Prevalence of von Willebrand disease in women with iron deficiency anaemia and menorrhagia in Taiwan

Summary.  Iron deficiency anaemia (IDA) is a frequently encountered disease, which can be attributed to menorrhagia. Most female patients with von Willebrand disease (VWD) have menorrhagia. The aim of this study was to investigate the prevalence of VWD in women with both IDA and menorrhagia in Taiwan. From January to December 2005 and November 2006 to January 2007, 56 consecutive patients with both IDA and menorrhagia were enrolled in this study. Their median age was 41 years (range 18–53). IDA was diagnosed by anaemia plus either low ferritin or transferrin saturation. Menorrhagia was evaluated by patient's menses history. Both von Willebrand factor antigen (VWF:Ag) and ristocetin cofactor activity (VWF:RCo) were measured for each patient. Bleeding time (BT) and platelet function analyser (PFA)-100 assay were determined as ancillary tests. The VWD diagnosis was established if: (i) both VWF:Ag (<50%) and VWF:RCo (<50%) were low; (ii) either VWF:Ag or VWF:RCo was low plus prolonged BT or prolonged PFA closure times. VWF multimer analysis was performed for subtype confirmation of VWD. Nine of the 56 (16.1%) patients were identified to have VWD. VWD patients with menorrhagia might develop IDA at younger age (34.3 vs. 39.7, P  = 0.09) and had more IDA recurrence (75% vs. 16%, P  = 0.03) than those patients without VWD. Of the eight VWD patients with VWF multimer analyses, all were revealed to have type I VWD. Our study demonstrates that VWD was not uncommon in women with both IDA and menorrhagia in Taiwan.     

Screening women with menorrhagia for underlying bleeding disorders: the utility of the platelet function analyser and bleeding time

Menorrhagia is a very common clinical problem among women of reproductive age and recent studies have suggested that underlying bleeding disorders, particularly von Willebrand's deficiency and platelet function defects, are prevalent in women presenting with menorrhagia. The objective of this study was to determine the utility of the platelet function analyser (PFA-100) and bleeding time (BT) as initial screening tests for underlying bleeding disorders in women with menorrhagia. In this study, 81 women with a physician diagnosis of menorrhagia underwent PFA-100 testing, BT and comprehensive haemostatic testing. The effectiveness of the PFA-100 and BT as screening tools in women with menorrhagia was assessed using results of haemostatic testing for von Willebrand's disease (VWD) and platelet dysfunction. In women presenting with menorrhagia, the PFA-100 had a sensitivity 80%, specificity 89%, positive predictive value (PPV) 33%, negative predictive value (NPV) 98% and efficiency 88% for VWD. For platelet aggregation defects, the PFA-100 closure time had a sensitivity 23%, specificity 92%, PPV of 75%, NPV of 52% and efficiency 55%. The data suggest that the PFA-100 may be useful in stratifying women with menorrhagia for further von Willebrand testing; however, neither the PFA-100 nor the BT tests are effective for purposes of classifying women for standard platelet aggregometry testing in women presenting with menorrhagia.     

The PFA‐100®: a potential rapid screening tool for the assessment of platelet dysfunction

The PFA‐100^® is a device that simulates high shear dependent platelet function in vitro and thus is particularly useful for screening for von Willebrand's disease (VWD). The aim of this study was to assess the overall potential of the PFA‐100^® as a primary clinical screening tool using the wide spectrum of clinical samples assessed for platelet function within our institution. The PFA‐100^® test was performed using both collagen/ADP (CADP) and collagen/epinephrine (CEPI) cartridges on samples from 337 patients with a wide variety of haemostatic defects. One hundred and eighty‐two patients were defined as having normal platelet function based on classical laboratory tests and von Willebrand factor levels. The overall clinical sensitivity of the PFA‐100^® for platelet abnormalities (including VWD) was 81% for CADP and 86% for CEPI. The overall specificity was found to be 82% for CADP and 80% for CEPI. When utilizing both cartridges in combination (with both results either higher or lower than the upper cutoff of the normal ranges), the overall false positive and false negative rates were 12% and 6%, respectively. The PFA‐100^® proved to be sensitive in detecting classical defects by giving prolonged closure times in samples from patients with major platelet function defects (e.g. von Willebrand's disease, Glanzmann's thrombasthenia and Bernard Soulier syndrome). However, there were a small number of false negative results (6%) obtained with various milder platelet defects (e.g. Hermansky Pudlak syndrome, storage pool and release defects, type I VWD and macrothrombocytopenia). The PFA‐100^® test provides a useful rapid screening tool and should increase the efficiency and reduce the cost of the routine diagnosis of platelet dysfunction.     

