InternalMed_Harrison

InternalMed_Harrison. Antiplatelet, Anticoagulant, and Fibrinolytic Drugs 756 side effects Like all anticoagulants, the major side effect of warfarin trimester of pregnancy. Central nervous system abnormalities can also is bleeding. A rare complication is skin necrosis. Warfarin crosses the occur with exposure to warfarin at any time during pregnancy. Finally, placenta and can cause fetal abnormalities. Consequently, warfarin maternal administration of warfarin produces an anticoagulant effect should not be used during pregnancy. in the fetus that can cause bleeding. This is of particular concern at delivery when trauma to the head during passage through the birth bleeding At least half of the bleeding complications with warfarin canal can lead to intracranial bleeding. Because of these potential prob-occur when the INR exceeds the therapeutic range. Bleeding compli-lems, warfarin is contraindicated in pregnancy, particularly in the firstcations may be mild, such as epistaxis or hematuria, or more severe,


InternalMed_Harrison

InternalMed_Harrison. the INR exceeds the therapeutic range. Bleeding compli-lems, warfarin is contraindicated in pregnancy, particularly in the firstcations may be mild, such as epistaxis or hematuria, or more severe, and third trimesters. Instead, heparin, LMWH, or fondaparinux can such as retroperitoneal or gastrointestinal bleeding. Life-threatening be given during pregnancy for prevention or treatment of thrombosis.intracranial bleeding can also occur. Warfarin does not pass into the breast milk. Consequently, warfarin


InternalMed_Harrison

InternalMed_Harrison. To minimize the risk of bleeding, the INR should be maintained can safely be given to nursing mothers.in the therapeutic range. In asymptomatic patients whose INR is special problems Patients with a lupus anticoagulant and those whobetween 3.5 and 10, warfarin should be withheld until the INR returns need urgent or elective surgery present special challenges. Although to the therapeutic range. If the INR is over 10, oral vitamin K should observational studies suggested that patients with thrombosis com-be administered, at a dose of 2.5–5 mg, although there is no evidence plicating the antiphospholipid antibody syndrome required higherthat doing so reduces the bleeding risk. Higher doses of oral vitamin intensity warfarin regimens to prevent recurrent thromboembolicK (5–10 mg) produce more rapid reversal of the INR but may render events, two randomized trials showed that targeting an INR of 2.0–3.0 patients temporarily resistant to warfarin when the drug is restarted.


InternalMed_Harrison

InternalMed_Harrison. is as effective as higher intensity treatment and produces less bleed-Patients with serious bleeding need more aggressive treatment. These ing. Monitoring warfarin therapy can be problematic in patients with patients should be given 5–10 mg of vitamin K by slow IV infusion. antiphospholipid antibody syndrome if the lupus anticoagulant pro-Additional vitamin K should be given until the INR is in the nor-longs the baseline INR; factor X levels can be used instead of the INRmal range. Treatment with vitamin K should be supplemented with in such patients.


InternalMed_Harrison

InternalMed_Harrison. fresh-frozen plasma as a source of the vitamin K–dependent clotting There is no need to stop warfarin before procedures associated withproteins. Four factor prothrombin complex concentrates, which con-a low risk of bleeding; these include dental cleaning, simple dentaltain all four vitamin K–dependent clotting proteins, are the treatment extraction, cataract surgery, or skin biopsy. For procedures associatedof choice for (1) life-threatening bleeds, (2) rapid restoration of the with a moderate or high risk of bleeding, warfarin should be stoppedINR into the normal range in patients requiring urgent surgery or 5 days before the procedure to allow the INR to return to normal levels. intervention, and (3) patients who cannot tolerate the volume load of Patients at high risk for thrombosis, such as those with mechanicalfresh-frozen plasma.


InternalMed_Harrison

InternalMed_Harrison. intervention, and (3) patients who cannot tolerate the volume load of Patients at high risk for thrombosis, such as those with mechanicalfresh-frozen plasma. heart valves, can be bridged with onceor twice-daily SC injections ofWarfarin-treated patients who experience bleeding when their INR LMWH when the INR falls to <2.0. The last dose of LMWH should beis in the therapeutic range require investigation into the cause of the given 12–24 h before the procedure, depending on whether LMWH isbleeding. Those with gastrointestinal or genitourinary bleeding often administered twice or once daily. After the procedure, treatment with have an underlying lesion. warfarin can be restarted. skin necrosis A rare complication of warfarin, skin necrosis usually is


InternalMed_Harrison

InternalMed_Harrison. warfarin can be restarted. skin necrosis A rare complication of warfarin, skin necrosis usually is New Oral Anticoagulants New oral anticoagulants are now availableseen 2–5 days after initiation of therapy. Well-demarcated erythemaas alternatives to warfarin. These include dabigatran, which targetstous lesions form on the thighs, buttocks, breasts, or toes. Typically, thrombin, and rivaroxaban, apixaban, and edoxaban, which targetthe center of the lesion becomes progressively necrotic. Examination factor Xa. All of these drugs have a rapid onset and offset of action of skin biopsies taken from the border of these lesions reveals thrombi and have half-lives that permit onceor twice-daily administration. in the microvasculature.


InternalMed_Harrison

InternalMed_Harrison. in the microvasculature. Designed to produce a predictable level of anticoagulation, the newWarfarin-induced skin necrosis is seen in patients with congenital oral agents are more convenient to administer than warfarin becauseor acquired deficiencies of protein C or protein S. Initiation of warfarin they are given in fixed doses without routine coagulation monitoring.


InternalMed_Harrison

InternalMed_Harrison. therapy in these patients produces a precipitous fall in plasma levels of proteins C or S, thereby eliminating this important anticoagulant mecHanism of action The new oral anticoagulants are small molecules pathway before warfarin exerts an antithrombotic effect through lower-that bind reversibly to the active site of their target enzyme. Table 143-9 ing of the functional levels of factor X and prothrombin. The resultant summarizes the distinct pharmacologic properties of these agents. procoagulant state triggers thrombosis. Why the thrombosis is localized to the microvasculature of fatty tissues is unclear. indications The new oral anticoagulants have been compared with


InternalMed_Harrison

InternalMed_Harrison. Treatment involves discontinuation of warfarin and reversal with warfarin for stroke prevention in patients with nonvalvular atrial vitamin K, if needed. An alternative anticoagulant, such as heparin or fibrillation in four randomized trials that enrolled 71,683 patients. A LMWH, should be given in patients with thrombosis. Protein C con-meta-analysis of these data demonstrates that compared with warfarin, centrate can be given to protein C–deficient patients to accelerate heal-the new agents significantly reduce stroke or systemic embolism by ing of the skin lesions; fresh-frozen plasma may be of value if protein 19% (p = .001), primarily driven by a 51% reduction in hemorrhagic C concentrate is unavailable and for those with protein S deficiency. stroke (p <.0001), and are associated with a 10% reduction in mortality Occasionally, skin grafting is necessary when there is extensive skin loss. (p <.0001). New oral anticoagulants reduce intracranial hemorrhage by


InternalMed_Harrison

InternalMed_Harrison. Because of the potential for skin necrosis, patients with known protein C or protein S deficiency require overlapping treatment with a parenteral anticoagulant when initiating war- farin therapy. Warfarin should be started in low doses in these patients, and the parenteral anticoagulant should be continued until the INR is therapeutic for at least 2–3 consecutive days. pregnancy Warfarin crosses the placenta and can cause fetal abnormalities or bleeding. The fetal abnormalities include a characteristic embryopathy, which consists of nasal hypopla-Monitoring No No No No sia and stippled epiphyses. The risk of embry-Interactions 3A4/P-gp 3A4/P-gp P-gp P-gp opathy is highest if warfarin is given in the first Abbreviations: bid, twice a day; P-gp, P-glycoprotein; qd., once a day.


