Under physiologic conditions, higher fluid shear stress elongates the vWF multimers from a globular state to an extended chain conformation, thereby exposing the cleavage site in the A2 domain to the metalloproteinase ADAMTS13 [10]. This causes a cleavage of high-molecular-weight multimers of vWF by this specific metalloprotease to shorter multimers [11]. This results in the presence of vWF multimers of different sizes that are characteristic of the circulating pool of vWF, ranging from a single up to 20 dimers (∼10,000 kDa) [12].

However, in supraphysiologic shear stress, an excessive forced cleavage of the vWF by ADAMTS13 occurs. Originally, an interrelation between elevated shear stress and AVWS has been described in patients with severe aortic stenosis [13], referring to the clinical symptoms originally described as the Heyde’s syndrome already in 1958 [14]. The same mechanism of action was further described in patients implanted with axial and centrifugal LVADs. The key feature of the acquired von Willebrand syndrome (AVWS) in patients with continuous-flow left ventricular assist devices (cfLVAD) is a lack of high-molecular-weight multimers (HMWM) of the vWF. Nevertheless, the reduction of HMWM is individual; therefore the percentage of remaining large multimers varies [2].

The larger multimers disappear significantly from the circulation by 2 h [15], ◘ Fig. 50.2. A recent publication documents in both in vitro and in vivo the vWF multimers variation even as early as within minutes of axial assist device operation [16]. The small vWF fragments have reduced hemostatic function [17]. Hereby, the primary hemostasis is disturbed [18]. The hemostatic potential of vWF multimers is governed by the multimer size [11]. These effects are explained by fewer binding sites of the smaller multimers and lower binding affinity between low vWF multimers and platelets, thus reducing both platelet adhesion and aggregation [19].

Patients exhibit increased bleeding from mucosa in the nasopharyngeal zone (epistaxis) and gastrointestinal tract (gastrointestinal bleeding) as well as prolonged bleeding after injury, during dental surgery, and prolonged menses and menorrhagia in women [11].

A patient after cfLVAD implantation with an AVWS shows an abnormal platelet function test (PFA-100^™). To diagnose an AVWS, the following tests are recommended: vWF antigen assays (vWF:Ag), vWF functional assays like vWF collagen-binding capacity (vWF:CB) and the functional ability of vWF to bind platelets (the ristocetin cofactor activity, vWF:RCo), and multimer analysis using electrophoretic separation. In AVWS a reduced vWF:RCo/vWF:Ag ratio of <0.6–0.7 indicates a selective loss or decrease in HMWM. A decrease in vWF:CB/vWF:Ag ratio may also indicate a loss or decrease in HMWM [20]. However, there is a general consensus to consider vWF multimer analysis as the gold standard for the detection of structural abnormalities in vWF indicating AVWS, since a decrease in HMWM may be the only way of detecting AVWS in patients with cardiovascular disorder who have normal vWF:RCo and vWF:CB and even normal vWF:RCo/vWF:Ag and vWF:CB/vWF:Ag ratios [3, 21].

In contrast to the first-generation volume-displacement assist devices [22], the acquired von Willebrand syndrome has been described in both axial and centrifugal long-term cfLVAD represented by the HeartMate II^® and HVAD^® (HeartWare^® Ventricular Assist Device) with device-specific features [23]. Consequently, the same was confirmed with a use of continuous-flow pumps for short-term circulatory support in ECMO circuits or short-term cfLVAD as Impella^® (Abiomed, Danvers, MA) or Levitronix^® CentriMag^® [24–26], and data shows a strong association with high prevalence of bleeding during the support and after transition to heart replacement therapy [24]. Preliminary analysis of HeartMate^® III suggests also a certain reduction in HMWM; however degree and features of the device-specific phenomenon still need to be determined. Longitudinal analysis of HeartMate. 3 suggests lesser degree of HMWM degradation in contrast to HeartMate II; nonetheless potential implications need to be determined in larger clinical outcomes matched series [27].

The coagulation disorder is reversible and thereby represents an indirect proof of the interplay between continuous-flow pumps and vWF. Patients after heart transplantation or LVAD explantation show reconstitution of its physiological pattern [28]. The vWF presence and function normalize during the first postoperative day after assist device explantation, thus supporting the observation of vWF turnover with a half-life of 12–20-h in vivo [29].

Current therapy still remains contentious. In a case report, the effect of human vWF/factor VIII concentrate was described [30]. In patients with aortic stenosis was described a reduced postoperative blood loss if desmopressin was administered during cardiac surgery (0.3 μg/kg in 100 mL of normal saline over 30 min) [31]. This therapeutic algorithm was adopted in some centers also for LVAD surgery.

Another approach is the inhibition of the metalloprotease ADAMTS13 which cleaves the vWF. In an in vitro study, the activity of ADAMTS13 could be reduced by the administration of doxycycline. Therefore, reduction of the smallest vWF degradation fragments was described. However, the dose was tenfold higher than the recommended daily allowance for antibiotic therapy [32].

A recent study also reported an up to 83±8% inhibition of the ADATMS13 activity with monoclonal antihuman anti-vWF antibodies that partially blocked vWF-ADAMTS13 interactions, but this is also an in vitro study and not certified for clinical use [33].

Ultimately, with current level of evidence, the only proven causal therapy of a vWF is the high rotational speed pump removal at a time of pump explantation, most commonly at a time of heart transplant.