Optimizing therapy with factor VIII/von Willebrand factor concentrates in von Willebrand disease

In von Willebrand disease, the main goals of treatment are to correct the dual defect of haemostasis caused by a reduced or abnormal von Willebrand factor (vWF), i.e. the prolonged bleeding time (BT) and the deficiency of factor VIII coagulant activity (FVIII:C). The synthetic vasopressin analogue, desmopressin (DDAVP), has reduced the need for transfusions in most of the mild forms of von Willebrand disease but DDAVP is ineffective in type 3 and in other severe cases of types 1 and 2 von Willebrand disease. For many years cryoprecipitate has been the mainstay of replacement therapy but, after the introduction of virucidal methods, concentrates containing FVIII/vWF have been considered much safer than cryoprecipitate and proposed in von Willebrand disease management. FVIII/vWF concentrates have been produced and tested by many authors but there is only one report describing four virus-inactivated FVIII/vWF concentrates evaluated in a cross-over randomized trial. According to these in vitro and pharmacokinetic data, the following information can be derived: (a) no FVIII/vWF concentrate had an intact multimeric structure similar to that of normal plasma or of cryoprecipitate; (b) all FVIII/vWF concentrates were equally effective in attaining normal and sustained levels of FVIII:C postinfusion, although peak levels were more delayed in the concentrate devoid of FVIII:C; (c) no FVIII/vWF concentrate consistently normalized the BT in a sustained fashion. On the other hand, clinical haemostasis can be achieved in the management of bleeding episodes and of surgery for most of von Willebrand disease cases regardless of whether the BT is corrected; in the few rare cases with mucosal bleeding not controlled by FVIII/vWF concentrates, infusion of DDAVP or platelet concentrates can be administered in addition.     

Diagnosis and management of von Willebrand disease

von Willebrand disease (vWD) is a bleeding disorder caused by quantitative or qualitative defects of von Willebrand factor (vWF). The diagnosis is based on measurements of plasma and platelet vWF, the ability of vWF to interact with its platelet receptor and the analysis of the mutlimeric composition of vWF. Due to the heterogeneity of vWF defects, a correct diagnosis of types and subtypes may be sometimes difficult but is very important for an appropriate therapy. The aim of treatment is to correct the dual defects of haemostasis, i.e. abnormal coagulation expressed by low levels of factor VIII (FVIII) and abnormal platelet adhesion expressed by a prolonged bleeding time (BT). Desmopressin is the treatment of choice in patients with type 1 vWD, who account for approximately 80% of cases, because it corrects the FVIII/vWF levels and the prolonged BT in most of these patients. In type 3 and in the majority of type 2 vWD patients, desmopressin is not effective and it is necessary to resort to plasma concen-trates containing FVIII and vWF. Treated with virucidal methods, these concentrates are effective and currently safe, but the BT defect is not always corrected by them. Platelet concentrates or desmopressin can be used as adjunctive treatments when poor correction of the BT after concentrates is associated with continued bleeding.     

von Willebrand factor containing factor VIII concentrates

There are several plasma derived von Wille-brand factors (vWF) containing factor (FVIII) concentrates that can be used in the treatment of von Willebrand disease (vWD). All concentrates are effective in attaining normal postinfusion levels or of FVIII:C but it is difficult to achieve normalization of the bleeding time even with concentrates containing almost all vWF multimers including those of high molecular weight. Haemate P (Centeon) may be considered as the golden standard concentrate available at present. However, the development of more purified vWF concentrates devoid of FVIII:C is the goal for future development.     

Guidelines for the diagnosis and management of von Willebrand disease in Italy

von Willebrand disease (vWD) is a bleeding disorder caused by quantitative (type 1 and 3) or qualitative (type 2) defects of von Willebrand factor (vWF). The molecular basis of type 2 and 3 vWD are now known and those of type 1 vWD are being understood. Phenotypic diagnosis is based on the measurements of plasma and platelet vWF, of the ability of vWF to interact with platelet receptors and the analysis of the multimeric structure of vWF. Due to the heterogeneity of vWF defects and the variables that interfere with vWF levels, a correct diagnosis of types and subtypes may sometimes be difficult but is very important for therapy. The aim of treatment is to correct the dual defects of haemostasis, i.e. abnormal intrinsic coagulation expressed by low levels of factor VIII (FVIII) and abnormal platelet adhesion. Desmopressin is the treatment of choice in patients with type 1 vWD, who account for approximately 70% of cases, because it corrects FVIII-vWF levels and the prolonged bleeding time (BT) in the majority of these patients. In type 3 and in severe forms of type 1 and 2 vWD patients, desmopressin is not effective and it is necessary to resort to plasma concentrates containing FVIII and vWF. Treated with virucidal methods, these concentrates are effective and safe, but they cannot always correct BT defect. Platelet concentrates or desmopressin can be used as adjunctive treatments when poor correction of BT after plasma concentrate treatment is associated with continued bleeding.     