von Willebrand disease: a clinical and laboratory study of sixty-five patients

von Willebrand disease (VWD) is the commonest inherited bleeding disorder, yet it has not been well recognized in Southeast Asia. The aim of this prospective study was to report our experience of VWD diagnosis and to establish the clinical presentations of VWD in Taiwan. From October 2003 to April 2010, 863 patients with suspicion of having an inherited bleeding disorder underwent VWD screening tests. Those with positive tests were selected for further clinical and laboratory evaluation. A nested gender- and age-matched control cohort underwent similar investigation for comparison. VWD was diagnosed by comprehensive laboratory tests including factor VIII clotting activity, von Willebrand factor antigen assay, VWF:ristocetin cofactor activity (VWF:RCo) and platelet function analyzer (PFA)-100 closure times. VWF multimer analysis was performed by western blot for disease subtype identification. Sixty-five (7.5%) patients from 55 unrelated families were discovered to have VWD. Their median age was 27 years with a range of 4 to 69 years. The most common and specific bleeding symptom in male and female patients was bleeding after dental extraction and menorrhagia, respectively, as compared with control subjects. PFA-100 epinephrine closure time was the most sensitive laboratory test for VWD diagnosis with a sensitivity of 85%, followed by VWF:RCo assay (73%). Among 49 patients with VWF multimer analysis, 37(75.5%) were revealed to have type 1 VWD. Our study demonstrates that VWD and its clinical manifestations and subtypes in Taiwan are similar to those in the West and represents the first report of its kind in a Southeast Asian population.     

The condensed MCMDM-1 VWD bleeding questionnaire as a predictor of bleeding disorders in women with unexplained menorrhagia

Menorrhagia is a common clinical problem and is unexplained in more than 50% of women. Many studies have suggested that underlying bleeding disorders are prevalent in menorrhagic women. However, the assessment and quantifying of hemorrhagic symptoms are still limited and not widely used. Thirty women aged 11-31 years with a clinical diagnosis of unexplained menorrhagia were investigated to assess the diagnostic utility of the condensed MCMDM-1VWD bleeding questionnaire as a predictive of bleeding disorders in these women. In addition to administration of the questionnaire, comprehensive hemostatic testing was performed to all women. The incidence of inherited bleeding disorders among this group was 66.6% (20/30). Eight patients had von Willebrand disease (VWD) and seven had possible Glanzmann's thrombasthenia. Rare bleeding disorders including hemophilia A carrier, Afibrinogenemia, Factor V deficiency and combined factor V and factor VIII deficiency were also identified. The receiver operator characteristic analysis of the condensed MCMDM-1 VWD bleeding questionnaire in menorrhagic women showed that the cutoff, sensitivity, specificity, positive and negative predictive values were 3.5, 85, 90, 89 and 86%, respectively. Bleeding score was strongly correlated to bleeding time in women with possible Glanzmann's thrombasthenia. In VWD, a significant inverse correlation between the bleeding score and the VW factor levels was detected with a significant increase of bleeding score in type III VWD compared with type I. Bleeding disorders are common in women with unexplained menorrhagia and the condensed MCMDM-1VWD bleeding questionnaire can distinguish between menorrhagic women with and without bleeding disorders and help assess their severity.     

