This may be an inerited disorder or blood coagulation or an acquired disease, secondary to a number of conditions, including certain drugs. Typically patients do not know they have the disease but may notice Frequent or prolonged nosebleeds, easy brusing, prolonged or heavy menstrual periods, and prolonged or unusual bleeding following a minor injury, surgery, or dental work. The problem is an abnormality of the vWF. This large protein is required for normal platelet adhesion. It is a carrier protein for Factor VIII, a key protein in the coagulation cascade fo the blood. Thus, vWF functions in both primary (involving platelet adhesion) by binding on platelets to its specific receptor glycoprotein Ib and acts as an adhesive bridge between the platelets and damaged subendothelium at the site of vascular injury. In secondary (involving FVIII) hemostasis, vWF protects FVIII from degradation and delivers it to the site of injury.
TYPE DEFECT INHERITANCE vWF 1 Partial quantitative decrease of qualitatively normal vWF and FVIII.
Proportional reduction in vWF activity, vWF antigen, and FVIII exists with type 1vWD. 2A Normal-to-reduced plasma levels of factor VIIIc (FVIIIc) and vWF AD
Relative reduction in intermediate and high molecular weight multimer complexes.
Ristocetin cofactor activity is greatly reduced, and the platelet vWF reveals multimeric abnormalities similar to those found in plasma.
2B Reduction in the proportion of high molecular weight vWF multimers, while the proportion of low molecular weight fragments are increased AD Measurements of FVIIIc and vWF in plasma are variable
Studies involving the use of titered doses of ristocetin reveal that aggregation of normal platelets is enhanced and induced by unusually small amounts of the drug.
2C Proportion of high molecular weight vWF multimers is reduced and the individual multimers are qualitatively abnormal Increases in small multimers also are evident AR Ristocetin cofactor activity may be decreased out of proportion to reductions in vWF 2M Decreased platelet-directed function that is not due to a decrease of high molecular weight multimers AR Decreased vWF activity, but vWF antigen, FVIII, and multimer analysis are found to be within reference range. 2N Markedly decreased affinity of vWF for FVIII, resulting in FVIII levels reduced to usually around 5% of the reference range. AR vWF antigen and ristocetin cofactor activity are usually normal
Confirmatory test for type 2N vWD is not routinely available
Type 3 Marked deficiencies of both vWF and FVIIIc in the plasma, the absence of vWF from both platelets and endothelial cells, and a lack of the secondary transfusion response and the response to DDAVP AR Multimeric analysis of the little vWF present yields variable results, in some cases revealing only small multimers.
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
Differential Diagnosis Prognosis Treatment Commonly Used Terms Internet Links
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS Hemophilia INCIDENCE One in 100
Over 3,000,000 people in the U.S. are affected
GEOGRAPHY All ethnic groups
DISEASE ASSOCIATIONS CHARACTERIZATION ABO BLOOD TYPE
Type 1 von Willebrand disease - a clinical retrospective study of the diagnosis, the influence of the ABO blood group and the role of the bleeding history.
Nitu-Whalley IC, Lee CA, Griffioen A, Jenkins PV, Pasi KJ.
Haemophilia Centre and Haemostasis Unit, Department of Haematology, Royal Free and University College Medical School of University College of London, Pond Street, London, UK.
Br J Haematol 2000 Feb;108(2):259-64 Abstract quote
This clinical retrospective study investigated the difficulties in diagnosing type 1 von Willebrand disease (VWD).
A total of 246 patients previously diagnosed with type 1 VWD were reclassified into 'possible' type 1 VWD (patients with low levels of VWF adjusted for the blood group and either a significant bleeding history or family history) and 'definite' type 1 VWD, requiring low levels of von Willebrand factor (VWF), a bleeding history and inheritance.
On reclassification, only 144/246 (59%) patients had low VWF levels adjusted for blood group, 88/246 (36%) patients met all the criteria for 'definite' type 1 VWD and 51/246 (21%) patients were 'possible' type 1 VWD. A significant proportion of patients, 102/246 (42%), remained an indeterminate group with blood type O, VWF levels between 35 and 50 U/dl and personal and/or family bleeding history. This subgroup might require reclassification as 'not VWD'. However, a similar bleeding tendency was found in two matched groups of patients of blood groups O and non-O and VWF levels between 35 and 50 U/dl.
These results suggest that the use of ABO adjusted ranges for VWF levels might not be essential for diagnosis, because bleeding symptoms may depend on the VWF level regardless of the ABO type. Of the diagnostic criteria, the bleeding history was of prime importance in the clinical decision to diagnose and treat type 1 VWD. These observations could help in the reconsideration of how the criteria for diagnosing type 1 VWD could be adjusted in order to maximize their clinical relevance.
Acquired von Willebrand factor abnormalities in myeloproliferative disorders and other hematologic diseases: a retrospective analysis by a single institution.
Sanchez-Luceros A, Meschengieser SS, Woods AI, Blanco AN, Kempfer AC, Casais P, Salviu MJ, Lazzari MA.
Hemostasis and Thrombosis Department, Hematologic Research Institute Mariano R. Castex, National Academy of Medicine, Pacheco de Melo 3081 (C1425AUM) Buenos Aires, Argentina.
Haematologica 2002 Mar;87(3):264-70 Abstract quote
BACKGROUND AND OBJECTIVES. Acquired von Willebrand syndrome (AVWS) is a rare acquired disorder. In most cases it is associated with lymphoproliferative disorders and monoclonal gammopathies, while less frequently myeloproliferative disorders (MPD) are involved. Although bleeding is the most important symptom, thrombotic complications have also been observed in cases associated with MPD. Our aim was to review the clinical and laboratory findings in AVWS patients from a single institution.
DESIGN AND METHODS. The records of 99 patients with AVWS were reviewed to identify the underlying diseases, the symptoms and the laboratory parameters.