Diagnosis of von Willebrand Disease

The haemorrhagic diathesis in von Willebrand disease (vWD) is caused by a quantitative deficiency or a qualitative defect in the von Willebrand factor (vWF) in plasma and/or platelets causing insufficient primary haemostasis. Since vWF binds and protects factor VIII (FVIII) towards random proteolysis, coagulation may also be impaired in patients with a low plasma level of vWF, and in instances where vWF displays insufficient binding capacity to FVIII. The entity of vWD displays a vast heterogeneity. Apart from rarely occurring acquired cases, vWD is an inherited disorder of autosomal linkage. The major clinical hallmark in vWD is an increased tendency to mucocutaneous bleeding that rarely reach life-threatening proportions, unless vWF is severely reduced or completely absent. Increased bleeding may also occur in sites such as muscles and joints when the level of FVIII is particularly low.
Significant progress has recently been achieved through extensive molecular genetic exploration of various forms of vWD. In order to guide treatment and to form a platform for genetic investigation, however, accuracy in diagnosis and phenotypic characterization is important. By means of various laboratory methods, major subclasses of vWD can be differentiated, as presented in another article of this series. Whereas most of the cases of vWD can quite easily be diagnosed and classified using today's diagnostic methods, the most frequently occurring bleeding disorder of all, vWd type 1 of mild degree, continues to challenge clinicians and diagnostic laboratories. The aim of this paper is to review the laboratory methods most commonly used in diagnostic investigation of the patient suspected of vWD.     

Advances in the therapy of von Willebrand disease

von Willebrand disease (vWD) is a very common autosomal inherited bleeding disorder, caused by a quantitative deficiency or a qualitative structural defect of von Willebrand factor (vWF). Two main therapeutic options are available for the treatment of spontaneous bleeding episodes and for prevention of bleeding: desmopressin (DDAVP) and replacement therapy with plasma products. DDAVP is the treatment of choice for most patients with type 1 vWD. In patients with the type 3 disease and in most subjects with type 2 disease, DDAVP alone is ineffective or contraindicated, and it is usually necessary to switch to plasma concentrates containing both factor VIII (FVIII) and vWF. Concentrates subjected to virucidal treatment (e.g. solvent/detergent treatment) during manufacture should always be used in preference to cryoprecipitate. A recombinant vWF concentrate is now undergoing preclinical development and preliminary data suggest it possesses good haemostatic function and may correct the bleeding in vWD after its administration in several animal models. Although treatment of vWD is relatively simple (assuming access to even basic laboratory facilities), actual diagnosis is often far from straightforward, and the patients should be well characterized phenotypically to tailor the treatment to the different types and subtypes of the disease. It is probably wise to refer samples for the characterization to expert laboratories.     

Haemostatic treatment in connection with surgery in patients with von Willebrand disease

Haemostatic treatment in patients with von Willebrand disease (vWD) in connection with surgery aims at normalizing the haemostatic defect in order to avoid bleeding complications. Factor VIII (FVIII) levels in plasma must be normalized in connection with major surgery, whereas the bleeding time is more important for mucous membrane bleedings. Most patients respond well to treatment with desmopressin which stimulates the endogenous release of FVIII and von Willebrand factor (vWF) and shortens the bleeding time. Non-responders to desmopressin are substituted with a plasma-derived factor concentrate which contains vWF and FVIII. This paper includes a summary of retrospective data from the last 10 years on haemostatic treatment in connection with surgery from four haemophilia centres in Sweden and Denmark on 40 invasive procedures in 27 vWD patients and on one normal delivery. If a FVIII-containing concentrate is given prior to surgery a dose of 30–40 IU VIII:C kg⁻¹ will normalize FVIII levels in most severe cases. If a pure vWF concentrate is used, a dose of 40–50 IU RCoF kg⁻¹ will normalize RCoF in most cases, but FVIII levels will not be normalized until after about 12 h or later. Repeated doses of FVIII-vWF concentrate may lead to very high levels of FVIII in plasma because of the combined effect of the exogenous FVIII-substitution and the endogenous FVIII-release induces by the infused vWF. Dosage should be adjusted according to FVIII levels in plasma.     

