Share this article on:

Unexpected Bleeding in the Operating Room: The Role of Acquired von Willebrand Disease

Lison, Susanne MD; Dietrich, Wulf MD, PhD; Spannagl, Michael MD, PhD

doi: 10.1213/ANE.0b013e318236b16a
Cardiovascular Anesthesiology: Review Article
Chinese Language Editions
Continuing Medical Education

Acquired von Willebrand disease (AvWD) is a rare bleeding disorder that occurs in association with a variety of underlying disorders and can lead to unforeseen bleeding in surgical patients. Cardiovascular as well as malignant and immunological diseases may be associated with AvWD, and several pathophysiological mechanisms have been proposed. von Willebrand factor (vWF) is a plasma glycoprotein that mediates platelet adhesion to subendothelial collagen and causes platelet aggregation under high shear stress. Additionally, vWF acts as a specific carrier for coagulation factor VIII (FVIII) in the plasma. AvWD results from a reduced rate of vWF synthesis, an increased rate of vWF removal, or a final generation of lower-molecular-weight, less active subunits or multimers. In contrast to inherited von Willebrand disease patients, who are characterized by lifelong bleeding episodes, AvWD patients present with a sudden onset of bleeding symptoms, which can induce acute bleeding episodes during critical surgical procedures. Typically, no family history of bleeding is found. The clinical visualization of AvWD is similar to that of the hereditary form with mucocutaneous bleeding and increased perioperative bleeding, ranging from mild to severe bleeding. Laboratory evaluation of AvWD is mainly based on the measurement of vWF activity and antigens as well as on the multimeric analysis of vWF. A variety of therapeutic approaches have been used depending on the underlying disease and pathophysiological mechanisms. Treatment options to control acute hemorrhages or to prevent bleeding complications during surgery include desmopressin, FVIII/vWF concentrates, high-dose IV immunoglobulins, and plasma exchange. Because the half-life of vWF is reduced in AvWD, high doses of FVIII/vWF concentrates administered at frequent intervals may be necessary during bleeding episodes. In cases of unresponsiveness to standard therapy, recombinant activated factor VIIa may be an alternative option. However, the most effective therapy is the resolution of the underlying disease. In the present review, we focus on the current understanding of AvWD, outlining the associated disorders, underlying pathophysiological mechanisms, and possible treatment options.

Published ahead of print October 24, 2011 Supplemental Digital Content is available in the text.

From the Department of Anaesthesiology, Working Group of Perioperative Hemostasis, University of Munich, Munich, Germany.

Conflict of Interest: See Disclosures at the end of the article.

Reprints will not be available from the authors.

Address correspondence to Wulf Dietrich, MD, PhD, Department of Anaesthesiology, Working Group of Perioperative Hemostasis, University of Munich, Winthirstr. 4, 80639 Munich, Germany. Address e-mail to wulf.dietrich@t-online.de.

Accepted August 10, 2011

Published ahead of print October 24, 2011

Unexpected bleeding during invasive procedures or during surgery in patients without any history of bleeding can occur. Acquired von Willebrand disease (AvWD) is a potential cause.1 In contrast to congenital von Willebrand disease (vWD), a syndrome characterized by an inherited pattern and a bleeding history starting in childhood, AvWD occurs in individuals without any family history of hemorrhagic diatheses who present with an acute onset of bleeding symptoms.2,3 AvWD is a rare bleeding disorder with different pathophysiological mechanisms but with clinical patterns that are similar to inherited vWD.2,3 The estimated prevalence for inherited vWD is 0.01% to 1.3% compared with 0.04% to 0.13% for AvWD.4,5 AvWD is also usually associated with another underlying disease, and laboratory findings may not always predict clinically relevant bleeding. In this overview, we discuss a case of AvWD and present a review of the associated disorders, proposed pathophysiological mechanisms, and the available treatment options.

The patient provided written informed consent for the anonymous use of his clinical information. In 2007, a 46-year-old man was hospitalized in a teaching hospital of the Technische Universitaet Muenchen, Munich, Germany, because of central spinal cord syndrome with progressive pain and acute dorsal flexor weakness. Magnetic resonance imaging revealed an L5/S1 disk prolapse. Routine preoperative laboratory screening tests detected an elevated activated partial thromboplastin time (aPTT) of 47 seconds (reference range: 25–42.0 seconds). His surgical history included a tonsillectomy, a herniotomy, and a dental extraction, without bleeding complications. There was no family history of bleeding disorders and the patient was not taking any medications. Because of persistent lumboischialgia, minimally invasive nucleotomy was rapidly performed on the day after admission. Under normal conditions in this kind of operation, the estimated blood loss ranges from 12 to 93 mL.6 However, in this patient, an increased bleeding was observed intraoperatively resulting in an estimated blood loss of >200 mL and a prolonged operative time. A subsequent, detailed reexamination of the patient's medical history revealed an increased mucosal bleeding tendency within the last 3 years. Because of a massive hematoma at the surgical site with worsening of the lumboischialgia symptoms, reexploration was necessary on postoperative day 9 and again on postoperative day 11.

