Effect of DDAVP on Platelet Activation and Platelet-Derived Microparticle Generation

2021 ◽  
Author(s):  
Matthieu Persyn ◽  
Nicolas Athanase ◽  
Marc Trossaërt ◽  
Marianne Sigaud ◽  
Catherine Ternisien ◽  
...  
Keyword(s):  
Factor Viii ◽  
Platelet Activation ◽  
Ex Vivo ◽  
Von Willebrand Disease ◽  
Factor Viii Deficiency ◽  
Platelet Counts ◽  
Definite Effect ◽  
Before And After ◽  
Combined Action ◽  
Von Willebrand

Abstract Background The way by which 1-deamino-8-D-arginine vasopressin (DDAVP) acts on platelets remains unclear. Data from the literature tend to show that there is no definite effect on platelet activation, but recent work has suggested that a subtype of platelets, activated by the combined action of collagen and thrombin, was triggered by DDAVP. Moreover, platelet microparticles (PMPs), which have been shown to be procoagulant, have rarely been studied in this context. The goal of this study was to analyze the effects of DDAVP on PMPs' release through platelet activation. Methods Fifteen out of 18 consecutive patients undergoing a therapeutic test with DDAVP were included. They were suffering from factor VIII deficiency or from von Willebrand disease. The expression of P-selectin and PAC-1 binding on platelets and the numbers of circulating PMPs were evaluated ex vivo before and after DDAVP infusion. Peripheral blood was collected on CTAD to limit artifactual platelet activation. Results DDAVP induced a significant decrease of platelet counts and volume. Only small changes of P-selectin expression and PAC-1 binding were observed. Considering PMPs, two populations of patients could be defined, respectively, with (120%, n = 6) or without (21%, n = 7) an increase of PMPs after DDAVP. The decrease in platelet counts and volume remained significant in the group of responders. Conclusion This study shows that DDAVP induces the generation/release of PMPs in some patients with factor VIII deficiency and von Willebrand disease 1 hour after DDAVP infusion.

Usefulness of Whole Blood Thromboelastography for the Diagnosis and Characterisation of Von Willebrand Disease.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2274-2274
Author(s):  
Catherine Lambert ◽  
Cedric R. Hermans
Keyword(s):  
Factor Viii ◽  
Whole Blood ◽  
Alpha Angle ◽  
Von Willebrand Disease ◽  
Factor Viii Deficiency ◽  
Closure Time ◽  
Significant Prolongation ◽  
Type 3 ◽  
Von Willebrand

Abstract Whole blood coagulation tests such as thromboelastography and platelet function analyser (PFA-100) are increasingly used for the investigation of haemostatic disorders. These global tests offer the advantages of a simple use and fast results. Although PFA-100 using the ADP cartridge has been validated as a useful tool to assess primary haemostatic disturbancies and has a high sensitivity to detect Von Willebrand disease (VWD), this test is neither specific for, nor predicitve of, any particular disorder of primary haemostasis. On the other hand, the potential usefulness of thromboelastography for the evaluation of VWD has so far not been investigated. The present study was undertaken in order to determine alterations of the thromboelastogram tracing in patients with VWD and evaluate its usefulness in adjunction to PFA-100 for the diagnosis and characterisation of VWD. Thromboelastographic analysis (Pentafarm RoTEM® ) was performed, as previously described by Sorensen et al. (J Thromb Haemost. 2003 Mar;1(3):551–8), over a 36 months period on all consecutive patients referred for bleeding work-up to the Haemostasis and Thrombosis Unit of the Cliniques universitaires Saint-Luc, Brussels, Belgium. Ninety-three patients fulfilling the diagnosis criteria of VWD were analysed (38 ± 18 year, 29 males-64 females). The distribution of VWD types was as follows: type 1 (59), type 2 (31) with subtypes 2A (12), 2M (17), 2B (2) and type 3 (3). The control population included 43 healthy individuals (24 females, 19 males, mean age: 38 ± 10 yr). For each patient, the following tests were performed: closure time measured by PFA-100 using the ADP cartridge, Von Willlebrand factor antigen (VWF:Ag) and activity (VWF:Ac) (collagen binding assay), factor VIII level (one-stage assay) and RoTEM®. The following parameters of the RoTEM® tracing were analysed: clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF), alpha angle and maximum clot lysis (ML). VWD was associated with a significant prolongation of the CT and the CFT. By contrast, the MCF, the alpha angle and the ML were not significantly different between patients and controls. By multiple regression analysis, the CT and CFT prolongation was found to be influenced only by the reduction of the factor VIII levels. The most important prolongations of the CT and the CFT were found in type 3 VWD reflecting the severe factor VIII deficiency. No significant differences of the RoTEM® parameters were found between type 1, subtypes 2A and 2M, which altogether represent the majority (94%) of the VWD population. CT and CFT prolongation was not correlated with other parameters (closure time, VWF:Ag and VWF:Ac). As expected, the closure time was determined by the level of VWF activity. In conclusion, although we observed a significant prolongation of the CT and the CFT in patients with VWD, RoTEM® appears to be of limited value for the diagnosis and characterization of VWD. Nevertheless, RoTEM® could be used as a screening tool to identify factor VIII deficiency present in a subset of patients with VWD.

