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ORIGINAL ARTICLE Table of Contents   
Year : 2010  |  Volume : 53  |  Issue : 3  |  Page : 486-489
Prevalence and spectrum of von Willebrand disease in Eastern Uttar Pradesh


1 Department of Pathology, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005 (U.P.), India
2 Department of Obstetric & Gynecology, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005 (U.P.), India
3 Department of Paediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005 (U.P.), India

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Date of Web Publication22-Oct-2010
 

   Abstract 

Context: Von Willebrand disease is the most common inherited bleeding disorder with a prevalence of ≈ 1% in the general population. Studies available from India are limited, showing a prevalence of ≈ 10% of vWD amongst inherited bleeding disorders. Aims: This study aims to know the prevalence and subtypes of vWD in patients presenting with various bleeding manifestations to university hospital. Settings and Design: We investigated 840 patients presenting with bleeding manifestations in the period from August 2004 to August 2008 for bleeding disorders. Materials and Methods: Tests performed for the diagnosis of vWD included platelet count, bleeding time (BT), prothrombin time (PT), activated partial thromboplastin time (APTT), Factor VIII:C assay, von Willebrand Factor Antigen assay and Ristocetin-induced platelet aggregation. Results: Amongst 840 patients, 230 (27.38%) had inherited bleeding disorder. Out of these, 40 (17.39%) patients were identified as vWD. Type 1 in 17 (42.5%), Type 2 in 11 (27.5%) and Type 3 vWD was present in 12 (30.0%) patients. Patients' age ranged from five months to 45 years, with 17 males and 23 females. Positive family history was seen in 12 patients (30%). Muco-cutaneous bleeding was the most common presentation. Menorrhagia was present in 100% women of reproductive age group, and hemarthrosis was seen in two male patients. Conclusions: We felt that Type I vWD with infrequent and mild bleeding episodes remain undiagnosed either because of unawareness of the disease in society or due to paucity of diagnostic facilities available in our country. Therefore, an awareness program along with enhancement of diagnostic facilities for vWD is required in our country to identify these patients for proper management thus avoiding hemorrhagic complications.

Keywords: Hybrid bleeding disorder, inherited bleeding disorders, menorrhagia, von Willebrand disease

How to cite this article:
Kumar S, Kishore R, Gupta V, Jain M, Shukla J. Prevalence and spectrum of von Willebrand disease in Eastern Uttar Pradesh. Indian J Pathol Microbiol 2010;53:486-9

How to cite this URL:
Kumar S, Kishore R, Gupta V, Jain M, Shukla J. Prevalence and spectrum of von Willebrand disease in Eastern Uttar Pradesh. Indian J Pathol Microbiol [serial online] 2010 [cited 2019 Feb 17];53:486-9. Available from: http://www.ijpmonline.org/text.asp?2010/53/3/486/68287



   Introduction Top


Von Willebrand disease (vWD) is the most common, predominantly autosomal dominant inherited bleeding disorder, which affects both sexes equally. It affects approximately 1% of general population. [1],[2] It is caused by quantitative deficiency (Type 1 and Type 3) or qualitative defect (Type 2) of von Willebrand factor (vWF). The vWF is synthesized in the endothelial cells and megakaryocytes. It is stored in Weibel Palade bodies in the endothelial cells and a-granules of the platelets. The plasma concentration of vWF is approximately 10μg/ml. In the plasma it exists in the multimeric dimer configuration ranging in size from small (500 kD) to very large (>10,000 kD) high molecular weight multimeric (HMWM) forms. The larger molecules have greater adhesive capacity due to increase number of individual adhesion sites. The vWF circulates in the plasma in association with factor VIII: coagulant protein (FVIII:C) as vWF : FVIII:C complex. The two most important functions of vWF are (i) it facilitates the adhesion of platelets to subendothelium at the site of injury, thus participating in primary haemostasis and (ii) it stabilizes FVIII:C in circulation and increases its half-life by five to 10 folds, thus it also participates in secondary haemostasis. vWD is a very heterogenous disorder because of different molecular mutations and variable penetrance. Within families there can be a range of phenotypes with variable bleeding manifestations that may change overtime. [3] There are varieties of assays to be performed by the laboratory undertaking the investigations for vWD. Due to the limitation of each laboratory assay, no single test procedure is sufficient to permit detection of all variants of vWD. [4] Because of all these reasons, vWD remains an under diagnosed entity in India. Very few studies are available from India mainly from the western part of the country showing a prevalence of approximately 10% of vWD amongst all inherited bleeding disorders. [5],[6] Hence the present study was undertaken to know the prevalence and spectrum of vWD in this part of our country. An attempt has also been made to subtype the different variants of vWD according to its recent classification. [7]


