Evaluation of the Abnormal Platelet Function in von Willebrand Disease by the Blood Filtration Test

1996 ◽  
Vol 76 (03) ◽  
pp. 460-468 ◽  
Author(s):  
Francesco I Pareti ◽  
Marco Cattaneo ◽  
Luca Carpinelli ◽  
Maddalena L Zighetti ◽  
Caterina Bressi ◽  
...  
Keyword(s):  
Platelet Function ◽  
Relevant Information ◽  
Von Willebrand Disease ◽  
Type I ◽  
Cumulative Number ◽  
Primary Hemostasis ◽  
Normal Platelet ◽  
Filter Test ◽  
Type 3 ◽  
Von Willebrand

SummaryWe have evaluated platelet function in different subtypes of von Willebrand disease (vWD) by pushing blood through the capillarysized channels of a glass filter. Patients, including those with type IIB vWD, showed lower than normal platelet retention and increased cumulative number of blood drops passing through the filter as a function of time. In contrast, shear-induced platelet aggregation, measured in the cone-and-plate viscometer, was paradoxically increased in type IIB patients. Treatment with l-desamino-8-D-arginine vasopressin (DDAVP) tended to normalize the filter test in patients with type I-platelet normal and type I-platelet low vWD, but infusion of a factor VUI/von Willebrand factor (vWF) concentrate lacking the largest vWF multimers was without effect in type 3 patients. Experiments with specific monoclonal antibodies demonstrated that the A1 and A3 domains of vWF, as well as the glycoproteins Ibα and Ilb-IIIa on platelets, are required for platelet retention in the filter. Thus, the test may reflect vWF function with regard to both platelet adhesion and aggregation under high shear stress, and provide relevant information on mechanisms involved in primary hemostasis.

PRODUCTION OF ANTIBODIES TO HUMAN VON WILLEBRAND FACTOR IN LAYING HENS. ISOLATION OF IMMUNOGLOBULINS AND APPLICATIONS TO THE DETECTION OF MOLECULAR DEFECTS OF VON WILLEBRAND FACTOR

1987 ◽  
Author(s):  
F Toti ◽  
A Stierlé ◽  
M L Wiesel ◽  
A Schwartz ◽  
J M Freyssinet ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Laying Hens ◽  
Protein A ◽  
Von Willebrand Disease ◽  
Primary Hemostasis ◽  
Normal Platelet ◽  
Electrophoretic Patterns ◽  
Egg Yolks ◽  
Von Willebrand ◽  
Willebrand Factor

Von Willebrand disease (vWD) is an inherited disorder of primary hemostasis caused by deficiency or structural abnormalities of von Willebrand factor (vWF). VWF circulates in plasma and is also present in platelets. Plasma vWF, the carrier protein for factor VIII, is a large multimeric glycoprotein composed of identical subunits linked by disulfide bridges. Plasma and platelet vWF display distinct multimeric electrophoretic patterns. The different vWD subtypes can be classified either by the determination of vWFantigen (vWFíAg) and/or by multimer distribution. Antibodies to human vWF were raised in laying hens by intramuscular injections of purified human vWF. Immunoglobulins were isolated from egg yolks by selective polyethylene glycol and ammonium sulfate precipitations. These antibodies appeared to be monospecific, as they did not react with the plasma proteins of a patient with severe vWD. The pullets received weekly 50 μg vWF for 4 weeks and then had monthly injections. The antibodies occurred as early as the third injection, the yield being 300 to 500 mg of immunoglobulin per week (6-7 eggs). The titre could be constant over periods greater than 1 year. These immunoglobulins to vWF were tested in vWFíAg electroimmunoassays and for the multimer analysis of plasma and platelet vWF by electrophoresis and immunoblotting techniques. In no case could a difference be detected between assays performed with rabbit monospecific antiserum or with yolk immunoglobulins to human vWF. Ten to 12 multimers could be revealed for normal plasma vWF and up to 12 to 14 bands for normal platelet vWF (1.7% agarose). In the case of vWD, the electrophoresis patterns were identical with both antibodies. Thus, antibodies to vWF raised in laying hens are a suitable tool to detect and to characterize vWD. Although they do not interact with protein A, yolk antibodies are certainly advantageous to produce, as they do not contain IgM or IgA. Immunoglobulin fractions can contain up to 10 % of specific antibodies. Since they are available in larger quantities and are easy to isolate, larger homogeneous batches of antibodies can be obtained. This method may easily be applied to develop antibodies to a variety of antigens.