Postoperative laboratory testing revealed a normal complete blood count, normal prothrombin time, prolonged aPTT of 45 seconds, factor VIII (FVIII) activity of 27%, von Willebrand factor (vWF) antigen (vWF:Ag) of 9.0%, vWF ristocetin cofactor activity (vWF:RCo) of <12%, and vWF collagen binding activity (vWF:CB) of 5%. In vitro bleeding time was evaluated by the PFA-100® function analyzer (Dade Behring, Marburg, Germany) using the collagen/ epinephrine (CEPI) and the collagen/adenosine (CADP) test cartridges, respectively (reference ranges: CEPI, 85–165 seconds; CADP, 71–118 seconds). Both test cartridges showed results >300 seconds. Furthermore, multimeric analysis revealed a preferential loss of the high-molecular-weight (HMW) vWF multimers and an amplified proteolysis (Fig. 1). Based on these results, the patient was diagnosed with AvWD. To prevent further hemorrhage and to promote wound healing, the patient received high-dose FVIII/vWF replacement therapy during the reexploration procedures and in the postoperative period with 4000 U Hemate P® (CSL Behring, Hattersheim, Germany) twice daily until wound healing. No further bleeding episodes occurred after the second intervention, no transfusion of red blood cells was necessary, and the patient was discharged from the hospital on postoperative day 30 with improving paresis symptoms.

Figure 1

Figure 1

Further investigation after discharge revealed a monoclonal gammopathy of undetermined significance as the underlying disorder. Serum studies demonstrated the presence of a monoclonal immunoglobulin G κ. A bone marrow biopsy was normal, and no clinical, radiographic, or laboratory signs of underlying lymphoma or solid tumors were observed. After a follow-up period of >3 years, no progression of the disorder could be demonstrated; the monoclonal gammopathy has remained stable since the diagnosis. Laboratory variables (vWF antigen and activity) are still abnormal and have been confirmed on several occasions. The patient experiences easy bruising and occasionally has episodes of mucosal bleeding, which are successfully treated with oral tranexamic acid. The patient has not required any further operations. In our patient, the diagnosis of AvWD was based on the following: (1) laboratory evidence of a deficiency and a dysfunction of circulating vWF, (2) a pathological vWF multimeric pattern in the plasma, (3) a late onset of bleeding with no history of prolonged bleeding during surgical procedures, (4) a negative family history, and (5) the presence of an underlying disorder that is known to be associated with the AvWD. In this patient, massive intraoperative and postoperative bleeding was the first obvious symptom of AvWD associated with monoclonal gammopathy.

Back to Top | Article Outline

THE FUNCTION OF vWF

vWF is a multimeric glycoprotein that is formed from a basic dimer subunit.7 HMW multimers are the hemostatically most active forms of vWF. vWF is synthesized by endothelial cells and megakaryocytes and is stored within the Weibel-Palade bodies of the endothelial cells or in the α granules of the megakaryocytes (Fig. 2).7 vWF has 2 major functions in hemostasis. First, it promotes the adhesion of platelets to the exposed subendothelium of injured vessel walls and causes platelet aggregation under high shear stress.7,8 Second, vWF acts as a specific carrier for FVIII in the plasma.7,9,10 By forming a noncovalent complex with FVIII, vWF protects FVIII from proteolytic degradation, thereby prolonging its half-life in the circulation.9,10

Figure 2

Figure 2

In response to various stimuli, stored vWF is released from its endothelial granules in the form of ultralarge (UL) vWF multimers.8 These prothrombotic (“sticky”) ULvWF multimers are not found in the circulation under normal conditions because, in areas of intact and functional endothelium, they are rapidly cleaved into smaller, less-adhesive multimers. The proteolysis of the ULvWF multimers is accomplished by a specific plasma metalloprotease, ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin-1-like domains 13) (Fig. 2).11,12 Severe ADAMTS-13 deficiency leads to a failure of ULvWF multimer cleavage and provokes pathological platelet aggregation and thrombus formation, which results in the “classic pathophysiologic mechanism” for the majority of patients with thrombotic thrombocytopenic purpura.12 14 In contrast, increased proteolysis of the hemostatically most relevant HMW vWF multimers by ADAMTS-13 induces bleeding.14

Back to Top | Article Outline

THE CLASSIFICATION AND CLINICAL FEATURES OF INHERITED vWD

vWD is the most prevalent inherited bleeding disorder and affects both females and males.5,15 vWD can be classified into 3 major categories: type 1, type 2, and type 3 (Table 1).5,15 Type 1 is the most common form of vWD and reflects a partial quantitative deficiency of vWF. Type 2 is characterized by several qualitative abnormalities of vWF; based on different pathophysiological mechanisms, 4 subtypes of type 2 vWD have been identified: 2A, 2B, 2M, and 2N. Patients with type 2A vWD show a marked decrease or absence of the most hemostatically active HMW vWF multimers (Fig. 1).5,15 Type 3 vWD is a rare disease that leads to a more or less total deficiency of vWF accompanied by low plasma levels of FVIII (Fig. 1).

Table 1

Table 1

The most common symptoms associated with vWD are easy bruising and mucosal bleeding, such as epistaxis, gastrointestinal bleeding, or heavy menstrual bleeding. In addition, patients with vWD may be at risk of bleeding during surgery or invasive procedures, traumatic injuries, or childbirth.16 18 However, the bleeding tendency varies widely from patient to patient and ranges from mild bleeding in type 1 vWD to severe, life-threatening bleeding in type 3 vWD.

Back to Top | Article Outline

ACQUIRED vWD

AvWD is a rare, but probably underestimated, bleeding disorder.2 The first description of AvWD occurred in 1968 in a patient with systemic lupus erythematosus.19 The key feature of AvWD is its late onset of bleeding diathesis without a family history of vWD and no history of prolonged bleeding after previous hemostatic challenges.20 The clinical symptoms, which are similar to those of inherited vWD, are not specific and include mucocutaneous bleeding and bleeding after surgery and trauma; however, soft tissue and joint bleeding, which occur in hemophilic patients, are uncommon in these patients.21 The severity of the bleeding manifestations in patients with AvWD depends largely on the mechanism and the degree of vWF deficiency that is caused by the underlying disorder. However, especially in critical surgical situations (e.g., neurosurgery) or in the case of epidural anesthesia, even mild to moderate bleeding can be extremely harmful.

