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Blood Jul 2022International guidelines conditionally recommend long-term prophylaxis in patients with von Willebrand disease (VWD) and severe and frequent bleeding. As recombinant von...
International guidelines conditionally recommend long-term prophylaxis in patients with von Willebrand disease (VWD) and severe and frequent bleeding. As recombinant von Willebrand factor (rVWF; vonicog alfa) may reduce the frequency of treated spontaneous bleeding events (BEs), we investigated the efficacy and safety of rVWF prophylaxis in adults with severe VWD. Patients with BEs requiring VWF therapy in the past year (on-demand VWF therapy [prior on-demand group] or plasma-derived VWF prophylaxis [pdVWF; switch group]) were enrolled in a prospective, open-label, nonrandomized, phase 3 study. The planned duration of rVWF prophylaxis was 12 months; starting rVWF dose was 50 ± 10 VWF: ristocetin cofactor (VWF:RCo) IU/kg twice weekly (prior on-demand group) or based on prior pdVWF weekly dose/dosing frequency (switch group). The primary endpoint was annualized bleeding rate (ABR) of treated spontaneous BEs (sABR) during rVWF prophylaxis. Over the 12-month study period, treated sABR decreased by 91.5% on-study vs historical sABR in 13 patients in the prior on-demand group, and by 45.0% in 10 patients in the switch group (model-based analysis ratio, 0.085; 95% confidence interval [CI], 0.021-0.346 and 0.550; 95% CI, 0.086-3.523, respectively). No treated spontaneous BEs were recorded in 84.6% (11/13) and 70.0% (7/10) of patients, respectively. The safety profile of rVWF was consistent with the previously established profile, with no new adverse drug reactions identified. Findings suggest that rVWF prophylaxis can reduce treated spontaneous BEs in patients previously receiving on-demand VWF therapy and maintains at least the same level of hemostatic control in patients who switch from prophylaxis with pdVWF to rVWF, with a favorable safety profile. This trial was registered at www.clinicaltrials.gov (#NCT02973087) and www.clinicaltrialsregister.eu (#EudraCT 2016-001478-14).
Topics: Adult; Hemorrhage; Hemostatics; Humans; Prospective Studies; Recombinant Proteins; von Willebrand Diseases; von Willebrand Factor
PubMed: 35439298
DOI: 10.1182/blood.2021014810 -
Indian Journal of Hematology & Blood... Jun 2016The hemorrhagic diseases are characterized by bleeding which can vary considerably according to their severity. The von Willebrand disease (VWD) is the most frequent... (Review)
Review
UNLABELLED
The hemorrhagic diseases are characterized by bleeding which can vary considerably according to their severity. The von Willebrand disease (VWD) is the most frequent hereditary hemorrhagic disease and the prevalence of clinically significant disease is probably closer to 1:1000, being an extremely heterogeneous and complex disorder that is related to the deficiency in concentration, structure or function of von Willebrand factor (VWF). The VWD is divided into type 1, with partial deficiency of the VWF, type 2, with qualitative defects in the molecule with four subdivisions, and type 3, with very low or undetectable levels of plasma and platelet VWF and ristocetin cofactor activity. The laboratory diagnosis of VWD is complex. Specific tests that assess the functionality and concentrations of the VWF and FVIII are needed. The routine tests are the bleeding time, the activated partial thromboplastin time and the platelet count, however, singly, they may not suggest the diagnosis of VWD, requiring further specific tests, such as VWF function evaluation through its ristocetin cofactor assay (VWF:RCo), VWF protein concentration immunoassay (VWF:Ag), the factor VIII coagulation assay (
FVIII
C), VWF binding to immobilized collagen (VWF:CB), ristocetin-induced platelet aggregation (RIPA), VWF multimers patterns, factor VIII binding of immobilized VWF (VWF:FVIIIB), among others. From the moment the diagnosis is confirmed, the appropriate treatment for each patient is sought, with the purpose of increasing plasma concentrations of the deficient protein, both in bleeding episodes, as for invasive procedures. Although diagnosis facilitates treatment other approach in the present scenario is prenatal diagnosis which, is the need of the hour.