The spectrum of bleeding disorders in women with menorrhagia: a report from Western India

In order to evaluate the incidence of hereditary bleeding disorders in patients presenting with menorrhagia, where the usual gynecological and endocrinal causes of bleeding were ruled out by various local ultrasonography (USG) and relevant endocrine investigations, 120 women aged between 18 and 35 years presenting with menorrhagia without any discernable cause were studied using an open design, where the investigators knew that these patients had menorrhagia. These patients were investigated for inherited coagulation defects. Of the 120 women investigated, 19.16% (23 cases) had an inherited coagulation disorder to account for their menorrhagia. Although a majority (11.6%) are patients with von Willebrands disease (VWD), other rare platelet disorders such as Glanzmanns thrombasthenia (3.3%), Bernard-Soulier syndrome (0.83%), coagulation factor deficiencies such as factor VIII (0.83%), factor X (0.83%), and factor XI (0.83%), and immune thrombocytopenia (0.83%) were also found. Taking a detailed history for bleeding from other sites howsoever minor, paternal consanguinity as well as family history of bleeding tendencies appeared as a very strong predictor for such kinds of disease in patients with menorrhagia. Patients with menorrhagia without a discernable cause, therefore, need evaluation for the congenital coagulation disorders.     

Inherited bleeding disorders in Indian women with menorrhagia

In order to define the prevalence of haemostatic defects in women presenting with menorrhagia in our region, the coagulation data on women bleeders investigated in the Department of Haematology, AIIMS, were analysed. A total of 337 of the 2200 menorrhagic women investigated were characterized to have an inherited bleeding disorder; 221 of these 337 women presented with menorrhagia alone while 116 also had other associated bleeding manifestations as prolonged bleeding from injury site, ecchymotic patches in the skin, epistaxis, haematomas, haemarthroses and major bleeds like intracerebral bleeding. The tests performed included bleeding time (BT), platelet count, prothrombin time (PT), prothrombin consumption index (PCI), activated partial thromboplastin time (APTT), PF3 release with adenosine diphosphate (ADP) at 0 and 20 min, total PF3 assay and platelet Aggregation studies with collagen, ADP, adrenaline, arachidonic acid and ristocetin. Coagulation factor assays, von Willebrand antigen estimation, ristocetin cofactor assay and electron microscopy were performed wherever necessary. Inherited platelet dysfunction was seen in 283 (83.9%) of the patients. Amongst these, isolated PF3 availability defect was seen in 163 (48.4%) cases. Glanzman's thrombasthenia was seen in 30 (8.9%) patients, Storage pool disease in eight (2.4%) patients, arachidonic acid pathway defect in five (1.5%) patients and Bernard-Soulier Syndrome in six (1.8%) patients. In 71 (21.1%) patients, the platelet function defect could not be classified into any specific subtypes. Inherited defects of coagulation were observed in 54 (16%) of the cases. Amongst these, von Willebrand disease (vWD) was the most frequent being seen in 40 (11.9%) of the cases. Factor XIII deficiency was seen in one (0.3%), factor X deficiency in four (1.2%), factor VII deficiency in one (0.3%) and factor XII deficiency in one (0.3%) of the patients. It is concluded that although hereditary platelet function defects constitute a large majority of women bleeders in India but among the coagulation defects, vWD is the commonest as reported from the caucasian population. It is thus suggested that in women presenting with menorrhagia, screening tests for haemostasis especially for vWD and inherited platelet function defects must be performed.     

Usefulness of multiple electrode aggregometry as a screening tool for bleeding disorders in a pediatric hospital

