Anticoagulation Coagulation Cascade

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Thrombin is a glycosylated serine protease that plays a fundamental role in thrombosis (117). Thrombin is generated from prothrombin by the prothrombinase complex, which includes factors Xa, Va, calcium, and phospholipids (Fig. 7). Its main action is to transform fibrinogen into fibrin. Thrombin is one of the most potent endogenous platelet activator (110-112). The active catalytic site lies within a relatively narrow canyon on the molecule's surface (Fig. 8) (118). Adjacent to this site is the substrate recognition site, also known as the anion-binding exosite, to which fibrinogen binds (118). In addition, there is a separate fibrin-binding site (17). Finally, there are several other well-characterized binding sites including an apolar binding site (119), which is involved in both substrate binding as well as platelet attachment via GP Ib, a heparin-binding site, and the primary platelet attachment site, which is an anion-binding exosite similar to the

Antithrombin Site Action

Fig. 7. The intrinsic and extrinsic pathways of the coagulation cascade and the sites of action of antithrombin agents (open arrowheads and dashed lines). Abbreviations: TF, tissue factor; TFPI, tissue factor pathway inhibitor; ATIII, antithrombin III; LMWH, low-molecular weight heparin; TAP, tick anticoagulant peptide; UFH, unfractionated heparin; F1.2, prothrombin fragment 1.2; FPA, fib-rinopeptide A.

Fig. 7. The intrinsic and extrinsic pathways of the coagulation cascade and the sites of action of antithrombin agents (open arrowheads and dashed lines). Abbreviations: TF, tissue factor; TFPI, tissue factor pathway inhibitor; ATIII, antithrombin III; LMWH, low-molecular weight heparin; TAP, tick anticoagulant peptide; UFH, unfractionated heparin; F1.2, prothrombin fragment 1.2; FPA, fib-rinopeptide A.

Catalytic Site And Exosites Thrombin
Fig. 8. Simplified depiction of thrombin and several of its key binding sites.

Table 2 Antithrombotic Agents

Indirect thrombin inhibitors: Heparin LMWHs Direct thrombin inhibitors: Hirudin Bivalirudin Argatroban Thrombin generation inhibitors: Factor Xa inhibitors LMWHs Pentasaccharide TAP TFPI

substrate recognition site, which binds to platelets using a tethered-ligand motif (111). Thrombin inhibition can be achieved either by binding to one of these critical sites or by inhibiting thrombin generation, which is achieved primarily by inhibiting Factor Xa (Fig. 7 and Table 2) (42,117,120,121).

Heparin

Pharmacology

Heparin is a glycosaminoglycan that contains a unique pentasaccharide sequence with high binding affinity for antithrombin III (ATIII) (19,122). When bound to heparin, ATIII undergoes a conformational change that results in an acceleration of its ability to inactivate both thrombin and factor Xa by acting as a "suicide substrate" (Fig. 9). Heparin also increases the rate of the thrombin-ATIII reaction by greater than 1000-fold by acting as a catalytic template to which both the inhibitor and the protease bind, thereby forming a ternary complex. (Note: ternary complex formation is not required for factor Xa inactivation.) Once thrombin binds to ATIII, heparin is released from the complex. There is also some evidence that part of heparin's anticoagulant effect is due to its ability to both stimulate the release and enhance the activity of tissue factor pathway inhibitor (123-125). Heparin molecules that contain fewer than 18 saccharide units (i.e., low-molecular-weight heparins [LMWHs]) are unable to bind thrombin and ATIII simultaneously and are, therefore, unable to form ternary complexes to accelerate thrombin inhibition (see below). Heparin is largely ineffective against fibrin monomer-bound (16) or clot-bound (17) thrombin (Figs. 9 and 10) and against factor Xa bound in the prothrombinase complex.

Heparin is a heterogeneous mixture of glycosaminoglycans of varying molecular sizes (126). This translates into heterogeneous anticoagulant activity for three reasons. First, only approx 30% of heparin molecules actually contain the specific pentasaccharide sequence mentioned above that is required for ATIII binding (122). Second, the anticoagulant profile of heparin in terms of the ratio of thrombin to factor Xa inhibition is influenced by the chain length (127). Third, the clearance of heparin is proportional to its molecular size (128).

Anticoagulation Cascade
Fig. 9. Interaction between thrombin and heparin. (A) Thrombin binding to its natural substrate fibrinogen. (B) Inactivation of thrombin by ATIII and heparin. (C) Fibrin-bound thrombin is enzymati-cally active but resistant to inactivation by ATIII and heparin.
Coagulation Cascade Anticoagulant

Fig. 10. Comparison of the inhibitory effects of heparin against fluid phase (open bars) and clot-bound (solid bars) thrombin activity. Thrombin or fibrin clots were incubated with citrated plasma in the presence or absence of heparin. FPA levels were then measured by radioimmunoassay, and the percent inhibition of FPA generation was calculated for each inhibitor concentration. Heparin concentrations of 0.2-0.4 U/mL span the therapeutic range for this agent. Reproduced with permission from ref. 17.

Fig. 10. Comparison of the inhibitory effects of heparin against fluid phase (open bars) and clot-bound (solid bars) thrombin activity. Thrombin or fibrin clots were incubated with citrated plasma in the presence or absence of heparin. FPA levels were then measured by radioimmunoassay, and the percent inhibition of FPA generation was calculated for each inhibitor concentration. Heparin concentrations of 0.2-0.4 U/mL span the therapeutic range for this agent. Reproduced with permission from ref. 17.

