HSCT-Associated Hepatic VOD Is Initiated With Preceding Appearance Of Unusually Large Von Willebrand Factor Multimers In Patient Plasmas

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3625-3625
Author(s):  
Masaki Hayakawa ◽  
Masanori Matsumoto ◽  
Yumi Yoshii ◽  
Hideo Yagi ◽  
Hiroshi Kimura ◽  
...  
Keyword(s):  
Body Weight ◽  
Board Of Directors ◽  
Plasma Levels ◽  
Combination Regimen ◽  
Adamts13 Activity ◽  
Advisory Committees ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Frozen Plasma ◽  
Platelet Transfusions

Abstract Backgrounds and Aims Hepatic veno-occlusive disease (VOD) associated with hematopoietic stem cell transplantation (HSCT) is characterized by a clinical triad of jaundice (total bilirubin, >2 mg/mL), hepatomegaly with right upper quadrant pain, and ascites and/or unexplained body weight gain (>5% of baseline) within 30 days after operation. Although the pathogenesis of hepatic VOD has not been fully elucidated, the common pathological features are thrombi formed in hepatic central vein. We previously reported that a significant decrease of plasma ADAMTS13 activity was noted in patients undergoing HSCT, who subsequently developed VOD (Park et al, BMT 2002). Then, we showed that plasma antigen levels of von Willebrand factor (VWF) has been kept higher in HSCT-patients with VOD than in those without, and in fact prophylactic infusions of fresh frozen plasma (FFP) with a dose of 10 ml/kg body weight 3 times per week were effective to reduce the frequency of VOD occurrence in high risk patients (Matsumoto et al, BMT 2007). However, more recent studies by ours indicate that FFP infusion alone is not enough to totally eliminate the occurrence (unpublished). Recently, it has been shown that the treatment with recombinant soluble thrombomodulin (rTM) is sometimes highly efficient to reverse VOD progression. But its pharmacokinetics and regimen for the treatment has not been established. As a first step to elucidate a possible combination regimen of FFP and rTM to VOD patients, here we have analyzed the transitional changes of unusually large VWF multimers (UL-VWFMs). The UL-VWFMs are released from damaged endothelial cells and induce platelet hyperagglutination under high shear stress generated in microvasculatures, and are often observed in patient plasmas undergoing HSCT. Patients and Methods During 2011-2012, 45 patients were received allogenic HSCT in the second internal medicine department of our university hospital. None of these patients ,however, were received planned prophylactic FFP infusions, and as a result six patients undergoing allogenic cord blood transplantation (CBT) developed VOD. Clinical features of these 6 patients are shown in Table 1. Under approval of Ethics Committee of Nara Medical University, we consecutively collected patient's citrated plasmas (ca 2.5 ml) and stored at -80°C until use. Using these deep-frozen plasma samples, we here extensively analyzed plasma levels of ADAMTS13 activity (ADAMTS13:AC), VWF antigen (VWF:Ag), and VWF collagen binding activity (VWF: CBA), together with VWF multimer analysis. More importantly, we also measured the corrected platelet count increment (CCI) to evaluate the efficiency of Platelet trsnsfusions. Then, we comprehensively evaluated these data with routine clinical and laboratory findings. Results and Discussion 1) Plasma levels of ADAMTS13:AC were moderately but consistently decreased during two months after HSCT, whereas those of VWF:Ag were kept high, usually more than 200% and often 500% of the normal. 2) The UL-VWFMs appeared soon after HSCT, and continued at least until absolute neutrophil count (ANC) increased to >500 (usually 20-30 days after HSCT). 3) Until platelet engraftment (usually 40-60 days after HSCT), platelet transfusions (every 2-3 days interval) are usually performed to prevent the bleeding complications. During that period, the CCI values were consistently low, but those values were significantly increased during the administration of rTM. 4) Excess platelet transfusions before platelet engraftment induced the consumption of larger VWFMs in patient's plasmas, and often almost simultaneously hepatic VOD developed. Thus, platelet transfusions during the appearance of UL-VWFMs in patient's plasmas may induce platelet clumping in microvasculatures, and lead to the development of thrombotic complications including hepatic VOD. 5) The measurement of plasma levels of VWF:CB activity appeared to well predict the presence of UL-VWFMs. A representative case is shown in Figure. Thus, a combination regimen of FFP and rTM might be advisable when the patients show the early clinical signs of hepatic VOD and the laboratory data such as VWF:CBA suggest the presence of UL-VWFMs in patient's plasmas. Disclosures: Matsumoto: Alexion Pharma: Membership on an entity’s Board of Directors or advisory committees. Fujimura:Alexion Pharma: Membership on an entity’s Board of Directors or advisory committees; Baxter International Inc: Membership on an entity’s Board of Directors or advisory committees.

scholarly journals Prolonged Circulation of Ultra-Large Von Willebrand Factor and a Reduction in ADAMTS13 Activity Promotes Microvascular Disease Following Traumatic Injury

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 444-444 ◽  
Author(s):  
William E Plautz ◽  
Mitchell Dyer ◽  
Margaret V. Ragni ◽  
Shannon Haldeman ◽  
Wyeth E Alexander ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Traumatic Injury ◽  
Microvascular Disease ◽  
Severe Trauma ◽  
Trauma Patients ◽  
Adamts13 Activity ◽  
Advisory Committees ◽  
Von Willebrand ◽  
Willebrand Factor