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InternalMed_Harrison. 52% compared with warfarin (p <.0001), but increase gastrointestinal bleeding by about 24% (p = .04). Overall, the new agents demonstrate a favorable benefit-to-risk profile compared with warfarin, and their relative efficacy and safety are maintained across a wide spectrum of atrial fibrillation patients, including those over the age of 75 years and those with a prior history of stroke. Based on these findings, dabigatran, rivaroxaban, and apixaban are licensed as alternatives to warfarin for stroke prevention in nonvalvular atrial fibrillation, and edoxaban is under regulatory consideration for this indication. Nonvalvular atrial fibrillation is defined as that occurring in patients without mechanical heart valves or severe rheumatic valvular disease, particularly mitral stenosis and/or regurgitation.


InternalMed_Harrison

InternalMed_Harrison. Dabigatran, rivaroxaban, and apixaban have been compared with enoxaparin for thromboprophylaxis after elective hip or knee arthroplasty. Currently, only rivaroxaban and apixaban are licensed for this indication in the United States. Rivaroxaban and dabigatran are also licensed for treatment of DVT or PE. Apixaban and edoxaban have also been investigated for treatment of patients with venous thromboembolism, but have not yet been approved for this indication. Rivaroxaban is licensed in Europe for prevention of recurrent ischemic events in patients who have been stabilized after an acute coronary syndrome. In this setting, rivaroxaban is usually administered in conjunction with dual antiplatelet therapy with aspirin and clopidogrel.


InternalMed_Harrison

InternalMed_Harrison. dosing For stroke prevention in patients with nonvalvular atrial fibrillation, rivaroxaban is given at a dose of 20 mg once daily with a dose reduction to 15 mg once daily in patients with a creatinine clearance of 15–49 mL/min; dabigatran is given at a dose of 150 mg twice daily with a dose reduction to 75 mg twice daily in those with a creatinine clearance of 15–30 mL/min; and apixaban is given at a dose of 5 mg twice daily with a dose reduction to 2.5 mg twice daily for patients with a creatinine >1.5 g/dL, for those 80 years of age or older, or for patients who weigh <60 kg.


InternalMed_Harrison

InternalMed_Harrison. For thromboprophylaxis after elective hip or knee replacement surgery, rivaroxaban is given at a dose of 10 mg once daily, whereas apixaban is given at a dose of 2.5 mg twice daily. For treatment of patients with DVT or PE, rivaroxaban is started at a dose of 15 mg twice daily for 3 weeks; the dose is then reduced to 20 mg once daily thereafter. After a minimum of a 5 day course of treatment with heparin or LMWH, dabigatran is given at a dose of 150 mg twice daily.


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InternalMed_Harrison. monitoring Although designed to be administered without routine monitoring, there are situations where determination of the anticoagulant activity of the new oral anticoagulants can be helpful. These include assessment of adherence, detection of accumulation or overdose, identification of bleeding mechanisms, and determination of activity prior to surgery or intervention. For qualitative assessment of anticoagulant activity, the prothrombin time can be used for factor Xa inhibitors and the aPTT for dabigatran. Rivaroxaban and edoxaban prolong the prothrombin time more than apixaban. In fact, because apixaban has such a limited effect on the prothrombin time, anti-factor Xa assays are needed to assess its activity. The effect of the drugs on tests of coagulation varies depending on the time that the blood is drawn relative to the timing of the last dose of the drug and the reagents used to perform the tests. Chromogenic anti-factor Xa assays and a dilute thrombin clotting time with


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InternalMed_Harrison. time that the blood is drawn relative to the timing of the last dose of the drug and the reagents used to perform the tests. Chromogenic anti-factor Xa assays and a dilute thrombin clotting time with appropriate calibrators provide quantitative assays to measure the plasma levels of the factor Xa inhibitors and dabigatran, respectively.


InternalMed_Harrison

InternalMed_Harrison. side effects Like all anticoagulants, bleeding is the most common side effect of the new oral anticoagulants. The new agents are associated with less intracranial bleeding than warfarin. The increased risk of intracranial bleeding with warfarin likely reflects the reduction in functional levels of factor VII, which precludes efficient thrombin generation at sites of microvascular bleeding in the brain. Because the new oral anticoagulants target downstream coagulation enzymes, they produce less impairment of hemostatic plug formation at sites of vascular injury. A downside of the new oral anticoagulants is the increased risk of gastrointestinal bleeding. This likely occurs because unabsorbed active drug in the gut exacerbates bleeding from lesions. Although dabigatran 757 etexilate is a prodrug, only 7% is absorbed. Although the remainder passes through the gut, at least two-thirds is metabolically activated to dabigatran by gut esterases.


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InternalMed_Harrison. Dyspepsia occurs in up to 10% of patients treated with dabigatran; this problem improves with time and can be minimized by administering the drug with food. Dyspepsia is rare with rivaroxaban, apixaban, and edoxaban. periprocedural management Like warfarin, the new oral anticoagulants must be stopped before procedures associated with a moderate or high risk of bleeding. The drugs should be held for 1–2 days, or longer if renal function is impaired. Assessment of residual anticoagulant activity before procedures associated with a high bleeding risk is prudent.


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InternalMed_Harrison. management of bleeding There are no specific antidotes for the new oral anticoagulants. With minor bleeding, holding one or two doses of drug is usually sufficient. The approach to serious bleeding is similar to that with warfarin except that vitamin K administration is of no benefit. Thus, the anticoagulant and antiplatelet drugs should be held, the patient should be resuscitated with fluids and blood products as necessary, and, if possible, the bleeding site should be identified and managed. Coagulation testing will determine the extent of anticoagulation. and renal function should be assessed so that the half-life of the drug can be calculated. Timing of the last dose of anticoagulant is important; administration of oral activated charcoal may help to prevent absorption of drug administered in the past 2–4 h. If bleeding continues or is life-threatening, procoagulants, such as prothrombin complex concentrate (either unactivated or activated) or factor VIIa, can be administered,


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InternalMed_Harrison. in the past 2–4 h. If bleeding continues or is life-threatening, procoagulants, such as prothrombin complex concentrate (either unactivated or activated) or factor VIIa, can be administered, although the evidence of their effectiveness is limited. Dialysis removes dabigatran from the circulation in patients with renal impairment; dialysis does not remove rivaroxaban, apixaban, or edoxaban because unlike dabigatran, these drugs are highly protein-bound.


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InternalMed_Harrison. pregnancy As small molecules, the new oral anticoagulants can all pass through the placenta. Consequently, these agents are contraindicated in pregnancy, and when used by women of childbearing potential, appropriate contraception is important. ongoing investigations Although the lack of antidotes has created concern about the risk of bleeding events in patients taking the new oral anticoagulants, emerging postmarketing data suggest that the rates of bleeding in the real-world setting are similar to those reported in the trials. Nonetheless, specific antidotes are under development. These include a humanized mouse monoclonal antibody fragment against dabigatran and a recombinant variant of factor Xa that serves as a decoy for the oral factor Xa inhibitors. Neither agent is currently available for clinical use.