Diagnosis of von Willebrand disease

Summary. von Willebrand disease (vWD) is a bleeding disorder caused by quantitative or qualitative defects of von Willebrand factor (vWF). vWF is synthesized by endothelial cells and megakaryocytes and circulates in plasma as a multimeric high molecular weight glycoprotein. vWF plays a major role in the early phases of ostasis by promoting platelet-vessel wall and plateletplatelet interactions under high shear conditions. It is also the carrier of coagulation factor VIII (FVIII) in plasma. A deficiency of vWF results in impairment of both primary and secondary phases of ostasis. Therefore, patients with vWD manifest bleeding symptoms that are typical of defects of primary ostasis (mucocutaneous haemorrhages) but, in case of severe deficiency of vWF, there are also haemarthroses and haematomas, which are typical of those seen with coagulation defects. Several types and subtypes of vWD have been described with a high degree of heterogeneity. The diagnosis is based on measurements of plasma and platelet vWF, the ability of vWF to interact with its platelet receptor and the analysis of the multimeric composition of vWF. Due to the heterogeneity of vWF defects, a correct diagnosis of types and subtypes may be sometimes difficult but is very important for an appropriate treatment of patients with vWD.     

von Willebrand disease: still an intriguing disorder in the era of molecular medicine

von Willebrand disease (vWD) is a single-locus disorder resulting from a deficiency of von Willebrand factor (vWF): a multimeric multifunctional protein involved in platelet adhesion and platelet-to-platelet cohesion in high shear stress vessels, and in protecting from proteolysis and directing circulating factor VIII (FVIII) to the site of injury. vWD is the most frequent bleeding disorder, with an estimated prevalence in the general population of 1%. Almost all these cases are represented by a partial quantitative deficiency of von Willebrand factor (vWF) (type 1 vWD). Type 1 is transmitted as an autosomal dominant trait with an extremely variable penetrance and expressivity. A consensus figure for the prevalence of cases with significant bleeding symptoms, requiring some form of treatment, is approximately 100 cases million-1. Among these cases, more than 70-80% are represented by type 1 and respond to deamino-D-arginine vasopressin (DDAVP; desmopressin) administration. The remaining cases are represented by type 2 vWD (qualitative), some of which require substitutive treatment. Only 3-5 cases million-1 result from a total deficiency of vWF in plasma and platelets because of the recessive inheritance of two defective alleles. These cases may have severe bleeding episodes and may require frequent substitutive treatment. The molecular basis of type 2 (missense mutation in the functional domains of the vWF subunit) and type 3 (nonsense or large deletions) is quite well understood. On the contrary the molecular basis for most type 1 cases remains largely unknown, and many genetic factors (e.g. ABO blood group) and environmental or circumstantial factors (e.g. age, stress, drugs, pregnancy, and inflammation) are superimposed on to the genetic background determined by the vWF gene to produce a continuous spectrum from normality to mild type 1 cases. It is extremely difficult to make a clear distinction between mild type 1 cases and normal people because of the wide 'normal' range of laboratory measurements (e.g. length of bleeding time, and levels of vWF and FVIII) and of bleeding symptoms. Molecular testing is useless in this situation, and only good history-taking and repeated laboratory testing of vWF-related measurements in the propositus and his/her family members can help in clinical diagnosis, albeit imprecisely. This difficult task is the main focus of this review which is aimed at alerting the physician toward a balanced approach that should take into consideration both the risk of over- and under-diagnosis of this frequent disorder and the unavoidable production of a number of false positive and false negative cases.     

Bleeding prophylaxis for major surgery in patients with type 2 von Willebrand disease with an intermediate purity factor VIII-von Willebrand factor concentrate (Haemate-P).

