Development of a plasma- and albumin -free recombinant von Willebrand factor

Turecek, Peter L.; Mitterer, Artur; Matthiessen, H. Peter; Gritsch, Herbert; Váradi, Katalin; Siekmann, Jürgen; Schnecker, K.; Plaimauer, Barbara; Kaliwoda, Martin; Purtscher, Martin; Woehrer, W.; Mundt, Wolfgang; Muchitsch, Eva-Maria; Suiter, Tobias M.; Ewenstein, Bruce M.; Ehrlich, Hartmut J.; Schwarz, Hans

doi:10.1055/s-0037-1617202

Cited by 33 publications

(13 citation statements)

References 29 publications

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“…All patients, except 1, had peripheral cannulation. The median day of blood sampling was ECMO day 7 (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), median pump speed was 3258 (2901-3556) revolutions per minute, and median ECMO circuit blood flow was 4.1 liters per minute (3.5-5). Mean platelet count was 134 ± 83 10 9 /L.…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Recombinant vWF contains ultralarge vWF multimers that are not present in plasma-derived vWF because recombinant vWF is not exposed to a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member-13 (ADAMTS-13) during the manufacturing process. 16 Both vWF concentrates were added to achieve a final concentration in whole blood samples based on international units (IU) of RCo. The total volume of whole blood used in experiments was 1 mL.…”

Section: Blood Sampling and In Vitro Vwf Supplementationmentioning

confidence: 99%

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In Vitro Comparison of Recombinant and Plasma-Derived von Willebrand Factor Concentrate for Treatment of Acquired von Willebrand Syndrome in Adult Extracorporeal Membrane Oxygenation Patients

Mazzeffi

Henderson

Krause

et al. 2021

Anesthesia &Amp; Analgesia

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BACKGROUND: Coagulopathic bleeding is common during adult extracorporeal membrane oxygenation (ECMO), and acquired von Willebrand syndrome is a contributing factor. We compared ECMO patient blood samples that were treated in vitro with recombinant von Willebrand Factor concentrate and plasma-derived von Willebrand Factor concentrate. Our hypothesis was that recombinant von Willebrand Factor (vWF) would have greater efficacy in increasing vWF function. Secondarily, we hypothesized that recombinant vWF would have less impact on thrombin generation. METHODS: Thirty ECMO patients and 10 cardiac surgical controls were enrolled in the study. ECMO patient blood samples were treated in vitro with low-and high-dose recombinant vWFs and low-and high-dose plasma-derived vWFs. Whole blood ristocetin-induced platelet aggregation (RIPA), plasma ristocetin cofactor activity (RCo), and thrombin generation were compared between ECMO patient blood samples and control blood samples and between vWF-treated ECMO patient blood samples and nontreated samples. RESULTS: ECMO patient blood samples had severely reduced median RIPA compared to control samples 2 ohms (1-12 [25th-75th percentile]) vs 20 ohms (11-42) (P < .001). Treatment of ECMO patient blood samples with high-dose recombinant vWF significantly increased median RIPA to 10 ohms (2-15) (P < .001), while low-dose recombinant vWF and low-and high-dose plasma-derived vWFs did not significantly increase RIPA; 6 ohms (3-14), 4 ohms (1-13), and 6 ohms (2-10), respectively (P = .25, >.99, and >.99). Treatment with high-dose recombinant vWF and low-and high-dose plasma-derived vWFs significantly increased median plasma RCo to 4.7 international units (IU)/mL (3.7-5.9), 3.3 IU/mL (2.7-4.8), and 3.9 IU/mL (3.4-5.3), respectively, compared to controls 1.8 IU/mL (1.5-2.3) (all P < .001). Treatment with low-and high-dose plasma-derived vWFs significantly increased mean endogenous thrombin potential (6270.2 ± 2038.7 and 6313.1 ± 1913.3) compared to nontreated samples (5856.7 ± 1924.6) (P = .04 and .006), whereas treatment with low-and high-dose recombinant vWFs had no significant effect on mean endogenous thrombin potential (5776.1 ± 2087.3 and 5856.2 ± 1946.4) (P > .99 for both comparisons). CONCLUSIONS: In vitro treatment of ECMO patient blood samples with high-dose recombinant vWF was superior to low-dose recombinant vWF and plasma-derived vWF in terms of improving RIPA. In addition, recombinant vWF treatment did not increase endogenous thrombin potential, which may reduce overall thrombotic risk if it used to treat acquired von Willebrand syndrome in ECMO patients. (Anesth Analg 2022;134:312-21) KEY POINTS• Question: Does in vitro treatment of extracorporeal membrane oxygenation (ECMO) patient blood samples with recombinant and plasma-derived von Willebrand Factor (vWF) concentrate equally improve ristocetin-induced platelet aggregation (RIPA)? • Findings: In vitro treatment of ECMO patient blood samples with high-dose recombinant vWF concentrate, but not low-dose recombinant or plasm...

