Introduction
Acquired von Willebrand syndrome (AVWS) is a rare acquired bleeding disorder characterized
by clinical symptoms and laboratory findings similar to those seen in inherited von
Willebrand disease (VWD). In contrast to AVWS, congenital VWD results from mutations
in the von Willebrand factor (VWF) gene.[1 ]
Patients with AVWS can present with bleeding symptoms such as epistaxis, gastrointestinal,
and surgical hemorrhage. Under conditions of major trauma or surgery, AVWS becomes
relevant and can be the reason for extensive bleeding. Life-threatening intracranial
bleedings, even though rare, may also occur.[2 ]
AVWS comprises hemorrhagic disorders in which the VWF is either qualitatively or quantitatively
abnormal. The major finding of AVWS is the loss of high-molecular-weight (HMW) multimers
of VWF which can be shear stress induced and ultimately leads to impaired function
of VWF (qualitative defect). The loss of HMW multimers of VWF results in diminished
capability of VWF to interact with collagen and/or with platelets which is identifiable
by decreased values for VWF:collagen-binding capacity (VWF:CB) and/or VWF ristocetin
cofactor (VWF:RCo), respectively. Therefore, the ratio of VWF:CB to the VWF:antigen
(VWF:CB/VWF:Ag) and the ratio of VWF:RCo to the VWF:antigen (VWF:RCo/VWF:Ag) are decreased.[3 ] The VWF:RCo assay measures the binding of VWF to glycoprotein Ib receptors of fixed
platelets. In addition, VWF activity (VWF:GPIbR) which investigates binding of VWF
to recombinant GPIb is also reduced. Therefore, in patients with AVWS, the ratio of
VWF activity (VWF:GPIbR) to VWF:antigen (VWF:GPIbR/VWF:Ag) is decreased as well. Diagnostic
criteria of AVWS are displayed in Textbox 1 .
Diagnostic criteria of AVWS
Multimeric analysis: loss of HMW multimers of VWF
↓ VWF:collagen-binding capacity
↓ VWF:ristocetin cofactor
↓ VWF:activity (VWF:GPIbR)
↓ Ratio of VWF:CB/VWF:Ag
↓ Ratio of VWF:RCo/VWF:Ag
↓ Ratio of VWF:GPIbR/VWF:Ag
In case of bleeding symptoms, several pharmacologic treatment options such as tranexamic
acid, desmopressin, VWF-containing factor VIII concentrate, VWF concentrate, and/or
recombinant factor VIIa are available[2 ]
[4 ] (Textbox 2 ).
Therapeutic options of children with AVWS
Usually, AVWS occurs in middle-aged and elderly patients. Although literature concerning
AVWS in children is rare, AVWS has been described in pediatric patients, often in
those with congenital heart disease and during mechanical circulatory support (MCS),[5 ] but also in children with other medical conditions. Probably, AVWS is underdiagnosed
in the younger age groups and the diagnosis may be delayed or missed. The various
causes of AVWS are summarized in Textbox 3 . AVWS can be reversible in most cases if the underlying condition can be cured (Textbox 4 ).
Causes of AVWS
Consumption: congenital heart defects, mechanical circulatory support
Immunological: lymphoproliferative or myeloproliferative disorders, systemic lupus
erythematosus, hypothyroidism
Drug-induced: valproic acid, ciprofloxacin
Prognosis of AVWS
AVWS is completely reversible
After surgical repair in case of CHD
After device explantation in case of MCS
After successful treatment of the underlying disease (e.g., CML, SLE)
Methods
A narrative review, including all published data from Medline and PubMed database
regarding AVWS in children, was conducted.
AVWS in Children with Congenital Heart Disease
In children with congenital heart defects (CHD), AVWS is mostly associated with septal
defects (ventricular septal defects, atrial septal defects, or combined atrioventricular
septal defects) and patent ductus arteriosus (PDA). Some patients with AVWS suffer
from aortic or pulmonary stenosis ([Table 1 ]).