Platelet function testing is a cornerstone in the diagnostic investigation of patients with a bleeding history. Multiple electrode aggregometry (MEA) has been shown to detect von Willebrand disease (VWD), platelet function disorders, and drug-induced bleeding disorders. However, there are few studies supporting its successful use in children. We have implemented and used MEA over 3 years in our hemostasis laboratory in order to study its usefulness to supplement and expedite diagnosis. This is a retrospective, single-center, cohort study of 109 hospitalized children who underwent a laboratory investigation of hemostasis and either had a reported bleeding history or an abnormal bleeding episode. Plasmatic coagulation testing, blood counts, plasmatic von Willebrand testing, platelet function analyzer (PFA-100), and impedance aggregometry (MEA) were performed in all children. Light transmission aggregometry testing was performed as needed. In 41 cases (37.6%), a working diagnosis was made; a primary hemostatic disorder was detected in 35 children (VWD (n = 16), platelet disorder (n = 15), and valproic acid therapy-induced bleeding disorder (n = 3), acetylsalicylic acid-related bleeding (n = 1). In patients diagnosed with VWD, MEA ristocetin-induced platelet aggregation test (RISTO) high test revealed abnormally low aggregation in six patients (43.8%); whereas in patients diagnosed with a platelet function disorder, abnormally low values were found by MEA in only three children (20%). Three of the four children with laboratory evidence of drug-induced platelet dysfunction had abnormalities on MEA. There were no cases in which an abnormal MEA result was used to make a previously undetermined diagnosis. Retrospectively, MEA has demonstrated limited additional diagnostic value beyond standard laboratory testing for detecting defects of primary hemostasis in children.     

Current understanding of von Willebrand's disease in women – some answers, more questions

Summary.  Considerable progress has been made in the past decade in describing the obstetrical and gynaecological aspects of von Willebrand's disease (VWD). In addition, epidemiological studies have established an approximately 11–16% prevalence of the laboratory diagnosis of VWD in women presenting with menorrhagia. However, it is not established presently whether an upfront VWD screening should be a part of the standard evaluation of menorrhagia. This is because it is presently not known whether therapy in the VWD patient tailored specifically for VWD will appreciably alter the natural history of menorrhagia compared with the non-VWD menorrhagia patient. There are also subtleties involved in securing the diagnosis of VWD in women presenting with menorrhagia in terms of fluctuation of von Willebrand factor (VWF) levels vis-à-vis the menstrual cycle and the potential impact of oral contraceptive on VWF levels. Regarding management of VWD-related menorrhagia, pending ongoing comparative trials of intranasal desmopressin (DDAVP), tranexamic acid, oral contraceptive and the levonorgestrel intrauterine device, specific recommendations cannot be made presently regarding the superiority of one intervention compared with the other. The management of VWD-related postpartum haemorrhage is also an area of active debate in terms of 'best practice' in type 1 (? prophylactic DDAVP), type 2 [? expectant management if factor VIII:C (FVIII:C) level normalizes] and type 3 patients (? intensity and duration of infusional therapy with a VWF-containing plasma-derived FVIII concentrate). This review summarizes the present state of knowledge and highlights numerous questions for future study based on our present understanding of VWD in women.     

Platelet von Willebrand factor determination does not improve the diagnosis of patients with suspected Type 1 von Willebrand disease

Summary.  Establishing a laboratory diagnosis of a bleeding disorder can be challenging for some patients who present with mucocutaneous bleeding symptoms. A common clinical scenario is an older patient with a prior diagnosis of von Willebrand disease (VWD) or a family history of VWD, who now has von Willebrand factor (VWF) values repeatedly within the normal range. Plasma VWF antigen levels have been shown to increase with age. Whether platelet VWF increases with age is unknown. We hypothesized that platelet VWF does not increase with age and low platelet VWF levels, despite normal plasma levels, could be a reason for continued bleeding symptoms in some patients. Therefore, we compared the platelet and plasma VWF antigen and activity as well as the platelet function analyzer (PFA)-100^® closure times in 35 patients with a history of mucocutaneous bleeding symptoms and consistently normal levels of VWF antigen and activity, despite a prior history of a VWD diagnosis and/or a positive family history of VWD. Overall in our patients (bleeders), the platelet VWF values correlated with the plasma values and only three patients had reduced platelet VWF. In the bleeding group, the PFA-100^® results showed an inverse correlation with plasma and platelet values, which was stronger for the plasma values. Therefore, platelet VWF determination was not helpful in the diagnosis of suspected mild type 1 VWD.     

