Coagulation

Basic Mechanisms of Coagulation

The coagulation process is activated by both an intrinsic and extrinsic system. The intrinsic, or contact, system is a cascade of reactions which require the formation of complexes between surface bound enzyme and cofactors. The intrinsic cascade begins with the complexing of three plasma proteins, high mo-

Table 4.4. Cardiac Drugs—Vasopressors

Phenylephrine (Neosynephrine) 100-300m IVP; 30mg/250ml(120m/ml),10-

500m/min, 30m/min=15ml/hr L Vasopressin (Pitressin) 100units/100ml(1units/ml).04-.1units/min

L Vasopressin is useful in cases of vasodilatory shock, such as that seen post cardiopulmonary bypass.

Vasodilators

Nitroglycerin 50mg/250ml(200mg/ml), 1-4m/kg/min

Nitroprusside 50mg/250ml(200mg/ml), 1-2m/kg/min

Phentolamine 10mg/100ml(100mg/ml) fast infusion

Prostaglandin E1 (PGE1, .05mg/kg/min

Prostin, Alprostadil)

Prostaglandin E1 is indicated primarily for pulmonary hypertension, and it is thus infused through a right atrial line. Concomitant infusion of a vasopressor through a left atrial line is usually necessary to maintain systemic pressures.

lecular weight kininogen, pre-kallikrein, and factor XII, with subendothelial collagen. Factor XII is then converted from an inactive to an active protease (XlIa). The cascade then proceeds as follows: activated factor XIIa->factor XIa->factor IXa.

The extrinsic system is mediated by a cell membrane lipoprotein, tissue factor, which complexes to factor VII and calcium. Thus, factor VII is converted to an active protease.

The reactions of the intrinsic and extrinsic pathways generate proteases which activate factor X. At this level prothrombin is converted to thrombin. Thrombin then converts fibrinogen to fibrin. Plasmin, which is activated from plasminogen by tissue plasminogen activator, degrades fibrin to low molecular weight fragments.

Antithrombin, protein C and protein S regulate the coagulation system.

Platelet function is regulated by the von Willebrand's factor, which binds the glycoprotein Ib receptor of the platelet to the vessel wall, and by fibrinogen, which binds platelets to each other through their respective glycoprotein IIb-IIIa receptors.

Coagulation Profile

Aside from such tests as the partial thromboplastin time (PTT), prothrombin time (PT), and thrombin time (TT), which examine the intrinsic, extrinsic, and fibrinogen to fibrin pathways, respectively, the coagulation profile can be assessed with the use of the thromboelastograph (TEG) or viscoelastograph (Sonoclot).Both the TEG and the Sonoclot record the entire coagulation process.

The TEG measures coagulation with a cuvette and piston which become coupled as a clot is formed. The shearing elasticity of this clot is translated onto thermal paper from the cuvette -piston coupling. The TEG thus records a:

1. reaction time, which corresponds to the rate of generation of thromboplastin,

2. coagulation time, which measures the time for a clot to begin to form,

3. clot formation rate, which measures the time for a solid clot to form,

4. maximum amplitude, which is related to clot elasticity, and

5. whole blood lysis time, which corresponds to fibrinolysis.

The Sonoclot represents the coagulation process as a "signature". A piston is used which detects the viscous drag as a clot is forming. This drag is quantified electronically as a change in electrical output. The resultant signal is then translated onto a chart as a tracing, or signature. The sonoclot thus records:

1. time of onset of fibrin formation, mediated by the both the intrinsic and extrinsic pathways. This is the activated clotting time of the sonoclot (SonACT),

2. the rate of conversion from fibrinogen to fibrin,

3. fibrin-platelet interaction, and (4) the rate of clot contraction, which is the rate at which the platelets contract the fibrin clot.

Pharmacologic Interventions

Three categories of procoagulant drugs are currently used to reduce perioperative bleeding: desmopressin (DDAVP), lysine analogues (epsilon aminocaproic acid and tranexamic acid), and serine protease inhibitor (aprotinin).

Desmopressin is a synthetic analogue of the antidiuretic hormone. It increases the activity of factor VIII and interacts with the glycoprotein 1b receptor on the platelet to induce adhesion of the platelet to the vascular subendothelium. It is effective in the treatment of bleeding diathesis in patients with renal failure, cirrhosis, or von Willebrand disease.

The lysine analogues exhibit antifibrinolytic activity by binding to a lysine site on plasminogen. In this way they inhibit activation of the plasminogen and thereby its interaction with fibrin.

The serine protease inhibitor aprotinin has been shown to be extremely effective in reducing bleeding. Its blocks various mediators such as kallikrein and plas-minogen and thus acts as both an antiinflammatory and an antifibrinolytic agent. Complement activation is also inhibited. Aprotinin protects platelet integrity by preventing destruction of the glycoprotein IIb-IIIa receptor by plasmin. These properties make aprotinin a very effective agent for open heart surgeries as it substantially reduces bleeding and thus the need for blood and blood product transfusions, particularly platelets which may in themselves aggravate complement activation. Because of its antiinflammatory effects aprotinin may also reduce the need for inotropic support in the post cardiopulmonary bypass period.

Severe anaphylactic reactions to aprotinin may occur if it had been administered previously within six months. Aprotinin rarely causes renal dysfunction or thrombosis even when used during circulatory arrest.

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