Administration Of Von Willebrand Factor Research Articles

Impact of Additional Administration of von Willebrand Factor Concentrates to Thrombocyte Transfusion in Perioperative Bleeding in Cardiac Surgery

Background: Von Willebrand factor (vWF) is an important part of blood coagulation since it binds platelets to each other and to endothelial cells. In traumatic and surgical haemorrhage, both blood cells and plasmatic factors are consumed, leading to consumption coagulopathy and fluid resuscitation. This often results in large amounts of crystalloids and blood products being infused. Additional administration of vWF complex and platelets might mitigate this problem. We hypothesize that administration of vWF concentrate additionally to platelet concentrates reduces blood loss and the amount of blood products (platelets, red blood cells [RBC], fresh frozen plasma [FFP]) administered. Methods: We conducted a monocentric 6-year retrospective data analysis of cardiac surgery patients. Included were all patients receiving platelet concentrates within 48 h postoperatively. Patients who additionally received vWF concentrates were allocated to the intervention group and all others to the control group. Groups were compared in mixed regression models correcting for known confounders, based on nearest neighbour propensity score matching. Primary endpoints were loss of blood (day one and two) and amount of needed blood products on day one and two (platelets, RBC, FFP). Secondary endpoints were intensive care unit (ICU) and in-hospital length of stay, ICU and in-hospital mortality, and absolute difference of platelet counts before and after treatment. Results: Of 497 patients analysed, 168 (34%) received vWF concentrates. 121 patients in both groups were considered for nearest neighbour matching. Patients receiving additional vWF were more likely to receive more blood products (RBC, FFP, platelets) in the first 24 h after surgery and had around 200 mL more blood loss at the same time. Conclusion: In this retrospective analysis, no benefit in additional administration of vWF to platelet concentrates on perioperative blood loss, transfusion requirement (platelets, RBC, FFP), length of stay, and mortality could be found. These findings should be verified in a prospective randomized controlled clinical trial (<ext-link ext-link-type="uri" xlink:href="http://www.clinicaltrials.gov" xmlns:xlink="http://www.w3.org/1999/xlink">www.clinicaltrials.gov</ext-link> identifier NCT04555785).

Assessment Of Endothelial Damage and Cardiac Injury In a Mouse Model Mimicking Thrombotic Thrombocytopenic Purpura

Background Thrombotic thrombocytopenic purpura (TTP) is a life-threatening illness caused by deficiency of the Von Willebrand factor (VWF) cleaving protease ADAMTS13. Endothelial injury is believed to be a key initiating event in the pathogenesis leading to platelet activation and formation of platelet-rich thrombi in microvasculature. However, the nature of endothelial injury in TTP is poorly defined and seems to differ among the microvascular territory. Especially, a cardiac injury has recently been identified and hypothesized as a major cause of death in TTP. Methods We used an animal model in which some TTP-like symptoms have been triggered in ADAMTS13 knockout mice (B6.129-ADAMTS13tm1Dgi ) by challenge with 2000 units/kg body weight of recombinant human VWF containing ultra large VWF (rhVWF, Baxter, Vienna Austria). rhVWF was also injected in 6 wild type mice (C57/bl6-B129 WT+VWF) while seven other wild type mice received placebo (WT). Cardiac involvement was assessed by transthoracic echocardiography using validated parameters i.e left ventricular ejection fraction (LVEF), fractional shortening (FS) and cardiac index (CI). Cardiac perfusion was determined by arterial spin labeling MRI (Biospec 47/40 advanced II, Brucker, Ettlingen, Germany). Ex vivo endothelial function analysis in isolated coronary, mesenteric and renal segments were performed using a myograph. Arteries were precontracted by phenylephrine or serotonin and the relaxations induced by increasing concentrations of acetylcholine (receptor-mediated, endothelium-dependent relaxation) or the nitric oxide (NO) donor sodium nitroprusside (SNP; endothelium-independent- relaxation) were assessed. Arteries were also incubated with the NO synthase-inhibitor N-Nitro L-Arginine (LNNA) to assess the contribution of NO to the relaxing responses to acetylcholine (endothelium-dependent NO-independent-relaxation). Results On day 1, VWF-challenged ADAMTS13 KO mice rapidly developed symptoms and severe thrombocytopenia (41.8G/L ± 6.9G/L vs 480.7G/L ± 86.5G/L (WT+VWF) and 1118.6G/L ± 160.8G/L (WT); p&lt;0.001), schistocytosis and a decrease in hematocrit levels (40.9% ± 0.8% vs WT+VWF: 51.3% ± 3,8%; p&lt; 0.05 and WT: 56.1% ± 3%; p&lt; 0.001). On day 2, necropsy revealed that macroscopic lesions were restricted to the heart and consisted of acute myocardial hemorrhage and necrosis. Myocardial necrosis was accompanied by infiltration of lymphocytes and interstitial edema. Minimal, acute tubular necrosis in the kidneys was seen in a few animals. Injection of rhVWF in ADAMTS13 KO mice resulted in a decrease in LVEF (73.8% ± 2.7% vs WT+VWF: 86.6% ± 1.3% and WT: 86.8% ± 1.3%; p&lt; 0.01), in FS (37.3% ± 2.1% vs WT+VWF: 50.1% ± 1.6%; p&lt;0.05 and WT: 50.9% ± 12.8%; p&lt; 0.01) and in CI (1.21 ml/min/g ± 0.09 vs WT+VWF: 1.70 ml/min/g ± 0.14 and WT: 1.66 ml/min/g ± 0.1; p&lt; 0.05) suggesting an early systolic dysfunction. However, cardiac perfusion was not significantly affected on day 2. Administration of rhVWF in ADAMTS13KO mice decreased the NO-mediated relaxing responses to acetylcholine in mesenteric (51.1% ± 14.8% vs WT+VWF: 94.4% ± 1.6%; p&lt; 0.05 and WT: 96.5% ± 2.3%; p&lt; 0.001) and coronary arteries (61.7% ± 12.4% vs WT+VWF: 89.9% ± 6.3% and WT: 96.8% ± 0.9%; p&lt; 0.05) but not in renal arteries. Interestingly, under LNNA, endothelium-dependent relaxations were also markedly affected in coronary arteries (19.3% ± 3.7% vs WT+VWF: 70.2% ± 4.7%; p&lt;0.001) in ADAMTS13KO mice suggesting the role of other endothelium-derived vasoactive factors. In parallel, the relaxing responses to SNP were slightly affected (47.8% ± 13.8% vs WT+VWF: 79.1% ± 13.3% and WT: 80.2% ± 7.2%; p&lt; 0.05), suggesting a strong coronary vascular dysfunction on day 2. Conclusions This experimental study reproduced an animal model in which TTP like symptoms are triggered in ADAMTS13 KO mice by administration of VWF and demonstrated that the heart is the most sensitive target organ with myocardial necrosis and systolic dysfunction. We showed for the first time a strong mesenteric and coronary endothelial dysfunction in an induced-TTP model. It may represent an important trigger of the systemic organs failure occurring in this disease, strengthening the need to define the mechanisms involved in this early vascular injury. Disclosures: Schiviz: Baxter: Employment.