Laboratory response to intranasal desmopressin in women with menorrhagia and platelet dysfunction

Summary.  Intranasal desmopressin (IN-DDAVP) is used for home treatment of menorrhagia in women with inherited bleeding disorders. The effect of IN-DDAVP on laboratory haemostatic parameters in women with menorrhagia related to platelet dysfunction is unknown. We evaluated the effects of IN-DDAVP on haemostatic parameters in women with menorrhagia and platelet dysfunction and correlated them with menstrual flow. Eleven women (aged 18–45) with menorrhagia and haemostatic abnormalities had determination of von Willebrand factor antigen (VWF:Ag), von Willebrand factor ristocetin cofactor (VWF:RCo) activity, factor VIII coagulant activity (FVIII:C), platelet aggregation and platelet adenosine tri-phosphate (ATP) release pre-IN-DDAVP and 60-min post-IN-DDAVP. Eight of eleven women underwent platelet function analyzer (PFA-100) closure time determination with collagen/adrenaline and collagen/adenosine diphosphate cartridges pretreatment and post-treatment. IN-DDAVP was administered during two consecutive menstrual cycles. Menstrual flow was assessed during each cycle using a pictorial blood assessment chart. Treatment with IN-DDAVP resulted in elevated VWF levels and shortened PFA-100 closure time with significant inverse correlation between shortening of PFA-100 closure times and increases in VWF levels. There were also significant inverse correlations between changes in menstrual flow and changes in VWF:Ag ( P  =   0.02), VWF:RCo ( P  =   0.04) and FVIII:C ( P  =   0.006), following treatment. In vitro platelet aggregation and platelet ATP release response did not correct and did not correlate with changes in menstrual flow. Our results demonstrate a correlation between haemostatic parameters and menstrual flow following IN-DDAVP in women with menorrhagia and platelet dysfunction.     

Spectrum of Von Willebrand disease and inherited platelet function disorders amongst Indian bleeders

Platelet function disorders (PFD) and Von Willebrand disease (VWD) are among the uncommon causes of bleeding in haematological practice. The inherited variety of PFD includes defects in platelet adhesion, aggregation, secretion and platelet procoagulant activities. VWD is classified into three major categories-type 1 and 3 (quantitative deficiency) and type 2 VWD (qualitative defect). In the present study, the profile and prevalence of inherited PFD and VWD in Indians are described. Two thousand eight hundred patients with history of muco-cutaneous bleeding and other bleeding disorders were investigated. The tests performed included platelet count, bleeding time, PT, APTT, F VIII assay, platelet factor 3 (PF3) availability, platelet aggregation studies, VWF:Ag, VWF:RCo and multimeric analysis. Out of 2,800 patients investigated, a total of 872 (31.1%) were characterized to have either inherited coagulation defects (64.2%) or inherited platelet function disorders (35.8%). Of these 872 patients, 312 (35.8%) cases were characterized to have inherited PFD and 94 (16.8%) patients as VWD. Among 312 inherited PFD patients, isolated PF3 availability defect (48.1%) was most common, followed by unclassified PFD (37.2%). Among 94 VWD patients, type 2 VWD was most common (44.7%), followed by type 3 VWD (34.5%) and type 1 VWD (21.3%), respectively. Bleeding manifestations included easy bruising (46%), undue prolonged bleeding from trivial injuries (50% in PFD and type 1 and type 2 VWD and 100% in type 3 VWD), menorrhagia (31%), gum bleeds (22%), epistaxis (55%), haematuria (6%), GI bleeds (11%) and rarely, haematomas and haemarthoses (4%). In conclusion, VWD and inherited platelet function disorders are not uncommon among Indian population presenting with bleeding disorders.     

Medical, reproductive and psychosocial experiences of women diagnosed with von Willebrand''s disease receiving care in haemophilia treatment centres: a case–control study

OBJECTIVE: To assess the medical, gynaecological and reproductive experiences of women with von Willebrand's disease (VWD) and to evaluate the impact of VWD on mental health and life activities. METHODS: A total of 102 women with VWD who were registered in haemophilia treatment Centres (HTCs) in the United States and 88 controls were interviewed regarding medical, gynaecological and reproductive history, life activities and symptoms of depression. Symptoms of depression were measured using the Center for Epidemiological Studies Depression Scale (CES-D). RESULTS: Excessive bleeding symptoms were reported in 74% of VWD cases compared with 6% of controls. Women with VWD had a higher prevalence of menorrhagia, excessive postpartum bleeding, other gynaecological conditions, arthritis and migraine headaches than did controls. More VWD cases than controls reported that menstruation had a negative impact on overall life activities. No difference in the prevalence of depression was found between cases and controls. DISCUSSION: Women with VWD experience menorrhagia and other gynaecological conditions at a higher frequency than women without bleeding disorders. Menstruation in women with VWD has a negative impact on life activities. The prevalence of depression was not elevated in this group of women whose VWD is being managed in an HTC.     

