Parenteral anticoagulants prevent the formation of which product as the final step of clotting?

Anticoagulants are widely used for the prevention and treatment of venous and/or arterial thrombosis. Anticoagulants comprise a chemically heterogeneous group of drugs acting at different steps within the coagulation cascade. Heparin and heparin-based anticoagulants are indirect anticoagulants that bind to antithrombin and enhance the inhibitory capacity of this natural anticoagulant. Coumarin derivatives (e.g., warfarin) interfere with the hepatic synthesis of coagulation factors (vitamin K antagonists). A third class comprises direct inhibitors of enzymes of the clotting cascade, primarily thrombin. Classic anticoagulants such as unfractionated heparin and coumarins have some clinical drawbacks. Heparin requires parenteral application, has serious adverse effects, and is difficult to dose and monitor due to variable and unpredictable pharmacokinetics. The orally active coumarin derivatives have a narrow therapeutic window and multiple interactions with food and drugs, necessitating individualized dosing and monitoring. During the past 10 years, the search for safer and more effective antithrombotic agents resulted in the development or discovery of new molecules, including fondaparinux and idraparinux (both selective inhibitors of factor Xa), thrombin inhibitors for parenteral use such as recombinant hirudin and hirulogs, and the orally active ximelagatran.

Intrinsic Anticoagulant Mechanisms

Once activated, regulation of hemostasis proves essential to limit clot propagation beyond the injury site. One simple, yet important, anticoagulant mechanism derives from flowing blood and hemodilution. The early platelet and fibrin clot proves highly susceptible to disruption by shear forces from flowing blood. Blood flow further limits localization and concentration of both platelets and coagulation factors such that a critical mass of hemostatic components may fail to coalesce.30,34 However, later in the clotting process, more robust counter-regulatory mechanisms are necessary to limit clot propagation. Four major counter-regulatory pathways have been identified that appear particularly crucial for down-regulating hemostasis: fibrinolysis, TFPI, the protein C system, and serine protease inhibitors (SERPINs).

The fibrinolytic system comprises a cascade of amplifying reactions culminating in plasmin generation and proteolytic degradation of fibrin and fibrinogen. As with the plasma-mediated coagulation cascade, inactive precursor proteins are converted to active enzymes, necessitating a balanced system of regulatory controls to prevent excessive bleeding or thrombosis (Fig. 50.3). The principal enzymatic mediator of fibrinolysis is the serine protease, plasmin, which is generated from plasminogen.35 In vivo, plasmin generation is most often accomplished by release of t-PA or urokinase from the vascular endothelium. Activity of t-PA and urokinase is accelerated in the presence of fibrin, which limits fibrinolysis to areas of clot formation. Factor XIIa and kallikrein of the intrinsic pathway also contribute to fibrinolysis through activation of plasminogen after exposure to foreign surfaces.36 Fortunately, fibrinolytic activity is limited by the rapid inhibition of free plasmin. In addition to enzymatic degradation of fibrin and fibrinogen, plasmin inhibits hemostasis by degrading essential cofactors V and VIII and reducing platelet glycoprotein surface receptors essential to adhesion and aggregation.37 Fibrin degradation products also possess mild anticoagulant properties.

TFPI and factor Xa form phospholipid membrane-bound complexes that incorporate and inhibit tissue factor/factor VIIa complexes.38 This inhibition leads to downregulation of the extrinsic coagulation pathway.39 As TFPI rapidly extinguishes tissue factor/VIIa activity, the critical role of the intrinsic pathway to continued thrombin and fibrin generation becomes apparent.28

The protein C system proves particularly important in down-regulating coagulation through inhibition of thrombin and the essential cofactors Va and VIIIa. After binding to TM, thrombin’s procoagulant function decreases and instead its ability to activate protein C is augmented.40 Protein C, complexed with the cofactor protein S, degrades both cofactors Va and VIIIa. Loss of these critical cofactors limits formation of tenase and prothrombinase activation complexes essential to formation of factor Xa and thrombin, respectively. Additionally, once bound to TM, thrombin is rapidly inactivated and removed from circulation, providing another mechanism by which the protein C pathway down-regulates hemostasis.40

Advantages of Serum Over Plasma

Anticoagulants and additives in plasma specimens can directly interfere with the analytical characteristics of the assay, protein binding with the analyte of interest, and sample stability. Furthermore, liquid anticoagulants may lead to improper dilution of the sample. For example, blood drawn in tubes with sodium citrate is diluted by 10%, but this may increase depending on whether the draw is complete. Moreover, incomplete mixing with anticoagulants can lead to the risk of clot formation. Also, the choice of anticoagulant will depend on their respective influences on the various assays offered by the clinical laboratory, and tubes with anticoagulants and additives are often more expensive.