Evaluation of the PFA-100® System in the Diagnosis and Therapeutic Monitoring of Patients with von Willebrand Disease

1999 ◽  
Vol 82 (07) ◽  
pp. 35-39 ◽  
Author(s):  
Augusto Federici ◽  
Anna Lecchi ◽  
Barbara Agati ◽  
Rossana Lombardi ◽  
Federica Stabile ◽  
...  
Keyword(s):  
Platelet Function ◽  
Bleeding Time ◽  
Von Willebrand Disease ◽  
Therapeutic Monitoring ◽  
High Shear ◽  
Before And After ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryWe have evaluated platelet function at high shear with the PFA-100® system in different subtypes of von Willebrand disease (vWD), before and after the intravenous infusions of desmopressin or a factor-VIII/von Willebrand factor (vWF) concentrate. Closure times with the PFA-100® system were determined for both the collagen/ADP and the collagen/epinephrine cartridges in 52 patients with vWD (9 type 1 “platelet normal”, 5 type 1 “platelet-discordant”, 8 type 1 “platelet-low”, 6 type 2A, 9 type 2B, 6 type 2M Vicenza, 6 type 3 and 3 acquired vWD) and 40 controls. Measurements were repeated 1 and 4 h after the i.v. infusion of desmopressin (0.3 μg/Kg) in 26 patients with types 1, type 2M Vicenza or type 2A vWD, or of a factorVIII/vWF concentrate (Alphanate HT, 60 U/Kg) in 4 patients with type 3 vWD. At all time points, vWF plasma levels and the bleeding time (Symplate II) were also determined. Baseline closure times were longer in vWD patients than in controls with both the collagen/ADP and the collagen/ epinephrine cartridges. The sensitivity of the PFA-100® system (88% and 87% with the two cartridges) was higher than that of the bleeding time (65%). Treatment with desmopressin normalized the closure times in patients with type 1 “platelet-normal” or type 2M Vicenza vWD, had no significant effects in patients with type 1 “platelet-low”, type 1 “platelet-discordant” or type 2A vWD. Infusion of a factorVIII/vWF concentrate in patients with type 3 vWD slightly shortened their prolonged closure times. In general, changes in PFA-100® were paralleled by shortenings of the bleeding times and increases in plasma vWF levels. The PFA-100® test reflects vWF-dependent platelet function under high shear stress and could be useful in the diagnosis and therapeutic monitoring of patients with vWD.

scholarly journals Heterogeneity of type I von Willebrand disease: evidence for a subgroup with an abnormal von Willebrand factor

Blood ◽  
1985 ◽  
Vol 66 (4) ◽  
pp. 796-802 ◽  
Author(s):  
PM Mannucci ◽  
R Lombardi ◽  
R Bader ◽  
L Vianello ◽  
AB Federici ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Plasma Concentrations ◽  
Sodium Dodecyl ◽  
Von Willebrand Disease ◽  
Type I ◽  
Normal Platelet ◽  
Complete Set ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Factor Antigen

Type I von Willebrand disease (vWD) is characterized by equally low plasma concentrations of von Willebrand factor antigen (vWF:Ag) and ristocetin cofactor (RiCof) and by the presence of all vWF multimers in sodium dodecyl sulfate (SDS)-agarose gel electrophoresis. For 17 patients (13 kindreds) diagnosed with these criteria, we have studied the platelet contents of vWF:Ag and RiCof and the changes of these in plasma after DDAVP infusion. Platelet vWF:Ag and RiCof were normal in four kindreds (called “platelet normal” subgroup); following 1-deamino- 8-D-arginine vasopressin; plasma vWF:Ag, RiCof and the bleeding time (BT) became normal. In six kindreds, platelet vWF:Ag and RiCof were equally low (platelet low); after DDAVP, plasma vWF:Ag and RiCof remained low, and the BT was prolonged. In three additional kindreds, platelets contained normal concentrations of vWF:Ag, but RiCof was very low (platelet discordant); even though a complete set of multimers was found in plasma and platelets, there was a relatively small amount of large multimers. After DDAVP, plasma vWF:Ag became normal, but RiCof remained low and the BT was very prolonged. These findings demonstrated that there can be an abnormal vWF (RiCof less than vWF:Ag) even in type I vWD, coexisting with a complete set of vWF multimers (platelet discordant); that the abnormal vWF can be shown more clearly in platelets than in plasma or else in plasma after DDAVP infusion; and that DDAVP normalizes the BT only in those patients with normal platelet levels of both vWF:Ag and RiCof (platelet normal).