AvWD occurs in association with various underlying diseases, which most frequently include lymphoproliferative and myeloproliferative disorders, malignancies, immunological disorders, and other miscellaneous conditions.2,3,22,23 AvWD has also been described in cardiovascular disorders, such as aortic stenosis,24,25 mitral valve prolapse,2 congenital ventricular, or atrial septal defects,26,27 and after implantation of ventricular assist devices.28,29 Several pathophysiological mechanisms have been described.2,3 Except for those patients with hypothyroidism,30 who show decreased vWF synthesis and release, normal or even increased quantities of vWF are synthesized and released into the circulation in patients with AvWD. Low levels of vWF are usually caused by the accelerated removal of the protein through various mechanisms, which include (1) specific or nonspecific autoantibodies that form circulating immune complexes and enhance the clearance of vWF, (2) adsorption of vWF onto tumor cells or platelets, and (3) specific or nonspecific increases in the proteolytic degradation of vWF and/or loss of HMW vWF multimers under high shear stress (Fig. 2).2,3 Furthermore, interactions with several drugs, including valproic acid, ciprofloxacin, tetracycline, and griseofulvin have been described.2,20 Because of a resulting decrease in plasma concentrations of vWF, high- and medium-molecular-weight hydroxyethyl starch can dose dependently induce AvWD.31,32

Back to Top | Article Outline

LABORATORY FINDINGS

The diagnosis of AvWD is based on the laboratory variables that are typical for inherited vWD.2 In addition to laboratory screening tests (complete blood count, aPTT, and prothrombin time), currently, the commonly performed tests include plasma levels of vWF:Ag, vWF:RCo, and vWF:CB.3,33 These tests measure the amount of von Willebrand protein that is present in the plasma (vWF:Ag) and the function of the von Willebrand protein (vWF:RCo, vWF:CB), respectively.5 FVIII determines the ability of vWF to serve as the carrier protein for FVIII.5 There are conflicting data regarding the use of the PFA-100 in the diagnosis of vWD.34,35 PFA-100 has a high sensitivity for impaired primary hemostasis and vWD, but has a low specificity for a particular disorder.35 37 Thus, especially in the perioperative setting (e.g., after cardiopulmonary bypass or major blood loss), derangement of hemostasis with a low platelet count, a low hematocrit, and an impaired platelet function may lead to inconclusive PFA-100 results.35 After an initial diagnosis, multimer analysis typically illustrates the distribution of plasma vWF multimers. vWF multimer distribution often shows a decrease in the HMW vWF multimers that is similar to that seen in type 2A inherited vWD. If the vWF antigen and activity levels are normal or increased, time-consuming multimer analysis is necessary for the diagnosis of AvWD.38,39 Of note, in contrast to other acquired hemostatic defects (e.g., acquired FVIII inhibitor), an inhibitor of vWF is detected in only a small number of patients with AvWD.2,4,21 Whereas initial tests are often readily available at larger hospitals, multimer analysis and the detection of an inhibitor are technically demanding evaluations. Therefore, the diagnostic process of AvWD is sometimes cumbersome and is not able to be performed during an emergency situation. However, in cases of unexpected bleeding situations, clinicians should take a closer look at routine laboratory variables, such as aPTT, thereby keeping acquired hemostatic defects such as AvWD in mind. Even though aPTT is not specific for the diagnosis of vWD or AvWD and the results for this test are only abnormal if FVIII is considerably reduced, determination of the aPTT could be helpful, as demonstrated in the presented case report.

Back to Top | Article Outline

AvWD IN CARDIAC PATIENTS

The role of increased shear stress in AvWD has been shown in severe aortic stenosis.24,25 Vincentelli et al.24 demonstrated a significant correlation between the increased high shear stress and the loss of HMW vWF multimers in vivo. The multimeric abnormalities were directly related to the aortic valve gradient, and they improved after valve replacement.24 However, mismatch between the patient and the valvular prosthesis can result in persistent pathological findings after surgery.24,40 Pathological shear stress due to a narrowed aortic valve changes the conformation of vWF and promotes its increased proteolysis by ADAMTS-13, which leads to the depletion of HMW vWF multimers.25,41 Thus, in these patients, there is a high prevalence of abnormal multimeric patterns, which is similar to inherited vWD type 2A.24,25,38 Similarly, the loss of HMW vWF multimers can also be observed in children with congenital heart defects26,42 and in patients with certain ventricular assist devices, particularly the assist devices with a nonpulsatile flow.28,29,43 However, in a considerable number of these patients, the reduction or absence of HMW vWF multimers does not correlate with vWF:Ag or vWF activity; normal or even supernormal vWF parameters can be observed in these patients because vWF is an acute phase protein.28,38,39 Thus, to identify low levels of vWF, repeated laboratory measurements are recommended, especially in cases of acute bleeding events and acute illness as well as after hospitalization or after surgery.5

In most patients, a complete correction of the hemostatic defect is observed after successful treatment of the underlying disorder. Although some of these cardiac patients may display a bleeding tendency before an operation,24,25 no increased bleeding is observed in the perioperative period in the majority of patients despite pathological laboratory findings.27,38 In a recently published study, Mikkelsen et al.44 did not observe increased blood loss during elective aortic valve replacement procedures in patients with severe aortic valve stenosis and with AvWD compared with patients with severe aortic valve stenosis without AvWD. Therefore, it is likely that the high prevalence of multimeric abnormalities is a laboratory phenomenon with limited clinical impact. Table 2summarizes the results of published studies and case reports on cardiac surgery in patients with AvWD and shows that only some patients with the diagnosis of AvWD demonstrated increased bleeding tendency and required special treatment during cardiac surgery. Nevertheless, clinicians should be aware that significant bleeding may occur after cardiac surgery, necessitating appropriate therapeutic management (e.g., in Heyde syndrome, which is defined as aortic stenosis combined with bleeding from gastrointestinal angiodysplasia).1,45 More recently, some authors have identified a relationship between AvWD and postoperative bleeding complications, particularly with gastrointestinal bleeding and/or epistaxis in patients after the implantation of continuous-flow ventricular assist devices.46,47 Thus, the preexistence of asymptomatic gastrointestinal and/or nasal angiodysplasias as well as the need for an anticoagulation therapy may be contributing factors to such bleeding complications.46