Table 1
AVWS in children with CHD or MCS
Cause of AVWS
Pathophysiology
Additional findings/information
Clinical symptoms
Prognosis
CHD/Vessel defect:
• Ventricular septal defects
• Atrial septal defects
• Atrioventricular septal defects
• Patent ductus arteriosus
• Aortic or pulmonary stenosis
Turbulent forces within the abnormal cardiac anatomy
=> enhanced shear rates and stress
=> mechanical degradation of VWF
Risk factor for intravascular bleeding and/or intravascular thrombosis
Mild bleeding problems in daily life; extensive bleeding may occur under conditions
of major trauma or surgery
AVWS resolves completely after surgical/interventional repair
MCS:
• Ventricular assist device
• Extracorporeal circulatory life support
• Extracorporeal membrane oxygenation
Interactions between blood components and foreign surfaces, changes in hemodynamics
and rheology
=> pathological flow condition, elevated shear stress
=> mechanical degradation of VWF
=> impaired interaction between VWF and collagen and platelets
AVWS developed in all children within 24 h,
2/3 of patients experienced bleeding complications,
no thromboembolic event after MCS termination
Mucocutaneous bleeding symptoms, thoracic and mediastinal bleeding (primarily located
in the surgical wound area)
AVWS is reversible, VWF parameters normalized within 24 h after weaning
Abbreviations: AVWS, acquired von Willebrand syndrome; CHD, congenital heart defect;
MCS, mechanical circulatory support; VWF, von Willebrand factor.
In children with CHD, flow dynamics are altered and predispose to areas of stasis,
and/or higher shear stress with platelet activation.[6 ] Shear stress in circulation can also lead to decrease or loss of VWF HMW multimers
and thus can lead to AVWS. Most probably, AVWS is relatively common in children with
CHD and completely resolves shortly after surgical or interventional repair.[7 ] Bleeding history of some of the children with CHD show mild bleeding symptoms. Even
if clinical symptoms are missing during everyday life, AVWS can be the reason for
extensive bleeding under conditions of major trauma or surgery. Cardiac surgery of
the newborn and infant with complex congenital CHD is associated with a high rate
of intraoperative bleeding complications.[8 ]
In some children with persistent PDA, deficiency of HMW multimers of VWF has been
reported. Following interventional PDA occlusion, the VWF HMW multimers normalized
shortly after the intervention in all patients, confirming the acquired nature of
the disorder.[9 ]
In addition, the frequency and relationship of AVWS in children with aortic and pulmonary
stenosis were investigated by Binnetoğlu et al.[10 ] AVWS was found to be associated with stenotic obstructive cardiac diseases. Therefore,
laboratory analyses should comprise comprehensive analysis of VWF parameters in these
patients besides whole blood count, prothrombin time, and activated partial thromboplastin
time.
AVWS in Children with Mechanical Circulatory Support
In critically ill children with advanced heart or respiratory failure, MCS, such as
ventricular assist device (VAD) or extracorporeal circulatory life support (ECLS),
and extracorporeal membrane oxygenation (ECMO) have extended survival and improved
quality of life.[6 ]
[11 ] However, bleeding and/or thrombotic complications remain a major cause of morbidity
and mortality in children with MCS. Complex interactions between blood components
and the foreign surfaces and changes in hemodynamics and rheology may lead to AVWS
with life-threatening bleeding episodes rather than thromboembolic events ([Table 1 ]). In addition, reduced platelet aggregation and increased platelet activation in
children during VAD or ECMO support may contribute to the imbalance of the hemostatic
system.[11 ]
[12 ]
Consistent with data from studies in adult patients, a study cohort of 30 children
with MCS (ECLS, n = 13; ECMO, n = 5; and VAD, n = 12) showed that all children developed AVWS which was usually diagnosed during
the very early postoperative course.[11 ] Laboratory analyses detected a loss of HMW VWF multimers ([Fig. 1 ]), decreased VWF:CB/VWF:Ag ratios, and reduced VWF:CB levels. Therefore, analyzing
clinical and biochemical data plays a major role in diagnosing AVWS which may be the
main cause of bleeding in these patients. Bleeding complications such as thoracic
and mediastinal bleeding (primarily located in the surgical wound area) were observed
in all three groups, requiring surgical revision in addition to conservative therapy
in some children. AVWS can develop within few hours after implanting VAD or starting
ECMO or ECLS support. Interestingly, AVWS in this cohort was always reversible within
3 to 24 hours after device explantation or cessation of ECMO/ECLS support which is
consistent with data from studies on adult patients. Interestingly, the patients in
this cohort did not show any thromboembolic event after MCS termination, despite upregulation
of VWF:Ag. This phenomenon may be due to the decrease of the VWF:CB and the reduced
VWF:CB /VWF:AG ratios.
Fig. 1 Sodium dodecyl sulfate (SDS)-agarose gel electrophoresis of von Willebrand factor
multimers, visualized by enzyme immunostaining after capillary transfer onto polyvinylidene
difluoride membranes. Multimeric analysis was performed by SDS-agarose gel electrophoresis
in 1.0% of SDS-agarose gels: (A ) (1) SHP, (2) before VAD, and (3) under VAD support. (B ) (1) SHP, (2) before ECLS, and (3) under ECLS support. ECLS, extracorporeal circulatory
life support; VAD, ventricular assist device.