Heparin can be administered either by continuous iv infusion or by intermittent subcutaneous injections with comparable efficacy, although there is a 1-2 h delay in achieving an anticoagulant effect via the subcutaneous route. The half-life of heparin varies depending on the dose given, but is approx 60-90 min.

Heparin-induced thrombocytopenia (HIT) is a well-documented complication of heparin administration (20). HIT type I occurs in approx 10% of patients receiving heparin and is manifested by mild thrombocytopenia occurring within 48 h of the initiation of therapy. The platelet count rarely falls below 100,000/mm3 and returns to normal within 5 d even if heparin therapy is continued. The mechanism is thought to be direct heparin-mediated platelet aggregation. Patients with HIT type I do not go on to have thrombotic complications. In contrast, HIT type II is marked by more severe thrombocytopenia and a greatly increased risk of thrombosis. This syndrome occurs in 1-5% of patients receiving heparin, approximately one-third of whom will go on to develop thrombosis. The platelet count usually starts to decrease after 5-12 d of therapy (and potentially earlier if the patient has been exposed to heparin before) and usually falls by more than 50% or drops to less than 100,000/mm3. If heparin is discontinued, the platelet count usually returns to normal in 4-10 d. The pathogenesis of this syndrome is believed to be due to antibodies forming against heparin-platelet factor 4 complexes (Fig. 11) (129,130). These immune complexes can then bind to Fc receptors on platelets and trigger platelet activation, thereby releasing more platelet factor 4. Platelet factor 4 can bind to heparin-like molecules on the surface of endothelial cells, providing a target for the above-mentioned antibodies and leading to endothelial cell injury and thrombosis.

Several investigators have reported a "rebound effect" after the cessation of heparin therapy in patients with acute coronary syndromes. In one trial that randomized patients with unstable angina to heparin, aspirin, both, or neither, there was a nearly threefold higher incidence of disease reactivation (i.e., recurrent unstable angina or myocardial infarction) in patients who had received heparin than in the other groups (13 vs 5%) (131). The majority of these recurrences were severe enough to require urgent intervention. Other investigators have noted that after the cessation of heparin in patients with acute coronary syndromes there is a transient increase in prothrombin fragment 1.2 and fibrinopeptide A levels, suggesting that both thrombin generation and activity were increased (132). Similar observations have been made after the discontinuation of heparin in patients undergoing coronary angioplasty (133). The mechanism underlying this rebound phenomenon is unclear but may be due to an accumulation of prothrom-botic factors during heparin therapy that then create a hypercoagulable state after the cessation of heparin.

Clinical Data

Trials with No Routine Aspirin. There have been 21 trials enrolling a total of approx 5000 patients that have examined the effects of heparin in acute myocardial infarction in the pre-aspirin era (i.e., pre-ISIS-2). Most of these trials were also in the prethrom-bolysis era as only 14% of the patients in these trials received thrombolytic therapy. A meta-analysis revealed that treatment with heparin resulted in a statistically significant 25% reduction in mortality (from 14.9 to 11.4%, p = 0.002) and a statistically nonsignificant 18% reduction in reinfarction (from 8.2 to 6.7%, p = 0.08) (Fig. 12) (134). Conversely, treatment with heparin was also associated with a near doubling of the major bleeding rate (1.9 vs 0.9%). Two trials (135,136) have examined the role of heparin in patients receiving a thrombolytic but not aspirin (Table 3). Treatment with heparin was associated with a higher infarct-related artery patency rate (136) and a lower mortality rate (135). However, the applicability of these data is limited now that treatment with aspirin has become standard of care.

Trials with Routine Aspirin. There have been six trials (137-143) enrolling approx 68,000 patients that have examined the effects of heparin in acute myocardial infarction in patients who did routinely received aspirin as part of the treatment protocol (Table 3). Ninety-three percent of the patients in these trials received thrombolytic therapy. A meta-analysis (134) revealed that treatment with heparin resulted in marginally statisti-

Effect Heparin Clotting Cascade

Fig. 11. HIT. Heparin interacts with platelet factor 4 (PF4), which is released in small quantities from circulating platelets to form PF4-heparin complexes (1). Specific IgG antibodies react with these conjugates to form immune complexes (2) that bind to Fc receptors on circulating platelets. Fc-mediated platelet activation (3) releases PF4 from a-granules in platelets (4). Newly released PF4 binds to additional heparin, and the antibody forms more immune complexes, establishing a cycle of platelet activation. PF4 can also bind to heparin-like molecules on the surface of endothelial cells (EC) to provide targets for antibody binding, potentially leading to immune-mediated EC injury (5) and thrombosis. Reproduced with permission from ref. 130.

Fig. 11. HIT. Heparin interacts with platelet factor 4 (PF4), which is released in small quantities from circulating platelets to form PF4-heparin complexes (1). Specific IgG antibodies react with these conjugates to form immune complexes (2) that bind to Fc receptors on circulating platelets. Fc-mediated platelet activation (3) releases PF4 from a-granules in platelets (4). Newly released PF4 binds to additional heparin, and the antibody forms more immune complexes, establishing a cycle of platelet activation. PF4 can also bind to heparin-like molecules on the surface of endothelial cells (EC) to provide targets for antibody binding, potentially leading to immune-mediated EC injury (5) and thrombosis. Reproduced with permission from ref. 130.

Coagulation Cascade Anticoagulant

Table 3

Randomized Trials of Heparin in Patients Receiving Thrombolysis for Acute Myocardial Infarction

Table 3

Randomized Trials of Heparin in Patients Receiving Thrombolysis for Acute Myocardial Infarction

Trial (reference)

Year

Aspirin

Heparin

Thrombolytic

Patients

SCATI1 (35)

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