Table 2

Table 2

Back to Top | Article Outline

THERAPEUTIC OPTIONS

The treatment of AvWD is a therapeutic challenge48 that has not yet been standardized. Similar to congenital vWD, the therapeutic options include desmopressin (DDAVP) and certain FVIII/vWF concentrates.4,21,49 Unfortunately, in AvWD, endogenously produced or exogenously administered vWF is rapidly cleared from the plasma, which results in a reduced half-life. Thus, the efficacy of this standard treatment is limited.

Other adjunctive treatment options, such as antifibrinolytic agents (e.g., tranexamic acid and ε-aminocaproic acid), may be used in association with standard treatment, particularly for oral interventions.50 Antifibrinolytic agents competitively inhibit the activation of plasminogen, thereby reducing the conversion of plasminogen to plasmin, a molecule responsible for the degradation of fibrin.16

However, the complete resolution of the hemostatic defect and the normalization of laboratory variables can only be achieved with the specific and successful treatment of the underlying disease that is responsible for the development of AvWD. Therapeutic options may include tumor resection, cardiovascular surgery (e.g., aortic valve replacement), chemotherapy, radiotherapy, immunosuppression, hormone replacement in hypothyroidism, and discontinuation of the offending agent.3,21 However, these are not options for an anesthesiologist confronted with a bleeding patient in the operating room, such as the case report illustrated in this review.

Back to Top | Article Outline

Desmopressin (DDAVP)

DDAVP releases preformed vWF from vascular endothelial cells, which restores the plasma levels of vWF and FVIII.49 In addition, DDAVP may also be useful via other prohemostatic effects as related to its ability to promote platelet adhesion and aggregation.51,52 DDAVP should be chosen as the initial treatment in patients with AvWD.2,50 It is usually administered by continuous IV infusion over 30 minutes at a dose of 0.3 μg/kg diluted in 50 mL saline. In vWD, this treatment increases plasma FVIII/vWF 3 to 5 times above baseline levels within 30 to 60 minutes. DDAVP dosing can be repeated at 12- to 24-hour intervals. Because of tachyphylaxis, however, most repeatedly treated patients become less responsive to therapy with DDAVP, and side effects, such as an antidiuretic action, must be considered.16 In AvWD, the use of desmopressin has a disadvantage in the short half-life of endogenous vWF because of the rapid degradation associated with AvWD.4,21 Thus, depending on the underlying pathophysiological mechanism, the response to desmopressin can vary considerably from patient to patient. In addition, the magnitude of the increase in plasma vWF concentration is typically not equivalent to that obtained with vWF replacement therapy. To test the patient's individual responsiveness and thus to predict the clinical efficacy of desmopressin, a therapeutic trial should be implemented in advance if AvWD is known preoperatively.4 Patients with a severe deficiency or patients with a known inhibitor will not respond sufficiently to desmopressin.53

Back to Top | Article Outline

FVIII/vWF Concentrates

FVIII/vWF concentrates are the mainstays of therapy in AvWD in cases of acute hemorrhage.4,21,54 Patients with AvWD who are unresponsive to desmopressin should be treated with FVIII/vWF concentrates. Most patients will respond with an increase in FVIII and vWF levels, but FVIII and vWF may have much shorter half-lives in these patients compared with those with congenital vWD.4,21,22 In vWD, the recommended initial loading dose of FVIII/vWF concentrates is 30 to 50 IU/kg.55 Postoperative factor administration should be repeated every 12 to 48 hours at a dose of 20 to 40 IU/kg.5,55 Because of the shortened half-life of exogenous vWF, higher doses of FVIII/vWF concentrates at shorter intervals may be necessary in AvWD, such as was required in the presented case report.4,21,56 In addition, postinfusion measurements of FVIII and vWF should be implemented for adjustment of the dosage and frequency of dosing intervals. However, in emergency situations, FVIII/vWF concentrates present the only therapeutic option for achieving high levels of vWF activity in a short period of time.

The efficacy of FVIII concentrates in the treatment of vWD and AvWD depends on the content and quality of FVIII and vWF. Thus, physicians treating patients with vWD and AvWD must be aware of the differences between the different FVIII concentrates. Although no vWF activity is present in the recombinant FVIII concentrates and low vWF activity is found in very highly purified FVIII concentrates, several intermediate and high purity human FVIII concentrates that contain high concentrations of vWF are currently available; a recombinant vWF concentrate is currently in development.55,57 FVIII concentrates are much more expensive than desmopressin. Currently available human FVIII/vWF concentrates have a low risk of transmission of blood-borne infections.

Back to Top | Article Outline

Immunomodulation

Corticosteroids or IV, high-dose immunoglobulins have been reported as possible treatment options.49 Prednisone is useful in resolving AvWD that is associated with underlying immunological disorders, such as systemic lupus erythematosus58 or in patients with lymphoproliferative diseases.49 Plasmapheresis and extracorporeal immunoadsorption can be considered for the elimination of vWF autoantibodies.49,59 However, mechanical elimination of vWF autoantibodies is limited by the requirements for a central venous catheter (i.e., bleeding risk), the overall risks of the method (i.e., hemodynamic instability, citrate/ allergic reactions), and because of the multiple procedures required.