   Materials and Methods Top


The study was conducted in the period from August 2004 to August 2008. All patients with abnormal bleeding manifestations attending University Hospital or referred from outside from adjoining districts of Bihar, Uttarakhand, Madhya Pradesh, Jharkhand and Chhattisgarh made the material for study. After taking the informed consent, a detailed proforma containing the nature of the bleeding episodes, age at the onset, frequency of bleeding, family history, mode of inheritance and history of prior medication including blood transfusion was filled along with detailed physical examination. For coagulation / platelet studies 9 ml blood was collected in 1 ml of 3.2% sodium citrate as anticoagulant (exact 9:1 ratio). The sample was processed within four hours of blood collection. Platelet rich plasma (PRP) was made by centrifuging the blood at 150-200 g for one minute and used for platelet studies. Platelet poor plasma (PPP) was made by centrifugation at 2000 g for 10 minutes and used for coagulation studies; 2 ml blood was collected in EDTA vial for complete blood count by auto analyzer (Lab life H3D Premier). At the time of blood collection some blood films were also made directly on slides without putting the blood in any anticoagulant. These smears were later stained by Leishman's stain and examined. For the diagnosis of vWD following studies were done, complete blood counts including platelet count and examination of peripheral blood films. For coagulation/ platelet studies, tests for PT, APTT, FVIII:C assay was done manually by standard techniques. [8] BT was done by modified Ivy's method. Amongst special tests for vWD, vWF:Ag level was estimated by enzyme-linked immunosorbent assay (ELISA -a kit from Diagnostica Stago, France). Ristocetin induced platelet aggregation (RIPA) was done by platelet aggregometry on dual channel chronolog aggregometer at ristocetin (Sigma) concentration of 1.5 mg / ml. Low dose RIPA (0.5 mg / ml, RIPA-LD) was also done wherever indicated to rule out Type 2B vWD/or platelet type vWD (pseudo vWD). [7] Based on these tests, vWD and its variants were identified as given in [Table 1].
Table 1 :Diagnosti c criteria for variants of vWD

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   Results Top


A total of 840 patients were investigated for abnormal bleeding manifestations. Out of these, 230 (27.38%) patients were diagnosed as hereditary bleeding disorders by appropriate tests done for coagulation/ platelet profile. The remaining 610 patients (72.62%) had some acquired cause of their abnormal bleeding tendencies or were remain undiagnosed. Out of these 230 patients of inherited bleeding disorders, vWD was identified in 40 (17.39%) by the above mentioned test panel. The age of these patients ranged from five months to 45 years. There were 17 males and 23 females with M:F ratio of 0.73. Amongst females, 17 patients were of reproductive age group (18-45 years). Positive family history was found in 12 cases (30%). Type 1 vWD was predominant subtype, found in 17 patients (42.5%) followed by Type 3 in 12 patients (30%) and Type 2 vWD in 11 patients (27.5%). Amongst Type 2 vWD, Type 2A was the most common type found in ten patients. Only one patient of Type 2N was seen. No patient of Type 2B or 2M was seen in this study. We would like to mention that as we have not done the vWF multimer study, it was very difficult to differentiate between Type 1 and Type 2A vWD (in type 1 vWD there is partial deficiency of vWF:Ag, but structurally normal multimers are seen, where as in Type 2A, vWF:Ag may be normal to low but only small multimers are seen with loss of intermediate and high molecular weight multimers).

In our study we have categorized patients with low vWF:Ag (< 40%) with normal to reduced RIPA in type 1 vWD and patients with normal to low vWF:Ag (>40%) with markedly diminished RIPA in type 2A vWD. However, we feel that there may be some overlapping between these two categories of patients in our study. The most severe form of vWD is Type 3 vWD, which is characterized by severe quantitative deficiency or complete absence of vWF. The diagnosis of this type was straightforward, with prolonged BT and APTT, marked reduction in FVIII:C assay, reduced vWF:Ag level and abnormal RIPA. Clinically, in Type 1 and Type 2A vWD, most of the patients presented with muco-cutaneous bleeding like epistaxis, gum bleeding, and small multiple ecchymotic patches. However, spontaneous bleeding and more frequent bleeding episodes were much more common in type 2A vWD than Type 1 vWD. All female patients in reproductive age group diagnosed in these categories had menorrhagia as a common symptom. These patients were referred to us from the department of Obstetrics and Gynecology for investigation of menorrhagia in whom all other organic causes of bleeding were excluded.