Heparin as an Anticoagulant

Since its discovery by Jay McLean, MD, in 1915, heparin has stood the test of time and remains the primary anticoagulant used in cardiac operations that require CPB. The mechanism underlying heparin’s anticoagulant effect centers on the heparin molecule’s ability to bind simultaneously to antithrombin III and thrombin. Modern nomenclature refers to antithrombin III as antithrombin (AT). The binding process is mediated by a unique pentasaccharide sequence that binds to AT. The proximity of AT and thrombin, mediated by the heparin molecule, allows AT to inhibit the procoagulant effect of thrombin by binding to the active-site serine residue of the thrombin molecule.79 The inhibitory effect of AT is increased 1000-fold in the presence of heparin. The heparin-AT complex can affect several coagulation factors, but factor Xa and thrombin are the most sensitive to inhibition by heparin, and thrombin is 10 times more sensitive to the inhibitory effects of unfractionated heparin than is factor Xa.80

Only approximately onethird of the heparin molecules in a dose of heparin contain the critical pentasaccharide segment that is needed for high-affinity binding to AT. Thus, relatively large doses are required to produce the anticoagulant effect necessary for CPB. In fact, dosing of heparin for CPB is somewhat empiric. After a baseline activated clotting time (ACT) is measured (the normal range is 80-120 seconds), a dose of 300 to 400 units/kg of heparin is given as an intravenous bolus. Commercially available assays are used for calculating the patient’s dose-responsiveness to heparin in vitro. Some practitioners administer heparin at the dose that is indicated by such an in vitro dose-response assay. Subsequent heparin dosing for extracorporeal circulation (ECC) is targeted at maintaining ACT values longer than 400 to 480 seconds. Also available is a heparin concentration monitor that uses protamine titration analysis for ex vivo calculation of the whole blood heparin concentration. This result is often used as an adjunct to the ACT value in confirming an adequate heparin concentration for CPB. Unfortunately, ACT test results vary substantially with clinical conditions and the particular platform used for measurement. Thus, the evidence supporting the use of a threshold of 400 or 480 seconds is almost entirely anecdotal.81

The dose of heparin used in patients on CPB is based on early landmark work published by Bull and coauthors in 1975.82 A small study that sought evidence of thrombin activity during CPB in nonhuman primates and pediatric patients found results supporting a safe lower limit for ACT of 400 seconds.83 In 1979, Doty and colleagues proposed a simplified dosing regimen guided by ACT values without dose-response curves.84 The data and recommendations from these few studies constitute the primary basis for current heparin dosing protocols.

Anticoagulants

Anticoagulants, such as brodifacoum and chlorophacinone, can cause morbidity and mortality in wild animals, especially those that feed on rodents. These small mammals are often the target of residential and commercial anticoagulant use and, when debilitated by the effects of the toxin, become easy prey for eagles, hawks, and owls. Most owls submitted to rehabilitation centers, regardless of clinical presentation, have elevated levels of anticoagulants detected in the blood or liver (Stone et al., 2003). As in rodents, exposure of birds to significant levels of anticoagulants can result in hemorrhage into body cavities, the gastrointestinal tract, or subcutaneous tissues. Relatively minor blunt trauma events may result in exaggerated hemorrhage at the point of impact, and death due to rapid blood loss. Low level, chronic exposure to anticoagulants often results in microvascular seepage of blood into the GI tract in the absence of frank hemorrhage (Figure 9). Postmortem changes consistent with chronic anticoagulant exposure include anemia with generalized soft tissue pallor; muscle wasting due to loss of protein through the GI tract; and scant, black, pasty gastrointestinal content. In raptors fitting this postmortem profile, anticoagulant exposure must be differentiated from lead ingestion by analysis of liver and/or blood samples.

Introduction

Anticoagulants continue to play a central role in the prevention of stroke. Unlike thrombolytics, anticoagulants do not degrade clot; rather, they prevent thrombus formation and propagation by reduction of fibrin formation. Anticoagulants act on different steps of the intrinsic and extrinsic coagulation pathways. Unfractionated heparin, low-molecular-weight heparins (LMWHs) and heparinoids are parenteral anticoagulants of rapid onset that act by indirect inhibition of thrombin and factor Xa via antithrombin. Warfarin (coumadin), the most commonly used oral vitamin K antagonist (VKA), inhibits the conversion of oxidized vitamin K epoxide into its reduced form, vitamin K. It diminishes the K-dependent γ-carboxylation of clotting factors II, VII, IX, and X, as well as the naturally occurring endogenous anticoagulant proteins C and S; the full antithrombotic effect of warfarin is not achieved for several days. During the past few years, a number of new oral anticoagulants (NOAC) have been added to the standard anticoagulant armamentarium. These novel anticoagulants selectively target thrombin (factor IIa) or factor Xa, have much more rapid onset (hours), better therapeutic window, and less drug and food interactions than VKAs (Fig. 167.1).