Introduction: Increases in plasma von Willebrand Factor (vWF) levels, accompanied by decreases in its respective metalloprotease, ADAMTS13, have been demonstrated in diseases of microvascular injury. We hypothesized that following severe trauma, a burst of ultra-large vWF (UL-vWF) is released into the bloodstream by damaged endothelium, resulting in increased thrombogenicity due to circulating vWF multimers. We further hypothesized that traumatic injury would lead to a deficit of ADAMTS13, promoting the accumulation of UL-vWF forms and, ultimately, the increased risk of microvascular disease, such as acute kidney injury (AKI). Methods: A cohort of 37 severely injured trauma patients was analyzed for antigen levels of plasma vWF and ADAMTS13 at 0- and 24-hours after admission. Circulating vWF multimeric composition from both time points was determined by vertical agarose gel electrophoresis. Multivariate analyses were performed with data abstracted from the electronic medical records to identify further dependences. A similar analysis was also performed on plasma from a cohort of 8 patients with trauma induced AKI at 0-, 24-, and 72-hours after admission; these patients were well matched against trauma patients without AKI. Finally, we utilized a murine model of polytrauma and hemorrhage, in conjunction with qRT-PCR of ADAMTS13 in total liver RNA, to specifically address how the expression of ADAMTS13 is altered by the systemic effects of traumatic injury. Results: Circulating vWF levels were increased in severe trauma patients when compared to healthy controls at presentation (189% (110-263) vs. 95% (74-120)) and persisted through 24-hours (213% (146-257) vs. 132% (57-160)). Ultra-large vWF forms were elevated at both 0- and 24-hours when compared to pooled normal plasma ((10.0% (8.9-14.3) and 11.3% (9.1-21.2), respectively, vs 0.6%). The largest vWF forms within trauma patient plasma circulated at 33±4 dimers vs 18±1 dimer in length within pooled normal plasma. Severe trauma patient ADAMTS13 activity was decreased at 0-hours (66% (47-86) vs. 100% (98-100)) and at 24-hours (72.5% (56-87.3) vs 103% (103-103)) when compared to healthy patients. Furthermore, the proportion of circulating low molecular weight multimeric (LMWM) vWF to total circulating vWF forms was directly dependent upon ADAMTS13 activity at 24-hours (Decreased ADAMTS13 Activity: 20.4% (15.0-22.7) LMWM vWF vs Normal Activity: 25.8% (22.7-35.2) LMWM vWF). Strikingly, ADAMTS13 activity independently predicted the development of coagulopathy, correlating with presentation INR (ρ =-0.63), activated clotting time of thromboelastography (TEG) (ρ=-0.36), and TEG maximum amplitude (ρ=0.36). ADAMTS13 activity also closely correlated with injury severity (ISS) (ρ=-0.34) and blood product transfusion (ρ =-.45). The cohort of 8 trauma patients who went on to develop AKI showed a 1.54-fold (1.02-2.05) increase in plasma vWF antigen levels between 0 and 72 hours, while those who did not develop AKI showed no change in vWF levels over this time period. Furthermore, those who developed AKI demonstrated a smaller proportion of LMWM vWF in plasma than those who did not (25.4% (23.4-28.0) vs 31.2% (27.2-35.6)), suggesting the increased thrombogenicity of their circulating vWF forms. Finally, qRT-PCR of total liver RNA in 6 mice demonstrated a 2-fold decrease in ADAMTS13 RNA expression levels between the times immediately before and 24-hours after trauma. Altogether, these data indicate that both circulating ADAMTS13 and its production are deficient in the days following severe injury. Conclusions: Severe traumatic injury alters the circulating composition of ADAMTS13 and its target, vWF, shifting their equilibrium to one that promotes thrombosis. Not only is the concentration of circulating ADAMTS13 decreased following traumatic injury, but hepatic expression of the enzyme is lacking as well. In the immediate moments following injury, these mechanisms contribute to life-saving hemostasis; however, as these changes extend into the following days, the early hemostatic benefit quickly shifts to burden that may exacerbate microvascular disease. Disclosures Ragni: Bioverativ/Sanofi: Consultancy, Research Funding; Sangamo: Research Funding; Shire/Takeda: Consultancy, Other: Study drug; Alnylam/Sanofi: Consultancy, Research Funding; Bayer: Consultancy; Spark Therapeutics: Consultancy, Research Funding; ICER: Consultancy; OPKO: Research Funding; Biomarin: Consultancy, Research Funding. Rollins-Raval:Bayer, Inc: Membership on an entity's Board of Directors or advisory committees. Raval:Sanofi: Membership on an entity's Board of Directors or advisory committees; Bayer, Inc: Research Funding. Neal:Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees.

