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Introduction: There is limited awareness of von Willebrand disease (VWD), leading to challenges in both diagnosis and defining the optimal treatment approach for these patients. Patients with VWD are typically treated on-demand, with short-term prophylaxis used during surgery. In contrast, early initiation, and long-term use of prophylaxis is the standard of care in patients with severe haemophilia and can be successfully used to prevent joint bleeding and reduce chronic arthropathy.
Aim: To provide an understanding of the current evidence for the prophylactic treatment of patients with VWD and compare this to the management of patients with haemophilia.
Methods: Review of published literature using a non-systematic search of PubMed and reference lists of sourced articles.
Results: The successes seen with prophylaxis in haemophilia provide the rationale for long-term prophylaxis in patients with severe forms of VWD; preventing spontaneous, excessive and sometimes life-threatening bleeding, and reducing chronic joint disease. Currently, there are a few clinical trials assessing the long-term benefits of prophylaxis in VWD, and guidelines for the optimal prophylaxis treatment approach are lacking. Greater attempts to provide comprehensive, long-term care for patients with VWD are needed but still lacking within the community. This review highlights the success of prophylaxis in haemophilia and how this knowledge might be applied and translated to patients with VWD.
Conclusions: Lessons can be learned from the use of prophylaxis in haemophilia and prophylaxis should be considered the standard of care for a subgroup of patients with severe VWD.
In patients with von Willebrand disease (vWD) the interest in age-related comorbidities has grown, because the life expectancy of these patients has increased. The research question of this study was whether patients with vWD show a different endothelial function compared to the general population. A total of 37 patients with type 1 (n = 23), type 2 (n = 10) and type 3 (n = 4) vWD, 14 controls and 38 patients with coronary artery disease (CAD) were included in this study. Five markers of endothelial dysfunction (MOED) were determined. Moreover, the endothelial function was examined using the Itamar Endo-PAT. The reactive hyperemia index (RHI) was calculated from the results. The markers soluble intercellular adhesion molecule-1 (p = 0.171), P-Selectin (p = 0.512), interleukin-6 (p = 0.734) and monocyte chemoattractant protein-1 (p = 0.761) showed higher levels in patients with vWD, but were not significantly different compared to the control group. RHI was impaired in CAD-patients (1.855), whereas vWD patients had mean results of 1.870 and controls 2.112 (p = 0.367). In this study, the endothelial function measurements of patients with von Willebrand disease were not significantly different compared to healthy controls.
Objectives and Methods: Intracranial hemorrhage (ICH) in acute myeloid leukemia (AML) patients is a major concern due to the increased risk of mortality. Few studies have examined ICH specifically in newly diagnosed AML patients receiving intensive induction chemotherapy (IC) and prophylactic platelet transfusions during thrombocytopenia <10/nL. This retrospective cohort study included 423 newly diagnosed AML patients without acute promyelocytic leukemia who underwent IC between 2007 and 2019. We assessed risk factors, clinical features, and outcomes of ICH.
Results: 17 of 423 patients (4%) suffered ICH during hospital stay, and 4 patients (24%) died directly because of ICH despite routine prophylactic platelet transfusions. Patients with ICH had a negatively impacted overall survival (median OS, 20.1 vs. 104.8 months) and were more likely not to continue with curative treatment. Main risk factors were female gender, severe thrombocytopenia, and decreased fibrinogen. Patients with subsequent ICH also had laboratory signs of liver dysfunction.
Conclusions: Intracranial hemorrhage remains a potentially deadly complication with notable incidence despite prophylactic platelet substitution, suggesting that additional prophylactic interventions may be required to further reduce the frequency of ICH in high-risk patients. Unrecognized genetic factors may simultaneously predispose to AML and platelet dysfunction with ICH.
Perioperative management for patients with von Willebrand disease: Defining the optimal approach
(2020)
von Willebrand disease (VWD) is the most common inherited bleeding disorder characterised by a quantitative or qualitative deficiency in von Willebrand factor (VWF). During invasive surgical procedures, patients with VWD require additional treatment to maintain haemostasis; however, due to the complexity of VWD, there is a lack of consensus on the optimal management. In the perioperative period, patients are usually treated with VWF and factor FVIII (FVIII)‐containing concentrates to provide an immediate haemostatic response to prevent excessive bleeding during both elective and emergency surgery. With the introduction of recombinant VWF (rVWF), there is a need for guidance on the use of the various VWF products in the perioperative period for all types of patients and surgeries. This review provides an overview of the current evidence for the surgical management of patients with VWD and, summarises the optimal treatment approach during the perioperative period, and highlights key unanswered questions and the research needed to address the evidence gaps.
