Pharmacokinetics, efficacy and safety of Humate‐P<sup>®</sup> in von Willebrand disease

Dobrkovská, Alena; Krzensk, Udo; Chediak, Juan

doi:10.1046/j.1365-2516.1998.0040s3033.x

Cited by 93 publications

(140 citation statements)

References 29 publications

(35 reference statements)

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“…The MRT was calculated to be 2.8 h. In this respect, human VWF is cleared from the murine circulation to the same extent as reported previously for human VWF in rats (22). The half-lives of VWF in these rodents are considerably shorter compared with the half-life of VWF in humans, which is ϳ14 h (36,37). Similar differences in the clearance rate between species have been reported for numerous other proteins, including coagulation factor IX.…”

Section: Table II Affinity Constants For the Interactions Between Vwfsupporting

confidence: 54%

An Experimental Model to Study the in Vivo Survival of von Willebrand Factor

Lenting

Westein

Terraube

et al. 2004

Journal of Biological Chemistry

135

189

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To explore the molecular basis of von Willebrand factor (VWF) clearance, an experimental model employing VWF-deficient mice was developed. Biodistribution was examined by the injection of radiolabeled VWF, which was primarily directed to the liver with minor amounts in other organs. Disappearance of VWF from plasma was characterized by a rapid initial phase (t1 ⁄2 ␣ ‫؍‬ 13 min) and a slow secondary phase (t1 ⁄2 ␤ ‫؍‬ 3 h), with a mean residence time (MRT) of 2.8 h. A similar clearance was observed for VWF consisting of only high or low molecular weight multimers, indicating that, in our experimental model, clearance is independent of multimeric distribution. This allowed us to compare the survival of fulllength VWF to truncated variants. Deletion of both the amino-terminal D -D3 and carboxyl-terminal D4-CK domains resulted in a fragment with a similar clearance to wild-type VWF. Deletion of only the D -D3 region was associated with an almost 2-fold lower recovery and increased clearance (MRT ‫؍‬ 1.6 h), whereas deletion of only the D4-CK region resulted in a significantly reduced clearance (MRT ‫؍‬ 4.5 h, p < 0.02). These results point to a role of the D -D3 region in preventing clearance of VWF. Furthermore, replacement of D3 domain residue Arg-1205 by His resulted in a markedly increased clearance (MRT ‫؍‬ 0.3 h; p ‫؍‬ 0.004). Therefore, this mutation seems to abrogate the protective effect of the D -D3 region. In vitro analysis of this mutant also revealed a 2-fold reduced affinity for VWF propeptide at low pH, showing that mutation of Arg-1205 results not only in an increased clearance rate but is also associated with an impaired pH-dependent interaction with VWF propeptide.von Willebrand factor (VWF) 1 is a multimeric plasma protein that participates in the hemostatic process. The absence of functional VWF is associated with an abnormal bleeding tendency known as von Willebrand Disease (VWD) (1, 2). VWF contributes to hemostasis in a dual manner. First, it promotes the adhesion of platelets at sites of vascular injury by acting as a molecular bridge between the sub-endothelial collagen matrix and the platelet-surface receptor complex glycoprotein (Gp) Ib␣/IX/V (3). In addition, VWF serves as a carrier protein for coagulation factor VIII (FVIII) in the circulation. This chaperone function results in stabilization of the FVIII heterodimeric structure (4) and protection of FVIII from premature clearance by the low density lipoprotein receptor-related protein (5, 6).VWF is produced and stored in endothelial cells and megakaryocytes. It is synthesized as pre-pro-VWF, a single chain polypeptide with the domain structure

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Section: Table II Affinity Constants For the Interactions Between Vwfsupporting

confidence: 54%

An Experimental Model to Study the in Vivo Survival of von Willebrand Factor

Lenting

Westein

Terraube

et al. 2004

Journal of Biological Chemistry

135

189

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“…5 Haemate ® P/Humate ® P, a pasteurized plasma-derived VWF/FVIII concentrate widely used in VWD, is characterized by a very high content of VWF (VWF:RCo IU, 2.4 for each IU of FVIII:C) with a relatively high percentage of large molecular weight VWF multimers. [6][7][8] Haemate ® P has also had an excellent safety record with regards to blood-borne infections over the past 25 years of clinical use. [9][10][11][12] Clinical efficacy data were collected for Haemate ® P through a large retrospective study organized by the Canadian Hemophilia Centers.…”

mentioning

confidence: 99%

Clinical use of Haemate(R) P in inherited von Willebrand's disease: a cohort study on 100 Italian patients