scholarly journals The Potential Role of Emicizuamb Prophylaxis in Severe Von Willebrand Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 20-20
Author(s):  
Assaf Arie Barg ◽  
Gili Kenet ◽  
Tami Livnat ◽  
Einat Avishai ◽  
Ivan Budnik ◽  
...  
Keyword(s):  
Factor Viii ◽  
Potential Role ◽  
Prophylactic Treatment ◽  
Ex Vivo ◽  
Peak Height ◽  
Von Willebrand Disease ◽  
Type 3 ◽  
Von Willebrand

Severe Von Willebrand's disease (VWD) may be associated with chronic joint damage and may require prophylactic therapy. In severe VWD, factor VIII (FVIII) levels are low due to rapid clearness. Emicizumab is a humanized bispecific antibody which mimics the function of coagulation factor VIII (FVIII). It has been approved for prophylaxis in hemophilia A. This is the first study assessing the potential role of emicizumab as an alternative prophylactic treatment in a cohort of patients with severe VWD. We present a TG model evaluating patients' hemostasis following ex vivo spiking of their plasma samples with emicizumab. We also report 24 weeks of successful emicizumab prophylaxis in a child with severe VWD and repeated hemarthroses. A cohort of twenty-four VWD patients were included in the study. Fifty-four percent of our patients were males and the cohort consisted of 14 children (≤18 years) and 10 adults. The majority of patients (96%) were of Caucasian origin. Hemarthrosis was encountered in most type 3 VWD patients, whereas none of the type 2 VWD patients had any joint bleeds. Prophylactic treatment was administered in the majority of type 3 VWD patients, whereas type 2 VWD patients largely required only intermittent on demand therapy applied for bleeding episodes or any surgical interventions. Thrombin generation analysis was carried out blindly in plasma obtained from thirteen type 3 VWD patients and eleven type 2 VWD patients. Seventeen healthy volunteers served as a control group. In plasma from type 3 VWD patients, TG was substantially lower than in plasma from type 2 VWD patients, with ETP of 765 nM×min (596-962) vs. 1954 nM×min (1483-2008) (P = 0•001) and peak height of 47 nM (36-65) vs. 262 nM (142-318) (P = 0•002) In order to examine the potential use of emicizumab as an alternative treatment option for type 3 VWD patients, an ex vivo spiking analysis comparing the effect of Haemate P and emicizumab on TG was performed. An improvement in peak height was demonstrated following spiking with both Haemate P concentrations (P = 0•001 for both) and with the higher emicizumab concentration (P = 0•011). Notably, whereas spiking with both Haemate P concentrations increased peak height to near-normal level, spiking with higher emicizumab concentration increased it to a lesser extent (the median was still lower than in normal controls (P = 0•005). Following the decision to treat our impetus patient with emicizumab prophylaxis, TG analyses were performed in the patient's plasma before and during emicizumab loading and maintenance (Figure 3). As expected, patient's initial TG was extremely low and improved following the first administration of emicizumab loading dose (at week 2 after therapy initiation), at which time emicizumab level was 21 µg/mL. Further significant improvement of TG was noted following loading period completion while emicizumab level was 62 µg/mL. Our patient has been treated with emicizumab for more than six months altogether and did not encounter any joint bleeds since the commencement of therapy. During this period, a single dose of Haemate P was administered following tooth exfoliation. Our study contributes towards a better understanding of TG as a surrogate marker of VWD patients' hemostasis. Our data suggests that some severe VWD patients could be safely and efficiently treated with emicizumab. The successful prophylaxis of our patient and our ex vivo laboratory findings should set the ground for further collaborative multicenter studies to examine the efficacy and safety of emicizumab prophylaxis in type 3 VWD patients. Disclosures Barg: roshe: Honoraria, Speakers Bureau. Kenet:PI Healthcare, CSL Behring: Honoraria; Bayer, Pfizer, Takeda, BioMarin, Novo Nordisk: Speakers Bureau; Bayer, Pfizer, Roche, Alnylam (Sanofi), Shire: Research Funding; Bayer, Pfizer, BioMarin, Takeda, Roche, Novo Nordisk, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The use of Emicizumab in sever Von Willebrand disease