The parameters to diagnose von Willebrand disease (vWD) include factor VIII coagulant activity (FVIII:C), von Willebrand factor antigen (vWF:Ag), von Willebrand factor ristocetin cofactor activity (vWF:RCo), and von Willebrand factor collagen binding activity (vWF:CB). Type 2 vWD is associated with a moderate bleeding diathesis due to low levels of vWF:RCo and vWF:CB as compared with near normal or normal values for FVIII:C and vWF:Ag. As the factor VIII/von Willebrand factor (vWF) concentrate, Haemate-P, is featured by a vWF:RCo/FVIII:C ratio of about 2.2, the recommended loading dose of 50 U/kg FVIII:C followed by 25 U/kg FVIII:C every 12 h for several days for bleeding prophylaxis in type 2 vWD patients undergoing major surgery demonstrated a predicted significant over-treatment reaching vWF:RCo levels above 2 U/ml. Therefore, we restricted Haemate-P substitution for major surgery to one loading dose of 40-50 U/kg FVIII:C (88-110 U/kg vWF:RCo) followed by 15-20 U/kg FVIII:C (33-44 U/kg vWF:RCo) every 12 h for several days and evaluated this strategy in a prospective pharmacokinetic and efficacy study for bleeding prophylaxis in five type 2 vWD patients. Pre-treatment and peak levels (1 h after Haemate-P loading dose) rose from 0.43-0.66 to 1.5-2.5 U/ml for FVIII:C, from 0.23-0.45 to 1.5-2.5 U/ml for vWF:Ag, from 0.10-< 0.20 to 1.5-2.5 U/ml for vWF:RCo, and from < 0.05-0.10 to 1.0-2.0 U/ml for vWF:CB. Mean in vivo recoveries per transfused IU FVIII:C/kg body weight were 3.2% for FVIII:C, 3.9% for vWF:RCo, and 2.8% for vWF:CB. Mean in vivo recoveries per transfused IU vWF:RCo/kg were 1.45% for FVIII:C, 1.7% for vWF:RCo and 1.25% for vWF:CB. The biological half-life times after transfused Haemate-P were about 12 h for both vWF:RCo and vWF:CB. Based on these pharmacokinetic data, we propose to adapt the loading dose factor VIII/vWF concentrate (Haemate-P) to 60-80 U/kg vWF:RCo followed by 30-40 U/kg vWF:RCo every 12 h for no longer than several days (less than 1 week) for bleeding prophylaxis during major surgery or trauma, and to one loading dose of 40-60 U/kg vWF:RCo for minor surgery, trauma or mucotaneous bleedings in patients with type 2 vWD unresponsive to DDAVP.     

Use of ristocetin cofactor activity in the management of von Willebrand disease

von Willebrand disease (vWD), the most common of the hereditary bleeding disorders, arises from quantitative or qualitative defects in von Willebrand factor (vWF). vWF is a multimeric plasma protein that plays a key role in primary and secondary haemostasis. In the current classification scheme, vWD is divided into six subtypes that are based on the nature of the vWF defect. Therapeutic strategies depend on the accurate identification of these subtypes. In most clinical situations, desmopressin is effective treatment for the great majority of patients with mild (type 1) disease, while replacement therapy with factor VIII/vWF concentrates that contain high levels of vWF activity is required for most type 2 and nearly all type 3 vWD patients. Several factor VIII/vWF replacement products are available, one of which (Humate P) has been approved for the treatment of vWD by the US Food and Drug Administration. Preliminary results of recent studies support the hypothesis that treatment with factor VIII/vWF concentrates based upon the content of vWF activity as reflected in the ristocetin cofactor assay is practicable, safe and efficacious. The establishment of optimal treatment regimens with respect to dose intensity and duration will require further study.     

Management of von Willebrand disease: a survey on current clinical practice from the haemophilia centres of North America.

The optimal treatment of patients with von Willebrand's disease (vWD) remains to be defined. Moreover, it has not been firmly established which, if any, commonly measured parameters of von Willebrand factor (vWF) protein in the plasma are useful in guiding treatment. To better understand what guidelines physicians follow in the management of vWD, we surveyed 194 North American physicians who are members of the Hemophilia Research Society. Ninety-nine per cent of responding physicians depend on factor VIII (FVIII):C, vWF:RCo activity and vWF:AG to diagnose vWD, while only 49% use the bleeding time. The minimal goals of treatment for patients undergoing major surgery/trauma or central nervous system haemorrhage were FVIII:C and vWF:RCo activity greater than 80% while levels of more than 50% for minor surgery and dental extractions were considered adequate. Treatment of vWD was based on the type of vWD with type 1 patients being treated most often with desmopressin acetate (DDAVP) alone, types 2A and 2B patients with a combination of DDAVP and a vWF-containing FVIII product, type 3 patients with vWF-containing concentrate. Viral infections, including human immunodeficiency virus, hepatitis A, B and C viruses, and parvovirus have been seen in vWD and the efficacy of viral attenuation processes is a major criterion for the selection of treatment by physicians. Based on this survey, prospective studies need to be designed to address the clinical efficacy, safety and predictive value of laboratory monitoring of patients with vWD.     

