Antithrombotic prophylaxis in patients with von Willebrand disease undergoing major surgery: when is it necessary?

2008 ◽  
Vol 28 (2) ◽  
pp. 215-219 ◽  
Author(s):  
Massimo Franchini ◽  
Giovanni Targher ◽  
Martina Montagnana ◽  
Giuseppe Lippi
Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 759-759
Author(s):  
Augusto Bramante Federici ◽  
Giancarlo Castaman ◽  
Alfonso Iorio ◽  
Emily Oliovecchio ◽  
Prodeswil Investigators

Abstract Introduction. Despite the fact that desmopressin (DDAVP) is considered the treatment of choice in the majority of patients with inherited von Willebrand disease (VWD), there are still open questions about the efficacy and safety of the use of DDAVP to manage recurrent bleeding episodes, delivery and major surgery. In fact, to avoid tachyphylaxis and possible side effects with repeated DDAVP injections, VWF concentrates are usually preferred to manage delivery and major surgery also in VWD patients proven to be DDAVP-responsive. No prospective data have been reported so far to correlate biological response with DDAVP clinical efficacy in VWD and guide clinical practice. Design, aims and methods. ProDesWilis an investigator-driven Pro spective study on D esmopressin e fficacy and s afety of patients with inherited von Wil lebrand disease assessed at enrolment for DDAVP biological response during a test-infusion. Inclusion criteria: VWD diagnosis without any age restriction according to bleeding score >4, VWF activity levels <45U/dL, and at least another affected member in the family. DDAVP Biological Response: VWD were classified as complete, partial or no-responders as previously reported (Blood 2008;111:3531). Treatment regimens: DDAVP given intravenously or subcutaneously (0.3 ug/Kg) or by nasal spray (4 ug/Kg) according to preparations available in different countries with or without standard doses of anti-fibrinolytic agents (Epsilon-amino-caproic acid, EACA or tranexamic acid, TA). In case of major surgery, DDAVP was used together with TA using a 3dayOn-4dayOff-3dayOn schedule. DDAVP efficacy-safety evaluated with criteria currently used for VWF concentrates, with poor efficacy defined when VWF concentrates were needed. Patients were prospectively followed up for 24 months by ProDesWil Investigators who reported detailed information about DDAVP therapy used for bleeds, deliveries, oral and minor/major surgeries Results. 268 patients were enrolled in this 24-month prospective study. DDAVP-biological response: 225/268 (85%) patients met inclusion criteria as VWD1(n=184), VWD1C (n=14), VWD2A(n=15), VWD2M(n=12). The 14 VWD1C with accelerated clearance carried C1130F and R1205H mutations. DDAVP biological response was complete, partial and absent in 89%, 10% and 1% of all VWD. DDAVP clinical efficacy and safety: during the 24-month follow-up 84/225 (37.3%) received DDAVP for bleeding episodes (n=104), oral surgeries (n=33), deliveries (n=12), other minor/major surgeries (n=25). Total DDAVP injections were 652 with median, range/episode during bleeds (2,1-12), oral surgeries (1,1-10), deliveries (3,1-13), minor/major surgeries (3.6,1-16). Clinical efficacy was excellent/good in bleeds (93.3%), oral surgery (100%), deliveries (91.7%), minor/major surgeries (92.3%). All VWD treated for oral surgery with (75%) and without (25%) EACA/TA had excelled/good outcomes. Efficacy was rated excellent/good in 96/104 bleeds, with 8 episodes rated poor during menorrhagia (n=4) in 2 VWD1 and 2 VWD2A, during nose (n=2) and gastrointestinal (n=2) bleeds in 3 VWD2A and 1 VWD1C. 11/12 deliveries had excellent/good outcome with poor response in only one VWD1C who required VWF concentrates after caesarean section. All the 11/25 cases with minor surgeries had excellent outcomes. Among the 14/25 major surgeries [abdominal (n=5), hysterectomy (n=3), tonsillectomy (n=3), orthopaedic and others (n=3)] 2 episodes (partial resection of kidney in VWD2A and tonsillectomy in VWD1) were rated poor. Side effects (16 cases) were mainly minor (flushing, headache, tachycardia) with water retention reported only in 2 patients who received >12 doses of DDAVP for delivery or major surgery. Conclusions: DDAVP is an effective, safe and cheap treatment for managing patients with mild-moderate VWD who showed complete biological response to this drug. Therefore, DDAVP must be always recommended as first line therapy in responsive VWD not only in bleeds and oral surgery but also in deliveries and major surgeries. On the other hands, DDAVP should be used with caution in VWD2A and VWD1 with partial response. The additional use of EACA/TA should be considered especially when DDAVP is required for more than 4 days. Disclosures No relevant conflicts of interest to declare.


