REVIEW URRENT C OPINION
Current management of von Willebrand disease and von Willebrand syndrome Marc E. Stone, Michael Mazzeffi, Jeffrey Derham, and Andre Korshin
Purpose of review Anesthesiologists frequently care for patients with altered hemostasis and coagulation. Where a clear history of familial and personal bleeding exists, a thoughtful plan can be developed in advance to manage the issue perioperatively. However, in some cases, it may not be known that the patient has a disorder until excessive bleeding is noted during or after surgery. Recognition of the issue and appropriate targeted therapy are the keys to successful management. Recent findings With an estimated prevalence approaching 1% of the population, von Willebrand disease (vWD) is the most common hereditary bleeding diathesis, but the estimated prevalence of acquired vWD (often termed von Willebrand syndrome or vWS) is now believed to be significantly higher, especially in patients with malignancies, autoimmune diseases, cardiac valvular lesions, and in patients on mechanical circulatory support devices. Acquired vWD may also occur with certain medications. Summary The mainstay of the diagnosis of vWD is laboratory testing. Preoperative clinical assessment and a high level of suspicion are often effective to alert the anesthesiologist to the possibility of vWS, thus allowing for appropriate testing and potential prophylaxis in elective situations, as well as appropriately targeted therapy of unexpected bleeding when a hemostatic derangement was not anticipated preoperatively. Keywords DDAVP, perioperative bleeding, von Willebrand disease, von Willebrand syndrome
INTRODUCTION von Willebrand factor (vWF) is critical to primary hemostasis because it facilitates the adhesion of platelets to the sites of endothelial injury (via GPIb) and the aggregation of platelets to each other (via GPIb and GPIIb/IIIa) [1]. Further, its binding to the platelet GPIa receptor helps activate platelets and expose fibrinogen receptor (GPIIb/IIIa) [2]. vWF is also critical to secondary hemostasis because it acts as a carrier protein for factor VIII (FVIII), slowing its breakdown and clearance from plasma [3]. When vWF levels are decreased or its functionality is altered, platelet plug formation becomes ineffective. Decreased levels of FVIII also lead to poor clot stability. Clinically, this manifests as a syndrome of excessive mucocutaneous or postsurgical bleeding. Bleeding severity depends on the particular variant of von Willebrand disease (vWD) (see Table 1). Essentially, types 1 and 3 vWD are quantitative defects, and type 2 disease is qualitative. Normal production of vWF occurs in both vascular endothelial cells and megakaryocytes [4]. vWF
is processed into multimers of differing molecular size which are then either stored in endothelial Weibel-Palade bodies and the a-granules of megakaryocytes, or secreted into the plasma and extracellular matrix at tonic levels [5,6]. The largest [high molecular weight (HMW)] multimers are the most prothrombotic and are subject to cleavage by the metalloprotease ADAMTS-13 in areas where the endothelium is intact. The genetic encoding for vWF is on chromosome 12 [7]. Numerous publications in the hematology literature discuss the exact mutations involved in the various hereditary forms of the disease [8].
Department of Anesthesiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA Correspondence to Marc E. Stone, MD, Department of Anesthesiology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, Box 1010, New York, NY 10029, USA. E-mail: [email protected] Curr Opin Anesthesiol 2014, 27:353–358 DOI:10.1097/ACO.0000000000000083
0952-7907 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-anesthesiology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Anesthesia and medical disease
KEY POINTS The prevalence of acquired von Willebrand syndrome is likely much higher than previously recognized. Acquired von Willebrand syndrome occurs in association with a variety of disease states, physiological processes, and medications. The mainstay of diagnosis is laboratory testing, but not all patients with risk factors for von Willebrand syndrome or laboratory abnormalities bleed excessively in the perioperative period. Preoperative clinical assessment of bleeding history can alert the anesthesia practitioner to the possibility of clinically relevant von Willebrand syndrome.