Introduction: Haemophilia (HA) and rheumatoid arthritis (RA) patients may develop joint damage caused by recurrent joint bleedings in HA or by chronic inflammation in RA. Only few data exist for biomarker studies in these patients.
Aim: The objective of the present study is to assess a large array of biomarkers in peripheral blood samples obtained from HA patients without or with arthropathy and to compare pattern to RA patients and healthy controls.
Methods: A panel of biomarkers was assessed in 129 men (40 HA patients without arthropathy, 23 HA patients with arthropathy, 23 RA patients and 43 control subjects). 37 different biomarkers (cytokines, angiogenesis‐related proteins) were analysed using a multiple analyte profiling technology and supplemented by acute phase proteins, coagulation and immunological parameters.
Results: Evidence for systemic inflammation was obtained by increased acute phase reactants in all patient groups. 13 or 14 from 42 soluble parameters demonstrated significant differences (p < .05) between HA patients without arthropathy and healthy controls, or between HA patients with arthropathy and healthy controls, respectively. Largely overlapping patterns were obtained except for interleukin‐7 being increased in HA patients without arthropathy and being decreased in HA in the presence of arthropathy.
Conclusions: In addition to data supporting systemic inflammation, we provide evidence for a common biomarker profile in HA patients and RA patients compared to healthy controls. A distinctive biomarker profile for HA patients with arthropathy did not appear except for interleukin‐7 demonstrating specific changes depending on the absence or presence of arthropathy in HA patients.
The novel coronavirus infection (COVID-19) is caused by the new coronavirus SARS-CoV-2 and is characterized by an exaggerated inflammatory response that can lead to severe manifestations such as adult respiratory syndrome, sepsis, coagulopathy, and death in a proportion of patients. Among other factors and direct viral effects, the increase in the vasoconstrictor angiotensin II, the decrease in the vasodilator angiotensin, and the sepsis-induced release of cytokines can trigger a coagulopathy in COVID-19. A coagulopathy has been reported in up to 50% of patients with severe COVID-19 manifestations. An increase in d-dimer is the most significant change in coagulation parameters in severe COVID-19 patients, and progressively increasing values can be used as a prognostic parameter indicating a worse outcome. Limited data suggest a high incidence of deep vein thrombosis and pulmonary embolism in up to 40% of patients, despite the use of a standard dose of low-molecular-weight heparin (LMWH) in most cases. In addition, pulmonary microvascular thrombosis has been reported and may play a role in progressive lung failure. Prophylactic LMWH has been recommended by the International Society on Thrombosis and Haemostasis (ISTH) and the American Society of Hematology (ASH), but the best effective dosage is uncertain. Adapted to the individual risk of thrombosis and the d-dimer value, higher doses can be considered, especially since bleeding events in COVID-19 are rare. Besides the anticoagulant effect of LMWH, nonanticoagulant properties such as the reduction in interleukin 6 release have been shown to improve the complex picture of coagulopathy in patients with COVID-19.
Postoperative thrombotic thrombocytopenic purpura (TTP) shows clinical presentation similar to classical TTP, whereas exact pathophysiological contexts remain unexplained. In this study, we investigated intraoperative and postoperative changes in ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin type 1 motifs, member 13), von Willebrand factor (VWF), large VWF multimers, and interleukin-6 (IL-6) in vascular surgery patients. The objective was to compare the impact of endovascular, peripheral, and aortic surgery on target parameters which are supposed to play a role in surgery-associated TTP. A total of 93 vascular surgery patients were included and divided into 4 groups according to the specific type of intervention they underwent. Blood samples were taken preoperatively, intraoperatively, and postoperatively on days 2 and 4. The ADAMTS-13 activity decreased significantly in 3 of the 4 groups during surgery (from median 81% to 49%, P < .001, in the group undergoing aortoiliacal interventions), whereas the percentage of large VWF multimers increased in all groups of patients. von Willebrand factor antigen increased significantly in all groups on postoperative day 2 and IL-6 increased significantly in the intraoperative and early postoperative period. There was no significant correlation between the intraoperative decrease in ADAMTS-13 and the increase in VWF or IL-6. No patient in this study showed clinical picture of TTP; the precise cause and clinical significance of moderately reduced ADAMTS-13 activity in the perioperative setting have not yet been definitely determined.
Introduction: Prophylaxis with factor VIII (FVIII) concentrates in children with haemophilia A (HA) is current standard of care. The benefit of prophylactic treatment for adult HA patients is not commonly accepted.
Aim: To investigate the benefit of prophylaxis over on‐demand treatment in adult and elderly patients with severe or non‐severe HA in a real‐life setting.
