Laboratory characterization of obligate carriers of type 3 von Willebrand disease with a potential role for Platelet Function Analyzer (PFA‐200)

Abstract A qualitative abnormality of platelet function should be considered in patients with mucocutaneous bleeding in the absence of thrombocytopenia or von Willebrand disease. Antiplatelet drugs are the most common cause of acquired platelet disorders leading to bleeding. Uremia, hepatic cirrhosis, myeloma and related disorders, polycythemia vera, essential thrombocythemia, and cardiopulmonary bypass have long been recognized as clinical situations in which platelet dysfunction may contribute to bleeding. When an acquired platelet disorder is suspected, it is useful to examine platelet function by measuring the bleeding time, examining platelet-dependent closure time in a platelet function analyzer and performing platelet aggregometry. When a specific acquired platelet disorder is diagnosed, many treatment options are available including controlling the underlying disease, giving platelet transfusions and administering a hemostatic drug.

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SENSITIVITY OF THE PLATELET FUNCTION ANALYZER (PFA-100) AS A SCREENING TEST FOR LABORATORY DIAGNOSIS OF VON WILLEBRAND DISEASE

Journal of Thrombosis and Haemostasis ◽

10.1111/j.1538-7836.2007.tb01939.x ◽

2007 ◽

Vol 5 ◽

pp. P-T-181-P-T-181

Author(s):

D. Coen Herak ◽

M. Milos ◽

R. Zadro

Keyword(s):

Platelet Function ◽

Screening Test ◽

Laboratory Diagnosis ◽

Von Willebrand Disease ◽

Function Analyzer ◽

Platelet Function Analyzer ◽

Von Willebrand

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The Platelet Function Analyzer (PFA-100) may not be suitable for monitoring the therapeutic efficiency of von Willebrand concentrate in type III von Willebrand disease

Annals of Hematology ◽

10.1007/s002770050542 ◽

1999 ◽

Vol 78 (9) ◽

pp. 426-430 ◽

Cited By ~ 11

Author(s):

A. Meskal ◽

F. Vertessen ◽

M. Van der Planken ◽

Z. N. Berneman

Keyword(s):

Platelet Function ◽

Von Willebrand Disease ◽

Therapeutic Efficiency ◽

Type Iii ◽

Function Analyzer ◽

Platelet Function Analyzer ◽

Von Willebrand

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

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650600 ◽

1996 ◽

Vol 76 (03) ◽

pp. 460-468 ◽

Cited By ~ 7

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.

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Description of an In Vitro Platelet Function Analyzer-PFA-100™

Seminars in Thrombosis and Hemostasis ◽

10.1055/s-0032-1313612 ◽

1995 ◽

Vol 21 (S 02) ◽

pp. 106-112 ◽

Cited By ~ 88

Author(s):

Sourav Kundu ◽

Eric Heilmann ◽

Reynaldo Sio ◽

Carmen Garcia ◽

Rosa Davidson ◽

...

Keyword(s):

Platelet Function ◽

Quantitative Measure ◽

Biologically Active ◽

High Shear Rates ◽

Function Analyzer ◽

Potential Applications ◽

Time Required ◽

Platelet Function Analyzer ◽

Von Willebrand

A new in vitro system for the detection of platelet dysfunction, PFA-100™* has been developed. It provides a quantitative measure of platelet function in anticoagulated whole blood. The system comprises a microprocessor-controlled instrument and a disposable test cartridge containing a biologically active membrane. The instrument aspirates a blood sample under constant vacuum from the sample reservoir through a capillary and a microscopic aperture cut into the membrane. The membrane is coated with collagen and epinephrine or adenosine 5’-diphosphate. The presence of these biochemical stimuli, and the high shear rates generated under the standardized flow conditions, result in platelet attachment, activation, and aggregation, slowly building a stable platelet plug at the aperture. The time required to obtain full occlusion of the aperture is reported as the m“closure time.” We have found that impairment of von Willebrand factor, or inhibition of platelet receptors glycoprotein Ib or IIblIIIa with monoclonal antibodies or peptides, resulted in abnormal closure times. An antifibrinogen antibody, in contrast, failed to show any effect. The test appears to be sensitive to platelet adherence and aggregation abnormalities. The PFA-100™ system has potential applications in routine evaluation of platelet function in the clinical setting because of its accuracy, ease of operation, and rapid turnaround of results. * Under evaluation

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Lack of association between aspirin responsiveness and seven candidate gene haplotypes in patients with symptomatic vascular disease

Thrombosis and Haemostasis ◽

10.1160/th08-05-0287 ◽

2009 ◽

Vol 101 (01) ◽

pp. 123-133 ◽

Cited By ~ 31

Author(s):

Shirley Williams ◽

Diane Nugent ◽

Paul Harrison ◽

Helen Segal ◽

Anila Syed ◽

...