RESULTS. In 75% of cases the AVWS was associated with MPD. The most frequent pattern was type 2 (67.7%). Abnormalities of bleeding time, factor VIII levels or platelet retention to glass beads were observed in 83.8% of cases. Bleeding was present in 38.4% of patients, more frequently in the not-MPD-associated (58.3%) vs. MPD-associated cases (32%) (p=0.022), with a significant predominance in females, irrespective of the underlying disease (p=0.0007). In 32% of patients with MPD, thrombotic manifestations, mostly microvascular and arterial episodes, were observed.
INTERPRETATION AND CONCLUSIONS. AVWS in MPD seems to be mainly a laboratory diagnosis, without clinical symptoms in most cases, although bleeding as well as ischemic events can be present. In contrast, AVWS in not-MPD-associated cases is most frequently associated with severe bleeding symptoms. Performing appropriate laboratory tests may be useful for screening for AVWS.
Hypopituitarism, deficiency of factors V and VIII and von Willebrand factor: an uncommon association.
Setian N, Tanaka CM, Damiani D, Dichtchekenian V, Carneiro JD, D'Amico EA.
Pediatric Endocrinology Unit, Instituto da Crianca Hospital das Clinicas, Sao Paulo University School of Medicine, Fundacao Pro-Sangue Hemocentro de Sao Paulo, Brazil
J Pediatr Endocrinol Metab 2002 Mar;15(3):331-3 Abstract quote
A 9 year-old boy with hypopituitarism and blood coagulation abnormalities is presented and discussed. The association between acquired von Willebrand disease and hypothyroidism has been reported but the combination of hypopituitarism and coagulopathy is unusual. C
ombined multiple clotting deficiencies are rare and, when present, factors V and VIII is the commonest association. Although it is known that hypothyroid patients may have a decrease in von Willebrand's factor (vWf) and factor VIII, there are no reports of hypopituitarism associated with combined deficiency of factors V, VIII, and vWf.
von Willebrand disease and other inherited bleeding disorders in women with diagnosed menorrhagia.
Dilley A, Drews C, Miller C, Lally C, Austin H, Ramaswamy D, Lurye D, Evatt B.
Centers for Disease Control and Prevention, National Center for Infectious Diseases, Hematologic Diseases Branch, Atlanta, GA, USA.
Obstet Gynecol 2001 Apr;97(4):630-6 Abstract quote
OBJECTIVE: To estimate the prevalence of von Willebrand disease and other bleeding disorders in women with and without diagnosed menorrhagia.
METHODS: Women with menorrhagia were identified among members of a health maintenance organization in the southeastern United States through a computer search for appropriate International Classification of Diseases, 9th Revision codes. A random sample of members with no such code was selected as controls. The study included 121 women with menorrhagia and 123 controls. Subjects were interviewed in person, and blood was drawn for coagulation testing. Laboratory results for menorrhagia patients were compared with those in controls using race and blood type specific ranges developed from the control group. A test was considered abnormal if it exceeded two standard deviations below the control mean.
RESULTS: Bleeding disorders (von Willebrand disease, factor deficiency, or a platelet abnormality) were diagnosed in 10.7% of menorrhagia patients and 3.2% of controls (P =.02). von Willebrand disease was present in eight menorrhagia patients (6.6%) and in one control (0.8%) (P =.02); separate analyses by race revealed a von Willebrand disease prevalence of 15.9% among white and 1.4% among black menorrhagia patients (P =.01). Women with bleeding disorders did not differ significantly from controls in other symptoms of bleeding.
CONCLUSION: The prevalence of inherited bleeding disorders among white women with menorrhagia was substantial, consistent with European data published recently. For unknown reasons, the prevalence of von Willebrand disease was lower among black women. These findings indicate the importance of considering inherited bleeding disorders as a cause of menorrhagia.
The Prevalence of von Willebrand disease in women with abnormal uterine bleeding.
Goodman-Gruen D, Hollenbach K.
Department of Family and Preventive Medicine, University of California, San Diego, California, USA.
J Womens Health Gend Based Med 2001 Sep;10(7):677-80 Abstract quote
Although a common symptom of von Willebrand disease is menorrhagia or metrorrhagia, the prevalence of this inherited bleeding disorder in women with heavy bleeding is not known.
This pilot study compared the prevalence rate of von Willebrand disease in women with dysfunctional uterine bleeding with the prevalence rate in the general population. On average, these women bled for 11.5 days per month and experienced heavy bleeding for >16 years. Over 60% had been treated previously for heavy bleeding. One woman was diagnosed with type 1 von Willebrand disease (5% prevalence rate).
Larger studies are needed to confirm this increased rate of von Willebrand disease in women with abnormal uterine bleeding.
PATHOGENESIS CHARACTERIZATION GENERAL
The von Willebrand factor gene and genetics of von Willebrand's disease.
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor.
Mayo Clin Proc 1991 May;66(5):506-15 Abstract quote
The von Willebrand factor (vWF) gene spans 178 kilobases in the human genome, is interrupted by 51 introns, and has been localized to human chromosome 12p12----12pter. In addition, a pseudogene that duplicates the midportion of the vWF gene has been identified on chromosome 22.
In several families, large vWF gene deletions have been identified as the basis for von Willebrand's disease (vWD). In most patients, however, the vWF gene is found to be grossly intact by Southern blot analysis, a result that implies a more subtle molecular defect. The advent of the polymerase chain reaction has allowed a more direct analysis in this group of patients. By this approach, missense mutations, all clustered within the same small region in the midportion of the vWF molecule, have been identified in several patients with type IIA vWD. Expression of mutant vWF by transfection into COS cells suggests that the characteristic loss of high-molecular-weight multimers seen in type IIA vWD may occur through at least two distinct mechanisms. In preliminary studies of nondeletional type III vWD, a family has been identified with decreased vWF as a result of failure of production of messenger RNA from the affected vWF allele.
This disorder could be due to defects in vWF gene transcription, RNA processing, or stability. As additional defects are identified, the accurate diagnosis of vWD at the molecular level may eventually become possible.
Molecular genetics of von Willebrand disease.
Mazurier C, Ribba AS, Gaucher C, Meyer D.
Laboratoire Francais du Fractionnement et des Biotechnologies, Lille, France.