The PFA-100: a potential rapid screening tool for the assessment of platelet dysfunction

The PFA-100 is a device that simulates high shear dependent platelet function in vitro and thus is particularly useful for screening for von Willebrand's disease (VWD). The aim of this study was to assess the overall potential of the PFA-100 as a primary clinical screening tool using the wide spectrum of clinical samples assessed for platelet function within our institution. The PFA-100 test was performed using both collagen/ADP (CADP) and collagen/epinephrine (CEPI) cartridges on samples from 337 patients with a wide variety of haemostatic defects. One hundred and eighty-two patients were defined as having normal platelet function based on classical laboratory tests and von Willebrand factor levels. The overall clinical sensitivity of the PFA-100 for platelet abnormalities (including VWD) was 81% for CADP and 86% for CEPI. The overall specificity was found to be 82% for CADP and 80% for CEPI. When utilizing both cartridges in combination (with both results either higher or lower than the upper cutoff of the normal ranges), the overall false positive and false negative rates were 12% and 6%, respectively. The PFA-100 proved to be sensitive in detecting classical defects by giving prolonged closure times in samples from patients with major platelet function defects (e.g. von Willebrand's disease, Glanzmann's thrombasthenia and Bernard Soulier syndrome). However, there were a small number of false negative results (6%) obtained with various milder platelet defects (e.g. Hermansky Pudlak syndrome, storage pool and release defects, type I VWD and macrothrombocytopenia). The PFA-100 test provides a useful rapid screening tool and should increase the efficiency and reduce the cost of the routine diagnosis of platelet dysfunction.     

Identification and management of women with inherited bleeding disorders: a survey of obstetricians and gynaecologists in the United Kingdom

A mail survey of members and fellows of Royal College of Obstetricians and Gynaecologists was carried out to determine current practices of obstetricians and gynaecologists in the United Kingdom in the management of women with inherited bleeding disorders. In total, 3929 questionnaires were sent, 707 returned and analysis was limited to 545 valid questionnaires. In the past 5 years, 91% have managed women with inherited bleeding disorders. The majority (83%) considered inherited bleeding disorders to be under diagnosed in obstetrics and gynaecology. More than 80% considered the prevalence of von Willebrand's disease (VWD) to be <0.2% in the general population and <1% in women with menorrhagia and no gynaecological pathology, although the reported prevalence is 1% and 5-25% respectively. Twelve percent of the respondents would arrange testing for VWD when reviewing an 18-year-old with menorrhagia and no pelvic pathology, while only 2% would do the same for a 35-year-old with the same presentation. Twenty-one percent thought elective caesarean section is indicated in all fetuses known to be at risk of being affected by haemophilia. Eighty-four percent considered vacuum extraction unsafe in these cases, but 76% would consider the use of low forceps. In conclusion, obstetricians and gynaecologists underestimate inherited bleeding disorders as an underlying cause for menorrhagia. Increased awareness and management guidelines are essential in minimizing haemorrhagic complications and improving quality of care of these women.     