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InternalMed_Harrison. Fibrinolytic drugs can be used to degrade thrombi and are administered systemically or can be delivered via catheters directly into the substance of the thrombus. Systemic delivery is used for treatment of acute MI, acute ischemic stroke, and most cases of massive PE. The goal of therapy is to produce rapid thrombus dissolution, thereby restoring antegrade blood flow. In the coronary circulation, restoration of blood flow reduces morbidity and mortality rates by limiting myocardial damage, whereas in the cerebral circulation, rapid thrombus dissolution decreases the neuronal death and brain infarction that produce irreversible brain injury. For patients with massive PE, the goal of thrombolytic therapy is to restore pulmonary artery perfusion.


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InternalMed_Harrison. Peripheral arterial thrombi and thrombi in the proximal deep veins of the leg are most often treated using catheter-directed thrombolytic therapy. Catheters with multiple side holes can be used to enhance drug delivery. In some cases, intravascular devices that fragment and extract the thrombus are used to hasten treatment. These devices can be used alone or in conjunction with fibrinolytic drugs. Antiplatelet, Anticoagulant, and Fibrinolytic Drugs FIGURE 143-7 The fibrinolytic system and its regulation. Plasminogen activators convert plasminogen to plasmin. Plasmin then degrades fibrin into soluble fibrin degradation products. The system is regulated at two levels. Type 1 plasminogen activator inhibitor (PAI-1) regulates the plasminogen activators, whereas α2-antiplasmin serves as the major inhibitor of plasmin.


InternalMed_Harrison

InternalMed_Harrison. Currently approved fibrinolytic agents include streptokinase; acylated plasminogen streptokinase activator complex (anistreplase); urokinase; recombinant tissue-type plasminogen activator (rtPA), which is also known as alteplase or activase; and two recombinant derivatives of rtPA, tenecteplase and reteplase. All of these agents act by converting plasminogen, the zymogen, to plasmin, the active enzyme (Fig. 143-7). Plasmin then degrades the fibrin matrix of thrombi and produces soluble fibrin degradation products.


InternalMed_Harrison

InternalMed_Harrison. Endogenous fibrinolysis is regulated at two levels. Plasminogen activator inhibitors, particularly the type 1 form (PAI-1), prevent excessive plasminogen activation by regulating the activity of tPA and urokinasetype plasminogen activator (uPA). Once plasmin is generated, it is regulated by plasmin inhibitors, the most important of which is α2antiplasmin. The plasma concentration of plasminogen is twofold higher than that of α2-antiplasmin. Consequently, with pharmacologic doses of plasminogen activators, the concentration of plasmin that is generated can exceed that of α2-antiplasmin. In addition to degrading fibrin, unregulated plasmin can also degrade fibrinogen and other clotting factors. This process, which is known as the systemic lytic state, reduces the hemostatic potential of the blood and increases the risk of bleeding.


InternalMed_Harrison

InternalMed_Harrison. The endogenous fibrinolytic system is geared to localize plasmin generation to the fibrin surface. Both plasminogen and tPA bind to fibrin to form a ternary complex that promotes efficient plasminogen activation. In contrast to free plasmin, plasmin generated on the fibrin surface is relatively protected from inactivation by α2-antiplasmin, a feature that promotes fibrin dissolution. Furthermore, C-terminus lysine residues, exposed as plasmin degrades fibrin, serve as binding sites for additional plasminogen and tPA molecules. This creates a positive feedback that enhances plasmin generation. When used pharmacologically, the various plasminogen activators capitalize on these mechanisms to a lesser or greater extent.


InternalMed_Harrison

InternalMed_Harrison. Plasminogen activators that preferentially activate fibrin-bound plasminogen are considered fibrin-specific. In contrast, nonspecific plasminogen activators do not discriminate between fibrin-bound and circulating plasminogen. Activation of circulating plasminogen results in the generation of unopposed plasmin that can trigger the systemic lytic state. Alteplase and its derivatives are fibrin-specific plasminogen activators, whereas streptokinase, anistreplase, and urokinase are nonspecific agents. Unlike other plasminogen activators, streptokinase is not an enzyme and does not directly convert plasminogen to plasmin. Instead, streptokinase forms a 1:1 stoichiometric complex with plasminogen. Formation of this complex induces a conformational change in plasminogen that exposes its active site (Fig. 143-8). The streptokinase-plasminogen complex then converts additional plasminogen to plasmin.


InternalMed_Harrison

InternalMed_Harrison. Streptokinase has no affinity for fibrin, and the streptokinaseplasminogen complex activates both free and fibrin-bound plasminogen. Activation of circulating plasminogen generates sufficient amounts of plasmin to overwhelm α2-antiplasmin. Unopposed plasmin not only degrades fibrin in the occlusive thrombus but also induces a systemic lytic state. StreptokinasePlasminogenSStreptokinasePlasminogenSFIGURE 143-8 Mechanism of action of streptokinase. Streptokinase binds to plasminogen and induces a conformational change in plas-minogen that exposes its active site. The streptokinase/plasmin(ogen) complex then serves as the activator of additional plasminogen.


InternalMed_Harrison

InternalMed_Harrison. When given systemically to patients with acute MI, streptokinase reduces mortality. For this indication, the drug is usually given as an IV infusion of 1.5 million units over 30–60 min. Patients who receive streptokinase can develop antibodies against the drug, as can patients with prior streptococcal infection. These antibodies can reduce the effectiveness of streptokinase. Allergic reactions occur in ~5% of patients treated with streptokinase. These may manifest as a rash, fever, chills, and rigors. Although anaphylactic reactions can occur, these are rare. Transient hypotension is common with streptokinase and has been attributed to plasminmediated release of bradykinin from kininogen. The hypotension usually responds to leg elevation and administration of IV fluids and low doses of vasopressors, such as dopamine or norepinephrine.


InternalMed_Harrison

InternalMed_Harrison. To generate this drug, streptokinase is combined with equimolar amounts of Lys-plasminogen, a plasmin-cleaved form of plasminogen with a Lys residue at its N terminus. The active site of Lys-plasminogen that is exposed upon combination with streptokinase is then masked with an anisoyl group. After IV infusion, the anisoyl group is slowly removed by deacylation, giving the complex a half-life of ~100 min. This allows drug administration via a single bolus infusion. Although it is more convenient to administer, anistreplase offers few mechanistic advantages over streptokinase. Like streptokinase, anistreplase does not distinguish between fibrin-bound and circulating plasminogen. Consequently, it too produces a systemic lytic state. Likewise, allergic reactions and hypotension are just as frequent with anistreplase as they are with streptokinase.


InternalMed_Harrison

InternalMed_Harrison. When anistreplase was compared with alteplase in patients with acute MI, reperfusion was obtained more rapidly with alteplase than with anistreplase. Improved reperfusion was associated with a trend toward better clinical outcomes and reduced mortality rate with alteplase. These results and the high cost of anistreplase have dampened the enthusiasm for its use. Urokinase is a two-chain serine protease derived from cultured fetal kidney cells with a molecular weight of 34,000. Urokinase converts plasminogen to plasmin directly by cleaving the Arg560-Val561 bond. Unlike streptokinase, urokinase is not immunogenic and allergic reactions are rare. Urokinase produces a systemic lytic state because it does not discriminate between fibrin-bound and circulating plasminogen.


InternalMed_Harrison

InternalMed_Harrison. Despite many years of use, urokinase has never been systemically evaluated for coronary thrombolysis. Instead, urokinase is often employed for catheter-directed lysis of thrombi in the deep veins or the peripheral arteries. Because of production problems, the availability of urokinase is limited. A recombinant form of single-chain tPA, alteplase has a molecular weight of 68,000. Alteplase is rapidly converted into its two-chain form by plasmin. Although singleand two-chain forms of tPA have equivalent activity in the presence of fibrin, in its absence, single-chain tPA has tenfold lower activity.