Evaluation of recombinant von Willebrand factor in a canine model of von Willebrand disease

Dutch Kooiker dogs with hereditary von Willebrand disease have undetectable levels of von Willebrand factor (vWF), resulting in spontaneous haemorrhage of mucosal surfaces similar to the clinical picture of von Willebrand disease in humans. We used this canine model of von Willebrand disease to study the in vivo effects of a new recombinant von Willebrand factor (rvWF) preparation that contained all species of vWF multimers compared with a rvWF fraction containing only low molecular weight multimers (LMW-rvWF) and with a plasma-derived factor VIII/vWF concentrate (pdvWF). Administration of rvWF in these vWF-deficient dogs resulted in a vWF:Ag half-life of 21.6 h in one dog and 22.1 h in a second dog. Administration of pdvWF resulted in a half-life for vWF:Ag of 7.7 h, and LMW-rvWF, 9 h. The in vivo recovery of vWF:Ag after administration of rvWF was 59%, 64% and 70% in three dogs, respectively; 33% after pdvWF, and 92% after LMW-rvWF. The in vivo recovery of ristocetin cofactor (RCoF) was 78%, 110% and 120% for rvWF, and 25% for pdvWF. Both rvWF and pdvWF caused increases in FVIII. Although no effect was seen on bleeding time at the dosages used, the rate of blood flow from cuticle wounds was reduced after a single bolus administration of rvWF. The rvWF was able to control a severe nose bleed in one dog.     

Recombinant von Willebrand factor: Potential Therapeutic Use

Human von Willebrand factor (vWF) produced by recombinant technology offers a new perspective in treatment of von Willebrand disease (vWD). Several limitations connected with plasma-derived vWF concentrates, such as proteolytic degradation during the manufacture process, variation in multimer composition, lack of high molecular weight multimers, and donor dependence, can be overcome by rec-vWF. Recombinant vWF (rec-vWF) is produced by continuous fermentation of transformed mammalian cells. Biotechnological processes have been developed to isolated rec-vWF fractions with low, medium, and high degrees of multimerization. Structural analysis of rec-vWF demonstrated that it undergoes post-translational modifications comparable with plasma-derived vWF, such as multimerization, pro-peptide processing, and glycosylation. Functional analysis showed that rec-vWF exhibited activities comparable with plasma-derived vWF, such as platelet binding, platelet aggregation, collagen binding, and coagulation factor VIII (FVIII) binding. Collagen binding and platelet aggregation activity increased with the increasing multimer size of rec-vWF. Infusion of rec-vWF in antibody-induced vWF-deficient mice resulted in a significant decrease in bleeding. Infusion of rec-vWF in vWF-deficient dogs and pigs with severe vWD caused an increase in the endodenous FVIII level. Stabilization of FVIII in vivo was mediated both by high and low molecular weight rec-vWF molecules. Apparently, rec-vWF resisted proteolytic degradation in the circulation and no satellite bands were formed. Functional analysis in vitro and in vivo demonstrated the therapeutic potentials of rec-vWF, correction of vWF level, and stabilization of FVIII in plasma.     

Pharmacokinetics and hemostatic effect of different factor VIII/von Willebrand factor concentrates in von Willebrand's disease type III