Ann Genet 1998;41(1):34-43 Abstract quote
Von Willebrand disease (vWD), the most common congenital bleeding disorder in man, is related to quantitative and/or qualitative abnormalities of von Willebrand factor (vWF). This multimeric glycoprotein serves as carrier protein of factor VIII, an essential cofactor of coagulation in plasma, and promotes platelet adhesion to the damaged vessel and platelet aggregation.
Distinct abnormalities of vWF are responsible for the three types of vWD. Types 1 and 3 are characterized by a quantitative defect of vWF whereas type 2, comprising subtypes 2A, 2B, 2M and 2N, refers to molecular variants with a qualitative defect of vWF. The knowledge of the structure of the vWF gene and the use of Polymerase Chain Reaction (PCR) have led to the identification of the molecular basis of vWD in a significant number of patients.
Type 2A is characterized by a decreased platelet-dependent function of vWF associated with the absence of high molecular weight (HMW) multimers of vWF. Most of the type 2A mutations have been identified in the A2 domain of vWF which contains a proteolytic site, while a few others have been found within the propeptide and the C-terminal part of vWF which are involved in its multimerization and dimerization, respectively.
In type 2B, defined by an increased affinity of vWF to platelet glycoprotein Ib (GPIb), various amino-acid (aa) substitutions or insertion have been localized within the A1 domain containing the GPIb binding site. In the latter domain have been also identified the few molecular abnormalities described in type 2M which is defined by a decreased platelet-dependent function not caused by the absence of HMW multimers. In type 2N, characterized by a defective binding of vWF to factor VIII, several aa substitutions have been identified within the factor VIII-binding domain in the N-terminal part of vWF. The identification of gene defects remains difficult in types 1 and 3. Whereas various abnormalities (total, partial or point deletions, point insertions, nonsense mutations) have already been identified in type 3, the molecular basis of type 1 is still unresolved in most cases.
The characterization of the molecular basis of vWD is of fundamental interest in providing further insight into the structure-function relationship and the biosynthesis of vWF.
Molecular genetics of type 2 von Willebrand disease.
Fressinaud E, Mazurier C, Meyer D.
INSERM U.143, Le Kremlin-Bicetre, Lille, France.
Int J Hematol 2002 Jan;75(1):9-18 Abstract quote
Type 2 von Willebrand disease (VWD) is characterized by a wide heterogeneity of functional and structural defects. These abnormalities' cause either defective von Willebrand factor (VWF)-dependent platelet function in subtypes 2A, 2B, and 2M or defective VWF-factor VIII (FVIII) binding in subtype 2N.
The diagnoses of types 2A, 2B, and 2M VWD may be guided by the observation of disproportionately low levels of ristocetin cofactor activity or collagen-binding capacity relative to VWF antigen. The abnormal platelet-dependent function is often associated with the absence of high molecular weight (HMW) multimers (type 2A, type 2B), but the HMW multimers may also be present (type 2M, some type 2B), and supranormal multimers may exist ("Vicenza" variant). The observation of a low FVIII-to-VWF:Ag ratio is a hallmark of type 2N VWD. in which the FVIII levels depend on the severity of the FVIII-binding defect. Today, the identification of mutations in particular domains of the pre-pro-VWF is helpful in classifying these variants and providing further insight into the structure-function relationship and the biosynthesis of VWF.
Thus, mutations in the D2 domain, involved in the multimerization process, are found in patients with type 2A, formerly named IIC VWD. Mutations located in the D' domain or in the N terminus of the D3 domain define type 2N VWD. Mutations in the D3 domain characterize Vicenza and IIE patients. Mutations in the A1 domain may modify the binding of VWF multimers to platelets, either increasing (type 2B) or decreasing (type 2M, 2A/2M) the affinity of VWF for platelets. In type 2A VWD, molecular abnormalities identified in the A2 domain, which contains a specific proteolytic site, are associated with alterations in folding, impairing VWF secretion or increasing its susceptibility to proteolysis.
Finally, a mutation localized in the carboxy-terminus CK domain, which is crucial for the dimerization of the VWF subunit, has been identified in a rare subtype 2A, formerly named IID.
New families with von Willebrand disease type 2M (Vicenza).
Zieger B, Budde U, Jessat U, Zimmermann R, Simon M, Katzel R, Sutor AH.
Univ. Children's Hospital, Freiburg, Germany.
Thromb Res 1997 Jul 1;87(1):57-64 Abstract quote
The variant von Willebrand disease (vWd) variant type 2M (Vicenza) was identified in 13 patients of 7 unrelated families. 11 patients were from different parts of germany and 2 patients from Turkey.
Hitherto this variant of vWd has been described only in two families originating from the province of Vicenza in Northern Italy. Characteristically this type of vWd shows the supranormal multimers of von Willebrand factor (vWf) in plasma similar to those seen in normal plasma after desmopressin infusion. Clinically, the patients present with bleeding symptoms. Other laboratory abnormalities include reduced values for vWf antigen (vWf: Ag), factor VIII coagulant activity (VII:C), ristocetin cofactor activity (RiCof) and collagen binding activity (vWf: CBA).
The hereditary transmission of this variant is consistent with an autosomal dominant mode of inheritance. The patients with vWd type 2M (Vicenza) could be allocated into two subgroups: type "platelet normal" with normal vWf properties in platelets and type "platelet low" with reduced vWf: Ag levels in platelets.
CHARACTERIZATION RADIOLOGIC LABORATORY MARKERS
Relative value of diagnostic studies for von Willebrand disease.
Werner EJ, Abshire TC, Giroux DS, Tucker EL, Broxson EH.
Division of Pediatric Hematology/Oncology, Eastern Virginia Medical School, Norfolk.
J Pediatr 1992 Jul;121(1):34-8 Abstract quote
Laboratory tests recommended to screen patients with mucosal bleeding for hemostatic disorders generally include determinations of prothrombin time, partial thromboplastin time, platelet count, and bleeding time.