InternalMed_Harrison

InternalMed_Harrison. Alteplase consists of five discrete domains (Fig. 143-9); the N-terminus A chain of two-chain alteplase contains four of these domains. Residues 4 through 50 make up the finger domain, a region that resembles the finger domain of fibronectin; residues 50 through 87 are homologous with epidermal growth factor, whereas residues 92 through 173 and 180 through 261, which have homology to the kringle domains of plasminogen, are designated as the first and second kringle, respectively. The fifth alteplase domain is the protease domain; it is located on the C-terminus B chain of two-chain alteplase.


InternalMed_Harrison

InternalMed_Harrison. The interaction of alteplase with fibrin is mediated by the finger domain and, to a lesser extent, by the second kringle domain. The affinity of alteplase for fibrin is considerably higher than that for fibrinogen. Consequently, the catalytic efficiency of plasminogen activation by alteplase is two to three orders of magnitude higher in the presence of fibrin than in the presence of fibrinogen. This phenomenon helps to localize plasmin generation to the fibrin surface. Although alteplase preferentially activates plasminogen in the presence of fibrin, alteplase is not as fibrin-selective as was first predicted. Its fibrin specificity is limited because like fibrin, (DD)E, the major


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InternalMed_Harrison. FIGURE 143-9 Domain structures of alteplase (tPA), tenecteplase (TNK-tPA), desmoteplase (b-PA), and reteplase (r-PA). The finger (F), epidermal growth factor (EGF), first and second kringles (K1 and K2, respectively), and protease (P) domains are illustrated. The glycosylation site (Y) on K1 has been repositioned in tenecteplase to endow it with a longer half-life. In addition, a tetra-alanine substitution in the protease domain renders tenecteplase resistant to type 1 plasminogen activator inhibitor (PAI-1) inhibition. Desmoteplase differs from alteplase and tenecteplase in that it lacks a K2 domain. Reteplase is a truncated variant that lacks the F, EGF, and K1 domains.


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InternalMed_Harrison. soluble degradation product of cross-linked fibrin, binds alteplase and 759 plasminogen with high affinity. Consequently, (DD)E is as potent as fibrin as a stimulator of plasminogen activation by alteplase. Whereas plasmin generated on the fibrin surface results in thrombolysis, plasmin generated on the surface of circulating (DD)E degrades fibrinogen. Fibrinogen degradation results in the accumulation of fragment X, a high-molecular-weight clottable fibrinogen degradation product. Incorporation of fragment X into hemostatic plugs formed at sites of vascular injury renders them susceptible to lysis. This phenomenon may contribute to alteplase-induced bleeding. A trial comparing alteplase with streptokinase for treatment of patients with acute MI demonstrated significantly lower mortality with alteplase than with streptokinase, although the absolute difference was small. The greatest benefit was seen in patients age <75 years with anterior MI who presented <6 h after symptom onset.


InternalMed_Harrison

InternalMed_Harrison. For treatment of acute MI or acute ischemic stroke, alteplase is given as an IV infusion over 60–90 min. The total dose of alteplase usually ranges from 90 to 100 mg. Allergic reactions and hypotension are rare, and alteplase is not immunogenic. Tenecteplase is a genetically engineered variant of tPA and was designed to have a longer half-life than tPA and to be resistant to inactivation by PAI-1. To prolong its half-life, a new glycosylation site was added to the first kringle domain (Fig. 143-9). Because addition of this extra carbohydrate side chain reduced fibrin affinity, the existing glycosylation site on the first kringle domain was removed. To render the molecule resistant to inhibition by PAI-1, a tetra-alanine substitution was introduced at residues 296–299 in the protease domain, the region responsible for the interaction of tPA with PAI-1.


InternalMed_Harrison

InternalMed_Harrison. Tenecteplase is more fibrin-specific than tPA. Although both agents bind to fibrin with similar affinity, the affinity of tenecteplase for (DD) E is significantly lower than that of tPA. Consequently, (DD)E does not stimulate systemic plasminogen activation by tenecteplase to the same extent as tPA. As a result, tenecteplase produces less fibrinogen degradation than tPA. For coronary thrombolysis, tenecteplase is given as a single IV bolus. In a large phase III trial that enrolled >16,000 patients, the 30-day mortality rate with single-bolus tenecteplase was similar to that with accelerated-dose tPA. Although rates of intracranial hemorrhage were also similar with both treatments, patients given tenecteplase had fewer noncerebral bleeds and a reduced need for blood transfusions than those treated with tPA. The improved safety profile of tenecteplase likely reflects its enhanced fibrin specificity.


InternalMed_Harrison

InternalMed_Harrison. Reteplase is a is a single-chain, recombinant tPA derivative that lacks the finger, epidermal growth factor, and first kringle domains (Fig. 143-9). This truncated derivative has a molecular weight of 39,000. Reteplase binds fibrin more weakly than tPA because it lacks the finger domain. Because it is produced in Escherichia coli, reteplase is not glycosylated. This endows it with a plasma half-life longer than that of tPA. Consequently, reteplase is given as two IV boluses, which are separated by 30 min. Clinical trials have demonstrated that reteplase is at least as effective as streptokinase for treatment of acute MI, but the agent is not superior to tPA.


InternalMed_Harrison

InternalMed_Harrison. Two new drugs are under investigation. These include desmoteplase (Fig. 143-9), a recombinant form of the full-length plasminogen activator isolated from the saliva of the vampire bat, and alfimeprase, a truncated form of fibrolase, an enzyme isolated from the venom of the southern copperhead snake. Clinical studies with these agents have been disappointing. Desmoteplase, which is more fibrin-specific than tPA, was investigated for treatment of acute ischemic stroke. Patients presenting 3–9 h after symptom onset were randomized to one of two doses of desmoteplase or to placebo. Overall response rates were low and no different with desmoteplase than with placebo. The mortality rate was higher in the desmoteplase arms.


InternalMed_Harrison

InternalMed_Harrison. Antiplatelet, Anticoagulant, and Fibrinolytic Drugs 760 Alfimeprase is a metalloproteinase that degrades fibrin and fibrinogen in a plasmin-independent fashion. In the circulation, alfimeprase is rapidly inhibited by α2-macroglobulin. Consequently, the drug must be delivered via a catheter directly into the thrombus. Studies of alfimeprase for treatment of peripheral arterial occlusion or for restoration of flow in blocked central venous catheters were stopped due to lack of efficacy. The disappointing results with desmoteplase and alfimeprase highlight the challenges of introducing new fibrinolytic drugs.


InternalMed_Harrison

InternalMed_Harrison. Thrombosis involves a complex interplay among the vessel wall, platelets, the coagulation system, and the fibrinolytic pathways. Activation of coagulation also triggers inflammatory pathways that may exacerbate thrombosis. A better understanding of the biochemistry of blood coagulation and advances in structure-based drug design have identified new targets and resulted in the development of novel antithrombotic drugs. Well-designed clinical trials have provided detailed information on which drugs to use and when to use them. Despite these advances, however, thromboembolic disorders remain a major cause of morbidity and mortality. Therefore, the search for better targets and more potent antiplatelet, anticoagulant, and fibrinolytic drugs continues.