A Large-Pore IEF Gel Electrophoresis Separates the Complex in Both of ADAMTS13 Bound to VWF and to the IgG Autoantibodies From the Unbound in Plasma Milieu

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1160-1160
Author(s):  
Masanori Matsumoto ◽  
Ayami Isonishi ◽  
Yuji Hori ◽  
Masaki Hayakawa ◽  
Kenji Soejima ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Gel Electrophoresis ◽  
Von Willebrand Disease ◽  
Adamts13 Activity ◽  
Advisory Committees ◽  
Normal Plasma ◽  
Large Pore ◽  
Severe Deficiency ◽  
Type 3 ◽  
Von Willebrand

Abstract Abstract 1160 Backgrounds and Aims: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening generalized disorder caused by a deficiency of ADAMTS13 activity due to its gene mutations (Upshaw-Schulman syndrome), and/or acquired autoantibodies to this enzyme. ADAMTS13 specifically cleaves the peptide bond between Tyr1605 and Met1606 within the A2 domain of von Willebrand factor (VWF). Recent studies with immunoprecipitation methods using anti-VWF antibody coated beads indicated that a small portion (3–4% of the total) of plasma ADAMTS13 is bound to VWF (Feys HB et al. JTH 7:2088, 2009). This experiment determined the amount of ADAMTS13 bound to VWF in an indirect fashion, but the complex may dissociate during washing procedures or by conformation change after binding to the antibody. Thus, we used an isoelectric focusing (IEF) to separate the complex in a direct fashion. However, the molecular size of VWF-ADAMTS13 complex is assumed to be enormously huge, and therefore a regular polyacrylamide IEF gel does not properly work. So, we employed a large-pore composite IEF gel consisting 0.75% agarose and 1.25% polyacrylamide containing 2% of Pharmalyte (pI range 3.0–10). By this method followed by western blot detection using a non-neutralizing anti-ADAMTS13 monoclonal antibody (WH2-11-1), we identified that an ADAMTS13-VWF complex is detected as a sharp band at pI 7.4. The specificity of this band was identified by a lack in plasma of type 3 von Willebrand disease (VWD), and a new emergence of the band in type 3 VWD plasma spiked with purified VWF (Hori et al, 57th ISTH meeting, P-MO-479). We applied this IEF analysis to detect the complex of ADAMTS13-its autoantibodies. Patients and Methods: ADAMTS13 activity was measured by chromogenic act-ELISA, and acquired idiopathic (ai-) TTP with severe deficiency of ADAMTS13 activity due the presence of its autoantibodies is a target in this study. VWF and ADAMTS13 were purified from normal plasma. A large-pore composite IEF gel electrophoresis was performed as previously described. Results and Discussion: Two forms of ADAMTS13, unbound (pI 5.3) and bound (pI 7.4) to VWF in a volume of 10 uL normal plasma (NP), were directly identified on the IEF gel followed by western blotting (Fig. left). Each plasma of type 3 VWD or USS lacked the complex (VWF-ADAMTS13) band with pI 7.4, but it was generated in vitro just after spiking the purified VWF or ADAMTS13 to the respective deficient plasma by the IEF (Fig. not shown). Next, when a volume of 3uL NP was analyzed, only one band with pI of 5.3 (5.1–5.5) was observed. In ai-TTP patients with severe deficiency of ADAMTS13 activity (<3% of the control), plasma had no or faint band of ADAMTS13 (Fig. middle). However, when we mixed the equal volume of patient plasma with ai-TTP with severe deficiency of ADAMTS13 activity and NP, the results on IEF gel showed appearance of 3 major bands with pIs of 5.3, 5.9 and 6.5, together with other many minor bands, and the unbound (free) ADAMTS13 almost disappeared (Fig. right). Then, the IgG purified from patient plasma of ai-TTP was mixed with NP or purified ADAMTS13, the complex band had a pI of 5.9 (5.5–6.3). These results indicated a possibility that the IEF analysis could be used to detect the autoantibodies to ADAMTS13, regardless of the neutralizing or non-neutralizing counterparts, in a totally different fashion to the enzyme immunoassay. Disclosures: Matsumoto: Alexion Pharma: Membership on an entity's Board of Directors or advisory committees. Soejima:The Chemo-Sero-Therapeutic Research Institute: Employment. Fujimura:Baxter BioScience: Membership on an entity's Board of Directors or advisory committees; Alexion Pharma: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Active and Ultra-Large Von Willebrand Factor Is Significantly Elevated in Patients with Immune Thrombotic Thrombocytopenic Purpura