Keyword(s):

Candidate Genes ◽

Platelet Function ◽

Purinergic Receptor ◽

Blood Platelet ◽

Function Analyzer ◽

Prostaglandin H ◽

Ischemic Attack ◽

Platelet Function Analyzer ◽

Von Willebrand ◽

Willebrand Factor

SummaryWe studied the effect of prophylactic aspirin (ASA) ingestion on platelet function in 463 patients with stroke, transient ischemic attack (TIA) or acute coronary disease (ACD), using the Platelet Function Analyzer-100 (PFA-100). We correlated ASA responsiveness with haplotypes of seven candidate genes, selected for their documented role in platelet function, namely, the genes for integrins α2β1and αIIbβ3 (ITGA2, ITGA2B, and ITGB3), platelet glycoproteins Ibα and VI (GPIBA and GP6), the purinergic receptor P2Y1 (P2RY1), and prostaglandin H synthase 1 (PTGS1 = COX1). Non-responsiveness to ASA was defined as the failure of prior ASA ingestion to prolong the PFA-100 closure time (CT) when blood was perfused through cartridges coated with collagen plus epinephrine (CEPI-CT). ASA non-responsiveness was observed in 114 of 463 patients (24.6 %), but was not associated with haplotypes of any of the seven candidate genes. There was also no association between any haplotypes and the CT when blood was perfused through cartridges coated with collagen plus ADP (CADP-CT). The ASA non-responsive cohort had significantly increased whole blood platelet counts (p = 0.03) and plasma von Willebrand Factor antigen levels (p<0.001), which likely contributes to resistance to the inhibitory effects of ASA in the PFA-100.

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Expression and characterization of von Willebrand factor dimerization defects in different types of von Willebrand disease

Blood ◽

10.1182/blood.v97.7.2059 ◽

2001 ◽

Vol 97 (7) ◽

pp. 2059-2066 ◽

Cited By ~ 51

Author(s):

Reinhard Schneppenheim ◽

Ulrich Budde ◽

Tobias Obser ◽

Jacqueline Brassard ◽

Kerstin Mainusch ◽

...

Keyword(s):

Von Willebrand Factor ◽

Recombinant Expression ◽

Von Willebrand Disease ◽

Disulfide Bonding ◽

Amino Terminal ◽

Carboxy Terminal ◽

Type 3 ◽

Von Willebrand ◽

Willebrand Factor

Abstract Dimerization defects of von Willebrand factor (vWF) protomers underlie von Willebrand disease (vWD) type 2A, subtype IID (vWD 2A/IID), and corresponding mutations have been identified at the 3′ end of the vWF gene in exon 52. This study identified and expressed 2 additional mutations in this region, a homozygous defect in a patient with vWD type 3 (C2754W) and a heterozygous frameshift mutation (8566delC) in a patient with vWD type 2A, subtype IIE. Both mutations involve cysteine residues that we propose are possibly essential for dimerization. To prove this hypothesis, transient recombinant expression of each of the 2 mutations introduced in the carboxy-terminal vWF fragment II and in the complete vWF complementary DNA, respectively, were carried out in COS-7 cells and compared with expression of vWD 2A/IID mutation C2773R and the wild-type (WT) sequence in COS-7 cells. Recombinant WT vWF fragment II assembled correctly into a dimer, whereas recombinant mutant fragments were monomeric. Homozygous expression of recombinant mutant full-length vWF resulted in additional dimers, probably through disulfide bonding at the amino-terminal multimerization site, whereas recombinant WT vWF correctly assembled into multimers. Coexpression of recombinant mutant and recombinant WT vWF reproduced the multimer patterns observed in heterozygous individuals. Our results suggest that a common defect of vWF biosynthesis—lack of vWF dimerization—may cause diverse types and subtypes of vWD. We also confirmed previous studies that found that disulfide bonding at the vWF amino-terminal is independent of dimerization at the vWF carboxy-terminal.

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