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Blood Sampling and In Vitro Vwf Supplementationmentioning

confidence: 99%

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In Vitro Comparison of Recombinant and Plasma-Derived von Willebrand Factor Concentrate for Treatment of Acquired von Willebrand Syndrome in Adult Extracorporeal Membrane Oxygenation Patients

Mazzeffi

Henderson

Krause

et al. 2021

Anesthesia &Amp; Analgesia

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“…Afterwards, CC and CC-C1q complexes were washed (as described above). For generation of CC-C1q-vWF complexes, 10 μg/ml recombinant vWF {provided by Baxalta, Lexington, MA, USA [former Baxter; characterization by Turecek et al (30)]}, diluted in PBS, was added to washed CC-C1q complexes, vortexed rigorously, and further incubated for 1 h at RT on a shaker (700 rpm). After another washing step, CC complexes were further incubated with monoclonal mouse anti-C1q [clone 32A6 cell supernatant (31)], diluted 1:20 in PBS, or polyclonal rabbit anti-vWF (Abcam, Cambridge, UK), diluted 1:1,000 in PBS, for 1 h at RT on a shaker (700 rpm).…”

Section: Methodsmentioning

confidence: 99%

Binding of von Willebrand Factor to Complement C1q Decreases the Phagocytosis of Cholesterol Crystals and Subsequent IL-1 Secretion in Macrophages

2019

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Complement C1q, the initiation molecule of the classical pathway, exerts various immunomodulatory functions independent of complement activation. Non-classical functions of C1q include the clearance of apoptotic cells and cholesterol crystals (CC), as well as the modulation of cytokine secretion by immune cells such as macrophages. Moreover, C1q has been shown to act as a binding partner for von Willebrand factor (vWF), initiation molecule of primary hemostasis. However, the consequences of this C1q-vWF interaction on the phagocytosis of CC by macrophages has remained elusive until now. Here, we used CC-C1q-vWF complexes to study immunological effects on human monocyte-derived macrophages (HMDMs). HMDMs were investigated by analyzing surface receptor expression, phagocytosis of CC complexes, cytokine secretion, and caspase-1 activity. We found that vWF only bound to CC in a C1q-dependent manner. Exposure of macrophages to CC-C1q-vWF complexes resulted in an upregulated expression of phagocytosis-mediating receptors MerTK, LRP-1, and SR-A1 as well as CD14, LAIR1, and PD-L1 when compared to CC-C1q without vWF, whereas phagocytosis of CC-C1q complexes was hampered in the presence of vWF. In addition, we observed a diminished caspase-1 activation and subsequent reduction in pro-inflammatory IL-1β cytokine secretion, IL-1β/IL-1RA ratio and IL-1α/IL-1RA ratio. In conclusion, our results demonstrate that vWF binding to C1q substantially modulates the effects of C1q on HMDMs. In this way, the C1q-vWF interaction might be beneficial in dampening inflammation, e.g., in the context of atherosclerosis.

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“…Also, a pd-VWF high purity concentrate containing little FVIII (Wilfactin ® ; LBF, Les Ulis, France) could be chosen in patients with mild FVIII reduction. In this case, the coadministration of a priming dose of FVIII is recommended in patients with basal FVIII:C levels <30 U/dL, when immediate hemostasis is required, since 6-8 hours are necessary for endogenous FVIII to reach levels higher 30 Vonicog alpha is a >99% pure r-VWF molecule with the full range of VWF multimers because ADAMTS13 is not present during the manufacturing process. Therefore, also the ultralarge multimers (ULMs) are present, which are the most active forms, 31 similarly to those observed after release in plasma from Weibel-Palade bodies of endothelial cells.…”

Section: Vwd Treatmentmentioning

confidence: 99%

Obstacles to Early Diagnosis and Treatment of Inherited von Willebrand Disease: Current Perspectives

Castaman

Linari

2021

JBM

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Von Willebrand disease (VWD), the most common inherited bleeding disorder, is highly heterogeneous, and its early diagnosis may be difficult, especially for mild cases and in qualitative von Willebrand factor (VWF) defects. Appropriate VWD diagnosis requires the combination of personal and/or family history of bleeding and abnormal VWF laboratory testing. The use of bleeding assessment tools has been helpful in standardizing bleeding history collection and quantification of bleeding symptoms to select patients who may benefit of further hemostatic testing. Type 1 and 3 VWD which represent quantitative VWD variants are relatively easy to diagnose. The diagnosis of type 2 VWD requires multiple assessments to evaluate the effects induced by the responsible abnormality on the heterogeneous functions of VWF. Sensitive and reproducible tests are needed to evaluate different VWF activities, starting from measuring VWF-platelet interaction. In the recent years, several increasingly sensitive, rapid and automated assays have been developed, but they are not widely available so far. Genetic testing for VWD diagnosis is not a common practice because VWF gene is very large and highly polymorphic and therefore it is used only in specific cases. It is evident that the early and correct VWD diagnosis allows optimal management of bleeding and situations at risk. Tranexamic acid, desmopressin, replacement therapy with plasmaderived concentrates with a variable content of VWF and FVIII, or the new recombinant VWF are the different therapeutic options available. Careful VWD classification guides treatment because desmopressin is widely used in type 1 while replacement therapy is the cornerstone of treatment for type 2 and 3 variants.

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Development of a plasma- and albumin -free recombinant von Willebrand factor

Cited by 33 publications

References 29 publications

In Vitro Comparison of Recombinant and Plasma-Derived von Willebrand Factor Concentrate for Treatment of Acquired von Willebrand Syndrome in Adult Extracorporeal Membrane Oxygenation Patients

In Vitro Comparison of Recombinant and Plasma-Derived von Willebrand Factor Concentrate for Treatment of Acquired von Willebrand Syndrome in Adult Extracorporeal Membrane Oxygenation Patients

Binding of von Willebrand Factor to Complement C1q Decreases the Phagocytosis of Cholesterol Crystals and Subsequent IL-1 Secretion in Macrophages

Obstacles to Early Diagnosis and Treatment of Inherited von Willebrand Disease: Current Perspectives

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