The severity of bleeding tendency among patients during MCS can vary and a direct
association with patients' ages, bleeding location, and overall outcome cannot always
be identified.[11 ] Therefore, comprehensive clinical and biochemical phenotyping is essential to perform
a risk-stratification of patients during MCS workup. It has been discussed, whether
very low VWF:CB and VWF:activity levels, respectively, and very low VWF:CB/VWF:Ag
and VWF:Act/VWF:Ag ratios may hint to a more severe form of AVWS. Interestingly, AVWS
seems to be more pronounced in patients with ECLS/ECMO compared with patients on VAD
support.[11 ]
[13 ] Accordingly, patients on ECLS/ECMO required more red blood cell and platelet transfusions.
The therapy for bleeding in those patients remains difficult. During ECLS/ECMO or
VAD support, patients were anticoagulated with unfractionated heparin.[11 ] For long-term therapy, patients with left VAD are switched to low-molecular-weight
heparin or phenprocoumon (vitamin K antagonist). In case of life-threatening bleeding,
substitution of VWF-containing factor VIII concentrates or VWF concentrates may be
considered.
AVWS in Children with Other Underlying Diseases
Lymphoproliferative, Myeloproliferative Disorders, Other Neoplasms, and Autoimmune
Diseases
AVWS can be associated with further underlying diseases such as lymphoproliferative
disorders, myeloproliferative disorders, other neoplasms, and autoimmune diseases[14 ] ([Table 2 ]). In rare cases, AVWS is also associated with hypothyroidism, uremia, and certain
drugs such as valproic acid and ciprofloxacin.[5 ] In younger patients, AVWS is also associated with renal tumors, glycogen storage
disease type 1a (GSD-1a), or systemic lupus erythematosus (SLE).[15 ] The pathophysiology of AVWS in children and adolescents is related to the underlying
diagnosis.
Table 2
Clinical picture of AVWS in children with various underlying diseases or taking certain
drugs
Cause of AVWS
Pathophysiology
Additional findings/information
Clinical symptoms
Prognosis
Lympho-myeloproliferative disorders
CML
Elevated platelet counts => loss of VWF high-molecular-weight multimers
Splenomegaly, pronounced leucocytosis, thrombocytosis
mild bleeding signs, rarely thrombosis
AVWS resolved after successful initiation of CML treatment
ET
Increased risk for bleeding or thrombotic events, splenomegaly, elevated numbers of
mature megakaryocytes
bleeding episodes (epistaxis, prolonged menstrual bleeding), visual impairment, palmar
and plantar stabbing pain
reduction of the platelet count led to normalization of the VWF ratio
PV
Loss of VWF high-molecular-weight multimers
Increased risk for bleeding or thrombotic events
After successful therapy (i.e., stem cell transplantation) normalization of parameters
Autoimmune diseases
SLE
Autoantibodies directed against the circulating VWF/FVIII complex
mucocutaneous bleeding symptoms, prolonged bleeding after dental extraction
AVWS can be cured by treatment of the underlying autoimmune disease with corticosteroids
or immunosuppression
Other diseases
Hypothyroidism
Reduced/defective synthesis of VWF
Possibility of bleeding
Rectal bleeding, anemia
Normalization of coagulation parameters after restoration of euthyroidism
Wilms' tumor (nephroblastoma)
Unknown
High serum levels of hyaluronic acid
Mild mucocutaneous bleeding symptoms
Abnormalities of coagulation resolved after chemotherapy and extirpation of the neoplasm
GSD-1a
Unknown
Easy bruising, epistaxis
IPAH
Increased shear stress throughout the pulmonary vasculature
Normal distribution pattern of VWF high-molecular-weight multimers
Mild to moderate bleeding symptoms
Normalization of the hemostatic defects following lung transplantation
Uremia
Proteolytic degradation of VWF
Increased risk for bleeding and/or thrombotic events
Drugs
Valproic acid
Unknown
No relationship between valproate dosage or duration of therapy and the incidence
of AVWS
Spontaneous bleeding unclear
Extensive bleeding may occur under conditions of major trauma or surgery
Abbreviations: AVWS, acquired von Willebrand syndrome; CML, chronic myeloid leukemia;
ET, essential thrombocythemia; GSD-1a, glycogen storage disease type 1a; IPAH, idiopathic
pulmonary arterial hypertension; PV, polycythemia vera; SLE, systemic lupus erythematosus;
VWF, von Willebrand factor.