Federici¹,

Castaman²,

Franchini³

et al. 2007

Haematologica

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“…9 Haemate P has demonstrated a good safety record in clinical practice. [10][11][12] The Importance of Pharmacokinetics…”

Section: Managing Von Willebrand Diseasementioning

confidence: 99%

“…9 Haemate P has demonstrated a good safety record in clinical practice. [10][11][12] The Importance of PharmacokineticsThe pharmacokinetic profiles of the various concentrates are important considerations in the treatment of vWD. Although they are all considered members of the same drug class, it is important to note that they are not equivalent products for the treatment of vWD.…”

mentioning

confidence: 99%

Importance of Pharmacokinetics in the Treatment of von Willebrand Disease

Kessler¹

2007

European Oncology &Amp; Haematology

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von Willebrand disease (vWD) and haemophilia A are the most frequent bleeding disorders in the general population, occurring in 66-100 people per million worldwide. 1 vWD is caused by both qualitative and quantitative defects in von Willebrand factor (vWF) resulting in a dual defect in haemostasis, i.e. the abnormal platelet adhesion due to reduced and/or dysfunctional vWF (primary haemostasis) and the abnormal coagulation due to low levels of factor VIII (FVIII) (secondary haemostasis).vWF serves as a bridge between platelets and subendothelium and is essential for the cohesion of platelets. Thus, vWF has a primary function in the formation of thrombi in blood coagulation. In addition, vWF binds to circulating FVIII and acts as a chaperone, protecting FVIII from proteolytic degradation. In the absence of or after a decrease in vWF, the half-life of FVIII in the circulation is reduced significantly. 2 However, the absence of vWF does not affect FVIII synthesis. Classification of von Willebrand DiseaseSince vWD is caused by both qualitative and quantitative mutations in vWF, the disease is classified according to the degree of qualitative and quantitative involvement (see Table 1). 3 Patients with type 1 vWD present with a decrease in the production of vWF and most remain mildly symptomatic. Type 2 vWD is the result of a vWF-dependent platelet function. 4,5 Type 3 vWD is the least common subtype and results from absent or profound reductions in plasma vWF and the absence of vWF in platelets and endothelial cells. In general, type 3 vWD is diagnosed in the first year of life due to severe and sometimes life-threatening bleeds. Managing von Willebrand DiseaseThe treatment options for vWD are dependent on the subtype of the disease.The main goal of treatment is to normalise the levels of both vWF and FVIII to achieve haemostasis. 6 Demopressin (DDAVP) is the gold standard for the treatment of type 1 vWD. DDAVP induces the release of endogenous vWF and helps to correct vWF/FVIII levels in the majority of these patients.However, DDAVP is not effective in type 3 vWD or in severe forms of types 1 and 2 vWD. Also, DDAVP is not recommended in patients with type 2A vWD because any increase in vWF is dysfunctional. 7 In patients with type 2B vWD, DDAVP can induce transient thrombocytopenia, thus it is generally contraindicated. 8 In patients in whom DDAVP either is not effective or is contraindicated, the current treatment option of choice is transfusional therapy with virally inactivated plasma-derived FVIII/vWF concentrates. Since the 1980s, plasma-derived FVIII/vWF concentrates have been used successfully to treat types 3 and 2B vWD patients and types 1 and 2 patients who are unresponsive to DDAVP. 9 Currently, recombinant-concentratecontaining vWF is unavailable, and the majority of products are intermediatepurity plasma-derived FVIII concentrates containing vWF. Approved in 1981, Haemate P has become the most widely used concentrate in vWD. 9 Haemate P has demonstrated a good safety record in clinical practice. [10][11...

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Pharmacokinetics, efficacy and safety of Humate‐P^® in von Willebrand disease

Cited by 93 publications

References 29 publications

An Experimental Model to Study the in Vivo Survival of von Willebrand Factor

An Experimental Model to Study the in Vivo Survival of von Willebrand Factor

Clinical use of Haemate(R) P in inherited von Willebrand's disease: a cohort study on 100 Italian patients

Importance of Pharmacokinetics in the Treatment of von Willebrand Disease

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Pharmacokinetics, efficacy and safety of Humate‐P® in von Willebrand disease

Cited by 93 publications

References 29 publications

An Experimental Model to Study the in Vivo Survival of von Willebrand Factor

An Experimental Model to Study the in Vivo Survival of von Willebrand Factor

Clinical use of Haemate(R) P in inherited von Willebrand's disease: a cohort study on 100 Italian patients

Importance of Pharmacokinetics in the Treatment of von Willebrand Disease

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Pharmacokinetics, efficacy and safety of Humate‐P^® in von Willebrand disease