Anticoagulant Rodenticides

Anticoagulant rodenticides (ARs) have been extensively used for rodent control, allowing secondary exposure and poisonings in nontarget predatory wildlife species, such as birds of prey that mainly feed on rodents or small birds. In spite of this, ARs have not been routinely included in biomonitoring studies. In those countries where monitoring schemes include these compounds (e.g., UK, USA), a high frequency of detection has been reported in bird samples. However, in those countries where there is not a monitoring scheme for these compounds, data regarding rodenticide levels in raptors are only restricted to cases of suspected poisoning or after use to eradicate plagues.

There are two generations of ARs called the first generation anticoagulant rodenticides (FGARs) and the second generation anticoagulant rodenticides (SGARs). The FGARs group includes the coumarin compounds: coumatetralyl and warfarin and the 1,3-indandiones; chlorophacinone and diphacinone. On the other hand, the SGARs group was introduced in the 1970s to avoid the rodent resistance to FGARs. They are more toxic and persistent than FGARs, and are based on derivatives of 4-hydroxycoumarins and include difenacoum, brodifacoum, difethialone, flocoumafen, and bromadiolone among others. SGARs have a greater affinity to binding sites in the liver and consequently display greater acute toxicity (approximately 100–600 times), accumulation, and persistence. The secondary exposure and poisoning is more common in predators feeding on rodents poisoned by SGARs, which is due to their longer tissue half-lives and accumulation after repeated sublethal exposures. SGARs bind and inhibit vitamin K epoxide reductase and persist for at least 6 months in organs and tissues containing this enzyme, such as the liver. Therefore, these compounds act as vitamin K antagonists disrupting normal blood clotting processes, and causing lethal hemorrhage. Prior to death, birds show typical clinical symptoms that include anemia, dyspnea, and lethargy. However, it is also known that a sublethal dose of rodenticides can produce significant clotting abnormalities and hemorrhages without causing death, which may increase the likelihood of death due to other causes or environmental stressors, such as food shortage or predation. The liver concentrations of SGARs associated with adverse effects and/or mortality in birds markedly vary among both individuals and species, and have not been defined for most raptor species. In the same manner, avian acute toxicity also varies between species. For example, brodifacoum LD50 values of 0.31, 0.72, and 19 mg kg−1 bw were calculated for mallard duck (Anas platyrhynchos), laughing gull (Leucophaeus atricilla), and Japanese quail (Coturnix coturnix japonica), respectively.

Source

Anticoagulant rodenticides are by far the most commonly used class, and they are frequently involved in accidental and malicious poisonings. These materials may be divided by chemical type into the indandiones (chlorophacinone and diphacinone) and the hydroxycoumarins. The latter class may be divided into first-generation anticoagulants (now being phased out due to increasing resistance among rodent populations), including warfarin and coumafuryl, and second-generation anticoagulants, such as brodifacoum, bromadiolone, difenacoum, and difethialone. The indandiones have similar toxicologic profiles to the second-generation hydroxycoumarins, and thus are often grouped with them.

Second-generation anticoagulants are highly toxic, requiring only a single feeding, and they persist in body tissues. However, their action may be delayed for several days, allowing multiple episodes of ingestion and accumulation of multiple lethal doses within a carcass, thereby increasing the risk of secondary poisoning in predators and scavengers.

Conclusions

Anticoagulants remain an important component of management of patients at risk for thromboembolic stroke, particularly secondary to AF and other high-risk cardiac diseases. These agents are generally not prescribed to patients with asymptomatic or symptomatic arterial diseases including both atherosclerosis and arterial dissection. Long-term administration of oral anticoagulants is recommended to prevent or treat deep vein thrombosis. Although these agents are effective in preventing ischemic thromboembolic events, they are associated with an increased risk of serious bleeding complications, including intracranial hemorrhage.

Emergency administration of anticoagulants is not recommended for treatment of patients with acute ischemic stroke. These medications are associated with an increased risk of symptomatic hemorrhage, especially among patients with major stroke, and they are not associated with improvement of neurological outcomes. They are also not effective in lowering the risk of early recurrent ischemic events. Parenteral administration of anticoagulants is recommended for lowering the risk of venous thrombosis among bedridden patients with recent stroke. Although data supporting the use of anticoagulants are limited, they are the usual first choice for treatment of patients with cerebral venous sinus thrombosis. Subsequent long-term oral anticoagulant treatment usually follows initial intravenous anticoagulation.

What are the parenteral anticoagulants?

Which time frame describes the onset of action for intravenous IV heparin?

What is an example of a parenterally administered anticoagulant?

What does anticoagulant therapy prevent?