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InternalMed_Harrison. Approach to the Patient with an Infectious Disease Neeraj K. Surana, Dennis L. Kasper HISTORICAL PERSPECTIVE The origins of the field of infectious diseases are humble. The notion that communicable diseases were due to a miasma (“bad air”) can be traced back to at least the mid-sixteenth century. Not until the work of Louis Pasteur and Robert Koch in the late nineteenth century was there credible evidence supporting the germ theory of disease—i.e., that microorganisms are the direct cause of infections. In contrast to this relatively slow start, the twentieth century saw remarkable advances in the field of infectious diseases, and the etiologic agents of numerous infectious diseases were soon identified. Furthermore, the discovery of antibiotics and the advent of vaccines against some of the most deadly and debilitating infections greatly altered the landscape of human health. Indeed, the twentieth century saw the elimination of smallpox, one of the great scourges in the history of


InternalMed_Harrison

InternalMed_Harrison. the most deadly and debilitating infections greatly altered the landscape of human health. Indeed, the twentieth century saw the elimination of smallpox, one of the great scourges in the history of humanity. These remarkable successes prompted noted scholar Aidan Cockburn to write in a 1963 publication entitled The Evolution and Eradication of Infectious Diseases: “It seems reasonable to anticipate that within some measurable time . . . all the major infections will have disappeared.” Professor Cockburn was not alone in this view. Robert Petersdorf, a renowned infectious disease expert and former editor of this textbook, wrote in 1978 that “even with my great personal loyalties to infectious diseases, I cannot conceive a need for 309 more [graduating trainees in infectious diseases] unless they spend their time culturing each other.” Given the enormous growth of interest in the microbiome in the past 5 years, Dr. Petersdorf’s statement might have been ironically clairvoyant, although


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InternalMed_Harrison. they spend their time culturing each other.” Given the enormous growth of interest in the microbiome in the past 5 years, Dr. Petersdorf’s statement might have been ironically clairvoyant, although he could have had no idea what was in store for humanity, with an onslaught of new, emerging, and re-emerging infectious diseases. Clearly, even with all the advances of the twentieth century, infec-tious diseases continue to represent a formidable challenge for patients and physicians alike. Furthermore, during the latter half of the century, several chronic diseases were demonstrated to be directly or indirectly caused by infectious microbes; perhaps the most notable examples are the associations of Helicobacter pylori with peptic ulcer disease and gastric carcinoma, human papillomavirus with cervical cancer, and hepatitis B and C viruses with liver cancer. In fact, ~16% of all malignancies are now known to be associated with an infectious cause. In addition, numerous emerging and


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InternalMed_Harrison. with cervical cancer, and hepatitis B and C viruses with liver cancer. In fact, ~16% of all malignancies are now known to be associated with an infectious cause. In addition, numerous emerging and re-emerging infectious diseases continue to have a dire impact on global health: HIV/AIDS, pandemic influenza, and severe acute respiratory syndrome (SARS) are but a few examples. The fear of weaponizing pathogens for bioterrorism is ever present and poses a potentially enormous threat to public health. Moreover, escalating antimicrobial resistance in clinically relevant microbes (e.g., Mycobacterium tuberculosis, Staphylococcus aureus, Streptococcus pneumoniae, Plasmodium species, and HIV) signifies that the administration of antimicrobial agents—once thought to be a panacea—requires appropriate stewardship. For all these reasons, infectious diseases continue to exert grim effects on individual patients as well as on international public health. Even with all the successes of the past


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InternalMed_Harrison. stewardship. For all these reasons, infectious diseases continue to exert grim effects on individual patients as well as on international public health. Even with all the successes of the past century, physicians must be as thoughtful about infectious diseases now as they were at the beginning of the twentieth century. 144 SEC TIon 1 BASIC ConSIDERATIonS In InfEC TIouS DISEASES PART 8: Infectious Diseases


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InternalMed_Harrison. Infectious diseases remain the second leading cause of death worldwide. Although the rate of infectious disease–related deaths has decreased dramatically over the past 20 years, the absolute numbers of such deaths have remained relatively constant, totaling just over 12 million in 2010 (Fig. 144-1A). As shown in Fig. 144-1B, these deaths disproportionately affect lowand middle-income countries (Chap. 13e); in 2010, 23% of all deaths worldwide were related to infectious diseases, with rates >60% in most sub-Saharan African countries.


InternalMed_Harrison

InternalMed_Harrison. Given that infectious diseases are still a major cause of global mortality, understanding the local epidemiology of disease is critically important in evaluating patients. Diseases such as HIV/AIDS have decimated sub-Saharan Africa, with HIV-infected adults representing 15–26% of the total population in countries like Zimbabwe, Botswana, and Swaziland. Moreover, drug-resistant tuberculosis is rampant throughout the former Soviet-bloc countries, India, China, and South Africa. The ready availability of this type of information allows physicians to develop appropriate differential diagnoses and treatment plans for individual patients. Programs such as the Global Burden of Disease seek to quantify human losses (e.g., deaths, disability-adjusted life years) due to diseases by age, sex, and country over time; these data not only help inform local, national, and international health policy but can also help guide local medical decision-making. Even though some diseases (e.g., pandemic


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InternalMed_Harrison. country over time; these data not only help inform local, national, and international health policy but can also help guide local medical decision-making. Even though some diseases (e.g., pandemic influenza, SARS) are seemingly geographically restricted, the increasing ease of rapid worldwide travel has raised concern about their swift spread around the globe. The world’s increasing interconnectedness has profound implications not only for the global economy but also for medicine and the spread of infectious diseases.


InternalMed_Harrison

InternalMed_Harrison. Normal, healthy humans are colonized with over 100 trillion bacteria as well as countless viruses, fungi, and archaea; taken together, these microorganisms outnumber human cells by 10–100 times (Chap. 86e). The major reservoir of these microbes is the gastrointestinal tract, but very substantial numbers of microbes live in the female genital tract, the oral cavity, and the nasopharynx. There is increasing interest in the skin and even the lungs as sites where microbial colonization might be highly relevant to the biology and disease susceptibility of the host. These commensal organisms provide the host with myriad benefits, from aiding in metabolism to shaping the immune system. With regard to infectious diseases, the vast majority of infections are caused by organisms that are part of the normal flora (e.g., S. aureus,


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InternalMed_Harrison. S. pneumoniae, Pseudomonas aeruginosa), with relatively few infections due to organisms that are strictly pathogens (e.g, Neisseria gonorrhoeae, rabies virus). Perhaps it is not surprising that a general understanding of the microbiota is essential in the evaluation of infectious diseases. Individuals’ microbiotas likely have a major impact on their susceptibility to infectious diseases and even their responses to vaccines. Site-specific knowledge of the indigenous flora may facilitate appropriate interpretation of culture results, aid in selection of empirical antimicrobial therapy based on the likely causative agents, and provide additional impetus for rational antibiotic use to minimize the untoward effects of these drugs on the “beneficial” microbes that inhabit the body. The title of this chapter may appear to presuppose that the physician knows when a patient has an infectious disease. In reality, this chapter can serve only as a guide to the evaluation of a patient in whom an


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InternalMed_Harrison. Approach to the Patient with an Infectious Disease Number of Deaths (in millions) 1990101519952000200520105Rate of Death (per 100,000) 200350150250300 FIGURE 144-1 Magnitude of infectious disease–related deaths globally. A. The absolute number (blue line; left axis) and rate (red line; right axis) of infectious disease–related deaths throughout the world since 1990. B. A map depicting country-specific data for the percentages of total deaths that were attributable to communicable, maternal, neonatal, and nutritional disorders in 2010. (Source: Global Burden of Disease Study,


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InternalMed_Harrison. Institute for Health Metrics and Evaluation.) infectious disease is a possibility. Once a specific diagnosis is made, the reader should consult the subsequent chapters that deal with specific microorganisms in detail. The challenge for the physician is to recognize which patients may have an infectious disease as opposed to some other underlying disorder. This task is greatly complicated by the fact that infections have an infinite range of presentations, from acute life-threatening conditions (e.g., meningococcemia) to chronic diseases of varying severity (e.g., H. pylori–associated peptic ulcer disease) to no symptoms at all (e.g., latent M. tuberculosis infection). While it is impossible to generalize about a presentation that encompasses all infections, common findings in the history, physical examination, and basic laboratory testing often suggest that the patient either has an infectious disease or should be more closely evaluated for one. This chapter focuses on these common


InternalMed_Harrison

InternalMed_Harrison. physical examination, and basic laboratory testing often suggest that the patient either has an infectious disease or should be more closely evaluated for one. This chapter focuses on these common findings and how they may direct the ongoing evaluation of the patient.