Methods: Data from 163 patients comprising 1202 patient‐years were evaluated for 7.5 (±5.3) years. The effects on the annual bleeding rate (ABR, including spontaneous and traumatic bleeds) of treatment with a plasma‐derived FVIII concentrate, the patient's age and disease severity were investigated. The effect of changing the treatment from on demand to continuous prophylaxis on the patients’ ABRs was further analysed.
Results: Prophylaxis had the greatest effect on the ABRs of patients of any age with severe or non‐severe HA. The difference in ABR of all patients treated on demand (median 31.4; interquartile range (IQR) 27.6; N = 83) compared with those treated prophylactically (median 1.3; IQR 3.6; N = 122) was statistically significant (P < .05), even for patients with non‐severe HA (median 8.4; IQR 15.5; N = 11) vs median 1.5; IQR 4.2 (N = 17), P < .05). Patients, aged up to 88 years, switching from on demand to continuous prophylaxis showed the lowest median ABR (1.1; N = 51) after their regimen change.
Conclusion: Any (even low‐frequency) prophylaxis results in lower ABR than on‐demand treatment. Patients switching to prophylaxis benefitted the most, irrespective of age or HA severity. Prophylactic treatment—even tertiary—is the regimen of choice for patients of any age, including elderly patients, with severe or non‐severe HA.
Evaluation of a rapid turn-over, fully-automated ADAMTS13 activity assay: a method comparison study
(2020)
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy caused by severely reduced activity of the von-Willebrand factor-cleaving protease ADAMTS13, mainly caused by anti-ADAMTS-13 antibodies. Although several test systems for ADAMTS13 measurement exist, long turn-around times hamper the usability in daily practice. We performed a method comparison study for two commercially available ADAMTS13 assays and evaluated the agreement between the fully-automated rapid turn-over HemosIL AcuStar ADAMTS13 Activity assay and the manually performed TECHNOZYM ADAMTS-13 Activity assay. Twenty-four paired test samples derived from 10 consecutively recruited patients (n = 8, acquired TTP; n = 1, atypical hemolytic uremic syndrome; n = 1, control), of which nine test samples were collected in case of clinically apparent TTP and 13 samples were collected from TTP patients in clinical remission were included. Overall correlation between the TECHNOZYM and AcuStar assay was good with a Pearson R of 0.93 (p < 0.001). Agreement between the assays assessed with the Passing–Bablok analysis showed high agreement with an Intercept of − 2.56 (95% confidence interval [CI], − 5.07 to − 0.86) and Slope of 1.04 (95% CI 0.84–1.17). The absolute mean bias was 2.54% (standard difference [SD], 6.38%; 95% CI to 10.0–15.05%). Intra-method reliability was high with an absolute mean bias of − 0.13% (SD 3.21%; 95% CI to 6.42–6.16%). The observer agreement for categorial thresholds (> or < 10% ADAMTS3 activity) was kappa = 0.82 (95% CI 0.59–1.0). Conclusively, overall agreement between the testing methods was sufficient and we support previously published data suggesting the AcuStar assay being a valuable and accurate tool for ADAMTS13 activity testing and TTP diagnostics.
Background: Acquired thrombotic thrombocytopenic Purpura (aTTP) is a life-threatening ultra-orphan disease with a reported annual incidence between 1.5 and 6.0 cases per million in Europe and mainly affecting otherwise young and healthy adults aged 40 years on average. The goal of this study was to assess the incidence of aTTP in Germany.
Methods: A systematic review was performed to determine the published evidence on the aTTP epidemiology in Germany. To obtain additional evidence on the proportion of aTTP cases within the national Thrombotic Microangiopathy (TMA) population a hospital-level study was performed, using a retrospective data collection approach. Diagnosis of aTTP was confirmed if ADAMTS13 level were < 10% and/or the medical records explicitly mentioned aTTP diagnosis. The aggregated hospital data were then projected to the national level using logistic regression techniques.
Results: The systematic literature search did not provide incidence estimates of aTTP in Germany. Eight centers (≈27% of the top 30 TMA hospitals) delivered data according to a predefined data collection form. On average (year 2014–2016) a total number of 172 aTTP episodes per year was projected (95% confidence interval [95%CI]: 132–212). The majority were newly diagnosed aTTP cases (n = 121; 95%CI: 105–129), and 51 were recurrent aTTP cases (95%CI: 27–84). The average annual projected incidence (year 2014–2016) of aTTP episodes was 2.10 per million inhabitants in Germany (95%CI: 1.60–2.58).
Conclusions: The determined annual incidence of newly diagnosed aTTP cases and the overall annual incidence of aTTP episodes in Germany confirm the ultra-orphan character of aTTP. An external validation against international registries (France, UK and USA) shows that our findings are quite comparable with those international incidence rates.