To determine the best tests to identify patients with von Willebrand disease (vWD), we reviewed the laboratory studies of 24 children with vWD and performed receiver operating characteristic analysis on the diagnostic studies. The vWD disease diagnostic tests included determinations of vWF activity (ristocetin cofactor activity), vWF factor antigen, and factor VIII procoagulant (VIII:c). The diagnosis of vWD required the presence of a personal and family history of bleeding symptoms and a documented abnormality of vWF activity or vWF antigen. vWF activity, vWF antigen, factor VIII:c and blood type were determined in 104 symptom-free children. There were no differences between patients and normal subjects for age, gender, or blood type. The bleeding time was abnormal in 43%, the partial thromboplastin time was abnormal in 25%, and either one or both were abnormal in 58% of the patients. The vWF activity, vWF antigen, and factor VIII:c were abnormal in 79%, 58%, and 33%, respectively. Receiver-operated-characteristic analysis showed the vWF activity to be superior to either the vWF antigen or factor VIII:c in establishing the diagnosis of vWD.
The combination of the activity, bleeding time, and partial thromboplastin time successfully identified 92% of the patients as abnormal. Determination of vWF activity should be included routinely in the evaluation of hemostasis in children with symptomatic disease.
Laboratory assessment as a critical component of the appropriate diagnosis and sub-classification of von Willebrand's disease.
Department of Haematology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, WSAHS, Australia.
Blood Rev 1999 Dec;13(4):185-204 Abstract quote
von Willebrand's disease (VWD) is now recognized to be most common inherited bleeding disorder. It arises from defects or deficiencies in a protein called von Willebrand factor (VWF). VWD is a heterogeneous disorder, and patients are typed according to pathophysiology.
The correct diagnosis and sub-classification of a patient's VWD is crucial because the presenting biological activity of VWF determines the haemorrhagic risk, and since subsequent clinical management will differ accordingly. Although clinical assessment of the propositus will provide the initial clue to, or an index of clinical suspicion for, a diagnosis of VWD, it is the laboratory process that will confirm or discount the diagnosis. A variety of assays may be employed by the laboratory undertaking the investigation, and these will not necessarily be restricted to an assessment of VWF. Due to the limitations of each potential laboratory assay, and because of VWD heterogeneity, no single test procedure is sufficiently 'robust' to permit detection of all VWD variants. This situation often leads to some clinical confusion in the process of laboratory interpretation regarding the likelihood of VWD, and the subtype of VWD.
Classically, the test panel might include any combination of the following: (i) determination of (skin) bleeding times, (ii) VWF antigen (VWF:Ag) levels, (iii) 'functional' activity of Factor VIII (i.e. FVIII:coagulant or FVIII:C), (iv) 'functional' activity of VWF (e.g. Ristocetin Cofactor [VWF:RCof] assay), and/or Ristocetin induced platelet aggregation [RIPA] analysis), and (v) assessment of the VWF molecular weight or structural profile (i.e. VWF multimeric analysis or VWF:Multimers).
There have also been a number of new diagnostic developments, and these are beginning to significantly influence the overall clinical VWD-diagnostic process. These include automation of existing assay procedures, a relatively new functional VWF assay called the Collagen Binding Assay (VWF:CBA), new automated platelet function analysers such as the PFA-100 and the Xylum Clot Signature Analyser, and specific VWF:FVIII binding assays.
The current report focuses on the recommended laboratory process for investigation of VWD. An analysis of this process shows that selection of an appropriate test panel is a critical component for the proper diagnosis and classification. This review also outlines those new and emerging technologies that will help streamline the diagnostic process. Because VWD is just one manifestation of a 'bleeding' disorder (albeit the most common), the review also briefly mentions other related diagnostic processes and general approaches to the investigation of 'bleeding disorders'. The review also provides two algorithms to assist clinicians in making appropriate diagnostic choices in response to the clinical findings. A number of summary tables describing each laboratory assay in detail, and summarising the likely diagnostic findings for each Type of VWD, are also provided.
This review should be of value to both haemostasis scientists and clinical specialists involved in VWD diagnosis.
FACTOR VIII BINDING ASSAYS
Use of the collagen-binding assay for von Willebrand factor in the analysis of type 2M von Willebrand disease: a comparison with the ristocetin cofactor assay.
Riddell AF, Jenkins PV, Nitu-Whalley IC, McCraw AH, Lee CA, Brown SA.
Katharine Dormandy Haemophilia Centre and Haemostasis Unit, Department of Haematology, Royal Free Hospital, Pond Street, London NW3 2QG, UK.
Br J Haematol 2002 Jan;116(1):187-92 Abstract quote
This study compares the utility of two functional assays for von Willebrand factor (VWF), the ristocetin cofactor assay (VWF:RCo) and the collagen-binding assay (VWF:CBA).
We analysed a group of 32 patients with type 2 von Willebrand disease (VWD) (25 patients with type 2M, six with type 2A and one with type 2B) and 22 normal control subjects. VWF:RCo/VWF antigen (VWF:Ag) ratios and VWF:CBA/VWF:Ag ratios were compared between the patient and control groups. In the six patients with type 2A VWD, both VWF:RCo/VWF:Ag ratios and VWF:CBA/VWF:Ag ratios were discordant (< or = 0.7). In the 25 type 2M VWD patients, the VWF:CBA/VWF:Ag ratios were concordant (> 0.7), but the VWF:RCo/VWF:CBA ratios were discordant (< or = 0.7) (P = 0.001) compared with control subjects.
Thus, VWF:RCo/VWF:Ag ratios were discordant in both type 2M and 2A VWD patient groups indicating a functional abnormality. However, VWF:CBA/VWF:Ag ratios were discordant in the type 2A VWD group but not in the type 2M VWD group.
Our study showed that VWF:CBA is sensitive to functional variants associated with the loss of high-molecular-weight multimers, i.e. type 2A and 2B in VWD, but the assay was unable to discriminate defective platelet-binding VWD variants with normal multimeric patterns such as type 2M VWD. It was concluded that the VWF:CBA assay should be used in association with rather than as a replacement for the VWF:RCo assay.
Large experience with a factor VIII binding assay of plasma von Willebrand factor using commercial reagents.
Caron C, Mazurier C, Goudemand J.
Department of Haematology, University Cardiological Hospital, Boulevard du Professeur J. Leclerq, 59037 Lille Cedex, France.