Summary Four different plasma-derived concentrates composed of coagulation factor VIII (FVIII) and von Willebrand factor (vWF) of varying quality (Hemate-P, Behring; Profilate, Alpha; and FVIII-VHP-vWF, C.R.T.S Lille), or almost purified vWF (Facteur Willebrand, C.R.T.S Lille) and one recombinant FVIII concentrate (Recombinate, Baxter) were given, in doses of 30–60 IU VIII:C/kg or 70–110 IU RCof/kg, to five patients with von Willebrand's disease type III, in order to evaluate the role of the vWF in factor FVIII concentrates. All plasma concentrates except Profilate had a multimeric vWF pattern almost similar to that of normal plasma. Bleeding time (b.t.), VIII:C, vWF: Ag, ristocetin cofactor activity, and multimeric pattern of the plasma-vWF were followed for 72 h. Both Duke b.t. and the multimeric pattern in plasma normalized after infusion of Hemate-P, FVIII-VHP-vWF, and Facteur Willebrand and, to a lesser extent, after Profilate. As expected, in response to Recombinate there was no effect on primary hemostasis, and the half-life of FVIII procoagulant activity (VIII:C) was very short. Normalization of the vWF is important not only for improving the primary hemostasis, but also for maintaining the plasma FVIII concentration on a high level, both by reducing the elimination rate of infused FVIII and via a secondary release of endogenous FVIII. If a prompt hemostatic effect is required, we recommend a concentrate containing both FVIII and all vWF multimers, but for prophylactic treatment, pure vWF may be used.     

Population differences in von Willebrand factor levels affect the diagnosis of von Willebrand disease in African-American women

Diagnosis of von Willebrand disease (vWD) is based on a panel of laboratory tests that measure the amount and function of von Willebrand factor (vWF). In population studies, vWF is higher in African Americans than Caucasians. Bleeding time, factor VIII activity (FVIII), vWF antigen (vWF:Ag), "vWF activity" ELISA (vWF:Act), ristocetin cofactor (vWF:RCof), and ristocetin-induced platelet aggregation (RIPA) were measured on 123 women with menorrhagia and 123 randomly selected control women; 70 cases and 76 controls were African American. Among controls, African Americans had significantly higher levels of vWF:Ag (mean 120 vs. 102 U/dl, P = 0.017). Among all subjects, African Americans had higher levels of vWF:Ag (mean 123 vs. 103, P = 0.001), vWF:Act (mean 101 vs. 89, P = 0.006), and FVIII (mean 118 vs. 104, P = 0.008). VWF:RCof did not differ between races (93 vs. 94 U/dl). RIPA was reduced in African Americans (P < 0.0001). In both races, women with type O blood differed significantly from those with other ABO types in vWF:Ag, vWF:Act, FVIII, and vWF:RCof. Based on criteria of two or more tests below race- and ABO-specific reference ranges, 6.5% of menorrhagia cases and 0.8% of controls were classified as having vWD, or its phenocopy. Among Caucasians, no controls and 7 cases (15.6%) were classified as affected, and in African Americans, 1 control (1.3%) and 1 case (1.4%) were so classified. Racial differences in vWF further complicate the issues surrounding diagnosis of vWD. The finding of increased vWF:Ag not accompanied by increased vWF:RCof has implications for understanding the structure-function relationships of vWF. Published 2001 Wiley-Liss, Inc.     

Replacement therapy in platelet-type von Willebrand disease

The response to infusions of cryoprecipitate and factor VIII concentrate was studied in a patient with platelet-type von Willebrand disease (vWD) who showed lack of the large multimers of von Willebrand factor in plasma, increased platelet aggregation with low concentrations of ristocetin, and in vitro platelet aggregation by normal plasma. The cryoprecipitate and factor VIII concentrate to be infused induced platelet aggregation when added to patient platelet-rich plasma at concentrations higher than 0.86 U/ml and 3 U/ml of factor VIII-related antigen (VIIIR:Ag), respectively. Administration of cryoprecipitate (41.9 U VIIIR:Ag/kg body weight) was followed by a shortening of the bleeding time, and hemostasis was achieved during tooth extractions. Factor VIII concentrate (70.2 U VIIIR:Ag/kg) failed to correct the prolonged bleeding time and proved ineffective to control the gum bleeding. No significant diminution of the platelet count was observed following any infusion. These results indicate that cryoprecipitate is hemostatically effective and safe when infused in such a dosage, but factor VIII concentrate is not effective in platelet-type vWD in analogy to what is observed in various types of vWD.     