The power of a standardized bleeding score in diagnosing paediatric type 1 von Willebrand’s disease and platelet function defects

Summary. A predictive standardized bleeding questionnaire (Vicenza score), previously validated for identifying individuals with type 1 von Willebrand’s disease (VWD), has never been prospectively validated in tertiary care paediatric settings. The aim of this study was to assess the Vicenza score’s predictive power in identifying type 1 VWD, low von Willebrand factor (VWF) and platelet function defects (PFD) in a prospective cohort of patients, 0–17 years old, referred to a paediatric haematology clinic for evaluation of a bleeding disorder. Before the initial visit, caregivers consented to answer the questionnaire via telephone. Patients’ medical records were reviewed after haematological evaluation. VWF:Ag or VWF:RCo<30 IU dL^?1 were labelled ‘definite type 1 VWD’ while 30–50 IU dL^?1 were labelled ‘Low VWF’. PFA‐100 screening followed by abnormal electron microscopy and/or platelet aggregation studies diagnosed a PFD. At least one haemorrhagic symptom was present in 99 of the 104 children who completed the study (mean number of symptoms 2.87, mean Vicenza score 3.24). Eight met criteria for ‘definite type 1 VWD’, 23 for ‘low VWF’ and 13 for ‘PFD’. The sensitivity, specificity, and positive and negative predictive value (NPV) of the Vicenza score demonstrated poor diagnostic utility with the exception of high specificity in ruling out ‘definite type 1 VWD’. The NPV was comparably high with qualitative (>2 bleeding symptoms) and quantitative (Vicenza score ≥2) criteria. The Vicenza score has limited predictive value in paediatric tertiary care settings. While the NPV of excluding ‘definite type 1 VWD’ is high, simpler qualitative criteria is similarly predictive.     

Evaluation of desmopressin effects on haemostasis in children with congenital bleeding disorders

Summary.  Desmopressin (DDAVP) affects haemostasis by the release of von Willebrand factor and coagulation factor VIII from endothelium. The aim of the study was to evaluate the results of DDAVP testing in paediatric patients with congenital bleeding disorders. Forty-one patients consisting of children with von Willebrand's disease (VWD, n  = 26) and platelet function defects (PFD, n  = 15) received DDAVP intravenously at a dosage of 0.3 μg/kg over 30 min. FVIII activity (FVIII), von Willebrand factor antigen (VWF:Ag), collagen-binding activity (VWF:CB) and PFA 100^® closure times (CT) were measured before, 60, 120 and 240 min after DDAVP. In VWD, the VWF:Ag increased threefold until 60 min and then it decreased continuously. Compared with baseline, VWF:Ag was significantly higher at 60 and 120 min but not at 240 min. In contrast, in PFD, the peak of VWF:Ag was reached after 120 min. Two hundred and forty minutes after DDAVP, the mean was still significantly elevated compared with baseline values. The course of VWF:CB corresponded to that of VWF:Ag. In patients with VWD and PFD, FVIII rose two- to threefold within 2 h after DDAVP. CT in patients with VWD shortened markedly within 120 min and then rose again. In all children with PFD, except one non-responder, the CT shortened within 240 min after DDAVP. Two non-responders with VWD were identified by the failed increase of VWF:Ag, VWF:CB and by prolonged CT. Haemostatic effects of DDAVP differ interindividually and dependent on the coagulation disorder. DDAVP was effective in most, but not in all patients. DDAVP testing is recommended to determine the individual haemostatic response.     