ACQUIRED VON WILLEBRAND SYNDROME vWD is the most common hereditary bleeding diathesis, with an estimated prevalence of the hereditary forms approaching 1% of the population. Although acquired von Willebrand syndrome (vWS) has been known to occur since 1968 [9], it is only recently understood that the diagnosis is likely more prevalent than previously thought. The clinical appearance of vWS is similar to vWD in that patients demonstrate mucocutaneous bleeding and excessive bleeding following trauma or surgery, but there is neither a family history nor always a previous personal history of bleeding. The severity is determined by the process inducing the acquired defect, but the mechanism of the syndrome generally involves enhanced clearance of vWF from the plasma (or, at least, a destruction of the large multimers). Causes underlying the acquired form differ from the inherited forms and include increased clearance because of: (1) antibodies associated with lymphoproliferative, neoplastic, or immunological diseases; (2) adsorption onto malignant cells or other surfaces; (3) destruction of large vWF multimers by shear stress (e.g., cardiac valvular lesions or defects, vascular narrowings, or extracorporeal circulation); (4) increased degradation by proteases as a result of high shear stress (or other specific mechanisms); (5) miscellaneous: medications, viruses, uremia, fibrinolytic processes, hypothyroidism, etc. Estimates place the prevalence of vWS at 0.04–0.13% [10,11], but specific subpopulations may exhibit a much higher prevalence. For example, a study of patients with aortic stenosis found 354
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platelet function abnormalities under conditions of high shear stress, decreased vWF collagen-binding activity (CBA) and loss of the largest vWF multimers, or a combination of these in 67–92% of patients with severe aortic stenosis. Further, there was a significant correlation with the severity of valve stenosis [12]. Since 1958, the term ‘Heyde’s syndrome’ has been applied to patients with aortic stenosis and bleeding from gastrointestinal angiodysplasias [13]. It is important to note that the source of bleeding in Heyde’s patients is from gastrointestinal vascular malformations and, further, that bleeding from such malformations usually resolves when the aortic valve is replaced [14]. The loss of HMW vWF multimers as a result of shear stress creates the acquired vWS resembling vWD type 2a. However, not all patients with aortic stenosis and confirmed laboratory abnormalities demonstrate excessive perioperative bleeding [15]. Risk for vWS is also imposed by other cardiac conditions associated with high shear stress, including intracardiac defects, mitral prolapse, left ventricular assist devices (LVADs), and extracorporeal membrane oxygenation [12,16–20], but laboratory abnormalities suggesting vWS in this population do not always result in clinical bleeding problems during cardiac surgery, as evidenced by the large number of published series in which no excessive bleeding was observed. Regardless, as anesthesiologists are more and more frequently caring for ‘cardiac’ patients having noncardiac surgery, especially in the endoscopy suite and other non-operating room anesthetizing locations, anesthesiologists must appreciate the potential for alterations in coagulation that occur in patients with identified risk factors (e.g., LVAD patients). Anesthesiologists must also be prepared for excessive blood loss in obstetric patients with vWD or vWS, because postpartum hemorrhage (PPH) still vies with hypertensive disorders as the leading cause of morbidity and mortality in parturients of the developed world [21]. Uterine atony is the most common cause of PPH, but vWD also presents a serious risk. Not only do parturients with known vWD require therapy at the time of delivery (as discussed below), but also therapy must often be continued for days following delivery, and some parturients require antifibrinolytics for some time following discharge.
DIAGNOSIS Diagnosis of vWD relies on the results of a panel of laboratory tests, including the vWF antigen (vWF:AG), the vWF-Ristocetin Cofactor Activity test (VWF:RCo), vWF HMW multimers, the FVIII Volume 27 Number 3 June 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
von Willebrand disease and syndrome Stone et al. Table 1. Classification of hereditary von Willebrand disease and von Willebrand syndrome
Type
Nature of defect
Percentage of all vWD cases
1
Quantitative
60–80%
Treatment and management for perioperative period
Risk of bleeding complications Low. Most are unaware of disease unless surgery or trauma. Some exhibit easy bruising or menorrhagia.