Br J Haematol 2002 Jun;117(3):716-8 Abstract quote
The present diagnostic assay for type 2N von Willebrand disease (VWD) is based on the in vitro measurement of the capacity of plasma von Willebrand factor (VWF) to bind exogeneous factor VIII (VWF:FVIIIB). We report a method using only commercially available reagents that is easy to perform. This method has been validated in a cohort of 144 patients with FVIII/VWF ratios < 0.6 using a plasma control mixture representative of intermediate VWF:FVIIIB.
In total, 15 patients were diagnosed with markedly decreased VWF:FVIIIB and five patients were shown to have moderately decreased VWF:FVIIIB. Specific type 2N mutations were identified in all these patients.
Von Willebrand factor collagen-binding (activity) assay in the diagnosis of von Willebrand disease: a 15-year journey.
Diagnostic Haemostasis Laboratory, Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Western Sydney Area Health Service, Westmead, NSW, Australia.
Semin Thromb Hemost 2002 Apr;28(2):191-202 Abstract quote
The correct diagnosis and classification of von Willebrand disease (vWD) is crucial because the presenting biological activity of von Willebrand factor (vWF) determines both the hemorrhagic risk and the subsequent clinical management. A variety of laboratory assays may be employed, not necessarily restricted to assessments of vWF. This article discusses the relative strengths and limitations of various functional or discriminatory vWF assays with a special focus on the vWF:collagen-binding activity (vWF:CBA) assay.
This is a functional vWF assay that relies on the property of vWF adhesion to collagen. The vWF:CBA was first described approximately 15 years ago. The journey from that time point has been an interesting one, and the vWF:CBA is now gaining more widespread acceptance. There are now many published studies confirming the superiority of the vWF:CBA over the vWF ristocetin cofactor (vWF:RCof) activity as a functional screening diagnostic test process for vWD. However, both tests may be required in order to appropriately diagnose all forms of vWD. The relationship of these assays with multimer analysis is also discussed.
In summary, an optimized vWF:CBA detects primarily high-molecular-weight (HMW) vWF forms and probably only about 30% of the total plasma vWF pool detected by vWF antigen (vWF:Ag). Because these HMW vWF forms are missing in types 2A and 2B vWD, the vWF:CBA is extremely useful in the detection of these qualitative vWD subtypes. In addition, however, concordance of vWF:CBA with vWF:Ag in unison with low vWF levels may alternatively suggest a type 1 vWD, and an absence of both vWF:Ag and vWF:CBA will suggest type 3 vWD. The vWF:CBA is also being investigated in various disease states, as is its usefulness as an effective marker of functional HMW vWF in both desmopressin (DDAVP) and factor-concentrate therapy in vWD.
Identification of von Willebrand Disease Type 2N (Normandy) in Australia
A Cross-Laboratory Investigation Using Different Methods
Susan E. Rodgers, MApplSc
Nancy V. Lerda
Emmanuel J. Favaloro, PhD, etal.
Am J Clin Pathol 2002;118:269-276 Abstract quote
We report on a cross-laboratory study of type 2N von Willebrand disease (vWD). We tested 101 selected plasma samples for factor VIII and factor VIII binding activity of von Willebrand factor (vWF). Of these plasma samples, 31 were cotested by 2 specialist centers using different detection procedures for vWFfactor VIII binding: there was good agreement between results obtained by chromogenic assay and enzyme-linked immunosorbent assay.
In total, 8 patients with type 2N vWD were identified. The 2-stage factor VIII assay detected a deficiency of factor VIII relative to vWF antigen in all 8 patients; the 1-stage factor VIII assay detected a relative deficiency in only 3 patients. Four patients were homozygous for the most common type 2N mutation (R854Q), 3 patients were presumed to be compound heterozygotes, and in 1 patient no type 2N mutations were identified.
In this study of patients from 5 specialist centers in Australia, type 2N vWD was found in 5 families.
The 2-stage factor VIII assay was more useful as a screening test than the 1-stage assay, and both vWFfactor VIII binding assays were equally effective.
FACTOR VIII/von WILLEBRAND FACTOR RATIO
The factor VIII/von Willebrand factor ratio discriminates between reduced synthesis and increased clearance of von Willebrand factor.
Eikenboom JC, Castaman G, Kamphuisen PW, Rosendaal FR, Bertina RM.
Department of Hematology, Hemostasis and Thrombosis Research Center, Leiden University Medical Center, The Netherlands
Thromb Haemost 2002 Feb;87(2):252-7 Abstract quote
It is often stated that a decrease in Von Willebrand factor (VWF), the carrier protein of factor VIII, results in a concordant change in factor VIII.
Clinical data suggest that this is not always the case and we hypothesized that the ratio between factor VIII and VWF depends on the genetic defect that causes the VWF deficiency. We have analyzed the ratio between plasma factor VIII and VWF in several subtypes of Von Willebrand Disease and we show that the ratio is increased when VWF synthesis is reduced, but that the ratio remains one when VWF clearance is increased.
These observations could be of clinical importance as an increased factor VIII/VWF ratio in combination with a borderline VWF level may indicate the presence of a true genetic defect, possibly a VWF null allele.
von Willebrand factor binding to heparin in various types of von Willebrand disease.
Rastegar-Lari G, Legendre P, Ajzenberg N, Warszawski J, Meyer D, Baruch D.
INSERM U143, Hopital de Bicetre, Paris, France.
Hematol J 2000;1(3):190-8 Abstract quote
INTRODUCTION: The purpose was to study von Willebrand factor (vWF) binding to heparin in different types of von Willebrand disease (vWD).
MATERIALS AND METHODS: Plasma samples from 92 patients were representative of most vWD subtypes as they included 13 type 1, ten type 2N, 27 type 2A, 23 type 2B, and 19 type 2M patients. We selected assay conditions suitable for the screening of plasma vWF concentrations as low as 15 U/dl vWF:Ag. We determined the range of vWF concentrations in plasma where the percentage of (125)I-MAb/vWF complexes bound to heparin-agarose beads was constant. This range of dilution allowed circumvention of potential competition by other plasma heparin-binding proteins.