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 523-523
Author(s):  
Wenjing Cao ◽  
Alicia Veninga ◽  
Elizabeth M. Staley ◽  
Adam Miszta ◽  
Nicole Kocher ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Von Willebrand Factor ◽  
Plasma Levels ◽  
Acute Episode ◽  
Healthy Controls ◽  
Plasma Samples ◽  
Adamts13 Activity ◽  
Thrombocytopenic Purpura ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Background: Immune thrombotic thrombocytopenic purpura (iTTP), a potentially fatal hematological emergency, is primarily caused by acquired deficiency of ADAMTS13 activity due to autoantibodies. Immunoglobulin G (IgG)-type autoantibodies bind ADAMTS13 and inhibit its ability to cleave endothelium-derived ultra large von Willebrand factor (ULVWF). However, it remains poorly understood whether plasma VWF status can be used as a disease marker for diagnosis and monitoring therapy in patients with acute iTTP. Objective: To address this question, we determined plasma levels of VWF antigen (VWF:Ag), collagen-binding activity (VWF:CB), active forms of VWF (VWF:Ac), and VWF multimers in iTTP patients during acute episode and in early remission. Patients and Methods: From the Alabama registry, we identified 69 unique patients with a confirmed diagnosis of iTTP in whom plasma ADAMTS13 activity was <10 U/dL with positive inhibitors and elevated anti-ADAMTS13 IgGs. Of 69 patients, 21 had longitudinal plasma samples collected. Plasma samples from 56 healthy individuals, who did not have a hematological disease, cancer, and infection, were recruited as controls. Plasma levels of VWF:Ag, VWF:CB, and VWF:Ac were determined by an ELISA-based assay. Plasma VWF multimer distribution was assessed by an in-gel Western blotting assay following electrophoresis on a 1% SDS-agarose gel. Results: The mean age for our cohort iTTP patients was 43.9 ± 13.4 years. Twenty-six patients were male and 43 were female with male to female ratio of 1 to 1.7. Fifty-three patients were African American descents, 14 Caucasians, 1 Hispanic, and 1 unknown race. Plasma levels of VWF:Ag in acute iTTP patients were 289.4 ± 17.7%, significantly increased compared with those in the healthy controls (144.9 ± 7.6%) (p<0.0001); plasma levels of VWF:CB in these patients were 241 ± 17.9%, also significantly elevated compared with those in the healthy controls (149.9 ± 12.01%) (p=0.0001); additionally, plasma levels of VWF:Ac (304.6 ± 23.2%), assessed by its ability to bind anti-VWF-A1 nanobody, were more dramatically elevated compared with those in the controls (101.6 ± 5.9%) (p<0.0001). More interestingly, while the ratios of VWF:CB to VWF:Ag in patients with acute iTTP (0.8 ± 0.04) were lower than those in the healthy controls (1.0 ± 0.05) (p=0.0036), the ratios of VWF:Ac to VWF:Ag were significantly higher in patients with acute episode (1.2 ± 0.1) than those in the controls (0.8 ± 0.05) (p=0.0003). Furthermore, there was no statistically significant difference in the patient plasma levels of VWF:Ag (p=0.69) and VWF:CB (p=0.08) during acute episode and during early remission. However, the plasma levels of VWF:Ac in patients with acute disease were significantly higher than those in the early remission (p=0.002). Surprisingly, 90% (36/40) of out iTTP patients during acute episode showed the presence of ULVWF in their plasma using in-gel Western blotting, which allows the ULVWF to be detected without the transfer step to avoid any potential loss of larger VWF multimers during protein transfer. These ULVWF multimers disappeared in 3/4 iTTP patients in remission when ADAMTS13 activity recovered. In 28 healthy control samples, only one showed ULVWF. Conclusion: Our results demonstrate, for the first time in a large cohort, that active forms of VWF and ultra large VWF multimers are present in iTTP patient's plasma during the acute period, which is reduced or disappears during the early remission. Therefore, measuring active forms of VWF and ultra large VWF multimers may aid in diagnosis of iTTP and help monitoring of disease processes following therapy. Our ongoing study is to determine whether these biomarkers can be used to predict responses to treatment and long-term outcome. Disclosures Zheng: Alexion: Research Funding, Speakers Bureau.

scholarly journals Treatment of Haemophilia a (HA) Patients with Inhibitors: Immune Tolerance Induction with a Single Factor VIII/Von Willebrand Factor Concentrate in an Observational Immune Tolerance Induction Study (ObsITI)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2482-2482
Author(s):  
C. Escuriola Ettingshausen ◽  
Erik Berntorp ◽  
Yesim Dargaud ◽  
Zeynep Gutowski ◽  
Claude Negrier ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Von Willebrand Factor ◽  
Immune Tolerance ◽  
Research Funding ◽  
Tolerance Induction ◽  
Advisory Committees ◽  
Immune Tolerance Induction ◽  
Inhibitor Titre ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Introduction and objectives: Development of neutralising inhibitors against factor VIII (FVIII) is one of the most serious and costly complications in the treatment of HA. An ongoing international, open-label, uncontrolled, multicentre observational study, ObsITI (ClinicalTrials.gov. NCT 02207894) started in 2005 to assess immune tolerance induction (ITI), the standard of care in patients with inhibitors. The study evaluates patient- and therapy-related variables on ITI course, outcome and morbidity in HA patients with inhibitors. ObsITI satellite studies additionally look at other factors related to tolerisation. Methods and Materials: As of February 2018, 193 patients from 20 countries undergoing ITI have been recruited in ObsITI. 152 patients completed the study and 41 are ongoing. A subgroup of more than 80 prospective patients were treated exclusively during the complete ITI course with a single plasma-derived (pd) FVIII concentrate that contains von Willebrand factor (VWF) in a VWF/FVIII ratio of 0.4 (Octapharma AG). According to the recommended Bonn protocol, low responders at ITI start received 50-100 IU FVIII kg-1 daily, or every other day; high responders received 100 IU FVIII kg-1 every 12 hours. Results: In this ongoing study, the majority of patients treated with the pdFVIII/VWF product achieved a negative inhibitor titre. ITI outcome was significantly correlated with the bleeding rate during ITI, the peak titre during ITI, the inhibitor titre at start of ITI >10 BU, and the number of poor prognosis factors. Conclusion: Treatment with this particular pdFVIII/VWF concentrate, mainly according to the Bonn protocol, resulted in a high ITI success rate in HA patients with inhibitors and corroborates previously published success rates (77.1% complete/partial success in 48 inhibitor patients undergoing ITI with the same product). Disclosures Escuriola Ettingshausen: SOBI: Honoraria, Research Funding; Shire: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Novo Nordisk: Honoraria; Roche: Honoraria; Grifols: Honoraria; Pfizer: Honoraria; LFB: Honoraria. Berntorp:Octapharma: Consultancy; CSL Behring: Consultancy; Shire: Consultancy, Other: honoraria for lecturing . Negrier:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LFB: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sobi/Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta/Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Research Funding. Pavlova:Novo Nordisk: Honoraria; Octapharma: Honoraria. Oldenburg:Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Swedish Orphan Biovitrum: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

scholarly journals Traumatic Hyphema in a Type 1 Von Willebrand Patient: Clinical Case and Management