DDAVP
Factor concentrates Cryoprecipitate Adjuncts (e.g., antifibrinolytics and topical hemostatics) 2 (A, B, M, N)
3
Qualitative
10–30%
Variable
2A: DDAVP may be tried
A: Reduced platelet binding via GP1b and decreased large multimers
2B: DDAVP best avoided (risk of increased platelet aggregation and thrombocytopenia)
B: Increased platelet binding via GP1b leading to increased clearance of VWF from plasma
M, N: Factor concentrates
M: Reduced platelet binding via GP1b with large multimers present
Adjuncts (e.g., antifibrinolytics, topical hemostatics)
N: Reduced FVIII binding
(caution with antifibrinolytics in 2B)
Severe quantitative
1–5%
High
Factor concentrates Adjuncts (e.g., antifibrinolytics and topical hemostatics)
Platelet-type vWD (pseudo vWD)
Defect is in platelet GPIb receptor resulting in increased vWF binding
Very rare
Platelet transfusion
Factor concentrates Cryoprecipitate Adjuncts (e.g., antifibrinolytics, topical hemostatics) (caution with antifibrinolytics) Acquired vWS
Increased clearance of vWF from plasma
Higher than previously thought
Destruction of HMW multimers
Variable
DDAVP Factor concentrates Cryoprecipitate Defect-specific therapies (e.g., IVIG, steroids, plasmapheresis, hormonal manipulation, valve replacement or other surgery) Adjuncts (e.g., antifibrinolytics and topical hemostatics)
DDAVP, arginine vasopressin, desmopressin; FVIII, factor VIII; HMW, high molecular weight; IVIG, intravenous immunoglobulin; vWD, von Willebrand disease; vWS, von Willebrand syndrome.
0952-7907 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-anesthesiology.com
355
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Anesthesia and medical disease
coagulant assay, vWFCBA, and the vWF propeptide (vWFpp). Specific subtypes and variants of vWD are suggested by the pattern(s) of abnormal panel results. Table 2 shows how to interpret such tests at a very basic level. In general, decreased vWF:AG is a hallmark of types 1 and 3 disease, and a decreased vWF:RCo/vWF:AG ratio is helpful to identify type 2 disease. In appropriate clinical situations, these two findings and a reduction or absence of HMW multimers suggest an acquired vWS. Bleeding time is generally prolonged in vWD, but platelet count and prothrombin time (PT) will be normal. Activated partial thromboplastin time (APTT) can be affected, but may also be normal. It is important to the anesthesiologist treating the bleeding patient to discern vWD from vWS, as the management might differ (as discussed below) and this distinction relies on subtle changes in the aforementioned laboratory tests not commonly available to or interpreted by the anesthesiologist [22 ]. Point-of-care (POC) testing has proven valuable to the anesthesiologist to appropriately manage coagulopathy in the perioperative setting [23]. Though the PFA-100 function analyzer (Dade Behring, Marburg, Germany) has demonstrated a high sensitivity for an impairment of primary hemostasis (including that accompanying vWD), it has a low specificity for the diagnosis of vWD itself [24], and results with this POC device can be confounded by other factors leading to derangements of hemostasis and coagulation. Common POC testing, such as Thromboelastography (e.g., TEG, Rotem), Plateletworks (Helena Laboratories, Beaumont, Texas, USA), and activated thrombin time (ACT), cannot reliably discern vWS [25]. However, new developments in POC testing are being made. For example, a modified Rotem assay (in which ristocetin is used to induce platelet agglutination by binding vWF) has been shown to be able to distinguish vWD in general and could potentially be of benefit in the bedside diagnosis of vWS [26]. &&
Nonsurgical bleeding occurs in as many as 50% of LVAD patients during support [27], including epistaxis, intracranial and gastrointestinal bleeding. It has been demonstrated that despite having normal levels of vWF antigen, LVAD patients exhibit marked alterations in the functional assays of vWF activity, such as the vWF:RCo assay and CBA assay [19]. Because these assays are dependent upon large vWF multimers, it is believed that the vWS in ventricular assist device (VAD) patients is most likely due to a decrease in the number of circulating large vWF multimers [19,27–29,30 ] as a result of high shear stress through the devices. The vWS in VAD patients thus resembles vWD type 2a. Clearly, perioperative or other bleeding because of any vWS present may be exacerbated by the requisite anticoagulation of the VAD-supported state. &