Some case reports described that children with acute lymphoblastic leukemia or chronic
myeloid leukemia (CML) had developed an AVWS-associated bleeding phenotype.[16 ]
[17 ] At diagnosis of CML, patients may present with elevated platelet counts. High cell
counts may result in thrombosis and/or secondarily in bleeding complications. Interestingly,
patients with pediatric CML frequently exhibit high platelet counts not resulting
in thrombosis because binding of VWF multimers to platelets can result in loss of
large VWF multimers ultimately leading to AVWS.
Children with myeloproliferative disorders such as essential thrombocythemia and polycythemia
vera can also develop AVWS due to the high platelet counts and changes regarding rheology
and shear stress.[18 ]
[19 ]
AVWS in patients with SLE is caused by autoantibodies directed against the circulating
VWF/FVIII (factor VIII) complex.[20 ]
[21 ] Binding of autoantibodies leads to large immune complexes which are rapidly cleared
by the reticuloendothelial system causing a deficiency of both VWF and FVIII. AVWS
in SLE can be cured by the treatment of the underlying autoimmune disease with corticosteroids
or immunosuppression.
AVWS associated with hypothyroidism is rare in children and mostly diagnosed during
the peripubertal period in the context of Hashimoto's thyroiditis.[22 ] The AVWS associated with hypothyroidism differs from the other forms of AVWS: there
is a reduction regarding the synthesis and release of VWF that is not associated with
a reduced half-life because of either autoantibodies or secondary structural changes
regarding the VWF multimers.[23 ]
AVWS has been described in some pediatric patients with Wilms' tumor and with embryonal
adenomas of the kidney.[24 ]
[25 ] There is no evidence of autoantibodies against VWF or adsorption of VWF onto tumor
cells. It is being discussed that abnormal vasculature and high blood flow through
the tumor vessels could produce conditions of high shear stress with physical disruption
of VWF multimers. High levels of hyaluronic acid secreted by some Wilms' tumors may
also contribute to the abnormal VWF parameters.[15 ] Accordingly, the coagulopathy disappears after successful chemotherapy or resection
of the tumor.
Glycogen Storage Disease Type 1a
AVWS can also be associated with GSD-1a, usually presenting with easy bruising and
troublesome epistaxis in late infancy or early childhood.[15 ]
[26 ]
Pulmonary Arterial Hypertension
Recently, a causative relationship between idiopathic pulmonary arterial hypertension
and AVWS was hypothesized.[27 ] Interestingly, VWF multimer distribution patterns seem to be normal in all pediatric
patients, while most patients demonstrated low-normal VWF parameters. Lung transplantation
led to postsurgical normalization of hemostatic abnormalities.
Epstein–Barr Virus
Bleeding symptoms in children have been also described following Epstein–Barr virus
(EBV) infection. However, causative relation of bleeding to prior EBV infection remains
uncertain. A 6-year-old girl developed petechiae and bruising 2 weeks after an EBV
infection.[28 ] She had a prolonged bleeding time, reduced values for FVIII activity, VWF:Ag, and
VWF:RCo and loss of VWF HMW multimers. AVWS resolved after 2 weeks and did not reoccur.
Anticonvulsive Medication
Patients with epilepsy, treated with valproic acid, may present with a variety of
coagulation defects: thrombocytopenia, platelet dysfunction, hypofibrinogenemia, reduced
vitamin K–dependent factors, factor XIII deficiency, and AVWS.[29 ] The cause of AVWS in patients taking valproic acid is unknown. Therefore, in children
taking anticonvulsive drugs and who present with bleeding symptoms, AVWS should be
investigated.
Conclusion
AVWS is a common, but still often unrecognized disorder in pediatric patients with
MCS, CHD, or further underlying diseases. The pathophysiology and management of acute
bleeding episodes depends on the primary underlying disease. VWF abnormalities in
AVWS are a result of increased shear stress followed by proteolysis of VWF in case
of MCS or CHD, VWF adsorption to surfaces of transformed cells or platelets, or antibody-mediated
clearance as well as functional interference. Clinically, AVWS can aggravate bleeding
tendencies in these children, especially if hepatic insufficiency, temporary thrombocytopenia,
and severe inflammation occur. Therefore, VWF parameters should be investigated in
children with MCS or CHD and in case of nonsurgical bleeding. Since the bleeding event
may be triggered by several causes, a score incorporating several parameters (i.e.,
pronounced hemolysis, infections or reduced ratios of VWF:RCo/VWF:Ag, VWF:GPIbR/VWF:Ag,
or VWF:CB/VWF:Ag) may help identify patients with an increased risk for bleeding complications.[11 ]
In summary, the diagnosis of AVWS should be suspected, if a pediatric patient presents
with an onset of bleeding symptoms and suffers from one of the diseases or conditions
mentioned earlier. The cause of the bleeding symptoms should be further investigated
especially before the child undergoes an invasive procedure.
