Factor VIII rise

Because it is a small protein, the factor IX molecule passes into the intravascular and the extravascular spaces. Therefore, the volume of distribution of recombinant factor IX is twice that of factor VIII. Consequently, 1 unit of factor IX administered per kilogram of body weight yields a 1% rise in the plasma factor IX level (0.01 unit/mL, or 1 IU/dL). Thus 1750 units of factor IX provides an incremental increase of 50% of normal (0.5 unit/mL, or 50 IU/dL), that is, 1750 units/70 kg x 0.01 unit/mL (1 IU/dL).12 Additionally, the recovery rate with recombinant factor IX is 20% lower than that with the plasma-derived products. Therefore, initial and subsequent maintenance doses should be adjusted accordingly. 

Heparin, which has an anticoagulation action, may give rise to heparin-induced thrombocytopenia, which is an immune-mediated condition that usually develops 5-10 days after the administration of the drug. When heparin is used, a platelet count should be measured before treatment and if administration is repeated, platelet counts should be monitored regularly. Signs of thrombocytopenia include a reduction in platelet count. It may present with spontaneous haemorrhage and heparin should be stopped. Factor VIII is used in the treatment and prophylaxis of haemorrhage in patients with haemophilia. 

Patients with bleeding disorders are at risk of developing antibodies against the protein that is absent, present in reduced amounts, or present in an inactive form in their blood. Such coagulation inhibitors make treatment very difficult. Inhibitors of factor VIII are the most common and develop in 5-20% of patients with hemophiha A. Inhibitors of factor IX develop in 1-4% of patients with hemophilia B (3,4). Patients with factor VIII inhibitors present clinically either as high responders who show a strong anamnestic response and a sharp rise in inhibitor concentrations after exposure to factor VIII, or low responders, who show little or no anamnestic response (5). 

Investigations into the Nature of the Acute Rise in Factor VIII Concentration. 211... 

Possible Mechanisms for the Rise in Assayable Factor VIII. 216... 

Under this heading it is possible to do little more as yet than record the situations in which a maintained rise in plasma factor VIII concentration has been observed. It seems worthwhile to do this because these facts will... 

Factor VIII levels up to 4 times normal have been reported at term (P5, S3, T3). Some other clotting factors also rise in concentration during pregnancy, for instance fibrinogen (16, M3, P5), factor VII (LI, Nl), and factor X (PI), but apparently not prothrombin (Dl). The significance of this pattern of changes is not known. 

A moderate rise in factor VIII concentration occurs in patients treated with the oral anticoagulants, which may continue until slightly after the end of treatment (E4, P3). 

Egeberg studied a number of acute states and found that a rise of factor VIII was associated with the induction of nonspecific fever (E6, ElO), intravenous infusion of serum (E7), intramuscular injection of blood (E8) or intravenous infusion of hemolyzed blood (E2), drug-induced diuresis in a patient with cardiac edema (Ell), and surgical operations (El). In the very acute changes, factor VIII alone rose in concentration, but where the process occupied several days there were normally associated increases in fibrinogen and in factor V. Other clotting factors remained at their previous levels. These investigations were all made in persons with normal hemostasis. 

Experimental study of the rise in factor VIII concentrations, now known to occur in so many situations, has been almost entirely confined for practical reasons to a study of the effects of exercise or adrenaline administration. These situations, it will be recalled, are those in which an isolated rise in factor VIII can be observed, unaccompanied by changes in fibrinogen or factor V. It is thus uncertain to what extent the results may be applied to the more protracted, combined increase in fibrinogen and factors V and VIII. 

First, it should be remembered that the basic observation, a rise in plasma factor VIII concentration, depends entirely upon a biological assay, in which the corrective effect of the test plasma is compared to that of a control plasma when both are added to plasma obtained from a severely affected hemophiliac, or to an artificial system containing necessary clotting factors other than factor VIII. In acute experiments it has been usual to assay the subject s pretreatment plasma as well as the plasma obtained after the experiment, or to use the pretreatment plasma as the standard (nominally 100%) for the assay. The second procedure eliminates errors due to differences between subjects, but uncertainty still remains regarding the effects of the experimental treatment upon the assay system, apart from a possible true increase in factor VIII concentration. A number of experiments have therefore been directed to testing the validity of the... 

Another possibility is that some other clotting factor is increased or activated in such a way that the assay system responds fortuitously to it in a way indistinguishable from the usual response to factor VIII, e.g., factors XI and XII factor XII is known to rise on exercise (II). That this might occur over a limited range of the dose-response curve in the thromboplastin generation test system was shown by experiments in which the addition of activation product (Wl) simulated an increased factor VIII concentration (author s unpublished observations, 1960 FI), although statistical invalidity would probably be detectable over a series of experiments if this were the explanation. This also was looked for, but was not found (14). It is interesting that, in a patient with severe factor VIII deficiency and partial factor XI deficiency (SI), adrenaline infusion was followed by a marked rise in factor XI concentration and the appearance of a trace of factor VIII (K. Schulz, personal communication, 1964). Furthermore, the confusion that arose some years ago over factor IX assay now seems to have been due to activation of the contact factors (P4), hence... 

However, the exercise effect has been demonstrated with assays involving (supposedly maximal) activation of factors XI and XII with kaolin (13), and a system to which activation product was added (VI) duly registered the adrenaline effect. Furthermore, a rise in factor VIII concentration has now been produced by exercise in patients with severe deficiencies of factors XI and XII. Egeberg (E13) tested two patients with gross deficiencies of factor XI, and Goudemand et al. (G2) and A. Parquet-Gemez (personal communication, 1964) tested factor Xll-deficient patients. 

Thus none of these experiments has produced evidence that the assayed rise in factor VIII can be discounted as spurious. Nevertheless this possibility should not be forgotten, for it may simply be that the correct experiments to demonstrate this have not yet been contrived. The ultimate test of an increase in factor VIII activity is the demonstration of greater hemostatic value in hemophilic bleeding this is imfortunately a very difficult test to apply. 

Goudemand el al. (Gl) considered the possibility that a quantity of factor VIII might be released from the spleen in response to adrenaline administration or release. Therefore they tested a series of previously splenectomized subjects in seven of them a rise in factor VIII after exercise could not be demonstrated, but adrenaline infusion produced a mean 2-fold increase in 11. 

In pregnancy, diabetes, and chronic inflammatory states there is a sustained rise in factor VIII concentration, accompanied by increases in other clotting factors, of which fibrinogen is the most constant and probably the most closely correlated quantitatively. In diabetes and atherosclerotic disease there is also an increase in the bleeding-time factor. Similar effects on the clotting factors can be produced by applying stresses which operate over a few days, such as the intramuscular injection of the subject s own blood. The rate of increase in factor VIII concentration indicated by serial assays is not more rapid than may be seen in patients with von Willebrand s disease after infusion of hemophilic plasma, and may therefore be reasonably ascribed to an increased rate of synthesis, since there is... 

How could a reserve of factor VIII be maintained sufficient to provide for a 2- to 6-fold rise in blood concentration ... 

It seems likely that the relatively slow rise in factor VIII concentration in response to subacute or chronic stress represents an increased sjm-thesis, and is comparable in rate to the increased synthesis seen in von Willebrand s disease after infusing normal or hemophilic plasma. The very rapid increase which can be produced by exercise or adrenaline infusion is more likely to be due to potentiation of factor VIII in the blood stream, but a type of potentiation satisfying the experimental data does not yet appear to have been demonstrated. 

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