THE POTENTIAL ROLE OF A FOCUSED PREOPERATIVE ASSESSMENT FOR BLEEDING HISTORY In contrast to those with hereditary forms of vWD, vWS generally occurs in patients without any familial history of bleeding, emphasizing the importance of preoperatively assessing the individual patient with risk factors. Previous work has demonstrated that the use of a standardized questionnaire to assess spontaneous bleeding symptoms and specific patterns of bleeding is able to identify type 1 vWD [31]. Specifically, a higher bleeding score on the questionnaire was related to an increased likelihood of vWD, and a history of mucocutaneous bleeding (e.g., epistaxis, cutaneous bleeding, and bleeding from minor wounds) was strongly associated with bleeding after surgery or tooth extraction. Further, the mucocutaneous bleeding score was equivalent to usual vW laboratory testing for predicting bleeding after tooth extraction and superior to usual vW laboratory testing for the prediction of surgical bleeding.
Table 2. Patterns of abnormalities commonly seen on laboratory testing for von Willebrand disease Type
vWF:AG or
1
vWF:RCo or
2A
or
2B
vWF:RCo or vWF:AG ratio
vWF HMW
>0.6
Normal
Normal
2N
Normal or
3
or Absent
Platelet-type vWD (pseudo vWD)
Normal
or
or
0.6
Normal
N/A
Absent
or Absent
Variable but may be
Current management of von Willebrand disease and von Willebrand syndrome Marc E. Stone, Michael Mazzeffi, Jeffrey Derham, and Andre Korshin
Purpose of review Anesthesiologists frequently care for patients with altered hemostasis and coagulation. Where a clear history of familial and personal bleeding exists, a thoughtful plan can be developed in advance to manage the issue perioperatively. However, in some cases, it may not be known that the patient has a disorder until excessive bleeding is noted during or after surgery. Recognition of the issue and appropriate targeted therapy are the keys to successful management. Recent findings With an estimated prevalence approaching 1% of the population, von Willebrand disease (vWD) is the most common hereditary bleeding diathesis, but the estimated prevalence of acquired vWD (often termed von Willebrand syndrome or vWS) is now believed to be significantly higher, especially in patients with malignancies, autoimmune diseases, cardiac valvular lesions, and in patients on mechanical circulatory support devices. Acquired vWD may also occur with certain medications. Summary The mainstay of the diagnosis of vWD is laboratory testing. Preoperative clinical assessment and a high level of suspicion are often effective to alert the anesthesiologist to the possibility of vWS, thus allowing for appropriate testing and potential prophylaxis in elective situations, as well as appropriately targeted therapy of unexpected bleeding when a hemostatic derangement was not anticipated preoperatively. Keywords DDAVP, perioperative bleeding, von Willebrand disease, von Willebrand syndrome
INTRODUCTION von Willebrand factor (vWF) is critical to primary hemostasis because it facilitates the adhesion of platelets to the sites of endothelial injury (via GPIb) and the aggregation of platelets to each other (via GPIb and GPIIb/IIIa) [1]. Further, its binding to the platelet GPIa receptor helps activate platelets and expose fibrinogen receptor (GPIIb/IIIa) [2]. vWF is also critical to secondary hemostasis because it acts as a carrier protein for factor VIII (FVIII), slowing its breakdown and clearance from plasma [3]. When vWF levels are decreased or its functionality is altered, platelet plug formation becomes ineffective. Decreased levels of FVIII also lead to poor clot stability. Clinically, this manifests as a syndrome of excessive mucocutaneous or postsurgical bleeding. Bleeding severity depends on the particular variant of von Willebrand disease (vWD) (see Table 1). Essentially, types 1 and 3 vWD are quantitative defects, and type 2 disease is qualitative. Normal production of vWF occurs in both vascular endothelial cells and megakaryocytes [4]. vWF
is processed into multimers of differing molecular size which are then either stored in endothelial Weibel-Palade bodies and the a-granules of megakaryocytes, or secreted into the plasma and extracellular matrix at tonic levels [5,6]. The largest [high molecular weight (HMW)] multimers are the most prothrombotic and are subject to cleavage by the metalloprotease ADAMTS-13 in areas where the endothelium is intact. The genetic encoding for vWF is on chromosome 12 [7]. Numerous publications in the hematology literature discuss the exact mutations involved in the various hereditary forms of the disease [8].
