Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
1998-12-11
2003-03-11
Low, Christopher S. F. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C530S380000, C530S382000, C530S383000, C530S384000, C514S012200
Reexamination Certificate
active
06531577
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a high-purity von Willebrand factor (vWF) preparation as well as to a process for making such preparation. The invention further relates to the use of such preparation for the treatment of bleeding disorders and to a pharmaceutical composition comprising such preparation and suitable for treating these disorders. In a further aspect, the present invention relates to a method for treating bleeding disorders. The bleeding disorder may suitably be von Willebrand's Disease (vWD), haemophilia A induced by vWF-dependent FVIII deficiency or haemophilia A not induced by such deficiency.
BACKGROUND OF THE INVENTION
vWF is an adhesive glycoprotein synthesised by megakaryocytes and endothelial cells. vWF circulates in plasma as an array of multimers of increasing size, from. the protomers of approximately 500 kD to the largest multimers having a molecular weight of approximately 20,000 kD. Each protomer of 500 kD is made up of two identical monomeric subunits and is therefore also referred to as dimer. The multimers are made up of repeating units of protomers. vWF plays an important role in normal haemostasis due to two main functions. Firstly, vWF is essential to coagulation due to its ability to serve as a carrier of coagulation factor VIII (FVIII), which is a plasma protein that participates in the intrinsic pathway of blood coagulation. The formation of such complexes protects FVIII from proteolytic inactivation. Secondly, vWF contributes, through different mechanisms, to platelet adhesion and aggregation.
Disturbances in blood plasma level of vWF and/or FVIII lead to very serious, sometimes life-threatening, bleeding disorders.
von Willebrand's Disease (vWD) is an autosomal inherited bleeding disorder, the onset of which is due to deficiency and/or abnormality of vWF. As a consequence, FVIII coagulant activity (FVIII:C) is often reduced, since, as mentioned above, vWF serves as a carrier of FVIII. The relevance of vWF for platelet adhesion to the damaged endothelium is reflected by the fact that patients with vWD also often have prolonged skin bleeding time.
vWD is the most common inherited bleeding disorder. It has been demonstrated that its prevalence in the general population is at least 0.8%, and a multiethnic paediatric survey (made in 1993) in the US has given a figure of 1.3%, confirming that the disease has no racial differences and is distributed world-wide.
Epistaxis, bleeding after dental extraction and menorrhagia are the most prominent symptoms, being present in about 60% of the affected patients. Often, bleeding symptoms lessen with age in patients with a mild form of the disease. Epistaxis is very frequent during childhood. Menorrhagia is the most frequent clinical problem in women with vWD, often requiring the combination of oral contraceptive pill and iron supplementation. In patients with classical vWF deficiencies, postpartum bleeding is not often encountered since vWF level usually increases during pregnancy, whereas patients with the variant forms usually require peripartum replacement therapy. Patients with severe disease may experience muscular or joint bleeding because of the concomitant markedly reduced FVIII levels. Furthermore, bleeding after surgery may be life-threatening.
Three main types of vWD have been identified. Type 1, with classical autosomal dominant inheritance, accounting for about 70% to 80% of cases, is characterised by equally low FVIII/vWF measurement, with no evidence of structural abnormality on multimeric analysis. Type 2 is usually characterised by the lack of large multimers and abnormally low levels of vWF:RCo in comparison with VWF:Ag. In this group, several subtypes, sometimes with recessive inheritance, have been observed. The phenotypes of type 2 is classified as A (patients with the absence of high molecular weight vWF-multimers and decreased platelet-dependent function), B (patients with hyperresponsiveness to ristocetin), M (patients with qualitative variants with decreased platelet-dependent function but with high molecular weight multimers present) and N (patients with defective FVIII-VWF binding). Type 3 is recessively transmitted and patients have very low or undetectable levels in all FVIII/vWF measurements.
vWF deficiency may also lead to phenotypical haemophilia A as vWF is essential for the function of FVIII. In these cases, the half-life of FVIII is decreased. Thus, patients suffering from vWD do often also suffer from FVIII deficiency. The reduced FVIII activity is not a result of a gene defect, but rather an indirect consequence of the vWF deviation. Normally, decreased ristocetin-cofactor activity and vWF antigen level are observed in vWD patients, whereas this is not the case in haemophilia A patients.
Haemophilia A is caused by partial or complete lack of the important coagulation protein FVIII, which circulates in the plasma completed with vWF, in the patient's blood. The disease is inherited in a X-chromosome recessive pattern, and therefore it mainly affects males, but heterozygous females are asymptomatic carriers of the disease. The FVIII gene has been located to the long arm of the X-chromosome.
The coagulation process is an enzymatic cascade reaction enrolling intricate feedback activating and inactivating mechanisms. Most of the activated enzymes of the cascade require co-factors to be efficient, and some of these co-factors are plasma proteins which exist in both an active and an inactive form. Coagulation FVIII is one of such co-factors. In haemophilia A patients, a delayed clot formation is observed leading to excessive bleeding and poor wound healing. Haemorrhagic episodes in patients with haemophilia A can be managed by substituting FVIII.
The main symptoms of haemophilia A are excessive and prolonged bleeding. In severe haemophilia (less than 1% FVIII present), the most common sites of bleeding are in the large joints of the limps and in the large muscles. Unless such bleeding is controlled promptly by infusion of FVIII, the main chronic complications of haemophilia, namely arthropathy and muscle atrophy will occur. In mild haemophilia A (5-40% FVIII present), bleeding usually does not occur except after trauma. Moderately severe haemophilia A (1-5% FVIII present) has clinical features in between severe and mild haemophilia A and may show the largest individual variation.
In vWD, the main goal of treatment is to correct the bleeding time and FVIII defects. This is conventionally accomplished by administering the synthetic drug desmopressin (DDAVP) or by replacement therapy with FVIII/vWF preparations.
However, some patients with vWD do not respond to DDAVP treatment. Furthermore, patients initially responsive to DDAVP treatment may become refractory, when repeated infusions are given to maintain hemostasis over long periods of time. In these situations, the most commonly used treatment is replacement therapy with blood products such as cryoprecipitates or other concentrates prepared from plasma.
Cryoprecipitates are vWF-rich preparations obtained by thawing frozen blood plasma to 2-4° C. and isolating the non-dissolved fraction. However, treatment with cryoprecipitates has been shown not to be sufficiently effective as correction of the bleeding time was only obtained in 24% of the cases, only partially in 36% of the cases, whereas no effect was observed in 40% of the cases (see Ref. 1). Furthermore, there is a high risk of transmitting life-threatening blood-borne viruses such as HIV and hepatitis viruses since virucidal methods cannot be applied directly to the cryoprecipitates normally used. Another disadvantage is the high content of fibrinogen and anti-A and anti-B agglutinins in these preparations, the presence of which may lead to hyper-fibrinogenaemia and anaphylactic reactions in patients with blood types A or B. Furthermore, due to the low concentration of vWF in this type of preparations, large volumes of fluid must be infused, and repeated infusions over time entail exposure to a large number of different donors ther
Barington Karina Alsoe
Kaersgaard Per
Darby & Darby
Hemasure Denmark A/S
Low Christopher S. F.
Lukton David
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