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 30-30
Author(s):  
Jason Lewis ◽  
Jatinder Dhami ◽  
Michael Langue ◽  
Gayle Smink
Keyword(s):  
Intraocular Pressure ◽  
Board Of Directors ◽  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
Advisory Committees ◽  
Increased Risk ◽  
Elevated Intraocular Pressure ◽  
Von Willebrand ◽  
Willebrand Factor

Von Willebrand disease (vWD) is the most common inherited congenital bleeding disorder. Type 1 is a deficiency, but not absence, of von Willebrand factor (vWF) and is the most common type. Bleeding episodes in patients with type 1 vWD vary and are related to the relative amount of von Willebrand factor produced. We report a case of a 15-year-old male with mild von Willebrand disease type 1 (vWF: 35%) who presented with a right eye grade lll hyphema and elevated intraocular pressure (IOP) following a traumatic injury. Despite medical management with Diamox, ophthalmic steroids, vWF replacement with Humate-P, the patient had a repeat bleeding event and worsening of his elevated intraocular pressure. Due to concern for corneal blood staining, the patient required surgical intervention with an anterior chamber washout. Von Willebrand factor replacement was given on presentation and prior to the procedure with goal von Willebrand factor (vWF) activity and Factor Vlll (FVlll) levels of 80-100 IU/dL. Factor replacement for a traumatic hyphema is necessary to reduce bleeding, but could lead to increased risk of thrombosis formation and increase risk of corneal staining. Balance between bleeding and thrombosis can lead to treatment challenges in patients with bleeding disorders including vWD. Disclosures Smink: Forma Therapeutics:Membership on an entity's Board of Directors or advisory committees;Highmark Insurance:Membership on an entity's Board of Directors or advisory committees.

scholarly journals Obtaining a Von Willebrand Evaluation at Time of Acute Heavy Menstrual Bleeding Presentation Leads to Overestimation of Von Willebrand Levels

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 627-627
Author(s):  
Megan C. Brown ◽  
Michael H. White ◽  
Robert F. Sidonio
Keyword(s):  
Factor Viii ◽  
Board Of Directors ◽  
Research Funding ◽  
Heavy Menstrual Bleeding ◽  
Menstrual Bleeding ◽  
Quality Improvement Initiative ◽  
Advisory Committees ◽  
Von Willebrand ◽  
Willebrand Factor

Background: Acute heavy menstrual bleeding (HMB) is common for adolescent females, with about a quarter of menstruating females seeking care for HMB over a 3-year time period (O'Brien et al, Blood 2018). Inherited bleeding disorders are common in this adolescent population, identified in 24.6% referred for hematologic evaluation (Zia et al, Blood 2016). The timing and contents of the hemostatic workup for acute HMB in adolescents is extrapolated from adults, although the causes of acute HMB varies significantly between adult women and adolescents. A consensus statement by the American College of Obstetrics and Gynecology recommends obtaining a variety of hemostatic tests including CBC, von Willebrand studies, factor VIII, prothrombin time, partial thromboplastin time, fibrinogen, and thyroid stimulating hormone at the time of presentation (Committee Opinion 557, ACOG 2011). Factor VIII and Von Willebrand studies are known to be increased in the setting of physiologic stress and supplemental estrogen use, questioning their diagnostic accuracy in the setting of acute bleeding. Repeat testing is often required for diagnosis of von Willebrand disease A von Willebrand factor antigen (VWF:Ag) or von Willebrand factor ristocetin cofactor level over 100IU/dL has been shown to have a negative predictive value (NPV) of 95%.(Doshi et al, ASH 2018). Methods: As part of a quality improvement initiative to improve the evaluation and management of adolescents with HMB at Children's Healthcare of Atlanta (CHOA), we instituted an acute HMB protocol for emergency department (ED) and inpatient use. This protocol was implemented at all CHOA emergency departments in metropolitan Atlanta. Subjects were included if they presented with acute HMB as determined by an adapted Philip Menorrhagia Screening Tool. Subjects with a previously diagnosed bleeding disorder, ITP, active rheumatologic disease, cancer, or anticoagulant use were excluded. Descriptive statistics were used to summarize demographics and clinical characteristics. Patients with a positive Philip screen underwent a uniform bleeding inventory and a standardized set of laboratory tests based on the adult consensus statement. Inpatient and outpatient treatments were standardized by hemoglobin level and symptomology. Follow up with hematology and gynecology was encouraged for all. Data was extracted using various heavy menstrual bleeding ICD-10 codes from January 1, 2017 to December 31, 2018. Individuals with von Willebrand studies at baseline and follow up were identified. T-tests and Wilcoxon rank sum tests were utilized to compare VWF:Ag, VWF:RCo and Factor VIII as baseline and follow up. Results: Over a 2-year period, 232 adolescent girls were seen in CHOA EDs for acute HMB with 88 (37.9%) requiring admission and 6 (2.6%) requiring intensive care. The population was primarily African American (63%) with a median age at presentation of 14.8 years (IQR 13.1-16.7). The majority of adolescents had the core hemostatic labs drawn (55.6%) as described per protocol. Thirty-six individuals had baseline and follow up VWD studies. Those with repeat VWD studies were younger (median 13.2 years vs 15.0 years), more commonly white (44.4% vs 21.2%), were more likely to have been admitted (83.3% vs 29.6%) and more likely to have had a hematology follow up appointment (63.4% vs 7.8%). Mean and median VWF:Ag, VWF:RCo and Factor VIII were significantly higher at presentation with HMB than at follow up. Of those with a baseline VWF:Ag and/or VWF:RCo &gt;100, there was a 96.4% NPV for the diagnosis of VWD. For individuals whose initial VWF:Ag and VCWF:RCo were both &gt;100, there was 100% NPV. Conclusions: Among the adolescents cared for at our institution with acute HMB who had confirmatory VWD testing, initial VWF:Ag and VWF:RCo &gt;100 ruled out VWD based on repeat testing. However, poor adherence with hematology or gynecology follow-up may give false reassurance against a diagnosis of VWD. Further improvements of our quality improvement initiative will include a limited hemostatic workup at presentation with a focus on improved adherence to follow up and subsequent hemostatic evaluation. Disclosures White: National Hemophilia Foundation: Other: Shire Clinical Fellowship Program. Sidonio:Kedrion: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees; Uniqure: Membership on an entity's Board of Directors or advisory committees.