Platelet factor VIII-related antigen: studies in vivo after transfusion in patients with von Willebrand disease

Blood ◽  
1978 ◽  
Vol 51 (4) ◽  
pp. 751-761 ◽  
Author(s):  
Y Sultan ◽  
C Jeanneau ◽  
J Lamaziere ◽  
P Maisonneuve ◽  
JP Caen
Keyword(s):  
Electron Microscopy ◽  
Factor Viii ◽  
Single Injection ◽  
Severe Form ◽  
Von Willebrand Disease ◽  
Platelet Factor ◽  
Factor Viii Related Antigen ◽  
Before And After ◽  
Von Willebrand

Four unrelated patients with a severe form of von Willebrand disease showed no detectable factor VIII-related antigen (VIIIR:AG) in either their plasma or their platelets. They received cryoprecipitate infusions, three patients in a single injection each and one every day for 9 days before and after surgery. Platelet VIIIR:Ag was studied at different times during and after transfusion using electroimmunoassay of platelet extracts and electron microscopy of the platelets incubated with anti-VIIIR:Ag antibodies coupled to peroxidase. No VIIIR-Ag was detected in or around the patients' platelets, although this antigen was detected in the circulating blood. These results that there was no VIIIR:Ag uptake from the plasma by the platelets and that platelet VIIIR:Ag came from megakaryocytes.

scholarly journals Response to desmopressin of factors XI, X and V in patients with factor VIII deficiency and von Willebrand disease

2004 ◽  
Vol 126 (1) ◽  
pp. 100-104 ◽  
Author(s):  
B. White ◽  
P. Lawler ◽  
A. Riddell ◽  
I. C. Nitu-Whalley ◽  
C. Hermans ◽  
...  
Keyword(s):  
Factor Viii ◽  
Von Willebrand Disease ◽  
Factor Viii Deficiency ◽  
Von Willebrand

Post-DDAVP Thrombocytopenia in Type 2B von Willebrand Disease Is not Associated with Platelet Consumption: Failure to Demonstrate Glycocalicin Increase or Platelet Activation

1999 ◽  
Vol 81 (02) ◽  
pp. 224-228 ◽  
Author(s):  
A. Steffan ◽  
E. Pontara ◽  
A. Zucchetto ◽  
C. Rossi ◽  
L. De Marco ◽  
...  
Keyword(s):  
Platelet Count ◽  
Platelet Activation ◽  
Surface Expression ◽  
Von Willebrand Disease ◽  
Platelet Surface ◽  
Platelet Counts ◽  
Normal Platelet ◽  
Thrombotic Complications ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryThrombocytopenia is frequently reported in type 2B von Willebrand disease (vWD), and thought to be related to the abnormally high affinity of 2B von Willebrand factor (vWF) for platelet GPIb-IX. To gain an insight into the nature of this thrombocytopenia, we measured plasma glycocalicin (GC) levels (as a marker of platelet turnover), and platelet surface expression of the alpha granule protein P-selectin (as a marker of platelet activation) in 9 patients with type 2B vWD before, and in 4 patients also following the infusion of 1-desamino-8-d-arginine vasopressin (DDAVP). Three patients presented a persistent decrease of platelet counts in the resting condition. GC levels were within the normal range, regardless of the platelet counts, in all but one patient who presented, on the other hand, a normal platelet count. Moreover, platelets expressed normal amounts of P-selectin on their surface, regardless of platelet counts. These findings suggest that the thrombocytopenia observed in type 2B vWD is not due to platelet activation and subsequent consumption in circulation.Despite a significant, albeit transient, decrease in platelet count, DDAVP did not induce an increase in plasma GC levels, nor enhance P-selectin expression. These observations indicate that the acute post-DDAVP thrombocytopenia in type 2B vWD is not related to platelet activation and consumption. We advance that the post-DDAVP 2B vWF is hemostatically more active, and able to induce agglutination but not aggregation of circulating platelets. This would explain both the prompt recovery of basal platelet counts after the post-DDAVP decrease, and the lack of reported thrombotic complications in this disorder.Therefore, even though 2B vWF is characterized by an enhanced affinity for the platelet surface, its binding to platelet GPIb-IX in the soluble phase is not able to induce true platelet aggregation; vWF thus appears to be mainly an adhesive protein, rather than an aggregating agent.

