Intrinsic Pathway

The intrinsic pathway was thought to activate blood coagulation by involving only substances present in the plasma. Initiation of coagulation via this pathway requires 'contact activation'. This occurs when pre kallikrein (PK) and factors XII and XI are activated in the presence of high molecular weight kininogen (HMWK) on exposure to certain surfaces; in vivo to negatively charged surfaces such as collagen, in vitro to glass or kaolin (Figure HA.15). The sequential activation of factors XI and IX then occurs culminating in the activation of factor X by factor IX with factor VIII as a co-factor.


Oral anticoagulant drug administration.

Liver disease, hepatocellular, (decreased production of factors II and VII obstructive (decreased absorbtion of vitamin K)

Vitamin K deficiency

Disseminated intravascular coagulation


Massive transfusion

Inherited deficiency of factor VII, X or V. Heparin

Figure HA.14

Intrinsic Pathway Nursing
Figure HA.15 Initiation of the intrinsic coagulation pathway

Activated Partial Thromboplastin Time (APTT)

This was designed to assess the potential of the intrinsic pathway. It is also known as the PTTK (partial thromboplastin time with kaolin) and the KCCT (kaolin clotting time). The plasma is pre incubated with kaolin and phospholipid to activate the contact factors, calcium chloride is then added and the time recorded for a clot to form. The sensitivities of different phospholipid reagents to deficiencies of the clinically important factors (VIII and IX) in the intrinsic pathway vary. APTT is used to monitor heparin therapy; unfortunately, it has not yet been possible to standardize these reagents for the monitoring of heparins in the same way that thromboplastins have been for oral anti-coagulant control, making local derivation of therapeutic ranges for heparin necessary. The most frequent causes of a prolonged APTT are shown in Figure HA. 16.

Final Common Pathway

The final common pathway sees the conversion of prothrombin to thrombin by factor Xa with factor Va as a co-factor. Thrombin has a central role in coagulation. Critically it cleaves fibrinogen to form fibrin monomers that then spontaneously aggregate to form fibrin strands that are subsequently cross-linked by factor XIIa resulting in a stable clot. Factor XII is activated by thrombin, as are the co-factors factor V and VIII, thrombin induces platelet aggregation and, by combining with thrombomodulin, activates protein C, an anti-coagulant protein, which results in the inactivation of factors V and VIII.


Heparin therapy

Sample contamination by heparin, e.g. by taking sample from a line through which heparin has been administered (including Hepflush')

Liver disease

Disseminated intravascular coagulation


Massive transfusion

Coagulation inhibitor, e.g. lupus anticoagulant, acquired factor VIII inhibitor

Inherited deficiency of factors xI, VIII, IX, x, PK or


Figure HA.16

Deficiency of factors X, V, II and fibrinogen cause prolongation of both the PT and the APTT. Hence, the function of the final common pathway can be monitored by using both tests. In reality, since isolated deficiency of factors X or V are rare, the commonest reason for prolongation of both tests in a patient not receiving oral anti-coagulants is hypofibrinogenaemia.

Thrombin Time (TT)

The TT tests the key reaction in the coagulation cascade; the conversion of fibrinogen to fibrin. Conceptually it is the most simple of all the coagulation tests as it consists of simply adding a solution of thrombin to platelet poor plasma and measuring the time taken for a clot to form, the addition of calcium is not necessary. TT is very sensitive to low levels of heparin, this probably being the most common reason for a prolonged TT, other reasons are shown in Figure HA.17. In many laboratories, the TT is not performed as part of a routine coagulation screen, instead the fibrinogen is measured. This can be done in an assay based loosely on the TT (Clauss method), but increasingly with the introduction of automation into the coagulation laboratory, fibrinogen is estimated during the performance of the PT by optometrical analysis of clot formation.


• Hypofibrinogenaemia

- Disseminated intravascular coagulation

- Fibrinolytic therapy

- Massive transfusion

- Inherited deficiency (rare)

• Dysfibrinogenaemia (abnormal fibrinogen molecule)

- Inherited (rare)

- Acquired (liver disease most common cause)

• Raised FDP levels - DIC or liver disease

Figure HA.17

A revised view of in vivo coagulation (Figure HA.18) takes into account the paradoxes offered by the above scheme, for example; while patients severely deficient in factors VIII and IX (haemophiliacs) bleed spontaneously those with factor XII, PK or HMWK deficiency do not have a bleeding diathesis but do have considerably prolonged APTTs. So it is clear that the classical cascade theory is important to understand what is occurring in the screening coagulation tests, but comprehension of in vivo coagulation requires alternative explanations.

It is important to realise that coagulation reactions occur on surfaces, e.g. platelets, activated endothelium, subendothelial collagen. When coagulation is initiated thrombin is formed in the absence of activated factors V and VIII, trace amounts of thrombin then activate factors V and VIII. These are large molecules that act as co-factors in their respective reactions and localize reactions to surfaces, the overall result is an increase by many thousand-fold in the efficiency of the coagulation mechanism.

Figure HA.18 A revised coagulation hypothesis

It is tissue factor that initiates coagulation in vivo by forming a complex with factor VIIa and then activating factor X (it is not clear how factor VII is activated); however, this complex also activates factor IX which is a significant departure from the classical hypothesis. The importance of this is only realised upon activation of factors V and VIII: the predominant action of factor VIIa/TF becomes activation of factor IX and massive amplification of the coagulation mechanism then occurs via two highly efficient reactions resulting in thrombin formation. Factor VIIa/TF complex is quickly inhibited by tissue factor pathway inhibitor, so factor Xa generation must occur via factor VIIIa/IXa. This is augmented by factor XIa, which is activated by thrombin, this being a late step in the pathway. The critical roles of factors XIa and VIIIa in this scheme reflect the severity of the bleeding when these factors are deficient. Contact activation has no place in in vivo coagulation.

Natural Inhibitors of Coagulation

The cascade structure of the coagulation system ensures very rapid activation of coagulation, for example, it has been estimated that 10 ml plasma can generate sufficient thrombin to clot all the body's fibrinogen in 30 s; clearly this may be deleterious, so equally powerful inhibitors of coagulation in the plasma ensure that the haemostatic response is confined to the vicinity of the platelet plug and vascular injury. Tissue factor pathway inhibitor has already been mentioned, but there are two other broad groups of coagulation inhibitors: serine protease inhibitors the most important of which is anti-thrombin (previously called anti-thrombin III) and the coagulation co-factor (VIIIa and Va) inhibitors which are proteins C and S.

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