From the cloning of the factor VIII gene in , ten years passed until recombinant factor VIII concentrates were registered for clinical use, preceded by publications on their safe and successful applications. This preparation has no addition of human albumin as a stabilizer, thereby showing a possibly even lower risk of viral transmission. In mild and moderate hemophilia A patients, sufficiently high factor VIII activity levels can be reached in most patients by administering desmopressin, an analogue to the diuretic hormone vasopressin.
This agent has not only the benefit of having no risk of viral transmission but it can also be provided to the patient intranasally. The factor VIII inhibitor titer vary greatly between patients. The titer is expressed in so called Bethesda units, defined by the use of a specified test system see below and may vary between 0. Patients are classified as high or low responders and it has recently been decided to use the term high responder for a patient who at any time presents with an antibody titer above 5 Bethesda units whereas patients who persistently have below 5 Bethesda units in spite of repeated treatments with factor VIII concentrates are denoted low responders.
Does the type of mutation affect the risk of developing factor VIII inhibitors? Yes, apparently patients with large deletions and nonsense mutations or gene inversions develop inhibitors to a larger extent than those with frameshift or missense mutations.
It also seems that the greatest risk of raising inhibitors is during the initial treatment. Does the type of factor VIII concentrate affect the development of inhibitors? Generally no, although it has been reported that modification of a concentrate during manufacturing resulted in antibody development in a patient.
On the other hand the type of concentrate to choose for treatment may play a role. Thus, if a patient has developed antibodies against the light chain of factor VIII, it may be preferable to administer a concentrate which is rich in vWF, since factor VIII then appears to be more slowly neutralized and hence more efficient.
Since, understandably, high responding patients may meet with life-threatening conditions, other treatment regimes have been developed. Thus, a high dosage of porcine factor VIII concentrate may be successfully used, although usually a patient can not receive many infusions until new antibodies appear. Another avenue is to use immunosuppression therapy in combination with extracorporeal adsorption of IgG and administration of factor VIII.
A third treatment regime with quite successful results with rapid achievement of normal hemostasis in many instances is infusion of recombinant factor VIIa. This will probably gain increasing use in the future. Cost is a prime issue in the treatment of hemophilia and it is a main obstacle in providing proper treatment worldwide. For patients with inhibitors the cost is approximately four-fold higher.
Thus the prospects of bringing efficient, modern treatment into global use are very meager and, sadly, in many countries transfusions of blood or plasma is the only option available, if at all. Since only minute amounts of factor VIII have to be present in plasma to warrant a proper hemostasis, great efforts are made in gene therapy research. The real challenge, apart from important safety issues, is to achieve a sustained production of factor VIII at a low level.
The first attempts were made in the early 90s and now a number of different approaches are being explored, including retroviral, adenoviral and non-viral gene deliveries and utilizing different target cells. Progress is being made and it seems possible that gene therapy may be available within a decade. It has been known since long that arterial thrombosis is a multifactorial disease and this has later been shown to be true also for venous thrombosis. Thus, combined abnormalities of factor V:Q factor V Leiden and inherited deficiency of either of antithrombin, protein C or protein S results in a significantly higher incidence of venous thrombosis.
Abnormalities of other plasma components are also being investigated as possible risk factors for thrombosis, such as hyperhomocysteinemia, dysfibrinogemia, factor XII deficiency, thrombomodulin mutants and elevated factor VIII activity. From a prevalence point of view, hyperhomocysteinemia and elevated factor VIII seem most important and much data have now accumulated on elevated factor VIII levels as an important risk factor.
In a prospective study indicated factor VIII to be a risk factor for arterial disease5 and other studies also suggested association of elevated factor VIII with both cardiac and cerebral vascular disease and increased morbidity or earlier fatal outcome. This has later been supported also in other studies, as well as by an experimental study in mice with controlled mild carotid artery injury and who received infusion of factor VIII, which study suggested a direct thrombogenic role for factor VIII.
In elevated factor VIII activity was found to be quite frequent also in patients with venous thrombosis and this was later confirmed in other studies. Thus, elevated factor VIII activity has been shown to be an independent, higly prevalent risk factor with an odds ratio of up to 6 and it is recommended to be included in the laboratory screening test panel on analysis of plasma from thrombotic patients. Persistence of high factor VIII activity upon repeated determinations. A comparison of results from a second determination of factor VIII activity made between 3 months and 4 years after the first determination in patients with venous thromboembolism.
There was also a close correlation to factor VIII antigen, demonstrating that there was an increased synthesis of the factor VIII protein and thus the rise in activity is not due to generation and circulation of activated factor VIII. However, factor VIII is an acute phase reactant and there were, quite understandable, early doubts as to whether elevated factor VIII levels has any causal role but perhaps rather were an effect of the disease.
Thus, elevated levels are associated with conditions such as trauma, infection and exercise and, in common to many other coagulation factors, factor VIII activity is also increased during pregnancy.
It was shown, however, that elevated factor VIII activities were not linked to any acute response and that they were indeed persistent with similarly high levels demonstrated upon repeated analysis after 3 months to 4 years.
Furthermore, heritability for elevated factor VIII activity has been demonstrated which remained after adjustment for blood group and vWF but so far no polymorphism of the factor VIII gene promoter has been found.