PubMed: 27065574
DOI: 10.1007/s12288-015-0627-x -
American Journal of Hematology Apr 2019von Willebrand factor (VWF) ristocetin cofactor activity (VWF:RCo) by platelet aggregometry has been considered the gold standard for evaluating the ability of VWF to... (Review)
Review
von Willebrand factor (VWF) ristocetin cofactor activity (VWF:RCo) by platelet aggregometry has been considered the gold standard for evaluating the ability of VWF to bind platelets for over 40 years. Many automated systems no longer require platelets and rather rely on agglutination of latex particles. Automated methods of measuring VWF activity have improved performance characteristics and are performed on the same coagulation instruments used for routine testing via immunoturbidimetric methodology. Alternatively, a newer chemiluminescence assay system for measuring VWF activity demonstrates excellent performance characteristics. As these methods are becoming widely used, it is important to assess their performance in diagnosing and monitoring different types of von Willebrand disease. We review the automated methodologies and the published performance of these VWF assays. Advantages and limitations of these automated methods are discussed.
Topics: Automation, Laboratory; Blood Coagulation Tests; Blood Platelets; History, 20th Century; History, 21st Century; Humans; von Willebrand Factor
PubMed: 30592326
DOI: 10.1002/ajh.25393 -
Blood Nov 2017Von Willebrand disease (VWD) is the most common inherited bleeding disorder, yet diagnosis and management remain challenging. Development and use of bleeding assessment... (Review)
Review
Von Willebrand disease (VWD) is the most common inherited bleeding disorder, yet diagnosis and management remain challenging. Development and use of bleeding assessment tools allows for improved stratification of which patients may require further assessment and which patients are most likely to require treatment of their VWD. New options for laboratory assessment of von Willebrand factor (VWF) activity include a new platelet-binding assay, the VWF:GPIbM, which is subject to less variability than the ristocetin cofactor activity assay, and collagen-binding assays that provide insight into a different function of VWF. Genetic testing may be helpful in some cases where a type 2 VWD variant is suspected but is usually not helpful in type 1 VWD. Finally, treatment options for VWD are reviewed, including the use of recombinant VWF. Despite these advances, still more work is required to improve diagnosis, treatment, and quality of life for affected patients.
Topics: Animals; Collagen; Genetic Variation; Hemorrhage; Humans; Platelet Glycoprotein GPIb-IX Complex; von Willebrand Diseases; von Willebrand Factor
PubMed: 29187375
DOI: 10.1182/blood-2017-05-782029 -
International Journal of Molecular... Jun 2023CXCL12, belonging to the CXC chemokine family, is a weak agonist of platelet aggregation. We previously reported that the combination of CXCL12 and collagen at low doses...
CXCL12, belonging to the CXC chemokine family, is a weak agonist of platelet aggregation. We previously reported that the combination of CXCL12 and collagen at low doses synergistically activates platelets via not CXCR7 but CXCR4, a specific receptor for CXCL12 on the plasma membrane. Recently, we reported that not Rho/Rho kinase, but Rac is involved in the platelet aggregation induced by this combination. Ristocetin is an activator of the von Willebrand factor that interacts with glycoprotein (GP) Ib/IX/V, which generates thromboxane A2 via phospholipase A2 activation, resulting in the release of the soluble CD40 ligand (sCD40L) from human platelets. In the present study, we investigated the effects of a combination of ristocetin and CXCL12 at low doses on human platelet activation and its underlying mechanisms. Simultaneous stimulation with ristocetin and CXCL12 at subthreshold doses synergistically induce platelet aggregation. A monoclonal antibody against not CXCR7 but CXCR4 suppressed platelet aggregation induced by the combination of ristocetin and CXCL12 at low doses. This combination induces a transient increase in the levels of both GTP-binding Rho and Rac, followed by an increase in phosphorylated cofilin. The ristocetin and CXCL12-induced platelet aggregation as well as the sCD40L release were remarkably enhanced by Y27362, an inhibitor of Rho-kinase, but reduced by NSC23766, an inhibitor of the Rac-guanine nucleotide exchange factor interaction. These results strongly suggest that the combination of ristocetin and CXCL12 at low doses synergistically induces human platelet activation via Rac and that this activation is negatively regulated by the simultaneous activation of Rho/Rho-kinase.