Patients with severe von Willebrand disease are insensitive to the releasing effect of DDAVP: evidence that the DDAVP-induced increase in plasma factor VIII is not secondary to the increase in plasma von Willebrand factor

Summary It is generally held that factor VIII (FVIII) does not increase in the plasma of severe von Willebrand disease (vWD) patients treated with DDAVP because they lack von Willebrand factor (vWF), which is the plasma carrier for FVIII. To test this hypothesis, FVIII plasma levels were monitored in severe vWD patients treated with DDAVP after normalization of vWF plasma levels with infusions of cryoprecipitate. Each of four severe vWD patients underwent four different treatments at intervals of at least 15 d: (1) cryoprecipitate plus DDAVP; (2) cryoprecipitate plus saline; (3) cryoprecipitate plus recombinant FVIII (rFVIII); (4) saline plus rFVIII. Cryoprecipitate increased the plasma levels of FVIII and vWF. The infusions of saline or DDAVP after cryoprecipitate did not further increase FVIII and vWF plasma levels and had no effect on the plasma levels of tissue plasminogen activator (tPA), which are raised by DDAVP in normal subjects and in patients with vWD of other types. The infusion of rFVIII further increased by 182 ± 32 U/dl (mean ± SEM) the plasma levels attained after cryoprecipitate, which disappeared from the circulation with a half-life of 11.95 ± 0.86 h. In contrast, the infusion of rFVIII after saline increased by only 107 ± 18 U/dl the plasma levels of FVIII, which disappeared from the circulation with a half-life of 2.68 ± 0.14 h, indicating that the vWF infused with cryoprecipitate is able to bind additional FVIII. These studies indicate that DDAVP does not increase the plasma levels of FVIII in patients with severe vWD even after normalization of plasma vWF. The possibility is discussed that severe vWD patients may be insensitive to the releasing effect of DDAVP.     

Role for platelet von Willebrand factor in supporting platelet-vessel wall interactions in von Willebrand disease

Twelve infusions of plasma concentrates of von Willebrand factor (vWF) were given to four patients with severe (type III) von Willebrand disease (vWD). Their prolonged bleeding times were either completely or partially corrected after five infusions and had not changed after the remaining seven. In contrast, the low platelet coverage of the subendothelial surface of rabbit aorta perfused with normal washed platelets and red cells resuspended in preinfusion patient plasma was completely or partially corrected in ten instances by replacing preinfusion plasma with postinfusion plasma and remained unchanged in two. Postinfusion improvement in surface coverage was greater than that in bleeding time, suggesting that vWF from normal platelets is needed to support optimal platelet-vessel wall interactions in vWD. This possibility was further explored through other perfusion experiments. The subendothelial surface covered by platelets from an untreated patient with type III vWD (containing no measurable vWF) or from a type IIA vWD patient (containing dysfunctional vWF) resuspended in normal plasma was much smaller than that covered by normal platelets resuspended in normal plasma. These results establish that platelet vWF is important in supporting platelet-vessel wall interactions in vWD and also provide experimental support in favour of the therapeutic transfusion of normal platelets in addition to vWF concentrates to correct the bleeding time in vWD patients.     

Guidelines for the evaluation of intravenous desmopressin and von Willebrand factor/factor VIII concentrate in the treatment and prophylaxis of bleedings in von Willebrand disease types 1, 2, and 3

The current standard for the diagnosis and management of patients with congenital von Willebrand disease (vWD) includes bleeding times (BTs), PFA-100 closure time (PFA-CT), factor (F) VIII:coagulant activity (C), vWF:antigen (Ag), vWF:ristocetin cofactor activity (RCo), a sensitive vWF:collagen-binding activity (CB), ristocetin-induced platelet aggregation (RIPA), analysis of vWF multimers in low- and high-resolution agarose gels, and the response to desmopressin. Guidelines and recommendations for prophylaxis and treatment of bleedings in vWD patients with vWF/FVIII concentrates should be derived from analysis of the content of these concentrates and from pharmacokinetic studies in different types of vWD patients with severe type 1, 2, or 3 vWD. The vWF/FVIII concentrates should be characterized by labeling with FVIII:C, vWF:RCo, vWF:CB, and vWF multimeric pattern, which will determine their predicted efficacy and safety in prospective management studies. Because the bleeding tendency is moderate in type 2 and severe in type 3 vWD, and because the FVIII:C levels are subnormal in type 2 and very low in type 3 vWD patients, new guidelines using vWF:RCo unit dosing for the prophylaxis and treatment of bleeding episodes are proposed. Such guidelines should be stratified for the severity of bleeding, the type of surgery (either minor or major), and also for the severity and type of vWD (i.e., either type 2 or 3 vWD).