The Dendritic Cell HLA-Class-II/Therapeutic Factor VIII (FVIII) Peptidome Is Influenced in Unanticipated Ways By the B-Domain of FVIII and the FVIII Chaperon Protein, Von Willebrand Factor: The Outrigger and Glycosylation-Umbrella (GUMB) Hypotheses

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 161-161
Author(s):  
Tom E. Howard ◽  
Bernadette W. Luu ◽  
Marco Hofmann ◽  
Marcio A. Almeida ◽  
Satish Kumar ◽  
...  
Keyword(s):  
Factor Viii ◽  
Board Of Directors ◽  
Von Willebrand Factor ◽  
Human Leukocyte ◽  
Class Ii ◽  
Hla Class Ii ◽  
Proteolytic Processing ◽  
Advisory Committees ◽  
Von Willebrand ◽  
Willebrand Factor

Background: Patients with the X-linked bleeding disorder hemophilia A have impaired blood clotting due to deficient or absent factor VIII (FVIII) coagulant activity. Bleeding can be managed by infusions of any of several plasma-derived (pd) or recombinant (r) therapeutic FVIII proteins (tFVIIIs). The efficacy of tFVIIIs can be eliminated, however, if neutralizing anti-tFVIII-antibodies called "inhibitors" develop. Since the development of inhibitors is T-helper-cell dependent, human leukocyte antigen (HLA)-class-II (HLAcII) molecules comprise an important early determinant. Accumulating evidence suggests that the presence of the FVIII chaperon protein, von Willebrand factor (VWF), in either pdFVIII or rFVIII concentrates, decreases the immunogenicity of these tFVIIIs by reducing their uptake by antigen presenting cells, especially dendritic cells (DCs). Objectives: Use a native (i.e., non-engineered) full-length (FL) tFVIII without ((−)) or with ((+)) pdVWF in DC-protein processing and presentation assays (PPPAs) followed by mass-spectrometric and peptide-proteomic analyses to identify and quantify the DP-, DQ-, and DR-bound/tFVIII-derived-peptides in individual HLAcII repertoires. Compare the number of peptides in the subset from any of the five globular domains (A1, A2, A3, C1 and C2) or three acidic-residue-rich connecting segments (a1, a2 and a3), which we collectively refer to as the non-B-domain (NBD) portion of a tFVIII, with the number of peptides from its non-globular "outrigger like" B-domain (BD) that contains ~80% of the N-linked glycans of a FL-FVIII molecule despite containing only 908 amino acid residues, i.e. slightly less than 40% of its 2,332 total residues. Methods: DC-PPPAs were performed using monocyte-derived (Mo)DCs obtained from 12 healthy blood donors. The tFVIII tested was a FL-rFVIII (Advate®) used (−) or (+) pdVWF (i.e., FL-rFVIII − pdVWF and FL-rFVIII + pdVWF) and the resulting data consists of counts of tFVIII-derived peptides presented on and extracted from HLAcII molecules. Difference of proportion tests were used to compare the effect of pdVWF as well as the NBD- and BD-regions of the FL tFVIII on the peptide counts. Results: FL-rFVIII − pdVWF yielded significantly more peptides (p&lt;0.05) than FL-rFVIII + pdVWF from the NBD portions but not the BD. Interestingly, for the FL-rFVIII − pdVWF preparation, the NBD portions yielded significantly more peptides (p&lt;0.05) than the BD, but this pattern was reversed for the FL-rFVIII + pdVWF preparation in that the NBD portions yielded significantly less peptides (p&lt;0.05) than the BD. Conclusions: The Outrigger Hypothesis posits that in the presence of VWF the heavily glycosylated BD acts as an "outrigger" and renders this portion of a FL tFVIII relatively more likely to be internalized, proteolytically processed and HLAcII-presented. However, in the absence of VWF, the N-linked glycans individually act to protect the amide bonds in the underlying peptide bond backbone of a tFVIII from proteolytic processing, as posited by the GUMB Hypothesis. Our results support both hypotheses as important determinants in the pathogenesis of inhibitor development. Disclosures Howard: Haplogenics Corporation: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Luu:Haplogenics Corporation: Employment. Hofmann:CSL Behring: Employment. Dinh:Haplogenics Corporation: Employment. Mead:CSL Behring: Employment. Powell:Haplogenics: Membership on an entity's Board of Directors or advisory committees. Escobar:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; National Hemophilia Foundation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees. Eugene:CSL Behring: Employment.

