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Congenital and acquired disorders of coagulation
Published in Jennifer Duguid, Lawrence Tim Goodnough, Michael J. Desmond, Transfusion Medicine in Practice, 2020
Jeanne M Lusher, Roshni Kulkarni
In the type 2 variants (which account for about 20% of cases), the haemostatically important higher MW forms of VWF are absent. Among the type 2 variants, the most common subtypes are 2A and 2B. In VWD type 2A, a genetic mutation in the A2 domain produces a VWF that is very susceptible to proteolysis. Affected individuals may have a normal or only slightly reduced levels of VWF and FVIII, lack the high- and intermediate-molecular-weight multimers of VWF, and generally have a mild to moderate bleeding tendency. In type 2B, missense mutations in the A1 domain result in a heightened affinity of VWF binding to platelets (platelet GP lb/IX). The patient’s VWF spontaneously binds to platelets and is unusually sensitive to the reagent ristocetin. Affected individuals often have some degree of thrombocytopenia due to in vivo platelet aggregation, and in vitro their platelets agglutinate with very low concentrations of ristocetin (enhanced ristocetin-induced platelet aggregation).
Congenital Platelet Dysfunction and von Willebrand Disease
Published in Harold R. Schumacher, William A. Rock, Sanford A. Stass, Handbook of Hematologic Pathology, 2019
Evaluation of the vWF/factor VIII complex was undertaken on the patient’s plasma. A Laurell “rocket” immunoelectrophoretic analysis revealed a significant decrease, to 24 U/dL. Functional activity of this vWF was assayed at 28 U/dL by the ristocetin cofactor assay, in which the patient’s plasma vWF is used to support the aggregation of formalin-fixed normal platelets. Performance of the factor VIII assay was less straightforward, with a significant deviation from linearity with the control plasma at all but the greatest dilutions of patient plasma; at these latter dilutions, however, the factor VIII activity did appear to be in the 25–35 U/dL range. A confirmatory chromogenic factor VIII assay gave a value of 27 U/dL. On a return visit, platelet-rich plasma was obtained from the patient, and ristocetin-induced platelet aggregation (RIPA) was studied using ristocetin concentrations ranging from 0.5 to 1.2 mg/mL. There was no aggregation in response to 0.5 mg/mL ristocetin (normal findings), and suboptimal responses to 0.9, 1.0, and 1.2 mg/mL ristocetin. The addition of exogenous vWF (in the form of cryoprecipitate) prior to the addition of the 1.2 mg/mL ristocetin concentration fully normalized the aggregation response.
Platelet Disorders Douglas Triplett
Published in Genesio Murano, Rodger L. Bick, Basic Concepts of Hemostasis and Thrombosis, 2019
Ristocetin-induced platelet aggregation is characteristically absent in patients with severe von Willebrand’s syndrome. Low and normal aggregation tracings, however, have been recognized in individuals with mild disease.53 It has also been noted that the ristocetin aggregation pattern can be corrected by adding normal platelet-poor plasma to the patient’s platelet-rich plasma.
Flow-diverting stent and delayed intracranial bleeding: the case for discussing acquired von Willebrand disease
Published in Platelets, 2021
A unique feature of the flow-diverting stent (FDS), namely braided mesh structure with small strut size, has rendered it useful in the endovascular treatment of selected intracranial aneurysms for the last decade. In our institution, a considerable amount of FDS experience has been accumulated since its first use in 2010 [1–4]. We have just assessed the activity of von Willebrand factor (vWF) by using the whole blood ristocetin induced platelet aggregation – RIPA – test (Multiplate Analyzer, Roche Diagnostics, Switzerland) in patients undergoing FDS implantation and revealed for the first time the relationship between FDS and reduced vWF activity [5]. Indeed, computational fluid dynamics (CFD) simulation has shown recently that FDS can create abnormally high supraphysiologic shear stress while blood flow passes through stent struts into the aneurysm [6]. The hemorrhagic complication after shear-generating dysfunctional native or prosthetic heart valves [7] and vascular devices such as left ventricular assist device (LVAD) [8] and extracorporeal membrane oxygenation (ECMO) [9] has causally been linked to acquired von Willebrand disease (AvWD). By analogy, the delayed intracranial hemorrhagic complication after “shear-generating” FDS may also be a consequence of AvWD [5].
Novel antiplatelet strategies targeting VWF and GPIb
Published in Platelets, 2021
Nithya Prasannan, Marie Scully
The humanized anti-glycoprotein Ib monoclonal antibody h6B4-Fab has also been evaluated in animal models. Fontayne et al [14] looked at the antithrombotic effect of h6B4-Fab on acute platelet-mediated thrombosis in baboons. Thrombus formation was induced at injured and stenosed femoral artery sites in this model followed by measurement of cyclic flow reduction (CFR). The pharmacokinetics of this drug was also evaluated by this group. Assessments revealed that 0.5 mg/kg of h6B4-Fab reduced CFR by 80%. Two additional doses which led to cumulative doses of 1.5 and 2.5 mg/kg completely abolished CFRs. Sixty percent GPIbα occupancy by this drug was required to inhibit thrombus formation, and 16.5% of GPIbα was found to be occupied by drug 24 hours post-administration. Significant prolongation of bleeding time was not seen with this anti-thrombotic effect. Furthermore, as previously shown with murine 6B4-Fab, h6B4-Fab caused a dose- and time-dependent inhibition of ristocetin induced platelet aggregation ex vivo. These findings demonstrate that h6B4-Fab is able to prevent thrombus formation in baboon models of arterial thrombosis and may, therefore, prove to be beneficial in acute arterial thrombosis[14].
High shear induces platelet dysfunction leading to enhanced thrombotic propensity and diminished hemostatic capacity
Published in Platelets, 2019
Zengsheng Chen, Nandan K. Mondal, Shirong Zheng, Steven C. Koenig, Mark S. Slaughter, Bartley P. Griffith, Zhongjun J. Wu
For the high NPSS of 150 Pa with the exposure time of 0.5 s, the AUC value for ristocetin-induced platelet aggregation decreased from 64.3 ± 5.8 AU*min for to the baseline blood sample to 49.9 ± 6.6 AU*min. But the reduction did not reach statistical significance. At the exposure time of 1.5 s, the platelet aggregation decreased significantly to 26.4 ± 2.2 AU*min. For the high NPSS of 300 Pa, the AUC value for ristocetin-induced platelet aggregation was 29.8 ± 4.6 AU*min for 0.5 s and 11.4 ± 6.9 AU*min for 1.5 s, respectively, which was significantly different from the AUC value for the baseline sample. Because ristocetin induces platelet aggregation by stimulating the binding of platelet GPIbα and VWF, a potential reason for the reduced ristocetin-induced platelet aggregation in the sheared samples may be the NPSS-induced shedding of the platelet GPIbα receptors.