Department of Anesthesiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA Correspondence to Marc E. Stone, MD, Department of Anesthesiology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, Box 1010, New York, NY 10029, USA. E-mail: [email protected] Curr Opin Anesthesiol 2014, 27:353–358 DOI:10.1097/ACO.0000000000000083
0952-7907 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-anesthesiology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Anesthesia and medical disease
KEY POINTS The prevalence of acquired von Willebrand syndrome is likely much higher than previously recognized. Acquired von Willebrand syndrome occurs in association with a variety of disease states, physiological processes, and medications. The mainstay of diagnosis is laboratory testing, but not all patients with risk factors for von Willebrand syndrome or laboratory abnormalities bleed excessively in the perioperative period. Preoperative clinical assessment of bleeding history can alert the anesthesia practitioner to the possibility of clinically relevant von Willebrand syndrome.
ACQUIRED VON WILLEBRAND SYNDROME vWD is the most common hereditary bleeding diathesis, with an estimated prevalence of the hereditary forms approaching 1% of the population. Although acquired von Willebrand syndrome (vWS) has been known to occur since 1968 [9], it is only recently understood that the diagnosis is likely more prevalent than previously thought. The clinical appearance of vWS is similar to vWD in that patients demonstrate mucocutaneous bleeding and excessive bleeding following trauma or surgery, but there is neither a family history nor always a previous personal history of bleeding. The severity is determined by the process inducing the acquired defect, but the mechanism of the syndrome generally involves enhanced clearance of vWF from the plasma (or, at least, a destruction of the large multimers). Causes underlying the acquired form differ from the inherited forms and include increased clearance because of: (1) antibodies associated with lymphoproliferative, neoplastic, or immunological diseases; (2) adsorption onto malignant cells or other surfaces; (3) destruction of large vWF multimers by shear stress (e.g., cardiac valvular lesions or defects, vascular narrowings, or extracorporeal circulation); (4) increased degradation by proteases as a result of high shear stress (or other specific mechanisms); (5) miscellaneous: medications, viruses, uremia, fibrinolytic processes, hypothyroidism, etc. Estimates place the prevalence of vWS at 0.04–0.13% [10,11], but specific subpopulations may exhibit a much higher prevalence. For example, a study of patients with aortic stenosis found 354
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platelet function abnormalities under conditions of high shear stress, decreased vWF collagen-binding activity (CBA) and loss of the largest vWF multimers, or a combination of these in 67–92% of patients with severe aortic stenosis. Further, there was a significant correlation with the severity of valve stenosis [12]. Since 1958, the term ‘Heyde’s syndrome’ has been applied to patients with aortic stenosis and bleeding from gastrointestinal angiodysplasias [13]. It is important to note that the source of bleeding in Heyde’s patients is from gastrointestinal vascular malformations and, further, that bleeding from such malformations usually resolves when the aortic valve is replaced [14]. The loss of HMW vWF multimers as a result of shear stress creates the acquired vWS resembling vWD type 2a. However, not all patients with aortic stenosis and confirmed laboratory abnormalities demonstrate