In patients with lymphoproliferative disorders or monoclonal gammopathies, the administration of IV immunoglobulins has been shown to be therapeutically beneficial.56,60 62 IV immunoglobulins can produce a more sustained response than DDAVP or FVIII/vWF concentrates in these patients with immune-mediated AvWD56,61,63; thereby, an effect that lasted up to 3 weeks after treatment has been observed.60,64 The therapeutic doses of IV immunoglobulins for AvWD are 1 g/kg/d for 2 days or 0.4 g/kg/d for 5 days. However, IV immunoglobulins usually have a delayed onset of action and require 2 to 3 days to normalize the plasma FVIII/VWF activity in most cases.60,61 In cases of hyporesponsiveness to IV immunoglobulin therapy alone, subsequent administration of FVIII/vWF concentrates after pretreatment with IV immunoglobulins may produce sufficient hemostasis in major surgery and in labor and delivery.65 67 Although the exact mechanism of the efficacy of IV immunoglobulins in AvWD is unclear, immunoglobulins probably interfere with the clearance of the vWF-antibody complexes.53,64 However, because of its delayed onset, IV immunoglobulin administration is not a therapeutic option for an acutely bleeding patient in the operating room.

Back to Top | Article Outline

Recombinant Activated Factor VII

If all of these options fail, there is a considerable risk of severe bleeding during surgery, which may be fatal in some cases.1 In these rare circumstances of intractable bleeding, alternative therapeutic options for effective treatment of hemorrhage are required.

Recombinant activated factor VII (rFVIIa) (NovoSeven; Novo Nordisk, Bagsvaerd, Denmark) has been introduced as a “bypassing agent” for the treatment of congenital hemophilic patients with inhibitors to FVIII or factor IX and has been approved for patients with acquired hemophilia.68 70 High-dose rFVIIa improves thrombin generation, increases fibrin stability, and restores platelet aggregation.71,72 In a limited number of patients with AvWD who did not respond to conventional therapies, off-label use of rFVIIa has been successfully applied.73,74 rFVIIa seems to be capable of compensating for the vWF defect. Therefore, in patients with AvWD, rFVIIa should be considered as an alternative treatment option if other therapeutic approaches fail. However, it should be noted that the clinical use of rFVIIa in patients with AvWD is described only in individual case reports.75 78 In these reports, there were considerable variations in the amounts of each rFVIIa bolus, the frequencies of dosing intervals, the durations of continuous infusion, and the total durations of treatment. Moreover, serious side effects, such as thromboembolic complications, must be considered, especially in patients with known cardiovascular disease.79,80 Additional clinical data are required to assess the safety of rFVIIa and to define the optimal therapeutic rFVIIa regimen in patients with AvWD that is refractory to standard therapy.

Back to Top | Article Outline

SUMMARY

Typically, AvWD is a sudden, unexpected manifestation of hemorrhage in individuals without an individual or family history of bleeding. This is in contrast to patients with inherited vWD, who display lifelong bleeding episodes. However, the diagnostic process is difficult and time-consuming and cannot be completed in most emergency situations. Therefore, awareness of AvWD is important for the appropriate and timely management of unexpected perioperative bleeding. The first-line treatment option in the operating room is DDAVP. Plasma-derived FVIII/vWF concentrates are potential options in emergency situations that require rapid therapeutic intervention. Finally, if all interventions fail and bleeding continues, rFVIIa is an additional off-label option. IV immunoglobulins and corticosteroids are not an option for emergent bleeding situations in the operating room.

Back to Top | Article Outline

DISCLOSURES

Name: Susanne Lison, MD.

Contribution: This author helped write the manuscript and search literature.

Conflicts of Interest: Susanne Lison received speaker honoraria from CSL Behring (Marburg, Germany) and Bayer (Leverkusen, Germany) and received study support from CSL Behring and The Medicines Company GmbH (Leipzig, Germany).

Attestation: Susanne Lison approved the final manuscript.

Name: Wulf Dietrich, MD, PhD.

Contribution: This author helped write the manuscript and search literature.

Conflicts of Interest: Wulf Dietrich received study support from and served as consultant for Bayer (Leverkusen, Germany) and The Medicines Company GmbH (Leipzig, Germany). He received study support from CSL Behring (Marburg, Germany) and received educational grants from Novo Nordisk (Bagsvaerd, Denmark).

Attestation: Wulf Dietrich approved the final manuscript.

Name: Michael Spannagl, MD, PhD.

Contribution: This author helped write the manuscript and search literature.

Conflicts of Interest: Michael Spannagl received speaker and consultant honoraria from Baxter (Vienna, Austria), Bayer (Leverkusen, Germany), Biotest (Dreieich, Germany), CSL Behring, Novo Nordisk (Bagsvaerd, Denmark), Octapharma (Lachen, Switzerland), and Pfizer (New York, NY). He worked on an advisory board for Biotest and Pfizer.

Attestation: Michael Spannagl approved the final manuscript.

This manuscript was handled by: Jerrold H. Levy, MD, FAHA.