scholarly journals Heterogeneity of type I von Willebrand disease: evidence for a subgroup with an abnormal von Willebrand factor

Blood ◽  
1985 ◽  
Vol 66 (4) ◽  
pp. 796-802 ◽  
Author(s):  
PM Mannucci ◽  
R Lombardi ◽  
R Bader ◽  
L Vianello ◽  
AB Federici ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Plasma Concentrations ◽  
Sodium Dodecyl ◽  
Von Willebrand Disease ◽  
Type I ◽  
Normal Platelet ◽  
Complete Set ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Factor Antigen

Abstract Type I von Willebrand disease (vWD) is characterized by equally low plasma concentrations of von Willebrand factor antigen (vWF:Ag) and ristocetin cofactor (RiCof) and by the presence of all vWF multimers in sodium dodecyl sulfate (SDS)-agarose gel electrophoresis. For 17 patients (13 kindreds) diagnosed with these criteria, we have studied the platelet contents of vWF:Ag and RiCof and the changes of these in plasma after DDAVP infusion. Platelet vWF:Ag and RiCof were normal in four kindreds (called “platelet normal” subgroup); following 1-deamino- 8-D-arginine vasopressin; plasma vWF:Ag, RiCof and the bleeding time (BT) became normal. In six kindreds, platelet vWF:Ag and RiCof were equally low (platelet low); after DDAVP, plasma vWF:Ag and RiCof remained low, and the BT was prolonged. In three additional kindreds, platelets contained normal concentrations of vWF:Ag, but RiCof was very low (platelet discordant); even though a complete set of multimers was found in plasma and platelets, there was a relatively small amount of large multimers. After DDAVP, plasma vWF:Ag became normal, but RiCof remained low and the BT was very prolonged. These findings demonstrated that there can be an abnormal vWF (RiCof less than vWF:Ag) even in type I vWD, coexisting with a complete set of vWF multimers (platelet discordant); that the abnormal vWF can be shown more clearly in platelets than in plasma or else in plasma after DDAVP infusion; and that DDAVP normalizes the BT only in those patients with normal platelet levels of both vWF:Ag and RiCof (platelet normal).

Treatment of Von Willebrand Disease

2001 ◽  
Vol 86 (07) ◽  
pp. 149-153 ◽  
Author(s):  
Pier Mannuccio Mannucci
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Spontaneous Bleeding ◽  
Primary Hemostasis ◽  
Bleeding Prophylaxis ◽  
Bleeding Episodes ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryIn von Willebrand disease, there are two main options for the treatment of spontaneous bleeding episodes and for bleeding prophylaxis: desmopressin and transfusional therapy with plasma products. Desmopressin is the treatment of choice for most patients with type 1, who account for approximately 70 to 80 per cent of all cases with the disease. This non-transfusional hemostatic agent raises endogenous factor VIII and von Willebrand factor three- to fivefold and thereby transiently corrects both the intrinsic coagulation and primary hemostasis defects. In patients with the more severe type 3 and in the majority of those with type 2 desmopressin is not effective or is contraindicated, so that it is usually necessary to resort to plasma concentrates containing factor VIII and von Willebrand factor. Concentrates treated with virus inactivation methods should be preferred to cryoprecipitate because they are equally effective and perceived as safer.