excessive perioperative bleeding [15]. Risk for vWS is also imposed by other cardiac conditions associated with high shear stress, including intracardiac defects, mitral prolapse, left ventricular assist devices (LVADs), and extracorporeal membrane oxygenation [12,16–20], but laboratory abnormalities suggesting vWS in this population do not always result in clinical bleeding problems during cardiac surgery, as evidenced by the large number of published series in which no excessive bleeding was observed. Regardless, as anesthesiologists are more and more frequently caring for ‘cardiac’ patients having noncardiac surgery, especially in the endoscopy suite and other non-operating room anesthetizing locations, anesthesiologists must appreciate the potential for alterations in coagulation that occur in patients with identified risk factors (e.g., LVAD patients). Anesthesiologists must also be prepared for excessive blood loss in obstetric patients with vWD or vWS, because postpartum hemorrhage (PPH) still vies with hypertensive disorders as the leading cause of morbidity and mortality in parturients of the developed world [21]. Uterine atony is the most common cause of PPH, but vWD also presents a serious risk. Not only do parturients with known vWD require therapy at the time of delivery (as discussed below), but also therapy must often be continued for days following delivery, and some parturients require antifibrinolytics for some time following discharge.
DIAGNOSIS Diagnosis of vWD relies on the results of a panel of laboratory tests, including the vWF antigen (vWF:AG), the vWF-Ristocetin Cofactor Activity test (VWF:RCo), vWF HMW multimers, the FVIII Volume 27 Number 3 June 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
von Willebrand disease and syndrome Stone et al. Table 1. Classification of hereditary von Willebrand disease and von Willebrand syndrome
Type
Nature of defect
Percentage of all vWD cases
1
Quantitative
60–80%
Treatment and management for perioperative period
Risk of bleeding complications Low. Most are unaware of disease unless surgery or trauma. Some exhibit easy bruising or menorrhagia.
DDAVP
Factor concentrates Cryoprecipitate Adjuncts (e.g., antifibrinolytics and topical hemostatics) 2 (A, B, M, N)
3
Qualitative
10–30%
Variable
2A: DDAVP may be tried
A: Reduced platelet binding via GP1b and decreased large multimers
2B: DDAVP best avoided (risk of increased platelet aggregation and thrombocytopenia)
B: Increased platelet binding via GP1b leading to increased clearance of VWF from plasma
M, N: Factor concentrates
M: Reduced platelet binding via GP1b with large multimers present
Adjuncts (e.g., antifibrinolytics, topical hemostatics)
N: Reduced FVIII binding
(caution with antifibrinolytics in 2B)
Severe quantitative
1–5%
High
Factor concentrates Adjuncts (e.g., antifibrinolytics and topical hemostatics)
Platelet-type vWD (pseudo vWD)
Defect is in platelet GPIb receptor resulting in increased vWF binding
Very rare
Platelet transfusion
Factor concentrates Cryoprecipitate Adjuncts (e.g., antifibrinolytics, topical hemostatics) (caution with antifibrinolytics) Acquired vWS
Increased clearance of vWF from plasma
Higher than previously thought
Destruction of HMW multimers
Variable
DDAVP Factor concentrates Cryoprecipitate Defect-specific therapies (e.g., IVIG, steroids, plasmapheresis, hormonal manipulation, valve replacement or other surgery) Adjuncts (e.g., antifibrinolytics and topical hemostatics)
DDAVP, arginine vasopressin, desmopressin; FVIII, factor VIII; HMW, high molecular weight; IVIG, intravenous immunoglobulin; vWD, von Willebrand disease; vWS, von Willebrand syndrome.
