Apc

-XIIIa

Figure 15.5 In vivo coagulation cascade.

Figure 15.6 In vitro coagulation cascade.

a vessel. Factor VII forms a complex with tissue thromboplastin and calcium. This complex converts factors X and Xa, which in turn converts prothrombin to thrombin. Thrombin then converts fibrinogen to fibrin. This process takes between 10 and 15 seconds.

Prothrombin time (PT) developed by Armond Quick in 1935 measures the extrinsic system of coagulation. It is dependent upon the addition of calcium chloride and tissue factor. It uses a lipoprotein extract from rabbit brain and lung.1

PT uses citrate anticoagulated plasma. After the addition of an optimum concentration of calcium and an excess of thromboplastin, clot detection is measured by an automated device for fibrin clot detection. The result is reported in seconds. PT is exclusive for factor VII, but this test is also sensitive to decreases in the common pathway factors. Therefore, if a patient presents with a prolonged PT and there is no other clinical abnormality or medication, the patient is most likely factor VII deficient. The PT is also used to monitor oral anticoagulation or warfarin therapy used to treat and prevent blood clots. In many instances, patients are placed on life-long therapy and the dosage is monitored by the PT test. The attempt in anticoagulant therapy is to impede thrombus formation without the threat of morbidity or mortality from hemorrhage.

Warfarin is an oral anticoagulant, which means it must be ingested. It was discovered in 1939 at the University of Wisconsin quite by accident. It seems that a farmer found that his cattle were hemorrhaging to death, for what appeared to be no reason. The cattle were grazing in a field eating sweet clover. This contains dicumarol, actually bis-hydroxy coumadin, which caused the cattle to bleed.6

There are several compounds of coumadin: dicumarol, indanedione, and warfarin. Dicumarol works too slowly, and indanedione has too many side effects. Warfarin or 4-oxycoumarin is the most commonly used oral anticoagulant. Coumadin works by inhibiting the y-carboxylation step of clotting and the vitamin K-dependent factors.15 Laboratory monitoring of oral anticoagulation therapy will be discussed in Chapter 19.

Intrinsic System

Contact activation is initiated by changes induced by vascular trauma. Prekallikrein is required as a cofactor for the autoactivation of factor XII by factor XIIa. XI is activated and requires a cofactor of HMWK. XIa activates IX to IXa, which in the presence of VIIIa converts X to Xa. Also present are platelet phospholipids PF3.

Calcium is required for the activation of X to proceed rapidly. The reaction then enters the common pathway where both systems involve factors I, II, V, and X. This results in a fibrin monomer polymerizing into a fibrin clot. Factor XIII, or fibrin stabilizing factor, follows activation by thrombin. This will convert initial weak hydrogen bonds, cross-linking fibrin polymers to a more stable covalent bond.

Activated Partial Thromboplastin Time aPTT measures the intrinsic pathway. The test consists of recalcifying plasma in the presence of a standardized amount of platelet-like phosphatides and an activator of the contact factors. It will detect abnormalities to factors VIII, IX, XI, and XII. The aPTT is also used to monitor heparin therapy. Heparin is an anticoagulant used to treat and or prevent acute thrombotic events such as deep vein thrombosis (DVT), pulmonary embolism (PE), or acute coronary syndromes. The action of heparin is to inactivate factors XII, XI, and IX in the presence of antithrombin. Laboratory monitoring of heparin therapy will be discussed in Chapter 19.

Common Pathway

The common pathway is the point at which the intrinsic and extrinsic pathways come together and factors I, II, V, and X are measured. It is important to note that the PT and the aPTT will not detect qualitative or quantitative platelet disorders, or a factor XIII deficiency. Factor XIII is fibrin stabilizing factor and is responsible for stabilizing a soluble fibrin monomer into an insoluble fibrin clot. If a patient is factor XIII deficient, the patient will form a clot but will not be able to stabilize the clot and bleeding will occur later. Factor XIII is measured by a 5 mol/L urea test that looks at not only the formation of the clot but also if the clot lyzes after 24 hours.