Back to Top | Article Outline

REFERENCES

1. Velik-Salchner C, Eschertzhuber S, Streif W, Hangler H, Budde U, Fries D. Acquired von Willebrand syndrome in cardiac patients. J Cardiothorac Vasc Anesth 2008;22:719–24
2. Veyradier A, Jenkins CS, Fressinaud E, Meyer D. Acquired von Willebrand syndrome: from pathophysiology to management. Thromb Haemost 2000;84:175–82
3. Tefferi A, Nichols WL. Acquired von Willebrand disease: concise review of occurrence, diagnosis, pathogenesis, and treatment. Am J Med 1997;103:536–40
4. Kumar S, Pruthi RK, Nichols WL. Acquired von Willebrand's syndrome: a single institution experience. Am J Hematol 2003;72:243–7
5. Nichols WL, Hultin MB, James AH, Manco-Johnson MJ, Montgomery RR, Ortel TL, Rick ME, Sadler JE, Weinstein M, Yawn BP. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia 2008;14:171–232
6. German JW, Adamo MA, Hoppenot RG, Blossom JH, Nagle HA. Perioperative results following lumbar discectomy: comparison of minimally invasive discectomy and standard microdiscectomy. Neurosurg Focus 2008;25:E20
7. Sadler JE. Biochemistry and genetics of von Willebrand factor. Annu Rev Biochem 1998;67:395–424
8. Reininger AJ. Function of von Willebrand factor in haemostasis and thrombosis. Haemophilia 2008;14:11–26
9. Wise RJ, Dorner AJ, Krane M, Pittman DD, Kaufman RJ. The role of von Willebrand factor multimers and propeptide cleavage in binding and stabilization of factor VIII. J Biol Chem 1991;266:21948–55
10. Weiss HJ, Sussman II, Hoyer LW. Stabilization of factor VIII in plasma by the von Willebrand factor: studies on posttransfusion and dissociated factor VIII and in patients with von Willebrand's disease. J Clin Invest 1977;60:390–404
11. Dong JF. Cleavage of ultra-large von Willebrand factor by ADAMTS-13 under flow conditions. J Thromb Haemost 2005;3:1710–6
12. Feys HB, Deckmyn H, Vanhoorelbeke K. ADAMTS13 in health and disease. Acta Haematol 2009;121:183–5
13. Moake J. Thrombotic thrombocytopenia purpura (TTP) and other thrombotic microangiopathies. Best Pract Res Clin Haematol 2009;22:567–76
14. Bowen DJ, Collins PW. Insights into von Willebrand factor proteolysis: clinical implications. Br J Haematol 2006;133:457–67
15. Sadler JE. A revised classification of von Willebrand disease. For the Subcommittee on von Willebrand factor of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost 1994;71:520–5
16. Federici AB, Castaman G, Mannucci PM. Guidelines for the diagnosis and management of von Willebrand disease in Italy. Haemophilia 2002;8:607–21
17. Silwer J. von Willebrand's disease in Sweden. Acta Paediatr Scand Suppl 1973;238:1–159
18. Budde U. Diagnosis of von Willebrand disease subtypes: implications for treatment. Haemophilia 2008;14:27–38
19. Simone JV, Cornet JA, Abildgaard CF. Acquired von Willebrand's syndrome in systemic lupus erythematosus. Blood 1968;31:806–12
20. van Genderen PJ, Michiels JJ. Acquired von Willebrand disease. Baillieres Clin Haematol 1998;11:319–30
21. Nitu-Whalley IC, Lee CA. Acquired von Willebrand syndrome: report of 10 cases and review of the literature. Haemophilia 1999;5:318–26
22. Federici AB, Rand JH, Bucciarelli P, Budde U, van Genderen PJ, Mohri H, Meyer D, Rodeghiero F, Sadler JE. Acquired von Willebrand syndrome: data from an international registry. Thromb Haemost 2000;84:345–9
23. Franchini M, Lippi G. Recent acquisitions in acquired and congenital von Willebrand disorders. Clin Chim Acta 2007;377:62–9
24. Vincentelli A, Susen S, Le Tourneau T, Six I, Fabre O, Juthier F, Bauters A, Decoene C, Goudemand J, Prat A, Jude B. Acquired von Willebrand syndrome in aortic stenosis. N Engl J Med 2003;349:343–9
25. Pareti FI, Lattuada A, Bressi C, Zanobini M, Sala A, Steffan A, Ruggeri ZM. Proteolysis of von Willebrand factor and shear stress-induced platelet aggregation in patients with aortic valve stenosis. Circulation 2000;102:1290–5
26. Gill JC, Wilson AD, Endres-Brooks J, Montgomery RR. Loss of the largest von Willebrand factor multimers from the plasma of patients with congenital cardiac defects. Blood 1986;67:758–61
27. Arslan MT, Ozyurek R, Kavakli K, Levent E, Ulger Z, Gurses D, Akyol B, Atay Y. Frequency of acquired von Willebrand's disease in children with congenital heart disease. Acta Cardiol 2007;62:403–8
28. Heilmann C, Geisen U, Beyersdorf F, Nakamura L, Benk C, Berchtold-Herz M, Trummer G, Schlensak C, Zieger B. Acquired von Willebrand syndrome in patients with ventricular assist device or total artificial heart. Thromb Haemost 2010;103:962–7
29. Geisen U, Heilmann C, Beyersdorf F, Benk C, Berchtold-Herz M, Schlensak C, Budde U, Zieger B. Non-surgical bleeding in patients with ventricular assist devices could be explained by acquired von Willebrand disease. Eur J Cardiothorac Surg 2008;33:679–84
30. Manfredi E, van Zaane B, Gerdes VE, Brandjes DP, Squizzato A. Hypothyroidism and acquired von Willebrand's syndrome: a systematic review. Haemophilia 2008;14:423–33
31. Jonville-Bera AP, Autret-Leca E, Gruel Y. Acquired type I von Willebrand's disease associated with highly substituted hydroxyethyl starch. N Engl J Med 2001;345:622–3