RESULTS: The multimeric composition of vWF had hardly any influence on the ability of vWF to bind to heparin. Results were expressed as the ratio of heparin-binding capacity of patients' plasma to that of normal pool plasma. We found a ratio of 0.99+/-0.004 (mean+/-s.e.m.) for 23 normal individual donors. Furthermore, when comparing the mean values of plasma vWF-heparin binding ratios by ANOVA F-test in the six groups (one normal and five vWD), we found significant differences between them (P<0.0001). Pairwise comparison of multiples by the Scheffe's test indicated that the mean values of ratios in type 2A on the one hand and type 2M on the other, were significantly lower than in normal plasma, type 2N, type 2B and type 1.
CONCLUSION: Our data suggest a relationship between the ability of vWF to bind to heparin and to the platelet GPIb receptor, since type 2B and 2N patients have an increased or normal ability to bind to GPIb whereas type 2A and 2M patients have an impaired interaction with that receptor.
von Willebrand disease.
Nichols WC, Ginsburg D.
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, USA.
Medicine (Baltimore) 1997 Jan;76(1):1-20 Abstract quote
Considerable progress has been made in characterizing the specific molecular defects responsible for the heterogeneous disorder known as von Willebrand disease (VWD). A large number of molecular defects have been identified and precise characterization may now be possible in the majority of type 2A, type 2B, type 2N, and potentially also type 3 VWD cases. However, the most common variant, type 1 VWD, still remains a major challenge.
Continued progress in this area will improve our understanding of the pathogenesis of VWD and lead to more rapid and precise diagnosis and classification for this common disorder. The problems of incomplete VWD penetrance and poor diagnostic sensitivity and accuracy for the curently available clinical laboratory tests provide strong incentives for the development of DNA-based diagnostics. In addition, prenatal diagnosis is now possible either at the level of single point mutations (for some subtypes) or by RFLP analysis (assuming linkage to the von Willebrand factor [VWF] gene) and will probably be applied with increasing frequency for VWD type 3 (17, 133, 175). Understanding the molecular basis of VWD also has important implications for VWF structure and function and is helping to define critical binding domains within the VWF molecule.
Insights gained from these studies may eventually lead to improved therapeutic approaches not only for VWD, but also for a variety of other genetic and acquired hemorrhagic and thrombotic disorders.
Acquired von Willebrand syndromes: clinical features, aetiology, pathophysiology, classification and management.
Michiels JJ, Budde U, van der Planken M, van Vliet HH, Schroyens W, Berneman Z.
Department of Haematology, University Hospital Antwerp, Belgium.
Best Pract Res Clin Haematol 2001 Jun;14(2):401-36 Abstract quote
Acquired von Willebrand syndrome (AVWS) associated with hypothyroidism is of type I, results from a decreased synthesis of factor VIII and von Willebrand factor (VWF), responds to desmopressin with normal half-life times for factor VIII and VWF parameters, and disappears after treatment with I-thyroxine.
AVWS type I or III, which occurs in a minority of patients with Wilms' tumour in the complete absence of an inhibitor against VWF and no absorption of factor VIII or VWF onto nephroblastoma cells, responds to chemotherapy and/or tumour resection. Hyaluronic acid produced by nephroblastoma cells may be the causative factor in atypical AVWS in Wilms' tumour.
AVWS associated with thrombocythaemia of various myeloproliferative disorders is characterized by normal factor VIII and von Willebrand factor antigen (VWF: Ag) levels and a selective deficiency of functional ristocetin co-factor activity (VWF: RCo) and collagen-binding activity (VWF: CBA). AVWS type II in thrombocythaemia is caused by a platelet-dependent proteolysis of large VWF multimers, given the inverse relationship between platelet count and large VWF multimers in plasma and specific increases in the number of proteolytic VWF fragments in plasma.
The laboratory findings of AVWS associated with systemic lupus erythematosus or IgG benign monoclonal gammopathy are characterized by a prolonged bleeding time and activated partial thromboplastin time, decreased or absent ristocetin-induced platelet activity, low to very low levels of factor VIII coagulant activity (mean 15%), VWF: Ag (mean 10.7%) and VWF: RCo (mean 6.2%), and a type II multimeric pattern of VWF. Neutralizing and non-neutralizing anti-VWF autoantibodies, usually IgG, have been detected in patient plasma either free or tightly bound to the intermediate and high molecular weight VWF factor VIII particles. The bound auto antibody-antigen complex is rapidly cleared from the circulation, resulting in low levels of factor VIII, VWF parameters as documented by a poor response to desmopressin and VWF factor VIII concentrate. High-dose intravenous immunoglobulin transiently corrects the factor VIII coagulant and VWF levels, lasting for a few weeks in AVWS type II associated with systemic lupus erythematosus or IgG benign monoclonal gammopathy. Prednisolone is effective in AVWS associated with autoimmune disorder. Prednisolone and chemotherapy will not affect AVWS associated with IgG benign monoclonal gammopathy because the monoclonal IgG protein remains to act as an anti-VWF autoantibody. An absorption of VWF to malignant cells has been documented in a few patients with various lymphoproliferative disorders or adrenal carcinoma and suggested to result in a depletion of VWF.
The clinical picture of AVWS associated with early-stage IgG multiple myeloma, chronic lymphocytic leukaemia or non-Hodgkin's lymphoma without a paraprotein or no detectable underlying disorder is similar to that of AVWS type II in IgG benign monoclonal gammopathy but poorly documented with regard to the underlying immune mechanism of AVWS. The mechanical destruction of large VWF multimers may be of relevance in conditions in which the shear rate of flowing blood is increased, as may occur in cases of aortic stenosis, other heart valve defects or stenosed vessels.
Drug-induced AVWS has been described in association with the use of pesticides valproic acid, ciprofloxacin, griseofulvin, tetracycline, thrombolytic agents and hydroxyethyl starch.
Acquired von Willebrand disease.
Kumar S, Pruthi RK, Nichols WL.
Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minn 55905, USA.