Topics: Humans; Blood Platelets; CD40 Ligand; Chemokine CXCL12; Phosphorylation; Platelet Activation; Platelet Aggregation; Platelet Glycoprotein GPIb-IX Complex; rho-Associated Kinases; Ristocetin; von Willebrand Factor; rac GTP-Binding Proteins
PubMed: 37298667
DOI: 10.3390/ijms24119716 -
Hematology. American Society of... Dec 2017Von Willebrand disease (VWD) is the most common inherited bleeding disorder, yet diagnosis and management remain challenging. Development and use of bleeding assessment... (Review)
Review
Von Willebrand disease (VWD) is the most common inherited bleeding disorder, yet diagnosis and management remain challenging. Development and use of bleeding assessment tools allows for improved stratification of which patients may require further assessment and which patients are most likely to require treatment of their VWD. New options for laboratory assessment of von Willebrand factor (VWF) activity include a new platelet-binding assay, the VWF:GPIbM, which is subject to less variability than the ristocetin cofactor activity assay, and collagen-binding assays that provide insight into a different function of VWF. Genetic testing may be helpful in some cases where a type 2 VWD variant is suspected but is usually not helpful in type 1 VWD. Finally, treatment options for VWD are reviewed, including the use of recombinant VWF. Despite these advances, still more work is required to improve diagnosis, treatment, and quality of life for affected patients.
Topics: Humans; Recombinant Proteins; von Willebrand Disease, Type 1; von Willebrand Disease, Type 2; von Willebrand Factor
PubMed: 29222282
DOI: 10.1182/asheducation-2017.1.379 -
Orphanet Journal of Rare Diseases Dec 2021Bleeding anomalies have been reported in patients affected by Noonan syndrome. No study has been performed in patients with molecularly confirmed RASopathy. We aimed to...
BACKGROUND
Bleeding anomalies have been reported in patients affected by Noonan syndrome. No study has been performed in patients with molecularly confirmed RASopathy. We aimed to characterize the frequency and types of bleeding disorders in patients with RASopathies and evaluate any significant association with laboratory findings.
PATIENTS AND METHODS
Forty-nine individuals (PTPN11, n = 27; SOS1, n = 7; RIT1, n = 3; SPRED1, n = 1; LZTR1, N = 3; RAF1, n = 2; BRAF, n = 4; MEK1, n = 1; MEK2, n = 1), and 49 age- and sex-matched controls were enrolled. The "Paediatric Bleeding Questionnaire Scoring Key" was administered to patients and families. Laboratory screening tests including clotting factors dosing, platelet count, Prothrombin Time and Partial Thromboplastin Time, were employed both in patients and controls to characterize the bleeding diathesis. A subgroup of 29/49 patients and 29/49 controls was also tested for platelet function.
RESULTS
Regardless of the gene involved, pathological paediatric bleeding scores were recorded in 14/49 (28.5%) patients. Indeed, 7 were mutated in PTPN11, 3 in SOS1, 2 in RIT1, 1 in BRAF, and 1 in MEK1. Compared to patients with normal bleeding scores, those with pathologic bleeding score showed higher prevalence of splenomegaly (p = 0.006), prolonged aPTT (p = 0.04), lower levels of coagulation factor V (FV, p = 0.001), FVII (p = 0.003), FX (p = 0.0008) and FXIII (p = 0.002), higher vWAg (p = 0.04), and lower platelet sensitivity to Ristocetin (p = 0.001), arachidonic acid (AA) (p = 0.009) and collagen (p = 0.01). The presence of hematomas inversely correlated with factor V (p = 0.002), factor VII (p = 0.003), factor X (p = 0.002) and factor XIII (p = 0.004) levels, and directly correlated with platelet response to collagen (p = 0.02) and AA (p = 0.01). The presence of splenomegaly directly correlated with the presence of hematoma (p = 0.006), platelet response to Ristocetin (p = 0.04) and AA (p = 0.04), and inversely correlated with factor V levels (p = 0.03).
CONCLUSIONS
Patients with RASopathies and a bleeding tendency exhibit multiple laboratory abnormalities, including platelet-related disorders. Splenomegaly is frequently detected and might be a suggestive sign for qualitative platelet dysfunction. A comprehensive clinical assessment should be carried out at diagnosis, during the follow-up and before any surgical procedures. Since there is currently no consensus on management of bleeding complications, it is important that physicians closely monitor these patients.