scholarly journals Platelet factor VIII-related antigen: studies in vivo after transfusion in patients with von Willebrand disease

Blood ◽  
1978 ◽  
Vol 51 (4) ◽  
pp. 751-761 ◽  
Author(s):  
Y Sultan ◽  
C Jeanneau ◽  
J Lamaziere ◽  
P Maisonneuve ◽  
JP Caen
Keyword(s):  
Electron Microscopy ◽  
Factor Viii ◽  
Single Injection ◽  
Severe Form ◽  
Von Willebrand Disease ◽  
Platelet Factor ◽  
Factor Viii Related Antigen ◽  
Before And After ◽  
Von Willebrand

Abstract Four unrelated patients with a severe form of von Willebrand disease showed no detectable factor VIII-related antigen (VIIIR:AG) in either their plasma or their platelets. They received cryoprecipitate infusions, three patients in a single injection each and one every day for 9 days before and after surgery. Platelet VIIIR:Ag was studied at different times during and after transfusion using electroimmunoassay of platelet extracts and electron microscopy of the platelets incubated with anti-VIIIR:Ag antibodies coupled to peroxidase. No VIIIR-Ag was detected in or around the patients' platelets, although this antigen was detected in the circulating blood. These results that there was no VIIIR:Ag uptake from the plasma by the platelets and that platelet VIIIR:Ag came from megakaryocytes.

Interleukin 11 significantly increases plasma von Willebrand factor and factor VIII in wild type and von Willebrand disease mouse models

Blood ◽  
2001 ◽  
Vol 97 (2) ◽  
pp. 465-472 ◽  
Author(s):  
Cécile V. Denis ◽  
Kyubum Kwack ◽  
Simin Saffaripour ◽  
Srinivas Maganti ◽  
Patrick André ◽  
...  
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Messenger Rna ◽  
Von Willebrand Disease ◽  
Continuous Exposure ◽  
Wild Type ◽  
Platelet Counts ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Interleukin (IL)-11 is a cytokine with thrombopoietic activity that has been shown to increase plasma von Willebrand factor (vWf) in preliminary clinical studies. This led to further evaluation of the effect of recombinant human (rh)IL-11 on vWf and factor VIII (FVIII) secretion. In vitro, rhIL-11 did not increase vWf production by cultured endothelial cells, which suggests an indirect mechanism. Also, in vivo, plasma vWf was not elevated in mice shortly after a single intravenous (IV) bolus injection of 250 or 1000 μg/kg rhIL-11. The effect of continuous exposure to rhIL-11 was accessed by treating wild type mice for 7 consecutive days with subcutaneous 250 μg/kg/d rhIL-11. Platelet counts increased by 25% and 40% after 4 and 7 days, respectively. Plasma vWf and FVIII levels increased 2-fold after 4 and 7 days. Surprisingly, no effect of rhIL-11 on vWf or FVIII messenger RNA was observed, which suggests that the regulation by rhIL-11 occurs after transcription. No increase in soluble P-selectin was observed after rhIL-11 treatment, indicating that platelet activation is not the source of elevated vWf. Similarly to wild type mice, vWf heterozygous mice responded to rhIL-11 treatment by a significant increase in platelet counts and vWf and FVIII levels. Importantly, in vWf-deficient mice, rhIL-11 also induced a significant increase in FVIII independent of vWf and was able to reduce skin bleeding time. These results suggest that a clinical evaluation of the effects of rhIL-11–induced vWf/FVIII elevation in maintaining hemostasis in mild hemophilia A or von Willebrand disease would be worthwhile.

von Willebrand Disease in Chronic Immune Thrombocytopenic Purpura Children.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3954-3954
Author(s):  
Ji Hye Lee ◽  
Hwi-Joong Yoon ◽  
Kun Soo Lee
Keyword(s):  
Factor Viii ◽  
Normal Level ◽  
Immune Thrombocytopenic Purpura ◽  
Von Willebrand Disease ◽  
Bleeding Tendency ◽  
Test Results ◽  
Thrombocytopenic Purpura ◽  
Platelet Counts ◽  
Chronic Immune Thrombocytopenic Purpura ◽  
Von Willebrand