32. Kozek-Langenecker SA. Effects of hydroxyethyl starch solutions on hemostasis. Anesthesiology 2005;103:654–60
33. Favaloro EJ, Lillicrap D, Lazzari MA, Cattaneo M, Mazurier C, Woods A, Meschengieser S, Blanco A, Kempfer AC, Hubbard A, Chang A. von Willebrand disease: laboratory aspects of diagnosis and treatment. Haemophilia 2004;10:164–8
34. Nichols WL, Rick ME, Ortel TL, Montgomery RR, Sadler JE, Yawn BP, James AH, Hultin MB, Manco-Johnson MJ, Weinstein M. Clinical and laboratory diagnosis of von Willebrand disease: a synopsis of the 2008 NHLBI/NIH guidelines. Am J Hematol 2009;84:366–70
35. Favaloro EJ. Clinical utility of the PFA-100. Semin Thromb Hemost 2008;34:709–33
36. Posan E, McBane RD, Grill DE, Motsko CL, Nichols WL. Comparison of PFA-100 testing and bleeding time for detecting platelet hypofunction and von Willebrand disease in clinical practice. Thromb Haemost 2003;90:483–90
37. Koscielny J, Ziemer S, Radtke H, Schmutzler M, Pruss A, Sinha P, Salama A, Kiesewetter H, Latza R. A practical concept for preoperative identification of patients with impaired primary hemostasis. Clin Appl Thromb Hemost 2004;10:195–204
38. Sucker C, Feindt P, Zotz RB, Stockschlaeder M, Scharf RE. Functional von Willebrand factor assays are not predictive for the absence of highest-molecular weight von Willebrand factor multimers in patients with aortic-valve stenosis. Thromb Haemost 2005;94:465–6
39. Tiede A, Priesack J, Werwitzke S, Bohlmann K, Oortwijn B, Lenting P, Eisert R, Ganser A, Budde U. Diagnostic workup of patients with acquired von Willebrand syndrome: a retrospective single-centre cohort study. J Thromb Haemost 2008;6:569–76
40. Yoshida K, Tobe S, Kawata M, Yamaguchi M. Acquired and reversible von Willebrand disease with high shear stress aortic valve stenosis. Ann Thorac Surg 2006;81:490–4
41. Tsai HM, Sussman II, Nagel RL. Shear stress enhances the proteolysis of von Willebrand factor in normal plasma. Blood 1994;83:2171–9
42. Rauch R, Budde U, Koch A, Girisch M, Hofbeck M. Acquired von Willebrand syndrome in children with patent ductus arteriosus. Heart 2002;88:87–8
43. Malehsa D, Meyer AL, Bara C, Struber M. Acquired von Willebrand syndrome after exchange of the HeartMate XVE to the HeartMate II ventricular assist device. Eur J Cardiothorac Surg 2009;35:1091–3
44. Mikkelsen MM, Fenger-Eriksen C, Johnsen SP, Christensen TD, Sorensen B. No excess surgical blood loss in patients with acquired type 2A von Willebrand disease. Scand Cardiovasc J 2011;45:120–6
45. Morishima A, Marui A, Shimamoto T, Saji Y, Tambara K, Nishina T, Komeda M. Successful aortic valve replacement for Heyde syndrome with confirmed hematologic recovery. Ann Thorac Surg 2007;83:287–8
46. Crow S, Chen D, Milano C, Thomas W, Joyce L, Piacentino V III, Sharma R, Wu J, Arepally G, Bowles D, Rogers J, Villamizar-Ortiz N. Acquired von Willebrand syndrome in continuous-flow ventricular assist device recipients. Ann Thorac Surg 2010;90:1263–9
47. Uriel N, Pak SW, Jorde UP, Jude B, Susen S, Vincentelli A, Ennezat PV, Cappleman S, Naka Y, Mancini D. Acquired von Willebrand syndrome after continuous-flow mechanical device support contributes to a high prevalence of bleeding during long-term support and at the time of transplantation. J Am Coll Cardiol 2010;56:1207–13
48. Michiels JJ, Budde U, van der Planken M, van Vliet HH, Schroyens W, Berneman Z. Acquired von Willebrand syndromes: clinical features, aetiology, pathophysiology, classification and management. Best Pract Res Clin Haematol 2001;14:401–36
49. Federici AB. Therapeutic approaches to acquired von Willebrand syndrome. Expert Opin Investig Drugs 2000;9:347–54
50. Castaman G, Rodeghiero F, Di Bona E, Ruggeri M. Clinical effectiveness of desmopressin in a case of acquired von Willebrand's syndrome associated with benign monoclonal gammopathy. Blut 1989;58:211–3
51. Coppola A, Di Minno G. Desmopressin in inherited disorders of platelet function. Haemophilia 2008;14:31–9
52. Sloand EM, Alyono D, Klein HG, Chang P, Yu M, Lightfoot FG, Kessler C. 1-Deamino-8-D-arginine vasopressin (DDAVP) increases platelet membrane expression of glycoprotein Ib in patients with disorders of platelet function and after cardiopulmonary bypass. Am J Hematol 1994;46:199–207
53. Kumar S, Pruthi RK, Nichols WL. Acquired von Willebrand disease. Mayo Clin Proc 2002;77:181–7
54. Alvarez MT, Jimenez-Yuste V, Gracia J, Quintana M, Hernandez-Navarro F. Acquired von Willebrand syndrome. Haemophilia 2008;14:856–8
55. Mannucci PM. Treatment of von Willebrand's disease. N Engl J Med 2004;351:683–94
56. Van Genderen PJ, Papatsonis DN, Michiels JJ, Wielenga JJ, Stibbe J, Huikeshoven FJ. High-dose intravenous gammaglobulin therapy for acquired von Willebrand disease. Postgrad Med J 1994;70:916–20
57. Batlle J, Lopez-Fernandez MF, Fraga EL, Trillo AR, Perez-Rodriguez MA. von Willebrand factor/factor VIII concentrates in the treatment of von Willebrand disease. Blood Coagul Fibrinolysis 2009;20:89–100