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InternalMed_Harrison. APPROACH TO THE PATIENT: See also Chap. 147. As in all of medicine, obtaining a complete and thorough history is paramount in the evaluation of a patient with a possible infectious disease. The history is critical for developing a focused differential diagnosis and for guiding the physical exam and initial diagnostic testing. Although detailing all the elements of a history is beyond the scope of this chapter, specific components relevant to infectious diseases require particular attention. In general, these aspects focus on two areas: (1) an exposure history that may identify microorganisms with which the patient may have come into contact and (2) host-specific factors that may predispose to the development of an infection.


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InternalMed_Harrison. Exposure History • History of infections or exposure to drug-resistant microbes Knowledge about a patient’s previous infections, with the associated microbial susceptibility profiles, is very helpful in determining possible etiologic agents. Specifically, knowing whether a patient has a history of infection with drug-resistant organisms (e.g., methicillin-resistant S. aureus, vancomycin-resistant Enterococcus species, enteric organisms that produce an extended-spectrum β-lactamase or carbapenemase) or may have been exposed to drug-resistant microbes (e.g., during a recent stay in a hospital, nursing home, or long-term acute-care facility) may alter the choice of empirical antibiotics. For example, a patient presenting with sepsis who is known to have a history of invasive infection with a multidrug-resistant isolate of P. aeruginosa should be treated empirically with an antimicrobial regimen that will cover this strain.


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InternalMed_Harrison. social History Although the social history taken by physicians is often limited to inquiries about a patient’s alcohol and tobacco use, a complete social history can offer a number of clues to the underlying diagnosis. Knowing whether the patient has any high-risk behaviors (e.g., unsafe sexual behaviors, IV drug use), potential hobby-associated exposures (e.g., avid gardening, with possible Sporothrix schenckii exposure), or occupational exposures (e.g., increased risk for M. tuberculosis exposure in funeral service workers) can facilitate diagnosis. The importance of the social history is exemplified by a case in 2009 in which a laboratory researcher died of a Yersinia pestis infection acquired during his work; although this patient had visited both an outpatient clinic and an emergency department, his records at both sites failed to include his occupation—information that potentially could have led quickly to appropriate treatment and infection control measures.


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InternalMed_Harrison. dietary Habits As certain pathogens are associated with specific dietary habits, inquiring about a patient’s diet can provide insight into possible exposures. For example, Shiga toxin–producing strains of Escherichia coli and Toxoplasma gondii are associated with the consumption of raw or undercooked meat; Salmonella typhimurium, Listeria monocytogenes, and Mycobacterium bovis with unpasteurized milk; Leptospira species, parasites, and enteric bacteria with unpurified water; and Vibrio species, norovirus, helminths, and protozoa with raw seafood.


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InternalMed_Harrison. animal exposures Because animals are often important vectors of infectious diseases, patients should be asked about exposures to any animals, including contact with their own pets, visits to petting zoos, or random encounters (e.g., home rodent infestation). For example, dogs can carry ticks that serve as agents for the transmission of several infectious diseases, including Lyme disease, Rocky Mountain spotted fever, and ehrlichiosis. Cats are associated with Bartonella henselae infection, reptiles with Salmonella infection, rodents with leptospirosis, and rabbits with tularemia (Chap. 167e).


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InternalMed_Harrison. travel History Attention should be paid to both international and domestic travel. Fever in a patient who has recently returned from abroad significantly broadens the differential diagnosis (Chap. 149); even a remote history of international travel may reflect patients’ exposure to infections with pathogens such as M. tuberculosis or Strongyloides stercoralis. Similarly, domestic travel may have exposed patients to pathogens that are not normally found in their local environment and therefore may not routinely be considered in the differential diagnosis. For example, a patient who has recently visited California or Martha’s Vineyard may have been exposed to Coccidioides immitis or Francisella tularensis, respectively. Beyond simply identifying locations that a patient may have visited, the physician needs to delve deeper to learn what kinds of activities and behaviors the patient engaged in during travel (e.g., the types of food and sources of water consumed, freshwater swimming,


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InternalMed_Harrison. the physician needs to delve deeper to learn what kinds of activities and behaviors the patient engaged in during travel (e.g., the types of food and sources of water consumed, freshwater swimming, animal exposures) and whether the patient had the necessary immunizations and/or took the necessary prophylactic medications prior to travel; these additional exposures, which the patient may not think to report without specific prompting, are as important as exposures during a patient’s routine daily living.


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InternalMed_Harrison. Host-Specific Factors Because many opportunistic infections (e.g., with Pneumocystis jirovecii, Aspergillus species, or JC virus) affect only immunocompromised patients, it is of vital importance to determine the immune status of the patient. Defects in the immune system may be due to an underlying disease (e.g., malignancy, HIV infection, malnutrition), a medication (e.g., chemotherapy, glucocorticoids, monoclonal antibodies to components of the immune system), a treatment modality (e.g., total body irradiation, splenectomy), or a primary immunodeficiency. The type of infection for which the patient is at increased risk varies with the specific type of immune defect (Chap. 375e). In concert with determining whether a patient is immunocompromised for any reason, the physician should review the immunization record to ensure that the patient is adequately protected against vaccine-preventable diseases (Chap. 148).


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InternalMed_Harrison. Similar to the history, a thorough physical examination is crucial in evaluating patients with an infectious disease. Some elements of the physical exam (e.g., skin, lymphatics) that are often performed in a cursory manner as a result of the ever-increasing pace of medical practice may help identify the underlying diagnosis. Moreover, serial exams are critical since new findings may appear as the illness progresses. A description of all the elements of a physical exam is beyond the scope of this chapter, but the following components have particular relevance to infectious diseases.


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InternalMed_Harrison. Vital Signs Given that elevations in temperature are often a hallmark of infection, paying close attention to the temperature may be of value in diagnosing an infectious disease. The idea that 37°C (98.6°F) is the normal human body temperature dates back to the nineteenth century and was initially based on axillary measurements. Rectal temperatures more accurately reflect the core body temperature and are 0.4°C (0.7°F) and 0.8°C (1.4°F) higher than oral and axillary temperatures, respectively. Although the definition of fever varies greatly throughout the medical literature, the most common definition, which is based on studies defining fever of unknown origin (Chap. 26), uses a temperature ≥38.3°C (101°F). Although fever is very commonly associated with infection, it is also documented in many other diseases (Chap. 23). For every 1°C (1.8°F) increase in core temperature, the heart rate typically rises by 15–20 beats/min. Table 144-1 lists infections that are associated with relative


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InternalMed_Harrison. many other diseases (Chap. 23). For every 1°C (1.8°F) increase in core temperature, the heart rate typically rises by 15–20 beats/min. Table 144-1 lists infections that are associated with relative bradycardia (Faget’s sign), where patients have a lower heart rate than might be expected for a given body temperature. Although this pulse-temperature dissociation is not highly sensitive or specific for establishing a diagnosis, it is potentially useful in low-resource settings given its ready availability and simplicity.