2011 ◽  
Vol 105 (06) ◽  
pp. 1072-1079 ◽  
Author(s):  
Mario von Depka-Prondzinski ◽  
Jerzy Windyga ◽  

SummaryThe aim of this study was to assess the efficacy of Wilate®, a new generation, plasma-derived, high-purity, double virus-inactivated von Willebrand factor (VWF) and factor VIII (FVIII) concentrate (ratio close to physiological 1:1) in the perioperative management of haemostasis in von Willebrand disease (VWD). Data for VWD patients who received Wilate® for perioperative management were obtained from four European, prospective, open-label, non-controlled, non-randomised, multicentre phase II or III clinical trials. A total of 57 surgical procedures were performed (major: n = 27; minor n = 30) in 32 patients. The majority of patients (n = 19, 59.4%) had type 3 VWD, 9 (28.1%) had type 2 VWD and four (12.5%) had type 1 VWD. During major surgery, median daily FVIII dose and mean number of infusions were 25 IU•kg-1 FVIII (VWF:RCô23 IU•kg-1) and 11.0, respectively. Corresponding values for minor surgery were 35 IU•kg-1 (VWF:RCo ~32 IU•kg-1) and 1.5. The efficacy of Wilate® was rated by the investigator as excellent or good in 51 of 53 (96%) procedures. Tolerability was rated as very good or good in 100% of major surgeries (27 of 27) and minor surgeries (29 of 29). Wilate® is an effective and well-tolerated VWF/FVIII replacement therapy in the perioperative management of haemostasis in patients with VWD. It can be administered at a similar FVIII dose, but at a lower VWF dose, as compared to older generation products. Clinical benefits were shown in a population with a high proportion of type 3 VWD patients.


Blood ◽  
2015 ◽  
Vol 125 (6) ◽  
pp. 907-914 ◽  
Author(s):  
Alberto Tosetto ◽  
Giancarlo Castaman

AbstractType 2 von Willebrand disease (VWD) includes a wide range of qualitative abnormalities of von Willebrand factor structure and function resulting in a variable bleeding tendency. According to the current classification, 4 different subtypes can be identified, each with distinctive phenotypic and therapeutic characteristics. Current available laboratory methods allow a straightforward approach to VWD subtyping, and although the precise molecular characterization remains complex, it is not required for appropriate treatment of the vast majority of cases. Desmopressin can be useful only in a few type 2 cases compared with patients with actual quantitative deficiency (type 1), most often in variants with a nearly normal multimeric pattern (type 2M). However, since no laboratory test accurately predicts response to desmopressin, a trial test should always be performed in all type 2 VWD patients, with the exception of type 2B ones. Replacement therapy with plasma-derived von Willebrand factor-factor VIII concentrates represents the safe mainstay of treatment of all patients, particularly those not responding to desmopressin or requiring a sustained hemostatic correction because of major surgery or bleeding. A significant patient bleeding history correlates with increased bleeding risk and should be considered in tailoring the optimal antihemorrhagic prophylaxis in the individual patient.