Mayo Clin Proc 2002 Feb;77(2):181-7 R Abstract quote
Acquired von Willebrand disease (AvWD) is a relatively rare acquired bleeding disorder that usually occurs in elderly patients, in whom its recognition may be delayed. Patients usually present predominantly with mucocutaneous bleeding, with no previous history of bleeding abnormalities and no clinically meaningful family history.
Various underlying diseases have been associated with AvWD, most commonly hematoproliferative disorders, including monoclonal gammopathies, lymphoproliferative disorders, and myeloproliferative disorders. The pathogenesis of AvWD remains incompletely understood but includes autoantibodies directed against the von Willebrand factor (vWF), leading to a more rapid clearance from the circulation or interference with its function, adsorption of vWF by tumor cells, and nonimmunologic mechanisms of destruction. Laboratory evaluation usually reveals a pattern of prolonged bleeding time and decreased levels of vWF antigen, ristocetin cofactor activity, and factor VIII coagulant activity consistent with a diagnosis of vWD.
Acquired vWD is distinguished from the congenital form by age at presentation, absence of a personal and family history of bleeding disorders, and, often, presence of a hematoproliferative or autoimmune disorder. The severity of the bleeding varies considerably among patients.
Therapeutic options include desmopressin and certain factor VIII concentrates that also contain vWF. Successful treatment of the associated illness can reverse the clinical and laboratory manifestations. Intravenous immunoglobulins have also shown some efficacy in the management of AvWD, especially cases associated with monoclonal gammopathies. Awareness of AvWD is essential for diagnosis and appropriate management.
DIFFERENTIAL DIAGNOSIS CHARACTERIZATION COLD ACTIVATION
- Potential laboratory misdiagnosis of hemophilia and von Willebrand disorder owing to cold activation of blood samples for testing.
Favaloro EJ, Soltani S, McDonald J.
Am J Clin Pathol. 2004 Nov;122(5):686-92. Abstract quote
To assess the potential for misdiagnosis of von Willebrand disorder (vWD) and hemophilia A while following current National Committee for Clinical Laboratory Standards (NCCLS) guidelines and consequent to a poorly recognized cold-activation phenomenon, we processed 39 normal citrate-anticoagulated samples by standard procedures (reference) or stored at low (~4 degrees C) or ambient (~22 degrees C) temperature for 3.5 hours before centrifugation and processing. Samples were tested in parallel for several hemostasis factors, including von Willebrand factor (vWF). Similar results were obtained for all samples for factors II, V, VII, IX, X, XI, and XII. For factor VIII (FVIII) and vWF, only samples stored at ambient temperature had results comparable to reference sample results. In most cases, low temperature storage led to much lower results.
Taking the lower reference limit as 50%, most would have been defined as "abnormal," and a misdiagnosis of vWD or hemophilia A could easily arise. ABO classification and age were associated with FVIII and vWF levels, but neither was associated conclusively with relative loss of plasma FVIII coagulant and vWF caused by the cold-activation phenomenon.
We advise laboratories following current NCCLS guidelines not to store or transport whole blood samples for FVIII and vWF testing at 2 degrees C to 4 degrees C because of the risk of misdiagnosing vWD or hemophilia A. Storage and transport at ambient temperature seem acceptable and provide results comparable to freshly centrifuged samples.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSTIC FACTORS TREATMENT
Treatment of von Willebrand's disease.
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, IRCCS Maggiore Hospital, University of Milano, Italy.
J Intern Med Suppl 1997;740:129-32 Abstract quote
von Willebrand's disease is the most frequent of inherited bleeding disorders (1:100 affected individuals in the general population).
The aim of therapy is to correct the dual defects of haemostasis, i.e. abnormal coagulation expressed by low levels of factor VIII and abnormal platelet adhesion expressed by a prolonged bleeding time. There are two main options available for the management of von Willebrand's disease: desmopressin and transfusion therapy with blood products. Desmopressin is the treatment of choice in patients with Type 1 von Willebrand's disease, who account for approximately 80% of cases. The pharmacological compound raises endogenous factor VIII and von Willebrand factor and corrects the prolonged bleeding time in most patients. In Type 3 and in the majority of Type 2 patients, desmopressin is not effective and it is necessary to resort to plasma concentrates containing factor VIII and von Willebrand factor.
Treated with virucidal methods, these concentrates are currently effective and quite safe, even though the bleeding time defect is not always corrected by them. Platelet concentrates or desmopressin can be used as adjunctive treatments when poor correction of the bleeding time is associated with continued bleeding.
Response of von Willebrand factor parameters to desmopressin in patients with type 1 and type 2 congenital von Willebrand disease: diagnostic and therapeutic implications.
Michiels JJ, Van De Velde A, Van Vliet HH, Van Der Planken M, Schroyens W, Berneman Z.
Department of Hematology, University Hospital Antwerp, Belgiu.
Semin Thromb Hemost 2002 Apr;28(2):111-32 Abstract quote
In the present study, we prospectively evaluated the contribution of the von Willebrand factor collagen-binding activity (vWF:CBA) assay, vWF multimeric analysis, and the response to intravenous desmopressin (DDAVP) to correctly diagnose and classify congenital von Willebrand disease (CvWD) in 24 probands with mild to moderate type 1 vWD, 6 probands with severe CvWD type 1, and 12 probands with type 2 CvWD. CvWD type 1 of mild to moderate severity is featured by proportionally decreased levels of vWF antigen (vWF:Ag), vWF ristocetin cofactor activity (vWF:RCof), and vWF:CBA between 0.20 and 0.60 u/mL and a normal response to DDAVP of factor (F) VIIIc and all vWF parameters.