scholarly journals the Diagnostic Value of Plasma Level, Activity, Ratios between von Willebrand Factor and ADAMTS13 in Patients with Cerebral Infarction

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5003-5003
Author(s):  
Le Qu ◽  
Changgeng Ruan ◽  
Yiming Zhao
Keyword(s):  
Cerebral Infarction ◽  
Von Willebrand Factor ◽  
Plasma Levels ◽  
Conflicts Of Interest ◽  
Large Population ◽  
Medical Science ◽  
Diagnostic Value ◽  
Adamts13 Activity ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Introduction: Large population studies have revealed that higher levels of von Willebrand Factor (VWF) and lower levels of ADAMTS13 activity (ADAMTS13) are associated with a risk of thrombosis. In this study, we aimed to investigate the relationship among the plasma levels of VWF, ADAMTS13 and the occurrence of cerebral infarction in patients. Methods: In a case-control study of 94 cerebral infarction patients (CIP) and 103 age-matched healthy controls (Control), the plasma levels of VWF antigen (VWF:Ag ), VWF ristocetin cofactor activity (VWF:Rcof), and VWF collagen binding activity (VWF:CB) were measured using ELISA. ADAMTS13 activity (ADAMTS13) was measured with FREST-VWF73. The study was approved by the institutional Ethics Committee at the First Affiliated Hospital of Soochow University, China. All participants were given write informed consents. Results: The levels of VWF:Ag and VWF:Rcof in cerebral infraction patients (mean±SEM, 223±15% and 256±20%) were significantly higher compared with controls (117±8% and 128±9%). Levels of ADAMTS13 and ratios of VWF:CB/VWF:Ag, ADAMTS13/VWF:Ag and ADAMTS13/VWF:Rcof in patients (107±4%, 0.73±0.08, 0.76±0.07 and 0.86±0.10, respectively) were significantly lower compared with controls (125±3%, 1.37±0.08, 1.69±0.14 and 1.45±0.10, P<0.001, respectively). However, there was no difference between cerebral infarction patients and controls in the levels of VWF:CB, VWF:Rcof/VWF:Ag and ADAMTS13/VWF:CB (P>0.05). Unconditional logistic regression analysis demonstrated the highest quartile of VWF:Ag (odds ratio [OR] = 5.11, 95% confidence interval [CI], 1.49-17.50), VWF:Rcof (OR = 5.04, 95% CI, 1.62-15.66), and the lowest quartile of VWF:CB/VWF:Ag (OR = 5.91, 95% CI, 1.95-17.93), ADAMTS13/VWF:Ag (OR = 9.11, 95% CI, 2.49-33.33), ADAMTS13/VWF:Rcof (OR = 3.73, 95% CI, 1.39-10.03) were associated with cerebral infarction (P<0.01). The receiver operating characteristic (ROC) curves analysis demonstrated the cutoff values of VWF:Ag (137.88%), VWF:Rcof (135.88%) and VWF:CB/VWF:Ag (0.538), ADAMTS13/VWF:Ag (0.974), ADAMTS13/VWF:Rcof (0.946) showed a better diagnostic value of cerebral infarction (AUC > 0.7). Conclusions: High levels of VWF:Ag, VWF:Rcof and lower levels of VWF:CB/VWF:Ag, ADAMTS13/VWF:Ag, ADAMTS13/VWF:Rcof are relative risk factors. The threshold of VWF:Ag ( > 137.88%), VWF:Rcof ( > 135.88%), VWF:CB/VWF:Ag ( ≤ 0.538), ADAMTS13/VWF:Ag ( ≤ 0.974), ADAMTS13/VWF:Rcof ( ≤ 0.946) can be diagnostic indicators of cerebral infarction. Research funding: This work was supported by grants from National Scientific Foundation of China (NSFC) (81270593), Jiangsu Provincial Special Program of Medical Science (BL2012005) and Jiangsu Province’s Key Medical Center (ZX201102), China Disclosures No relevant conflicts of interest to declare.