Topics: Blood Coagulation Tests; Blood Platelets; Child; Hemorrhage; Hemostatics; Humans; Noonan Syndrome; Transcription Factors
PubMed: 34857025
DOI: 10.1186/s13023-021-02122-7 -
Clinical and Applied... Apr 2017Aortic valve stenosis (AVS) is the most common valve disease in adults. Severe forms are associated with acquired von Willebrand syndrome (aVWS) with loss of the largest...
Aortic valve stenosis (AVS) is the most common valve disease in adults. Severe forms are associated with acquired von Willebrand syndrome (aVWS) with loss of the largest von Willebrand factor (VWF) multimers. Diagnostic gold standard is the VWF multimer analysis. Valve replacement rapidly restores the VWF structure. Uncertainty exists if this effect is permanent and how functional VWF assays perform compared with multimer analysis. We studied 21 consecutive patients with severe AVS before and 6 to 18 months after valve surgery and compared them with 14 controls without valve disease referred for coronary angiography. The VWF multimers, VWF antigen (VWF:Ag), VWF collagen binding capacity (VWF:CB), VWF:CB/VWF:Ag ratio, in vitro bleeding time (PFA-100), factor VIII coagulation activity (FVIII:C), and VWF ristocetin cofactor activity (VWF:RCo) were determined. In all patients with AVS, the large VWF multimers were strongly reduced (56 ± 13% of normal plasma); all controls had normal multimers. The PFA-100 collagen/ADP closure times (coll/ADP CT) were prolonged in patients with AVS compared with the controls (175 ± 56 seconds vs 86 ± 14 seconds, P < .001). The VWF:CB/VWF:Ag ratio was pathological in 20 of the 21 patients but normal in controls. After surgery, the multimers normalized in all patients and coll/ADP CT shortened (pre 184 ± 65 seconds vs post 102 ± 22 seconds; P < .001). The VWF:CB/VWF:Ag ratio strongly improved ( P < .001) and normalized in 14 of 17 patients. In conclusion, all consecutive patients with severe AVS had an aVWS. The combination of coll/ADP CT and VWF:CB/VWF:Ag ratio detected the aVWS in all patients. More than 6 months after valve replacement, the VWF multimers were still normalized in all patients indicating a permanent cure of the aVWS.
Topics: Aortic Valve Stenosis; Bleeding Time; Blood Coagulation Tests; Case-Control Studies; Heart Valve Prosthesis Implantation; Humans; Protein Multimerization; von Willebrand Diseases; von Willebrand Factor
PubMed: 27481874
DOI: 10.1177/1076029616660759 -
Research and Practice in Thrombosis and... Jan 2018Clinically, von Willebrand disease (VWD) presents as mucosal bleeding caused by a decreased quantity or quality of von Willebrand factor (VWF). Diagnosis of VWD requires... (Review)
Review
Clinically, von Willebrand disease (VWD) presents as mucosal bleeding caused by a decreased quantity or quality of von Willebrand factor (VWF). Diagnosis of VWD requires careful consideration of patient specific factors, bleeding symptoms, and laboratory results. Patients with borderline low VWF levels remain challenging, given that low VWF is not necessarily a guarantee of bleeding, but is present in many patients with symptoms, and treatment of low VWF may improve bleeding. Laboratory diagnosis of VWD is complex and no single test can determine the presence or absence of functional VWF. Historically, VWF binding to platelet GPIbα was measured by the ristocetin cofactor assay (VWF:RCo); a new assay using platelet GPIbα in the absence of ristocetin (VWF:GPIbM) is gradually replacing the VWF:RCo due to improved accuracy in diagnosis. VWF binding to collagen is a separate function, and requires specific testing to determine if a collagen binding defect is present. Regardless of these laboratory complexities, clinicians can empirically treat VWD to alleviate bleeding symptoms by raising VWF levels through desmopressin or VWF concentrate. Recombinant VWF is now available, but clinicians may need to add an initial dose of FVIII when treating emergency bleeds.
PubMed: 30046704
DOI: 10.1002/rth2.12064