P-097 Von Willebrand's disease and recurrent 1st trimester miscarriage: Successful outcome after administration of von Willebrand factor

P-097 Von Willebrand's disease and recurrent 1st trimester miscarriage: Successful outcome after administration of von Willebrand factor

Pharmacokinetic Studies with FVIII/von Willebrand Factor Concentrate Can Be a Diagnostic Tool to Distinguish between Subgroups of Patients with Acquired von Willebrand Syndrome

Acquired von Willebrand syndrome (AVWS) has been associated mainly with monoclonal gammopathy of uncertain significance (MGUS), clonal lymphoproliferative or myeloproliferative disorders and autoimmunity. In the present work we studied 6 patients with AVWS: four with MGUS IgG (lambda or kappa), one with small lymphocytic lymphoma and one with agnogenic myeloid metaplasia (AMM). All the patients underwent a pharmacokinetic analysis at presentation in order to study potential differences in recovery, clearance (CL) or terminal half-life (THL) following administration of von Willebrand factor (VWF) concentrate. In all the patients with AVWS an increase in clearance and a decrease in THL was observed as compared to these parameters in patients with hereditary type 3 von Willebrand disease (VWD). No difference in recovery was observed among the groups. The increase in clearance and the decrease in THL were significantly more pronounced in the group of MGUS patients (57.93 +/- 25.6 ml/h/kg, and 1.39 +/- 0.5 h, respectively) as compared to these parameters in the AMM (8.06 ml/h/kg, and 6.96 h, respectively) or the lymphoma (4.76 ml/h/kg, and 6.76 h. respectively) patients (p = 0.03 for clearance and 0.001 for THL). These data indicate that the pharmacokinetic analysis can be a useful tool to distinguish between MGUS-related and other causes of AVWS, and to plan an appropriate treatment accordingly.

Reduction of r-hirudin induced bleeding in pigs by the administration of von Willebrand factor

To prevent r-hirudin induced excess bleeding an animal model was established in pigs for the investigation of an anti-bleeding strategy. We used the Simplate® device to monitor skin bleeding time (SBT) at the inner site of the ear. r-Hirudin infused in a dose of 0.3 mag per h induced a prominent increase of SBT. The aim of our studies was to reverse r-hirudin induced bleeding by enhancing platelet adhesion to the endothelium via the administration of von Willebrand Factor (vWF). Pigs were treated with vWF containing solutions (Haemate® and a vWF-concentrate) at 3h after the start of the r-hirudin infusion. Both compounds suppressed SBT 1h after administration and significantly prevented bleeding until the termination of the experiment. SBT values (given in times of baseline) in the placebo group were 3.32 ± 0.9, 1.51 ± 0.14 in the Haemate® and 1.85 ± 0.42 in the vWF concentrate group (P = 0.008 or 0.032, in a two-sided Kruskall-Wallis-test). Coagulation parameters (aPTT, PT) were unaltered by the treatment, as were the r-hirudin plasma levels suggesting that vWF is not an antidote in its strict sense. It is concluded that vWF reverses bleeding without altering the anticoagulant effect of r-hirudin. Addition of 20 mg/kg per h aspirin resulted in a further increase of SBT. Aspirin, moreover, suppressed platelet aggregation but did not alter platelet counts. In a further study, bleeding induced by r-hirudin and aspirin was antagonized by Haemate® (66 Ukg i.v. bolus + 187 Ukg per h for 2 h infusion) and a significant reduction of bleeding time occurred.