In nine patients, menorrhagia was the only finding whereas other eight patients, when intensively inquired, admitted that some other type of muco-cutaneous bleeding like epistaxis, gum bleeding, ecchymosis, bruises or continuous oozing of blood after tooth extraction also occurred occasionally in their lifetime along with menorrhagia. Two patients of Type 2A vWD also gave history of postpartum hemorrhage (PPH), which required blood transfusion to stop bleeding. All the patients of type 3 vWD had severe life threatening bleeding episodes. One male patient of type 2N vWD and one of Type 3 vWD also had hemarthrosis of knee and elbow joints, respectively. The differentiation of these patients from hemophilia A was done by prolonged BT, reduced to absent RIPA [Figure 1]a,b,c, low vWF:Ag level and a negative X-linked family history. Bleeding manifestations and laboratory parameters of different variants of vWD are presented in [Table 2] and [Table 3], respectively.
Table 2 :Spectrum of bleeding manifestati ons in vWD pati ents (n=40)

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Table 3 :Laboratory parameters of vWD variants

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Figure 1 :(a) RIPA showing normal platelet aggregati on
Figure 1b: Reduced platelet aggregati on
Figure 1c: RIPA showing markedly reduced platelet aggregati on


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   Discussion Top


A wide spectrum of bleeding manifestations was found in the patients of vWD. Although vWD is a 'hybrid' disease between platelets and coagulation factor deficiency, muco-cutaneous bleeding is much more common than coagulation type of bleeding like hemarthroses and hematomas in these patients. In our study also muco-cutaneous bleeding like epistaxis, ecchymoses, gum bleeding and bleeding from minor cuts were most common clinical presentation. Menorrhagia was found in 100% women presenting in reproductive age group. No case of petechiae or purpura was seen in this study. In our study, female patients outnumbered males. It may be because we have included 17 female patients of idiopathic menorrhagia which were referred to us for the investigation of bleeding disorders from the department of Obstetrics and Gynecology. Routinely, such patients are often missed because of unawareness about the disease in the society and among healthcare providers as well. Repeated testing done once or even twice is needed to identify vWD in many patients with mild disease. In our study, Type 1 vWD was most common (42.5%), followed by Type 3 (30%) and Type 2 (27.5%).

Most of the studies from India report a high prevalence of Type 2 and Type 3 vWD i.e. much more severe forms of disease than Type 1 vWD. Gupta et al.[9] from AIIMS, New Delhi reported a high frequency of vWD type 2 and 3 in a cohort of Indian patients and emphasized the role of multimeric analysis in the diagnosis of disease. Gupta et al. [10] and Ahmad et al.[11] again in different studies from AIIMS reported almost similar findings. Trasi et al.[12] from IIH Mumbai also reported Type 3 vWD as the most common type amongst vWD subtypes. Comparatively lesser prevalence of Type 1 vWD and higher prevalence of Type 3 and Type 2 vWD in our study as well as those reported by these workers is in contrast to reports available from Western countries showing a high prevalence of type 1 vWD (70-80%) as compared to Type 2 (15-22%) and Type 3 (1-3%). [3],[7] All these studies are compared with our study [Table 4]. Srivastav et al.[13] from Vellore during an epidemiologic study of vWD in developing world also reported a very high frequency of severe vWD (types not mentioned) in Asian countries, amongst which India was on the top with a prevalence of 52% as against 8% (Singapore), 32% (Oman) and 50% (Iran). A strong association between consanguinity and severe vWD was also observed in this study.
Table 4 :Comparati ve study of subtypes of vWD in India

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Further, it is pertinent to mention that almost all of these studies are hospital based and therefore disease is identified only in those patients who presented themselves for investigation thus giving a higher prevalence of severe forms of disease. In contrast, most of the studies done in Western countries are epidemiological studies done in general population giving an overall prevalence of vWD ranging from 0.7% to 1.6% with an average prevalence of ≈ 1% and a very high prevalence of Type 1 disease. [14],[15] Identification of Type 1 vWD (mild form) is very important as these patients are either asymptomatic or suffer from mild and infrequent bleeding episodes which make them to consider their bleeding tendencies as normal. If they are not identified, they may bleed profusely after getting major haemostatic challenges like surgery and trauma. In India, characterization of vWD is difficult in general population because of financial constraints, inadequate awareness and lack of support for these patients from health care system. The complexities involved in its diagnosis requiring a battery of tests which are not widely available even in major hospitals, need of the tests to be repeated for correct diagnosis, make this disease an underestimated entity in India. Efforts are needed to develop national registries and to make basic services for diagnosis widely available so that patients of vWD could be managed properly avoiding morbidity and mortality during major hemostatic challenge or after any invasive procedure done on them.