The search for a genetic contribution is actively pursued, though, and it should be expected that our knowledge in this field is expanded within the next few years.
In addition to an inheritance for elevated factor VIII activity, there may possibly also be an association with cytomegalovirus infection, which seem to be linked with high factor VIII levels and with thrombosis. In conclusion, there is now a substantial amount of data which points to a causal role for elevated factor VIII activity and at least venous thrombosis and it should be expected that analysis of factor VIII activity will be increasingly introduced in routine laboratory investigations of thrombotic patients.
The so far most widely used method for factor VIII activity determination in plasma is the one-stage clotting method which is based upon the activated partial thromboplastin time APTT and using congenital severe hemophilia A plasma or artificially prepared factor VIII deficiency plasma as a substrate.
In the assay system, phospholipids are added to citrated plasma along with a negatively charged surface activator, e. Upon addition of calcium ions, factor IX is activated by factor XIa and factor Xa is then generated by the tenase complex intrinsic system , in which factor VIII serves as a cofactor, and the time for fibrin clot formation due to cleavage of fibrinogen by generated thrombin is recorded.
A standard curve is constructed from assaying different dilutions of a normal plasma with a known factor VIII activity and it is most common to express the results in a double logarithmic plot with log factor VIII activity vs log clotting time. The factor VIII activities of assayed plasma samples are then derived from the standard curve.
The importance of optimizing the contact activation step was realized in the early 60s and the one-stage method has remained essentially unchanged since then, but for the use of mixtures of purified well-defined phospholipids as an alternative to crude phospholipid extracts from brain or soybean. The one-stage method has the advantage of being rapid and easy to perform.
At the same time it must be realized that the assay is deceptively simple since it indeed comprises a complex biochemical system with a short total reaction time and there are built-in shortcomings such as a great sensitivity to preactivated clotting factors which will result in overestimation of factor VIII activity and furthermore Lupus anticoagulants will interfere.
Some of this variability could be explained by improper standardization and less satisfactory instrument performance. With the introduction of international standards of plasma and factor VIII concentrate and with the increasing use of automated coagulation instruments, the situation has improved but there is still a considerable variability which probably can be explained by the use of different sources of phospholipid, contact activator and factor VIII deficiency plasma.
It is also possible that the increasing use of prophylaxis for severe hemophilia A patients will limit the availability of congenital factor VIII deficiency plasma and therefore the quality of artifically prepared factor VIII deficiency plasma may be of increasing importance. This method was also developed in the 50s and it is based upon a first step whereby activated factors V and X are generated in an amount which is related to the sample factor VIII activity.
In a second step, prothrombin and fibrinogen are added, usually in the form of normal plasma, and the clotting time is recorded. This method makes no use of factor VIII deficiency plasma. It is claimed to show a better precision in general and also to be more sensitive than the onestage method. These properties resulted in the two-stage method being selected as the reference method for determination of the factor VIII potency of factor VIII concentrates for several decades.
Full length external icon. Skip directly to site content Skip directly to page options Skip directly to A-Z link. Section Navigation. Facebook Twitter LinkedIn Syndicate. Treatment of Hemophilia. Minus Related Pages. Treatment Centers.
Information For…. Links with this icon indicate that you are leaving the CDC website. Linking to a non-federal website does not constitute an endorsement by CDC or any of its employees of the sponsors or the information and products presented on the website. You will be subject to the destination website's privacy policy when you follow the link. Doses are rounded UP to the nearest vial size.
There are standard and extended half life products Standard half life factor VIII products have a half life of approximately hours Extended half life factor VIII products have an increase in half life between 1. Does NOT contain von Willebrand Factor and is not indicated for the treatment of bleeding in von Willebrand's disease.
Used to treat bleeding episodes and prevent surgical bleeding in patients with von Willebrands disease. There are standard and extended half life products Standard half life factor IX products have a half life of approximately hours Extended half life factor IX products have an increase in half life between 3 to 5 times that of standard half life FIX products.
The product of choice for the prevention and treatment of bleeding associated with Haemophilia B Factor IX deficiency. Indicated and licensed for the treatment of bleeding episodes in haemophilia patients with inhibitors antibodies to factors VIII or IX. The half life of activated Factor VII is 2 hours. After reconstitution with the supplied diluent each vial contains 1.
Do not mix with other intravenous solutions or medications. Administer as close to the IV cannula as possible. Flush with Sodium Chloride 0. Do not shake, draw into syringe slowly. These look for antibodies in the blood that could deactivate factor VIII. You may also have a von Willebrand factor test. The von Willebrand factor is a protein that "glues" platelets together to help form a clot.
It protects factor VIII from breaking down. If you are female and have a family history of hemophilia, your healthcare provider may order molecular genetic testing to find out whether you are a carrier.
Test results may vary depending on your age, gender, health history, the method used for the test, and other things. Your test results may not mean you have a problem.
Ask your healthcare provider what your test results mean for you. If you have bleeding problems with normal to decreased level of factor VIII, you may have von Willebrand disease. Your healthcare provider will look at your factor VIII test result along with the results of other tests to better understand what the results mean. The test is done with a blood sample. A needle is used to draw blood from a vein in your arm or hand.
0コメント