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InternalMed_Harrison. Lymphatics There are ~600 lymph nodes throughout the body, and infections are an important cause of lymphadenopathy. A physical examination should include evaluation of lymph nodes in multiple aPrimarily early in the course of infection with Marburg or Ebola virus.


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InternalMed_Harrison. Approach to the Patient with an Infectious Disease regions (e.g., popliteal, inguinal, epitrochlear, axillary, multiple cervical regions), with notation of the location, size (normal, <1 cm), presence or absence of tenderness, and consistency (soft, firm, or shotty) and of whether the nodes are matted (i.e., connected and moving together). Of note, palpable epitrochlear nodes are always pathologic. Of patients presenting with lymphadenopathy, 75% have localized findings, and the remaining 25% have generalized lymphadenopathy (i.e., that involving more than one anatomic region). Localized lymphadenopathy in the head and neck region is found in 55% of patients, inguinal lymphadenopathy in 14%, and axillary lymphadenopathy in 5%. Determining whether the patient has generalized versus localized lymphadenopathy can help narrow the differential diagnosis, as various infections present differently.


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InternalMed_Harrison. Skin The fact that many infections have cutaneous manifestations gives the skin examination particular importance in the evaluation of patients (Chaps. 24, 25e, 72, and 156). It is important to perform a complete skin exam, with attention to both front and back. Specific rashes are often extremely helpful in narrowing the differential diagnosis of an infection (Chaps. 24 and 25e). In numerous anecdotal instances, patients in the intensive care unit have had “fever of unknown origin” that was actually due to unrecognized pressure ulcers. Moreover, close examination of the distal extremities for splinter hemorrhages, Janeway lesions, or Osler’s nodes may yield evidence of endocarditis or other causes of septic emboli.


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InternalMed_Harrison. Foreign Bodies As previously mentioned, many infections are caused by members of the indigenous microbiota. These infections typically occur when these microbes escape their normal habitat and enter a new one. Thus, maintenance of epithelial barriers is one of the most important mechanisms in protection against infection. However, hospitalization of patients is often associated with breaches of these barriers—e.g., due to placement of IV lines, surgical drains, or tubes (such as endotracheal tubes and Foley catheters) that allow microorganisms to localize in sites to which they normally would not have access (Chap. 168). Accordingly, knowing what lines, tubes, and drains are in place is helpful in ascertaining what body sites might be infected.


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InternalMed_Harrison. Laboratory and radiologic testing has advanced greatly over the past few decades and has become an important component in the evaluation of patients. The dramatic increase in the number of serologic diagnostics, antigen tests, and molecular diagnostics available to the physician has, in fact, revolutionized medical care. However, all of these tests should be viewed as adjuncts to the history and physical examination—not a replacement for them. The selection of initial tests should be based directly on the patient’s history and physical exam findings. Moreover, diagnostic testing should generally be limited to those conditions that are reasonably likely and treatable, important in terms of public health considerations, and/ or capable of providing a definitive diagnosis that will consequently limit other testing.


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InternalMed_Harrison. White Blood Cell (WBC) Count Elevations in the WBC count are often associated with infection, though many viral infections are associated with leukopenia. It is important to assess the WBC differential, given that different classes of microbes are associated with various leukocyte types. For example, bacteria are associated with an increase in polymorphonuclear neutrophils, often with elevated levels of earlier developmental forms such as bands; viruses are associated with an increase in lymphocytes; and certain parasites are associated with an increase in eosinophils. Table 144-2 lists the major infectious causes of eosinophilia.


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InternalMed_Harrison. Inflammatory Markers The erythrocyte sedimentation rate (ESR) and the C-reactive protein (CRP) level are indirect and direct measures of the acute-phase response, respectively, that can be used to assess a patient’s general level of inflammation. Moreover, these markers can be followed serially over time to monitor disease progress/resolution. It is noteworthy that the ESR changes relatively slowly, and its measurement more often than weekly usually is not useful; in contrast, CRP concentrations change rapidly, and daily measurements can be useful in the appropriate context. Although these markers are sensitive indicators of inflammation, neither is very specific. An extremely elevated ESR (>100 mm/h) has a 90% predictive value for a serious underlying disease (Table 144-3). Work is ongoing to identify other potentially useful inflammatory markers (e.g., procalcitonin, serum amyloid A protein); however, their clinical utility requires further validation.


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InternalMed_Harrison. Analysis of Cerebrospinal Fluid (CSF) Assessment of CSF is critical for patients with suspected meningitis or encephalitis. An opening pressure should always be recorded, and fluid should routinely be sent for cell counts, Gram’s stain and culture, and determination of glucose and protein levels. A CSF Gram’s stain typically requires >105 bacteria/mL for reliable positivity; its specificity approaches 100%. Table 144-4 lists the typical CSF profiles for various infections. In general, CSF with a lymphocytic pleocytosis and a low glucose concentration suggests either infection (e.g., with Listeria,


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InternalMed_Harrison. M. tuberculosis, or a fungus) or a noninfectious disorder (e.g, neoplastic meningitis, sarcoidosis). Bacterial antigen testing of CSF (e.g., latex agglutination tests for Haemophilus influenzae type b, group B Streptococcus, S. pneumoniae, and Neisseria meningitidis) is not recommended as a screening assay, given that these tests are no more sensitive than Gram’s stain; however, these assays can be helpful in presumptively identifying organisms seen on Gram’s stain. In contrast, other antigen tests (e.g., for Cryptococcus) and some CSF serologic testing (e.g., for Treponema pallidum, Coccidioides) are highly sensitive and are useful for select patients. In addition, polymerase chain reaction (PCR) analysis of CSF is increasingly being used for the diagnosis of bacterial (e.g., N. meningitidis, S. pneumoniae, mycobacteria) and viral (e.g., herpes simplex virus, enterovirus) infections; while these molecular tests permit rapid diagnosis with a high degree of sensitivity and specificity,


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InternalMed_Harrison. S. pneumoniae, mycobacteria) and viral (e.g., herpes simplex virus, enterovirus) infections; while these molecular tests permit rapid diagnosis with a high degree of sensitivity and specificity, they often do not allow determination of antimicrobial resistance profiles.


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InternalMed_Harrison. Cultures The mainstays of infectious disease diagnosis include the culture of infected tissue (e.g., surgical specimens) or fluid (e.g., blood, urine, sputum, purulence from a wound). Samples can be sent for culture of bacteria (aerobic or anaerobic), fungi, or viruses. Ideally, specimens are collected before the administration of antimicrobial therapy; in instances where this order of events is not clinically feasible, microscopic examination of the specimen (e.g., Gram-stained or potassium hydroxide [KOH]–treated preparations) is particularly important. Culture of the organism(s) allows identification of the etiologic agent, determination of the antimicrobial susceptibility profile, and—when there is concern about an outbreak—isolate typing. While cultures are extremely useful in the evaluation of patients, determining whether culture results are clinically meaningful or represent contamination (e.g., a non-aureus, non-lugdunensis staphylococcal species growing in a blood culture)


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InternalMed_Harrison. of patients, determining whether culture results are clinically meaningful or represent contamination (e.g., a non-aureus, non-lugdunensis staphylococcal species growing in a blood culture) can sometimes be challenging and requires an understanding of the patient’s immune status, exposure history, and microbiota. In some cases, serial cultures to demonstrate clearance of the organism may be helpful.