   Acknowledgment Top


The authors wish to acknowledge the excellent technical assistance of Mr. Somaru Ram and Mr. Pawan Pandey, Laboratory Technicians, Coagulation Laboratory, Department of Pathology, IMS, BHU, Varanasi.

 
   References Top

1.Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand's disease. Blood 1987;69:454-9.  Back to cited text no. 1  [PUBMED]  [FULLTEXT]  
2.Abshire TC. Prophylaxis and von Willebrand's disease (vWD). Thromb Res 2006;118:S3-7.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]  
3.Friedman KD, Rodgers GM. Inherited Coagulation Disorders. 11th ed. Wintrobe's Clinical Hematology. In: Greer JP, Foerster J, Leuken JN, Rodgers GM, Paraskevas F, Glader B, editors. Philadelphia: Lippincott Williams and Wilkins Press; 1999. p. 1628-37.  Back to cited text no. 3      
4.Favaloro EJ. Appropriate laboratory assessment as a critical facet in the proper diagnosis and classification of von Willebrand disorder. Best Pract Res Clin Haematol 2001;14:299-319.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]  
5.Manisha M, Ghosh K, Shetty S, Nair S, Khare A, Kulkarni B, et al. Spectrum of inherited bleeding disorders from western India. Haematologica (Budap) 2002;32:39-47.  Back to cited text no. 5      
6.Srivastava A. Delivery of hemophilia care in the developing world. Haemophilia 1998;4:33-40.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]  
7.Montgomery RR, Gill JC, Scott JP. Hemophilia and von Willebrand Disease. 5th ed. Nathan and Oski's Hematology of Infancy and Childhood. In: Nathan DG, Orkin SH, editors. Philadelphia: W. B. Saunders Company; 1998. p. 1631-59.  Back to cited text no. 7      
8.Laffan M, Manning R. Investigation of haemostasis. 10th ed. Dacie and Lewis Practical Haematology. In: Lewis SM, Bain BJ, Bates I, editors. Philadelphia: Churchill Livingstone; 2006. p. 380-440.  Back to cited text no. 8      
9.Gupta PK, Ahmad RP, Sazawal S, Choudhary VP, Saxena R. Relatively high frequency of VWD types 3 and 2 in a cohort of Indian patients: the role of multimeric analysis. J Thromb Haemost 2005;3:1321-2.  Back to cited text no. 9      
10.Gupta PK, Charan VD, Saxena R. Spectrum of Von Willebrand disease and inherited platelet function disorders amongst Indian bleeders. Ann Hematol 2007;86:403-7.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]  
11.Ahmad F, Kannan M, Ranjan R, Bajaj J, Choudhary VP, Saxena R. Inherited platelet function disorders versus other inherited bleeding disorders: an Indian overview. Thromb Res 2008;121:835-41.  Back to cited text no. 11  [PUBMED]  [FULLTEXT]  
12.Trasi S, Shetty S, Ghosh K, Mohanty D. Prevalence and spectrum of von Willebrand disease from western India. Indian J Med Res 2005;121:653-8.  Back to cited text no. 12      
13.Srivastava A, Rodeghiero F. Epidemiology of von Willebrand disease in developing countries. Semin Thromb Hemost 2005;31:569-76.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]  
14.Werner EJ, Broxson EH, Tucker EL, Giroux DS, Shults J, Abshire TC. Prevalence of von Willebrand disease in children: a multiethnic study. J Pediatr 1993;123:893-8.  Back to cited text no. 14  [PUBMED]    
15.Riddel JP Jr, Aouizerat BE. Genetics of von Willebrand disease type 1. Biol Res Nurs 2006;8:147-56.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]  

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Correspondence Address:
Jyoti Shukla
Department of Pathology, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221 005 (U.P.)
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.68287

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