scholarly journals Von Willebrand Factor to Prevent Postpartum Hemorrhage

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1400-1400 ◽  
Author(s):  
Nicoletta Machin ◽  
Margaret V. Ragni ◽  
Andra H. James ◽  
Craig D. Seaman ◽  
Lynn M. Malec ◽  
...  
Keyword(s):  
Blood Loss ◽  
Board Of Directors ◽  
Research Funding ◽  
Structured Interviews ◽  
First Line ◽  
Vascular Medicine ◽  
Advisory Committees ◽  
Thrombosis Risk ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Background: Von Willebrand disease (VWD) is the most common inherited bleeding disorder and is characterized by deficient and/or defective von Willebrand factor (VWF) which results in spontaneous and traumatic mucosal bleeding. In women with VWD, pregnancy is associated with excess blood loss and poor quality of life. Recently, a prospective cohort study by James et al Haemophilia 2015, determined that even when treatment is given, women with VWD had lower VWF levels, greater blood loss at delivery, and lower hematocrit than controls without VWD. The reason for this finding remains unknown. Current VWF dosing is weight-based, but does not account for the ~1.4-1.5-fold increase in blood volume during pregnancy. To address this, we conducted a feasibility study for a prospective, randomized phase III trial comparing weight-based, 50 IU/kg, with volume-based, 80 IU/kg, VWF to prevent postpartum hemorrhage (PREVENT PPH Trial). Methods: To establish trial feasibility: 1) we compared pre-pregnancy and 8th-month VWF levels in women with VWD with and without PPH (≥500 cc blood loss in the 1st 24 hours) following vaginal delivery; 2) we evaluated VWF dosing in women with PPH in the James study; 3) we assessed thrombosis risk and VWF concentrate dose by literature review; 4) we surveyed current practice regarding VWF concentrate use at delivery by U.S. hemophilia treatment center (HTC) MDs; and 5) we conducted structured interviews of MDs and VWD patients to determine trial acceptability. Analysis was by Student's t-test for continuous data, and Fisher's exact test for discrete data. Results:In the Retrospective VWD-PPH Study of 16 women with VWD (14 type 1; 2 type 2) undergoing vaginal delivery, PPH was associated with higher pre-delivery weight, pre: 88.1 vs. 67.6 kg; 8thmonth: 99.9 vs. 75.0 kg; and delivery: 104.0 vs. 78.6 kg, all p<0.005; and a family bleeding history, 75.0% vs. 12.5%, p=0.041. Women with PPH had lower pre-pregnancy VWF:RCo, 0.34 IU/ml vs. 0.48 IU/ml, non-significant, p=0.067; similar 8th month VWF:RCo, 1.31 IU/ml vs. 1.45 IU/ml, p=0.484, and were more likely to be treated with VWF, 75.0% vs. 37.5%, p=0.315. Pre-pregnancy bleeding score (BS) correlated directly with EBL (blood loss) at delivery, r=0.663, p=0.005. VWF Dosing Data from James co-authors indicated a mean VWF dose of 46 IU/kg (median 50 IU/kg), range 28-83 IU/kg, at delivery, followed by 3.8 days (median 3 days), range 2-19 days, postpartum treatment. The Literature Review identified 13 publications between 1992-2015 reporting pharmacokinetic, safety, and/or efficacy studies in a total of 570 patients (none pregnant) at VWF doses 10-222 IU/kg. Thrombosis rate was low, 0.4%, including 2 of 353 (0.6%) receiving plasma-derived (pd) VWF and none of 95 (0%) receiving recombinant (r) VWF: these two patients included one with injection-site phlebitis and one with a remote postoperative VTE, each receiving VWF≤100 IU/kg. An HTC Survey distributed to 70 MDs, 19 (27.1%) of whom responded, 16/18 (88.9%) reported VWF was first-line therapy at delivery, mean dose 50 IU/kg; DDAVP was the most common second-line therapy in 7/17 (41.2%), and anti-fibrinolytic therapy was third-line, 8/10 (80.0%). All 19 indicated interest and willingness to participate in a trial comparing weight-based, 50 IU/kg, vs. 1.6-fold higher volume-based, 80 IU/kg, VWF at delivery. In Structured Interviews of 18 MDs and 18 VWD patients, the trial was acceptable to MDs if staff costs are covered, if the drug is safe re thrombosis, if there are sufficient patients, and if there is obstetrician collaboration to facilitate in-hospital dosing and blood draws. The trial was also acceptable to VWD patients if the drug is safe for mother and child, if childcare and travel costs are covered, and if visits are minimized in the postpartum period. Conclusions: The findings of this feasibility study indicate that pre-pregnancy VWF:RCo may be a better predictor of PPH than 8thmonth VWF:RCo. High pre-delivery weight which is associated with high blood volume may increase PPH, possibly through dilution of VWF levels. A VWF dose of ~50 IU/kg, which is the first line of therapy at delivery and the current standard of practice, may not prevent PPH. Thrombosis risk with VWF in published studies is low even at doses >80 IU/kg. Drug safety, local obstetric collaboration, and coverage of staff, travel, and childcare costs are critical issues to address in trial design. Disclosures Ragni: SPARK: Research Funding; Genentech: Research Funding; Tacere Benitec: Consultancy; Vascular Medicine Institute: Research Funding; OPKO: Research Funding; Novo Nordisk: Research Funding; Alnylam Pharmaceuticals: Consultancy, Research Funding; Baxalta: Research Funding; Biogen: Consultancy, Research Funding; Biomarin: Consultancy; Shire: Consultancy; CSL Behring: Research Funding. James:Intramural University of Ghana Research Fund: Research Funding; Vanderbilt University Medical Center Gift Funds: Research Funding. Malec:Biogen: Consultancy; Vascular Medicine Institute: Research Funding; Biogen: Research Funding; Baxalta: Research Funding. Kessler:Octapharma: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; Grifols: Consultancy; Genentech: Consultancy, Research Funding; Biogen: Consultancy; Bayer: Consultancy, Research Funding; Pfizer: Consultancy; Baxalta: Consultancy, Research Funding; LFB: Other: Member of DSMB. Kouides:CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta: Consultancy. Neff:Shire: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: DSMB Chair for research study; ABIM: Other: Hematology Exam committee; CSL Behring: Membership on an entity's Board of Directors or advisory committees; HEMA Biologics: Membership on an entity's Board of Directors or advisory committees. Philipp:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: Data Safety Monitoring Board. Brooks:Gilead Sciences: Research Funding.

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