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InternalMed_Harrison. Pathogen-Specific Testing Numerous pathogen-specific tests (e.g., serology, antigen testing, PCR testing) are commercially available, and many hospitals now offer some of these tests in-house to facilitate rapid turnaround that ultimately enhances patient care. The reader is directed to relevant chapters on the pathogens of interest for specific details. Some of these tests (e.g., universal PCRs) identify organisms that currently are not cultivable and have unclear relationships to disease, thereby complicating diagnosis. As these tests become more commonplace and the work of the Human Microbiome Project progresses, the relevance of some of these previously unrecognized bacteria to human health will likely become more apparent.


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InternalMed_Harrison. aThere are numerous noninfectious causes of eosinophilia, such as atopic disease, DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome, and pernicious anemia, which can cause mild eosinophilia; drug hypersensitivity and serum sickness, which can cause mild to moderate eosinophilia; collagen vascular disease, which can cause moderate eosinophilia; and malignancy, Churg-Strauss syndrome, and hyper-IgE syndromes, which can cause moderate to extreme eosinophilia. bMild: 500–1500 cells/μL; moderate: 1500–5000 cells/μL; extreme: >5000 cells/μL. cCan also affect the liver and the eyes. dCan also affect the lungs. eCan also affect the eyes and the central nervous system. fLevels are typically higher with pulmonary infections. Approach to the Patient with an Infectious Disease


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InternalMed_Harrison. Approach to the Patient with an Infectious Disease Radiology Imaging provides an important adjunct to the physical examination, allowing evaluation for lymphadenopathy in regions that are not externally accessible (e.g., mediastinum, intraabdominal sites), assessment of internal organs for evidence of infection, and facilitation of image-guided percutaneous sampling of deep spaces. The choice of imaging modality (e.g., CT, MRI, ultrasound, nuclear medicine, use of contrast) is best made in consultation with a radiologist to ensure that the results will address the physician’s specific concerns.


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InternalMed_Harrison. Physicians often must balance the need for empirical antibiotic treatment with the patient’s clinical condition. When clinically feasible, it is best to obtain relevant samples (e.g., blood, CSF, tissue, purulent exudate) for culture prior to the administration of antibiotics, as antibiotic treatment often makes subsequent diagnosis more difficult. Although a general maxim for antibiotic treatment is to use a regimen with as narrow a spectrum as possible (Chap. 170), empirical regimens are necessarily somewhat broad, given that a specific diagnosis has not yet been made. Table 144-5 lists empirical antibiotic treatment regimens for commonly encountered infectious presentations. These regimens should be narrowed as appropriate once a specific diagnosis is made. In addition to antibiotics, there is sometimes a role for adjunctive therapies, such as intravenous immunoglobulin G (IVIG) pooled from healthy adults or hyperimmune globulin prepared from the blood of individuals with high


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InternalMed_Harrison. there is sometimes a role for adjunctive therapies, such as intravenous immunoglobulin G (IVIG) pooled from healthy adults or hyperimmune globulin prepared from the blood of individuals with high titers of specific antibodies to select pathogens (e.g., cytomegalovirus, hepatitis B virus, rabies virus, vaccinia virus,


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InternalMed_Harrison. Etiologic Category (% of Cases) Specific Causes Clostridium tetani, varicella-zoster virus, Clostridium botulinum toxin). Although the data suggesting efficacy are limited, IVIG is often used for patients with suspected staphylococcal or streptococcal toxic shock syndrome. When evaluating a patient with a suspected infectious disease, the physician must consider what infection control methods are necessary to prevent transmission of any possible infection to other people. In 2007, the U.S. Centers for Disease Control and Prevention published guidelines for isolation precautions that are available for download at www.cdc.gov/hicpac/2007IP/2007isolationPrecautions .html. Persons exposed to certain pathogens (e.g., N. meningitidis, HIV, Bacillus anthracis) should receive postexposure prophylaxis to prevent disease acquisition. (See relevant chapters for details on specific pathogens.)


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InternalMed_Harrison. At times, primary physicians need assistance with patient management, from a diagnostic and/or therapeutic perspective. Multiple studies have demonstrated that an infectious disease consult is associated with positive outcomes for patients with various diseases. For example, in a prospective cohort study of patients with S. aureus bacteremia, infectious disease consultation was independently associated with a 56% reduction in 28-day mortality. In addition, infectious disease specialists provide other services (e.g., infection control, antimicrobial stewardship, management of outpatient antibiotic therapy, occupational exposure programs) that have been shown to benefit patients. Whenever such assistance would be advantageous to a patient with a possible infection, the primary physician should opt for an infectious disease consult. Specific situations that might prompt a consult include (1) difficult-todiagnose patients with presumed infections, (2) patients who are not responding to


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InternalMed_Harrison. opt for an infectious disease consult. Specific situations that might prompt a consult include (1) difficult-todiagnose patients with presumed infections, (2) patients who are not responding to treatment as expected, (3) patients with a complicated medical history (e.g., organ transplant recipients, patients immunosuppressed due to autoimmune or inflammatory conditions), and (4) patients with “exotic” diseases (i.e., diseases that are not typically seen within the region).


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InternalMed_Harrison. The study of infectious diseases is really a study of host-bacterial interactions and represents evolution by both the host and the bacteria—an endless struggle in which microbes have generally been more creative and adaptive. Given that nearly one-quarter of deaths worldwide are still related to infectious diseases, it is clear that the war against infectious diseases has not been won. For example, a cure for HIV infection is still lacking, there have been only marginal improvements in the methods for detection and treatment of tuberculosis after more than a half century of research, new infectious diseases (e.g., pandemic influenza, viral hemorrhagic fevers) continue to emerge, and the threat of microbial bioterrorism remains high. The subsequent chapters in Part 8 detail— on both a syndrome and a microbe-by-microbe basis—the current state of medical knowledge about infectious diseases. At their core, all of these chapters carry a similar message: Despite numerous advances in the


InternalMed_Harrison

InternalMed_Harrison. and a microbe-by-microbe basis—the current state of medical knowledge about infectious diseases. At their core, all of these chapters carry a similar message: Despite numerous advances in the diagnosis, treatment, and prevention of infectious diseases, much work and research are required before anyone can confidently claim that “all the major infections have disappeared.” In reality, this goal will never be attained, given the rapid adaptability of microbes.


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InternalMed_Harrison. aNumbers indicate typical results, but actual results may vary. bCerebrospinal fluid characteristics depend greatly on the specific organism. cNeutrophils may predominate early in the disease course. dPatients typically have striking eosinophilia as well. eSensitivity can be increased by examination of a smear of protein coagulum (pellicle) and the use of acid-fast stains. Abbreviations: PMNs, polymorphonuclear neutrophils; WBC, white blood cell. Septic shock Staphylococcus aureus, Streptococcus pneumoniae, enteric gram-negative bacilli Meningitis S. pneumoniae, Neisseria meningitidis CNS abscess Streptococcus spp., Staphylococcus spp., anaerobes, gram-negative bacilli Endocarditis S. aureus, Streptococcus spp., coagulasenegative staphylococci Community-S. pneumoniae, acquired, Mycoplasma pneuoutpatient moniae, Haemophilus influenzae, Chlamydia pneumoniae Inpatient, non-ICU Above plus Legionella spp. Inpatient, ICU Above plus S. aureus