Formation of Thrombin

When plasma fibrinogen is activated by thrombin, this conversion results in a stable fibrin clot. This clot is a visible result that the action of the protease enzyme thrombin has achieved fibrin formation. Thrombin is also involved in the XIII-XIIIa activation due to the reaction of thrombin cleaving a peptide bond from each of two alpha chains. Inactive XIII along with Ca2+ ions enables XIII to dissociate to XIIIa. If thrombin were allowed to circulate in its active form (Ia), uncontrollable clotting would occur. As a result thrombin circulates in its inactive form prothrombin (II).Thrombin, a protease enzyme, cleaves fibrinogen (factor I) which results in a fibrin monomer and fibrinogen peptides A and B. These initial monomers polymerize end to end due to hydrogen bonding.

Formation of fibrin occurs in three phases:

1. Proteolysis: Protease enzyme thrombin cleaves fibrinogen resulting in a fibrin monomer, A and B fibrinopeptide.

2. Polymerization: This occurs spontaneously due to fibrin monomer that line up end-to-end due to hydrogen bonding.

3. Stabilization: This occurs when the fibrin monomers are linked covalently by XIIIa into fibrin polymers forming an insoluble fibrin clot.

Feedback Inhibition

Some activated factors have the ability to destroy other factors in the cascade. Thrombin has the ability to temporarily activate V and VIII, but as thrombin increases it destroys V and VIII by proteolysis. Likewise, factor Xa enhances factor VII, but through a reaction with tissue factor pathway inhibitor (TFPI), it will prevent further activation of X by VIIa and tissue factor. Therefore, these enzymes limit their own ability to activate the coagulation cascade at different intervals.

Thrombin feedback activation of factor IX can possibly explain how intrinsic coagulation might occur in the absence of contact factors. Tissue factor is expressed following an injury forming a complex with VIIa, then activating X and IX. TFPI prevents further activation of X. Thrombin formation is further amplified by factors V, VIII, and XI, which leads to activation of the intrinsic pathway. This feedback theory helps to enforce why patients with contact factor abnormalities (factors XI and XII) do not bleed.8 See Figure 15.7 for a diagram of feedback inhibition.

Fibrinolysis

The fibrinolytic system is responsible for the dissolution of a clot. Fibrin clots are not intended to be permanent. The purpose of the clot is to stop the flow of blood until the damaged vessel can be repaired. The presence or absence of hemorrhage or thrombosis depends on a balance between the procoagulant and the fibrinolytic system. The key components of the system are plas-minogen, plasminogen activators, plasmin, fibrin, fibrin/FDP, and inhibitors of plasminogen activators and plasmin.6 Fibrinolysis is the process by which the hydrolytic enzyme plasmin digests fibrin and fibrino-gen, resulting in progressively reduced clots. This system is activated in response to the initiation of the activation of the contact factors. Plasmin is capable of digesting either fibrin or fibrinogen as well as other factors in the cascade (V, VIII, IX, and XI). Normal plasma contains the inactive form of plasmin in a precursor called plasminogen. This precursor remains dormant until it is activated by proteolytic enzymes, the kinases, or plasminogen activators. Fibrinolysis is controlled by the plasminogen activator system. The components of this system are found in tissues, urine, plasma, lysosomal granules, and vascular endothelium.

An activator, tissue-plasminogen activator (tPA) results in the activation of plasminogen to plasmin resulting in the degradation of fibrin. The fibrinolytic system includes several inhibitors. Alpha-2-antiplasmin is a rapid inhibitor of plasmin activity and alpha-2-macroglobulin is an effective slow inhibitor of plas-

Feedback Inhibition:

Factor XI-►Factor XIa-► Factor IX ^-Tissue factor + Factor VIIa

Factor IXa -Facr X

Factor VIII-► Factor VIIIa

Factor Va + Factor Xa

Factor VII

Figure 15.7 Feedback inhibition. Note the role of thrombin in the activation and deactivation of coagulation factors.

Thrombin IIa

Factor V Factor II

Thrombin IIa

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