How I treat patients with von Willebrand disease

Blood ◽  
2001 ◽  
Vol 97 (7) ◽  
pp. 1915-1919 ◽  
Author(s):  
Pier Mannuccio Mannucci
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Spontaneous Bleeding ◽  
Primary Hemostasis ◽  
Bleeding Prophylaxis ◽  
Bleeding Episodes ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Von Willebrand disease (vWD) is a frequent inherited disorder of hemostasis that affects both sexes. Two abnormalities are characteristic of the disease, which is caused by a deficiency or a defect in the multimeric glycoprotein called von Willebrand factor: low platelet adhesion to injured blood vessels and defective intrinsic coagulation owing to low plasma levels of factor VIII. There are 2 main options available for the treatment of spontaneous bleeding episodes and for bleeding prophylaxis: desmopressin and transfusional therapy with plasma products. Desmopressin is the treatment of choice for most patients with type 1 vWD, who account for approximately 70% to 80% of cases. This nontransfusional hemostatic agent raises endogenous factor VIII and von Willebrand factor 3 to 5 times and thereby corrects both the intrinsic coagulation and the primary hemostasis defects. In patients with the more severe type 3 and in most patients with type 2 disease, desmopressin is ineffective or is contraindicated and it is usually necessary to resort to plasma concentrates containing both factor VIII and von Willebrand factor. Concentrates treated with virucidal methods should be preferred to cryoprecipitate because they are equally effective and are perceived as safer.

scholarly journals Cryptogenic oozers and bruisers

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 85-91
Author(s):  
Kristi J. Smock ◽  
Karen A. Moser
Keyword(s):  
Platelet Function ◽  
Coagulation Factor ◽  
Fibrin Clot ◽  
Von Willebrand Disease ◽  
Bleeding Disorders ◽  
Diagnostic Challenge ◽  
Primary Hemostasis ◽  
Platelet Function Disorders ◽  
Number Of Patients ◽  
Von Willebrand

Abstract Bleeding disorders with normal, borderline, or nondiagnostic coagulation tests represent a diagnostic challenge. Disorders of primary hemostasis can be further evaluated by additional platelet function testing modalities, platelet electron microscopy, repeat von Willebrand disease testing, and specialized von Willebrand factor testing beyond the usual initial panel. Secondary hemostasis is further evaluated by coagulation factor assays, and factor XIII assays are used to diagnose disorders of fibrin clot stabilization. Fibrinolytic disorders are particularly difficult to diagnose with current testing options. A significant number of patients remain unclassified after thorough testing; most unclassified patients have a clinically mild bleeding phenotype, and many may have undiagnosed platelet function disorders. High-throughput genetic testing using large gene panels for bleeding disorders may allow diagnosis of a larger number of these patients in the future, but more study is needed. A logical laboratory workup in the context of the clinical setting and with a high level of expertise regarding test interpretation and limitations facilitates a diagnosis for as many patients as possible.

A Novel Mutation Glyl672→Arg in Type 2A and a Homozygous Mutation in Type 2B von Willebrand Disease

1996 ◽  
Vol 76 (02) ◽  
pp. 253-257 ◽  
Author(s):  
Takeshi Hagiwara ◽  
Hiroshi Inaba ◽  
Shinichi Yoshida ◽  
Keiko Nagaizumi ◽  
Morio Arai ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Novel Mutation ◽  
Point Mutations ◽  
Japanese Patients ◽  
Von Willebrand Disease ◽  
Homozygous Mutation ◽  
Missense Mutations ◽  
Reaction Products ◽  
Type 3 ◽  
Von Willebrand

SummaryGenetic materials from 16 unrelated Japanese patients with von Willebrand disease (vWD) were analyzed for mutations. Exon 28 of the von Willebrand factor (vWF) gene, where point mutations have been found most frequent, was screened by various restriction-enzyme analyses. Six patients were observed to have abnormal restriction patterns. By sequence analyses of the polymerase chain-reaction products, we identified a homozygous R1308C missense mutation in a patient with type 2B vWD; R1597W, R1597Q, G1609R and G1672R missense mutations in five patients with type 2A; and a G1659ter nonsense mutation in a patient with type 3 vWD. The G1672R was a novel missense mutation of the carboxyl-terminal end of the A2 domain. In addition, we detected an A/C polymorphism at nucleotide 4915 with HaeIII. There was no particular linkage disequilibrium of the A/C polymorphism, either with the G/A polymorphism at nucleotide 4391 detected with Hphl or with the C/T at 4891 detected with BstEll.

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