There are fascinating interactions between the components of the tenase system and of the protein C anticoagulant system which affect the rate of inactivation of factor VIIIa. However, protein S abrogates the protecting effect of factor X and, in the absence of factor IXa, also stimulates the rate of cleavage at considerably.
Corresponding regulatory roles for factor Xa and protein S have also been demonstrated for the APC-dependent inactivation of factor V. Some data indicate that inactivation of factor Va is the crucial effect of APC and it has also been shown in mutagenesis studies that both APC cleavage sites had to be blocked before a significant impairment of the rate of thrombin generation was registered in an APTT-based method and that indeed the major inactivation of factor VIIIa may be caused by dissociation of the A2 subunit.
Hemophilia A is a serious bleeding disorder which is caused by a deficiency or complete absence of factor VIII activity which affects about 1 in males and its prevalence show no ethnic differences. The obvious bleeding symptoms mean that this disorder, initially named haemorraphilia love of bleeding can be traced back to very early observations and in the disease was described as a protein disorder.
Within only a few years later the first blood transfusion was administered to a patient for treatment of his bleeding. Since then tremendous progress has been made in the treatment of hemophilia patients who nowadays in many cases in the Western countries receive highly purified plasma factor VIII or recombinant factor VIII concentrates with a minimal risk of transmittance of viral infections.
Depending on the factor VIII activity, which is related to the bleeding severity, hemophilia A is classified according to the table above. These levels are normal in hemophilia patients. Severe hemophilia A patients typically meet with bleedings in joints and muscles and sustained and dangerous bleedings after trauma and surgery and these patients may, unless treated, develop permanent disability. In moderate or mild hemophilia A bleeding episodes are more rare and occur usually in connection with trauma or surgery.
The only available treatments for hemophilia A patients for many decades were whole blood or plasma but this was often not sufficient to rapidly achieve proper hemostasis. This preparation was also rapidly introduced for treatment of hemophilia A patients.
After this pioneering work a further important step forward was the discovery that factor VIII is recovered in plasma cryoprecipitate, which allowed an effective replacement therapy. Still, though, the specific activity was low, about 0. The next step forward in purification was the introduction in the late 70s of immunoaffinity purification of factor VIII by using matrix-bound antibodies against vWF and elution of factor VIII with calcium ions.
Much lower doses are used for prophylaxis, whereby the target factor VIII levels are above 0. The availability and introduction of factor VIII concentrates for treatment of acute bleedings and for prophylaxis has had a dramatic improvement of the life expectancy of severe hemophilia A patients. Thus, until the end of the 50s, the median life expectancy of such patients in Sweden was still only about years, whereas it had increased to about 57 years twenty years later and is now about 70 years at the entry of the 21st century.
In parallel, the development and progression of joint disease has decreased significantly. The use of blood products is connected with a risk of viral transmission such as hepatitis B and C, and many hemophiliacs developed chronic liver disease but the great benefits of the therapy was considered to justify the treatment.
This was a tragedy not only to the patients and their families but certainly also to all clinicians and other medical staff who showed a great engagement and commitment to good hemophilia care. Development of concentrates with maximal safety against viral transmission was made by two routes, which luckily has resulted in no new HIV infections of hemophilia patients.
One route was through introduction of extensive heat treatment or use of solvent-detergent treatment of plasma derived factor VIII concentrates, the other through the development of recombinant factor VIII concentrates. 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. Gene expression data and calculations. S2 Dataset. Correlation coefficients data. S3 Dataset. S4 Dataset.
S5 Dataset. S6 Dataset. S7 Dataset. Intensity data of fibroblasts after fluorescent immunostaining. S8 Dataset. S1 Fig. S2 Fig. S3 Fig. S4 Fig. S1 Table. S2 Table. Alexa Fluor AF -labeled secondary antibodies. S3 Table. Threshold cycle numbers for each cell type. S4 Table. Comparison of mRNA copy numbers. S5 Table. Fluorescent intensities of fibroblasts stained with secondary detection antibodies with and without primary antibodies to VWF. References 1. Acta Naturae.
The light chain of factor VIII comprises a binding site for low density lipoprotein receptor-related protein. J Biol Chem. The life cycle of coagulation factor VIII in view of its structure and function. Role of the low density lipoprotein-related protein receptor in mediation of factor VIII catabolism. New cytoplasmic components in arterial endothelia.
J Cell Biol. ADAMTS rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions. The physiological function of von Willebrand's factor depends on its tubular storage in endothelial Weibel-Palade bodies.
Dev Cell. FVIII production by human lung microvascular endothelial cells. Human liver sinusoidal endothelial cells but not hepatocytes contain factor VIII. J Thromb Haemost. Activation of human endothelial cells from specific vascular beds induces the release of a FVIII storage pool. Endothelial cell processing and alternatively spliced transcripts of factor VIII: potential implications for coagulation cascades and pulmonary hypertension. PLoS One. Mannucci PM. J Pediatr Hematol Oncol. Pediatr Blood Cancer.
Expression of factor VIII by murine liver sinusoidal endothelial cells. Murine coagulation factor VIII is synthesized in endothelial cells. A conditional knockout mouse model reveals endothelial cells as the principal and possibly exclusive source of plasma factor VIII. Turner NA, Moake J. Factors IXa and VIII and X appear to form a functional complex, all of which need to be present and active simultaneously for optimal activation of factor X.
The mechanism by which factor VIII promotes activation of factor X by factor IXa is not known, but the major effect is to increase the rate of the reaction. It is not known whether limited proteolytic cleavage is required absolutely for the expression of factor VIII activity or if it only increases an activity already expressed by the uncleaved protein. More than 1, alterations in this gene have been identified. Some of these mutations change single DNA building blocks base pairs in the gene, while others delete or insert multiple base pairs.
The most common mutation in people with severe hemophilia A is a rearrangement of genetic material called an inversion. This inversion involves a large segment of the F8 gene. Mutations in the F8 gene lead to the production of an abnormal version of coagulation factor VIII or reduce the amount of this protein.
The altered or missing protein cannot participate effectively in the blood clotting process. As a result, blood clots cannot form properly in response to injury. These problems with blood clotting lead to excessive bleeding that can be difficult to control. Some mutations, such as the large inversion described above, almost completely eliminate the activity of coagulation factor VIII and result in severe hemophilia.
Other mutations reduce but do not eliminate the protein's activity, resulting in mild or moderate hemophilia.
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