58. Michiels JJ, Schroyens W, van der Planken M, Berneman Z. Acquired von Willebrand syndrome in systemic lupus erythematodes. Clin Appl Thromb Hemost 2001;7:106–12
59. Silberstein LE, Abrahm J, Shattil SJ. The efficacy of intensive plasma exchange in acquired von Willebrand's disease. Transfusion 1987;27:234–7
60. Federici AB. Use of intravenous immunoglobulin in patients with acquired von Willebrand syndrome. Hum Immunol 2005;66:422–30
61. Hayashi T, Yagi H, Suzuki H, Nonaka Y, Nomura T, Sakurai Y, Shibata M, Matsumoto M, Yamamoto Y, Fujimura Y. Low-dosage intravenous immunoglobulin in the management of a patient with acquired von Willebrand syndrome associated with monoclonal gammopathy of undetermined significance. Pathophysiol Haemost Thromb 2002;32:33–9
62. Michiels JJ, van Vliet HH. Acquired von Willebrand disease in monoclonal gammapathies: effectiveness of high-dose intravenous gamma globulin. Clin Appl Thromb Hemost 1999;5:152–7
63. Eikenboom JC, Tjernberg P, Van Marion V, Heering KJ. Acquired von Willebrand syndrome: diagnostic problems and therapeutic options. Am J Hematol 2007;82:55–8
64. Mohri H. Acquired von Willebrand syndrome: features and management. Am J Hematol 2006;81:616–23
65. Frank RD, Kunz D, Wirtz DC. Acquired von Willebrand disease: hemostatic management of major orthopedic surgery with high-dose immunoglobulin, desmopressin, and continuous factor concentrate infusion. Am J Hematol 2002;70:64–71
66. Maddox JM, Anderson JA, Plews D, Ludlam CA. Management of acquired von Willebrand's syndrome in a patient requiring major surgery. Haemophilia 2005;11:633–7
67. Lipkind HS, Kurtis JD, Powrie R, Carpenter MW. Acquired von Willebrand disease: management of labor and delivery with intravenous dexamethasone, continuous factor concentrate, and immunoglobulin infusion. Am J Obstet Gynecol 2005;192:2067–70
68. Abshire T, Kenet G. Recombinant factor VIIa: review of efficacy, dosing regimens and safety in patients with congenital and acquired factor VIII or IX inhibitors. J Thromb Haemost 2004;2:899–909
69. Poon MC. The evidence for the use of recombinant human activated factor VII in the treatment of bleeding patients with quantitative and qualitative platelet disorders. Transfus Med Rev 2007;21:223–36
70. Franchini M, Zaffanello M, Veneri D. Recombinant factor VIIa: an update on its clinical use. Thromb Haemost 2005;93:1027–35
71. Lisman T, De Groot PG. Mechanism of action of recombinant factor VIIa. J Thromb Haemost 2003;1:1138–9
72. Lisman T, Adelmeijer J, Heijnen HF, de Groot PG. Recombinant factor VIIa restores aggregation of alphaIIbbeta3-deficient platelets via tissue factor-independent fibrin generation. Blood 2004;103:1720–7
73. Sucker C, Scharf RE, Zotz RB. Use of recombinant factor VIIa in inherited and acquired von Willebrand disease. Clin Appl Thromb Hemost 2009;15:27–31
74. Franchini M, Veneri D, Lippi G. The use of recombinant activated factor VII in congenital and acquired von Willebrand disease. Blood Coagul Fibrinolysis 2006;17:615–9
75. Karger R, Weippert-Kretschmer M, Budde U, Kretschmer V. Diagnosis and therapeutic management in a patient with type 2B-like acquired von Willebrand syndrome. Blood Coagul Fibrinolysis 2011;22:144–7
76. Perez-Montes R, Arce O, Bermudez A, Yanez L, Sedano C, Zubizarreta A. Recombinant factor VIIa as a hemostatic agent in acquired von Willebrand disease. J Thromb Haemost 2003;1:1129
77. Friederich PW, Wever PC, Briet E, Doorenbos CJ, Levi M. Successful treatment with recombinant factor VIIa of therapy-resistant severe bleeding in a patient with acquired von Willebrand disease. Am J Hematol 2001;66:292–4
78. Smaradottir A, Bona R. A case of acquired von Willebrand syndrome successfully treated with recombinant factor VIIa during thyroidectomy. Thromb Haemost 2004;92:666–7
79. Basso IN, Keeling D. Myocardial infarction following recombinant activated factor VII in a patient with type 2A von Willebrand disease. Blood Coagul Fibrinolysis 2004;15:503–4
80. Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med 2010;363:1791–800
81. Rinder MR, Richard RE, Rinder HM. Acquired von Willebrand's disease: a concise review. Am J Hematol 1997;54:139–45
    82. Hennessy BJ, White B, Byrne M, Smith OP. Acquired von Willebrand's disease. Ir J Med Sci 1998;167:81–5
      83. Sanchez-Luceros A, Meschengieser SS, Woods AI, Blanco AN, Kempfer AC, Casais P, Salviu MJ, Lazzari MA. Acquired von Willebrand factor abnormalities in myeloproliferative disorders and other hematologic diseases: a retrospective analysis by a single institution. Haematologica 2002;87:264–70
        84. Yoshida K, Tobe S, Kawata M. Acquired von Willebrand disease type IIA in patients with aortic valve stenosis. Ann Thorac Surg 2006;81:1114–6
          85. Sardesai MP, Sabik J, Koch CG. Perioperative management of acquired von Willebrand disease in cardiac surgery: type 2B or not 2B? J Cardiothorac Vasc Anesth 2011;25:131–3
            © 2012 International Anesthesia Research Society