2016 ◽  
Vol 17 (2) ◽  
pp. 59-65
Author(s):  
Giancarlo Castaman

BACKGROUND: Replacement therapy with von Willebrand factor (VWF)/factor VIII (FVIII) concentrates represents an effective approach for patients with von Willebrand disease (VWD) who are unresponsive to desmopressin. However, various concentrates are available, with heterogeneous VWF content and VWF/FVIII ratio.AIM: To compare the costs associated to the replacement therapy with VWF/FVIII concentrates in Italy.METHODS: A cost-minimization analysis was performed to compare the pharmaceutical costs per patient of alternatives available for replacement therapy of VWD in the prospective of the Italian National Health Service. For each alternative the analysis calculated the number of vials, and relative costs, required to reach the target levels of VWF:RCo in patients who undergone to major surgery, minor surgery, spontaneous bleeding and prophylaxis.RESULTS: Haemate P® is associated with the lowest FVIII dosage, numbers of vials used and costs in all the clinical situations and at all the dosages considered. With Haemate P® the average costs in major surgery, minor surgery, spontaneous bleeding, and prophylaxis was € 710.94, € 592.45, € 473.96, and € 592.45, respectively. While the costs associated to Fanhdi®, Wilate®, and Wilfactin® was: € 1,309.28, € 1,071.23, € 952.20, and € 1,190.25; € 1,512.45, € 1,344.40, € 1,176.35, and € 1,344.40; € 3,814.09, € 3,269.22, € 3,269.22, and € 3,814.09.CONCLUSIONS: Treatment with Haemate P®, which presents a low FVIII content, allows to reach the target level of VWF:RCo with a lower number of vials and lower costs for the NHS.[Article in Italian]


Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3951-3951
Author(s):  
M. Elaine Eyster ◽  
Charles L. Sexauer ◽  
Simon Brown ◽  
Richard A. Lipton ◽  
Craig M. Kessler ◽  
...  

Abstract Objective: To assess the efficacy of Alphanate® as replacement therapy in subjects with congenital VWD undergoing surgical or invasive procedures. Methodology: Retrospective data from 5 hospitals and accounting for 8 years of chart review has been collected. The study protocol and the subject’s informed consent were approved by the local Institutional Review Boards. To date, 35 treated events (27 subjects) have been evaluated. Events were classified by local investigators and an independent referee committee as major or minor surgery, and invasive procedures. Treatment efficacy was rated using a 4-point verbal rating scale. Replacement therapy was considered effective if the treatment outcome was rated as excellent or good, and non-effective when the outcome was rated as poor or none. Results: Efficacy results (number and percentage) obtained by local investigators and the referee committee are presented in Tables 1 and 2. Conclusions: Since there may be bias in the interpretation of responses made by the participating physicians, it was felt that true responses might better be assessed retrospectively by an adjudication committee. Therefore, both Tables were presented here. Much of the discrepancies between these 2 tables was generated by oral surgery. There was a high level of efficacy agreement between investigators and the referree committee. Therefore, it is concluded that Alphanate® is effective in preventing excessive bleedings during surgeries and invasive procedures in subjects with congenital VWD. Table 1. Efficacy Results Obtained by Investigators Major surgery (n=9) Minor surgery (n=17) Invasive procedure (n=9) Total (n=35) Excellent 6 (66.7%) 14 (82.4%) 8 (88.9%) 28 (80.0%) Good 3 (33.3%) 1 (5.9%) 1 (11.1%) 5 (14.3%) Poor 0 (0.0%) 1 (5.9%) 0 (0.0%) 1 (2.9%) None 0 (0.0%) 1 (5.9%) 0 (0.0%) 1 (2.9%) Table 2. Efficacy Results Obtained by Referee Committee Major Surgery (n=12) Minor Surgery (n=11) Invasive Procedure (n=12) Total (n=35) Excellent 8 (66.7%) 11 (100%) 11 (91.7%) 30 (85.7%) Good 1 (8.3%) 0 (0.0%) 0 (0.0%) 1 (2.9%) Poor 3 (25.0%) 0 (0.0%) 1 (8.3%) 4 (11.4%) None 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)


Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1120-1120
Author(s):  
John C. Chapin ◽  
Jacqueline Bamme ◽  
Fraustina Hsu ◽  
Paul Christos ◽  
Maria Teresa De Sancho

Abstract Introduction Adults with hemophilia and von Willebrand disease (VWD) frequently require surgical and invasive procedures. There is variability in current practice of peri-operative management in major surgery and in the management of invasive procedures. The purpose of this study was to evaluate outcomes and management strategies in patients with hemophilia and VWD undergoing surgical and invasive procedures in a comprehensive hemophilia center at a tertiary care hospital. Methods A retrospective review of electronic medical records was carried out from patients with hemophilia and VWD seen at the Weill Cornell Hemophilia Treatment Center undergoing surgery or an invasive procedure from January 2006 to December 2012. Information on demographics, diagnosis, severity, and presence of inhibitors was also collected. Procedures and treatment strategies were reviewed including the type of procedure, use of factor bolus/DDAVP, continuous infusion(CI), and antifibrinolytics. Outcomes from these cases were reviewed for acute bleeding (<48 hours after procedure), delayed bleeding (>48 hours after procedure), transfusion of blood products, inhibitor development, and post-procedure thrombosis. Data were compared using Fischer’s exact test. Results Our study population consisted of 59 patients (mean age=58, range 21-77). Our hemophilia group included 41 with hemophilia A and 7 with hemophilia B. Our hemophilia patients were severe (n=24), mild-mod (n=12), and 12 had inhibitors. We also identified 5 female carriers of hemophilia A.We identified 6 VWD patients including Type 1 (n=3), 2A (n=1), 3 (n=2). We reviewed 34 major surgeries (26 orthopedic, 8 non-orthopedic) and 91 invasive procedures. We covered all patients an initial dose of either factor VIII/IX or DDAVP. In addition, 55.9% of major procedures were covered by continuous factor infusion (CI), whereas only 9.9% of minor procedures were covered by CI. Conversely, antifibrinolytics were used in 14.7% of major surgeries and 34.1% of minor procedures. Antifibrinolytics were used in all types of minor procedures except those involving the genitourinary tract. Hematologic outcomes are shown in Table 1. We identified 4 cases of acute bleeding and 10 cases of delayed bleeding. We also identified 5 cases of inhibitor development. We identified one thrombotic episode in an orthopedic surgery case. We further examined several classes of procedures including dental, GI endoscopies, GU procedures, biopsies, and GYN procedures in carriers. One transfusion was needed in the case of a liver biopsy; acute bleeding was noted in 2 biopsies and 1 endoscopy. Delayed bleeding accompanied 28.6% of GU procedures and 16.1% of dental procedures. Inhibitor development was noted after 1 GU procedure and 2 dental procedures. Conclusions Our adult hemophilia and VWD population undergoing minor procedures showed similar rates of adverse hematologic outcomes compared to major surgery. This finding highlights the significant risk of even minor procedures in adults with bleeding disorders. Appropriate treatment standards should be designed to take into account patient responses, procedure type, and anticipated outcomes. Disclosures: No relevant conflicts of interest to declare.


Hematology ◽  
2019 ◽  
Vol 2019 (1) ◽  
pp. 604-609 ◽  
Author(s):  
James S. O’Donnell ◽  
Michelle Lavin