Epidemiology, diagnosis, and management of von Willebrand disease in India

Von Willebrand disease (VWD) in all developing countries including India is considered a rare coagulation disorder, contrary to many reports from Western countries. Prevalence data based on hospital referrals identifies type 3 VWD as the most common subtype followed by type 1 and type 2. Approximately 60 to 70% cases of type 3 VWD are reportedly born of consanguineous marriages. The discriminatory diagnostic tests mainly include assays for factor (F)VIII:C and ristocetin-induced platelet agglutination and Von Willebrand factor (VWF) antigen either by immunoelectrophoresis or by enzyme-linked immunosorbent assay. VWD-type assisting tests like VWF collagen binding, VWF ristocetin cofactor assay, VWF-FVIII binding assay, and multimer analysis are occasionally used but not routinely applied in many laboratories. Among women, menorrhagia is an important presenting manifestation. Except for a handful of centers mainly in metropolitan cities, most laboratories in the remote parts of the country have no facilities for VWD-related investigations, resulting in occasional misdiagnoses of VWD as hemophilia A. Genetic diagnosis is being offered in two or three centers using the indirect linkage method in type 3 VWD, and efforts are continuing to implementing a direct mutation detection technique for routine practice in a few laboratories. Depending on the subtype or the severity of VWD, desmopressin, cryoprecipitate, fresh-frozen plasma, and factor VIII/VWF concentrates are used for management. Antifibrinolytic agents like epsilon-aminocaproic acid and tranexamic acid are widely used as an adjuvant therapy. In women with menorrhagia, oral contraceptives as a supplementary treatment are also being widely advocated to reduce bleeding. Products like danazol, ethenyl estradiol, thalidomide, and atorvastatin have been used in individual patients; acquired VWD associated with hypothyroidism has been managed successfully with thyroid hormone treatment. Both minor and major surgical procedures are performed in a few centers with judicious use of cryoprecipitate or FVIII concentrate containing VWF along with other supplementary therapeutic products to achieve adequate hemostasis. Awareness about the disease, establishment of the comprehensive coagulation laboratory, and treatment centers will be successful in increasing diagnosis of VWD and consequently better management of affected patients. This is likely to tilt the ratios of different VWD types, and VWD is likely to emerge as the most common of all coagulation disorders in the near future.     

Advances in the diagnosis and management of type 1 von Willebrand disease

Von Willebrand disease (VWD) is an autosomally inherited bleeding disorder caused by a deficiency and/or abnormality of von Willebrand factor (VWF). VWF is a multimeric adhesive protein that plays an important role in primary hemostasis by promoting platelet adhesion to the subendothelium at sites of vascular injury and platelet-platelet interactions at high-shear rate conditions. Furthermore, VWF is the carrier of factor VIII, thus indirectly contributing to the coagulation process. Most cases have a partial quantitative deficiency of VWF (type 1 VWD) with variable bleeding tendency, whereas qualitative variants (type 2 VWD), due to a dysfunctional VWF, are clinically more homogeneous and account for approximately 20-30% of cases. Type 3 VWD is rare and these patients have moderate-to-severe bleeding diathesis, display a recessive pattern of inheritance and virtual absence of VWF. The diagnosis of VWD may be difficult, especially in type 1 disease, since the laboratory phenotype of the disorder is very heterogeneous and confounded by the influence on VWF levels by factors outside the VWF gene (e.g., blood group). An array of tests are usually required to characterize the several types of the disorder in order to predict the best treatment modality. Desmopressin is the treatment of choice for most patients with type 1 VWD because it corrects the the dual defects of hemostasis, that is, abnormal coagulation expressed by low levels of factor VIII and abnormal platelet adhesion expressed by the reduction of VWF.     

Bleeding disorders,menorrhagia and iron deficiency: impacts on health‐related quality of life

von Willebrand disease (VWD) is a bleeding disorder that occurs in up to 1% of the general population. The great majority of females with VWD experience menorrhagia. The morbidity burden in females with VWD may relate to iron deficiency resulting from menorrhagia. To explore relationships between bleeding disorders, menorrhagia, iron deficiency and the outcomes of health‐related quality of life (HRQL) and educational attainment. All subjects with VWD, and females with other bleeding disorders, in the Canadian national registry who were more than 12 years of age were eligible for survey. Survey measures included the HEALTH UTILITIES INDEX^®; abridged Clinical History Assessment Tool; socio‐demographic questions and serum ferritin. Statistical analyses included testing differences among groups of means using analysis of variance and of proportions using chi‐squared test. Significant size differences in mean HRQL scores were detected between VWD females and both females with other bleeding disorders [diff = (?0.08); P = 0.017] and VWD males [diff = (?0.07); P = 0.039]. Mean HRQL scores differed between females with and without menorrhagia (P < 0.001). Mean HRQL scores were not significantly different between females with and without iron deficiency. Educational attainment was not associated with disease group, menorrhagia status or iron status. Females with VWD have a greater morbidity burden than females in the general population, females with other bleeding disorders and males with VWD. Menorrhagia is associated with low HRQL scores in females with bleeding disorders, including VWD. Further investigation should assess how menorrhagia impacts HRQL in females with bleeding disorders.