0952-7907 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-anesthesiology.com
355
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Anesthesia and medical disease
coagulant assay, vWFCBA, and the vWF propeptide (vWFpp). Specific subtypes and variants of vWD are suggested by the pattern(s) of abnormal panel results. Table 2 shows how to interpret such tests at a very basic level. In general, decreased vWF:AG is a hallmark of types 1 and 3 disease, and a decreased vWF:RCo/vWF:AG ratio is helpful to identify type 2 disease. In appropriate clinical situations, these two findings and a reduction or absence of HMW multimers suggest an acquired vWS. Bleeding time is generally prolonged in vWD, but platelet count and prothrombin time (PT) will be normal. Activated partial thromboplastin time (APTT) can be affected, but may also be normal. It is important to the anesthesiologist treating the bleeding patient to discern vWD from vWS, as the management might differ (as discussed below) and this distinction relies on subtle changes in the aforementioned laboratory tests not commonly available to or interpreted by the anesthesiologist [22 ]. Point-of-care (POC) testing has proven valuable to the anesthesiologist to appropriately manage coagulopathy in the perioperative setting [23]. Though the PFA-100 function analyzer (Dade Behring, Marburg, Germany) has demonstrated a high sensitivity for an impairment of primary hemostasis (including that accompanying vWD), it has a low specificity for the diagnosis of vWD itself [24], and results with this POC device can be confounded by other factors leading to derangements of hemostasis and coagulation. Common POC testing, such as Thromboelastography (e.g., TEG, Rotem), Plateletworks (Helena Laboratories, Beaumont, Texas, USA), and activated thrombin time (ACT), cannot reliably discern vWS [25]. However, new developments in POC testing are being made. For example, a modified Rotem assay (in which ristocetin is used to induce platelet agglutination by binding vWF) has been shown to be able to distinguish vWD in general and could potentially be of benefit in the bedside diagnosis of vWS [26]. &&
Nonsurgical bleeding occurs in as many as 50% of LVAD patients during support [27], including epistaxis, intracranial and gastrointestinal bleeding. It has been demonstrated that despite having normal levels of vWF antigen, LVAD patients exhibit marked alterations in the functional assays of vWF activity, such as the vWF:RCo assay and CBA assay [19]. Because these assays are dependent upon large vWF multimers, it is believed that the vWS in ventricular assist device (VAD) patients is most likely due to a decrease in the number of circulating large vWF multimers [19,27–29,30 ] as a result of high shear stress through the devices. The vWS in VAD patients thus resembles vWD type 2a. Clearly, perioperative or other bleeding because of any vWS present may be exacerbated by the requisite anticoagulation of the VAD-supported state. &
THE POTENTIAL ROLE OF A FOCUSED PREOPERATIVE ASSESSMENT FOR BLEEDING HISTORY In contrast to those with hereditary forms of vWD, vWS generally occurs in patients without any familial history of bleeding, emphasizing the importance of preoperatively assessing the individual patient with risk factors. Previous work has demonstrated that the use of a standardized questionnaire to assess spontaneous bleeding symptoms and specific patterns of bleeding is able to identify type 1 vWD [31]. Specifically, a higher bleeding score on the questionnaire was related to an increased likelihood of vWD, and a history of mucocutaneous bleeding (e.g., epistaxis, cutaneous bleeding, and bleeding from minor wounds) was strongly associated with bleeding after surgery or tooth extraction. Further, the mucocutaneous bleeding score was equivalent to usual vW laboratory testing for predicting bleeding after tooth extraction and superior to usual vW laboratory testing for the prediction of surgical bleeding.
Table 2. Patterns of abnormalities commonly seen on laboratory testing for von Willebrand disease Type
vWF:AG or
1
vWF:RCo or
2A
or
2B
vWF:RCo or vWF:AG ratio
vWF HMW
>0.6
Normal
Normal
2N
Normal or
3
or Absent
Platelet-type vWD (pseudo vWD)
Normal
or
or
0.6
Normal
N/A
Absent
or Absent
Variable but may be