Abstract Surgical procedures represent a serious hemostatic challenge for patients with von Willebrand disease (VWD), and careful perioperative management is required to minimize bleeding risk. Risk stratification includes not only the nature of the surgery to be performed but the baseline plasma von Willebrand factor (VWF) levels, bleeding history, and responses to previous challenges. Baseline bleeding scores (BSs) may assist in identification of patients with a higher risk of postsurgical bleeding. There remains a lack of consensus between best practice guidelines as to the therapeutic target and assays to be monitored in the postoperative period. Hemostatic levels are maintained until bleeding risk abates: usually 3 to 5 days for minor procedures and 7 to 14 days for major surgery. Hemostatic supplementation is more complex in VWD than in other bleeding disorders owing to the combined but variable deficiency of both plasma VWF and factor VIII (FVIII) levels. For emergency surgery, coadministration of VWF and FVIII is required to ensure hemostasis; however, for elective procedures, early infusion of VWF replacement therapy will stabilize endogenous FVIII. Because endogenous FVIII production is unaffected in patients with VWD, repeated VWF supplementation (particularly with plasma-derived FVIII-containing products) may lead to accumulation of FVIII. Frequent monitoring of plasma levels and access to hemostatic testing are, therefore, essential for patients undergoing major surgery, particularly with more severe forms of VWD.


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4692-4692
Author(s):  
Abiola Oladapo ◽  
Yanyu Wu ◽  
Mei Lu ◽  
Sepehr Farahbakhshian ◽  
Bruce Ewenstein

Background: von Willebrand disease (VWD), a rare, inherited bleeding disorder, is associated with impaired hemostasis resulting from a quantitative or qualitative deficit in von Willebrand factor. Limited information exists on the economic burden associated with major surgeries in this patient population, and real-world data may help determine the impact of these procedures. Aims: To estimate the incremental economic burden associated with major surgeries in patients with VWD compared with patients without VWD who had similar types of surgery. Methods: Accessing data from the Truven US health care database (January 2008 to December 2018), we analyzed data from patients with VWD (based on ≥2 diagnoses from different hospital admissions/physician visits, excluding laboratory and radiology orders) and patients without VWD who had undergone a major surgical procedure. The surgical procedure was defined as a medical claim associated with a major therapeutic operating room procedure (International Classification of Diseases, 9th/10th revision codes) or a major procedure (Current Procedural Terminology code). For patients with VWD, the surgical procedure had to have occurred on or after their first VWD diagnosis. Patients without VWD who had undergone major surgeries were selected from a 1% random sample of the Truven database. Patients from both groups (ie, VWD and non-VWD) were included in the study if they had continuous health care plan enrollment ≥12 months prior to (baseline period) and ≥12 months following (study period) their first major surgery, no diagnosis of acquired coagulation factor deficiency, and not undergone surgery used to reduce bleeding associated with VWD (ie, uterine ablation, nasal ablation, or hysterectomy). Patients with VWD were matched (1:1) with patients without VWD using propensity score matching. Health care resource utilization (HCRU: inpatient [IP] admission, emergency room [ER] visits, and outpatient [OP] visits) and associated costs (pharmacy or medical; adjusted to 2018 US dollars [USD] using the medical component of the Consumer Price Index) were measured over the 12-month study period. Adjusted analyses controlling for age, sex, region, health plan, index year, Charlson Comorbidity Index (CCI), comorbidity profile (anemia, anxiety, depression, fatigue, and obesity), and baseline HCRU were conducted using generalized linear regression models. Results: After propensity score matching, 2972 patients with VWD and 2972 patients without VWD who had ≥1 major surgery were selected for analysis (mean [SD] age, 40.53 [20.56] and 40.94 [20.33] years, respectively; female, 73.3% and 73.6%, respectively). Mean (SD) CCI was 0.66 (1.26) and 0.64 (1.30), respectively; and anemia, anxiety, depression, fatigue, and obesity were present in a similar proportion of each group (7−18% of patients with or without VWD). The most common major surgeries were musculoskeletal or digestive in patients with or without VWD (39.6% and 25.0% vs 37.1% and 23.4%, respectively). Patients with VWD were significantly (P<0.0001) more likely to have an IP admission (odds ratio [OR], 1.71; 95% confidence interval [CI], 1.52−1.92) or ER visit (OR, 1.41; 95% CI, 1.25−1.59) than patients without VWD. They also had significantly (P<0.0001) more frequent IP admissions (incidence rate ratio [IRR], 1.47; 95% CI, 1.35−1.60), ER visits (IRR, 1.44; 95% CI, 1.31−1.59), and OP visits (IRR, 1.16; 95% CI, 1.11−1.21) than patients without VWD. Patients with VWD incurred significantly (P<0.0001) higher total health care costs than patients without VWD ($50,733.89 USD vs $30,154.84 USD). The majority of costs were medical: $41,943.22 USD in patients with VWD and $26,233.83 USD in patients without VWD. Conclusions: In this large retrospective analysis of a US commercial health care database, patients with VWD incurred significantly higher HCRU and associated costs following major surgeries compared with patients without VWD who had similar surgeries. Disclosures Oladapo: Baxalta US Inc., a Takeda company: Employment, Equity Ownership. Wu:Shire US Inc., a Takeda company: Employment, Other: a Takeda stockowner. Lu:Baxalta US Inc., a Takeda company: Employment, Equity Ownership. Farahbakhshian:Shire US Inc., a Takeda company: Employment, Equity Ownership. Ewenstein:Baxalta US Inc., a Takeda company: Employment, Equity Ownership, Other: a Takeda stock owner.


Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3385-3385 ◽  
Author(s):  
Giancarlo Castaman ◽  
Alberto Tosetto ◽  
Augusto B. Federici ◽  
Francesco Rodeghiero

Abstract Background. von Willebrand disease Vicenza (VWD-VI) is characterized by severely reduced FVIII and VWF levels, the presence of ultra-large multimers in plasma, heightened response to desmopressin and increased clearance of VWF after desmopressin. Increased clearance of VWF has been identified in other VWF mutations, such as C1130F with similarly low FVIII/VWF levels as in VWD-VI. So far, the bleeding risk of these patients has not been formally established and it is unclear whether they need a different treatment approach. Aims, Design of the study, Patients and Methods. We prospectively evaluated the clinical history of 60 patients (32 M, 28 F) with VWD Vicenza (carrying R1205H mutation) and 23 patients (9 M, 14 F) with C1130F mutation, both characterized by increased VWF clearance. All in-hospital visits for bleeding symptoms, treatments and prophylaxis prior to invasive procedures were recorded together with home-treatments. All the remaining patients were contacted yearly to update their bleeding symptoms, if any. The study lasted from January 2002 to December 2007. Results. During follow-up, 21/60 (35 %) and 9/23 (39 %) of patients with VWD-VI or C1130F respectively did not require treatment for bleeding or prior to invasive procedures. Ten patients with VWD-VI and 5 with C1130F had 1 to 3 tooth extraction instances treated with a single desmopressin infusion plus oral tranexamic acid for 5 days, without mishap. A single patient carrying out dental extraction without any prophylaxis had bleeding promptly stopped by a single desmopressin infusion. Four women with VWD-VI and 6 with C1130F had 1 or 2 pregnancies during follow-up, and successfully completed delivery by using two or three desmopressin infusions over 24-48 hours after vaginal delivery. Epistaxis requiring consultation or treatment was almost limited to pediatric age and a single adult patient only required treatment for an isolated episode. A single post-traumatic joint bleeding required a successful treatment with desmopressin. Only 3/15 (20 %) women in fertile age with VWD-VI required treatment for menorrhagia (iron suppletion, combined oral estroprogestinic pill, tranexamic acid) compared to 8/9 (89 %) with C1130F mutation. Most minor surgical interventions were successfully covered with desmopressin while major surgery required FVIII/VWF concentrates since prolonged hemostasis was required. Conclusions. Spontaneous bleeding in patients with VWD-VI and C1130F appeared to be mainly limited to epistaxis in pediatric age and menorrhagia in females. Most of clinical situations are successfully manageable with desmopressin, as usually occurs for other type 1 VWD patients, and despite the short FVIII and VWF half-life post-infusion.


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