Severe type 1 CvWD with vWF parameters below 0.10 or 0.20 u/mL is associated with a decreased response to DDAVP of all vWF parameters, indicating a defective synthesis or secretion vWF by endothelial cells, or both. CvWD 2M may present as severe type 1 CvWD, as type 1 "platelet-discordant" CvWD, or with the combination of a discrepant vWF:RCof/Ag ratio and the presence of all vWF multimers. Ristocetin-induced platelet aggregation (RIPA) is normal in type 1 CvWD. CvWD 2M is typically featured by decreased RIPA, normal or near normal vWF multimers, and no or only a poor response to DDAVP of vWF:RCof as compared with a fairly good response to DDAVP of vWF:Ag and vWF:CBA. CvWD Vicenza is characterized by unusually large vWF multimers and very low levels of FVIIIc, vWF:Ag, and vWF:RCof. CvWD Vicenza differs from CvWD 2M because the vWF:RCof/Ag ratios are completely normal before and after DDAVP; the response to DDAVP is equally good for FVIIIc, vWF:Ag, vWF:RCof, and vWF:CBA and is followed by very short half-life times for FVIIIc and all vWF parameters. Pertinent findings in type 2A and 2B CvWD included prolonged Ivy bleeding time (BT), low vWF:RCof/Ag and vWF:CBA ratios, absence of the high vWF multimers, and, depending on the severity of the absence of intermediate vWF multimers, pronounced increase of low vWF multimers and vWF degradation products because of increased proteolysis of the high and intermediate vWF multimers. RIPA is normal in CvWD 2A and increased in CvWD 2B.
The response to DDAVP in CvWD 2A is normal for FVIIIc and vWF:Ag but is transient with partial correction and short half-life times of vWF:CBA and vWF:RCof. DDAVP does not correct BT and multimeric patterns in CvWD type 2B, despite significant increase of vWF parameters. CvWD types 2C, 2D, and 2E are featured by very low functional vWF parameters, the presence of typically abnormal vWF multimers, a very poor response of vWF:CBA, a decreased response of vWF:RCof, and a fairly good response of vWF:Ag to DDAVP with no correction of prolonged Ivy BT and no correction of the vWF multimeric pattern as the consequence of a multimerization or dimerization defect of the vWF molecules. CvWD type 2N usually presents with much lower levels for FVIIIc as compared with vWF, normal Ivy BT, and normal vWF multimeric pattern.
The response to DDAVP is normal for all vWF parameters but is decreased for FVIIIc with shortened half-life times.
Treatment of von Willebrand disease with a high-purity factor VIII/von Willebrand factor concentrate: a prospective, multicenter study.
Mannucci PM, Chediak J, Hanna W, Byrnes J, Ledford M, Ewenstein BM, Retzios AD, Kapelan BA, Schwartz RS, Kessler C; Alphanate Study Group.
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, IRCCS Maggiore Hospital and University of Milan, Italy.
Blood 2002 Jan 15;99(2):450-6 Abstract quote
Among patients with von Willebrand disease (VWD) who are unresponsive to desmopressin therapy, replacement with plasma-derived concentrates is the treatment of choice.
Because prospective studies are lacking, such treatment has been largely empirical. A multicenter, prospective study has been conducted in 81 patients with VWD (15 patients with type 1, 34 with type 2, and 32 with type 3 disease) to investigate the efficacy of a high-purity factor VIII/von Willebrand factor (FVIII/VWF) concentrate for treatment of bleeding and surgical prophylaxis.
Two preparations of the concentrate-one virally inactivated with solvent detergent, the other with an additional heat-treatment step--were evaluated. Pharmacokinetic parameters were similar for both preparations. Using pre-established dosages based on the results of pharmacokinetic studies, 53 patients were administered either preparation for the treatment of 87 bleeding episodes, and 39 patients were treated prophylactically for 71 surgical or invasive procedures. Sixty-five (74.7%) and 10 (11.5%) of the bleeding episodes were controlled with 1 or 2 infusions, respectively. Patients with severe type 3 VWD typically required more infusions and higher doses, at shorter time intervals, than did patients with generally milder types 1 and 2. Among patients undergoing surgical procedures, blood loss was lower than that predicted prospectively, and losses exceeding the predicted value did not correlate with the postinfusion skin bleeding time.
In conclusion, the concentrate effectively stopped active bleeding and provided adequate hemostasis for surgical or invasive procedures, even in the absence of bleeding time correction.
Acquired von Willebrand disease--hemostatic management of major orthopedic surgery with high-dose immunoglobulin, desmopressin, and continuous factor concentrate infusion.
Frank RD, Kunz D, Wirtz DC.
Department of Nephrology and Clinical Immunology, University Hospital RWTH Aachen, Pauwelsstrasse 30, D-52057 Aachen, Germany.
Am J Hematol 2002 May;70(1):64-71 Abstract quote
Acquired von Willebrand disease (aVWD) is a rare bleeding disorder that mimics congenital VWD in previously healthy individuals; it is most frequently associated with monoclonal gammopathy. Hemostatic therapy of aVWD is challenging due to the extremely shortened half-life of endogenous and exogenous VWF. High-dose intravenous immunoglobulin (ivIG) is recommended as the treatment of choice, usually rapidly normalizing coagulation; but in case of failure, alternative treatment options are not well explored.
We report successful major orthopedic surgery in a 61-year-old woman with multiple myeloma IgG lambda and aVWD. IvIG alone failed to correct hemostasis. However, ivIG pretreatment improved the VWF ristocetin cofactor (VWF:RCo) half-life from only 1.5 hr to more than 4 hr, allowing desmopressin infusions twice daily to maintain sufficient VWF:RCo levels. Because of diminishing desmopressin effect, we attempted for the first time in aVWD a continuous VWF/FVIII infusion (Haemate HS), 2.1-2.7 FVIII U/kg/hr or 51-64 U/kg/day, respectively 4.6-6.0 VWF:RCo U/kg/hr or 110-145 U/kg/day) to reach constant factor levels. The steady-state clearance was 2.4 mL/kg/hr for FVIII:C and 13.5 mL/kg/hr for VWF:RCo. During surgery, VWF:RCo, FVIII:C, and PFA-100 closure time were normalized. Until day 5, VWF:RCo was kept above 50%, from day 6 to 10 at least 30% activity were attained. FVIII:C levels were always >70%. The clinical course was uneventful without bleeding. Two weeks after hip surgery the patient was discharged from the hospital without complaints. The therapy described can be recommended as safe and feasible for further evaluation in aVWD patients who are hyporesponsive to ivIG treatment alone.
Continuous VWF/FVIII infusion can improve substitution therapy in aVWD.
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