Abstract Purpose: von Willebrand disease (vWD) is the most common hereditary bleeding disorder and type 2B combines thrombocytopenia. So it must be considered in patients found to have low platelet counts, particularly if there is a family history of mucocutaneous hemorrhage. We performed this study to diagnose the type 2B vWD in chronic immune thrombocytopenic purpura (ITP) children. Methods: Seventeen cases among chronic ITP children over 6 months at the Department of Pediatrics, Kyungpook National University Hospital, Daegu, Korea from October, 1995 to June, 2007 were participated in this study. We performed screening coagulation tests such as platelet counts, activated partial thromboplastin time (aPTT), and bleeding time (BT) and specific tests for vWD such as von Willebrand factor related antigen (vWF: Ag), vWF ristocetin cofactor (vWF: RCo), factor VIII, and vWF multimer on these patients. These tests were also performed their family when the patient was diagnosed vWD. And we reviewed their past and family histories about bleeding tendency. Results: There were four boys and thirteen girls and their mean age was 11.6 years (range: 2.8∼18.5 years). Five cases (5/17, 29.4%) were diagnosed vWD: one had lower level of vWF: RCo and factor VIII with normal level of vWF: Ag and others had lower level of vWF: RCo and vWF: Ag with normal level of factor VIII. Among these, two cases showed abnormal screening test results, prolongation of aPTT or BT. We could perform the vWF multimer test in two cases, but two had normal pattern. Among five vWD children, we could obtain the past and family bleeding tendency histories except one case and three families showed bleeding tendency. But all families showed normal screening and specific test results. Conclusions: von Willebrand disease was combined in 5 cases (29.4%) among 17 chronic thrombocytopenic children. More evaluation such as vWF multimer and ristocetin induced platelet aggregation test (RIPA) is needed to confirm the subtype. And we should repeat the evaluation to the family who had bleeding history but showed normal results for diagnosis or exclusion of vWD.

Platelet Activation and Aggregation Induced by Recombinant von Willebrand Factors Reproducing Four Type 2B von Willebrand Disease Missense Mutations

1998 ◽  
Vol 79 (01) ◽  
pp. 211-216 ◽  
Author(s):  
Lysiane Hilbert ◽  
Claudine Mazurier ◽  
Christophe de Romeuf
Keyword(s):  
Platelet Aggregation ◽  
Platelet Activation ◽  
Von Willebrand Disease ◽  
Platelet Glycoprotein ◽  
Missense Mutations ◽  
Inhibit Platelet Aggregation ◽  
Wild Type ◽  
A1 Domain ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryType 2B of von Willebrand disease (vWD) refers to qualitative variants with increased affinity of von Willebrand factor (vWF) for platelet glycoprotein Ib (GPIb). All the mutations responsible for type 2B vWD have been located in the A1 domain of vWF. In this study, various recombinant von Willebrand factors (rvWF) reproducing four type 2B vWD missense mutations were compared to wild-type rvWF (WT-rvWF) for their spontaneous binding to platelets and their capacity to induce platelet activation and aggregation. Our data show that the multimeric pattern of each mutated rvWF is similar to that of WT-rvWF but the extent of spontaneous binding and the capacity to induce platelet activation and aggregation are more important for the R543Q and V553M mutations than for the L697V and A698V mutations. Both the binding of mutated rvWFs to platelets and platelet aggregation induced by type 2B rvWFs are inhibited by monoclonal anti-GPIb and anti-vWF antibodies, inhibitors of vWF binding to platelets in the presence of ristocetin, as well as by aurin tricarboxylic acid. On the other hand, EDTA and a monoclonal antibody directed against GPIIb/IIIa only inhibit platelet aggregation. Furthermore, the incubation of type 2B rvWFs with platelets, under stirring conditions, results in the decrease in high molecular weight vWF multimers in solution, the extent of which appears correlated with that of plasma vWF from type 2B vWD patients harboring the corresponding missense mutation. This study supports that the binding of different mutated type 2B vWFs onto platelet GPIb induces various degrees of platelet activation and aggregation and thus suggests that the phenotypic heterogeneity of type 2B vWD may be related to the nature and/or location of the causative point mutation.

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