Priyanka Kasatkar

JAK2 Mutations Across a Spectrum of Venous Thrombosis Cases

The JAK2(V617F)mutation is recurrent in polycythemia vera and essential thrombocythemia, which are myeloproliferative neoplasms frequently associated with arterial and venous thromboembolism. It has also been reported as a marker for occult myeloproliferative disorder (MPD) in patients with splanchnic venous thrombosis. Limited data are available regarding the prevalence of the JAK2(V617F) mutation in patients with thrombosis outside the splanchnic region. For the study, 321 cases of venous thrombosis in the splanchnic and nonsplanchnic regions (cerebral venous thrombosis [CVT], 70; deep venous thrombosis [DVT], 36; Budd-Chiari syndrome [BCS], 137; portal venous thrombosis [PVT], 78) were studied for the presence of JAK2 mutations. The prevalence values for the JAK2 mutation were 3% (1/36), 8.8% (12/137), 5% (4/78), and 3% (2/70) in DVT, BCS, PVT, and CVT, respectively; 19 (5.9%) of 321 cases were positive for the JAK2 mutation. Of 111 healthy subjects screened for this mutation, none were found to be carriers. Determination of the JAK2(V617F) mutation may be useful to identify patients who should be carefully observed for the development of overt MPDs. The significance of screening for this mutation in nonsplanchnic thrombosis cases needs to be analyzed in a larger series.

Pathophysiology of acquired von Willebrand disease: a concise review.

Acquired von Willebrand disease (AVWD) is a rare, underdiagnosed hemorrhagic disorder, which is similar to congenital VWD with regard to the clinical and laboratory parameters; however, it is found in individuals with no positive family history and has no genetic basis. The etiology is varied, the commonest being hematoproliferative disorders and cardiovascular disorders. Other disorders associated with AVWD are autoimmune disorders such as systematic lupus erythematosus, hypothyroidism, and neoplasia, or it may also be drug induced. In quite a few cases, the etiology is unknown. The pathogenic mechanisms are different in different underlying disorders or they may be overlapping among these disorders. Some of the proposed mechanisms include the development of autoantibodies, selective absorption of high molecular weight von Willebrand factor (VWF) multimers, non‐selective absorption of VWF, mechanical destruction of VWF under high shear stress, and increased proteolysis. This report presents a concise review of the pathophysiological mechanisms of AVWD in these various underlying conditions.

Prenatal diagnosis in severe von Willebrand disease families from India using combination of phenotypic and genotypic assays

This study aimed to offer genetic diagnosis to affected type 3 severe von Willebrand disease families.

Delayed vitamin K deficiency as a cause of bleeding: still a concern in the 21st century!

Delayed haemorrhage due to vitamin K deficiency in early infancy has rarely been the cause of acquired hemostatic disorders. We report here 11 cases of vitamin K deficiency bleeding (VKDB), despite receiving appropriate dosage of injectible vitamin K at birth. Bleeding symptoms ranged from excessive bleed from cuts to intracranial bleed. Tuberculosis, diarrhea with intermittent antibiotic therapy were some of the associated symptoms. Laboratory tests confirmed acquired bleeding diathesis due to vitamin K deficiency, which was corrected after adequate vitamin K supplementation. VKDB is not an uncommon phenomenon and should be considered in the differential diagnosis of a child with bleeding diathesis.

The genetics of Canadian type 3 von Willebrand disease: further evidence for co-dominant inheritance of mutant alleles: a rebuttal.

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Acquired von Willebrand syndrome: A rare disorder of heterogeneous etiology

CONTEXT Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder that mimics the inherited form of von Willebrand disease (VWD) in terms of laboratory findings and clinical presentation. AIMS To study the etiology of acquired VWD. SETTINGS AND DESIGN The patients referred from various hospitals in and out of Mumbai were included in the study. MATERIALS AND METHODS Six patients with AVWS diagnosed at this center over the last 10 years were analyzed against 171 patients with inherited VWD. The differential diagnosis of AVWS was made based on reduced levels of von Willebrand antigen and von Willebrand ristocetin cofactor, decrease in ristocetin induced platelet aggregation, absence of correction in mixing studies with no prior history of bleeding problems and a negative family history for bleeding disorders. RESULTS In three patients, the disease was associated with systematic lupus erythematosus, out of which one was also associated with Kikuchi lymphadenitis and second with autoimmune hemolytic anemia. Fourth case was associated with hypothyroidism and fifth was a case of dermatitis and vitiligo. The last patient was a case of hemophilia A with Burkitts lymphoma, who developed autoantibodies to von Willebrand factor. Except two patients, all other patients responded to immune suppressive therapy with corticosteroids, while the patient with hypothyroidism responded to oral thyroxine. CONCLUSION AVWS is a rare condition and may often be missed or diagnosed as inherited disease associated with heterogeneous disease conditions.

Additional markers for genetic diagnosis of type 3 von Willebrand disease in Indian population

von Willebrand disease (VWD) encompasses a wide spectrum of bleeding disorders with severity ranging from moderate bleeding tendency to severe life threatening haemorrhage, estimated to affect approximately 0.5 2 per cent of the population in the Western countries1. Patients present with mucocutaneous bleeding symptoms, epistaxis, mucosal bleeding, prolonged bleeding from cuts, post-dental extraction bleeding, menorrhagia and gastrointestinal bleeding. These are classified as types 1, 2 and 3, depending on the qualitative and quantitative defects in von Willebrand factor (VWF) antigen. Diagnosis, genetic counselling, carrier and antenatal diagnosis play an important role in the comprehensive management of these cases.

Sense, missense, and nonsense: a novel mechanism of premature termination codon (PTC) mutation in a severe von Willebrand disease (VWD) patient

Dear Editor, The human von Willebrand factor gene (VWF) is located on the short arm of chromosome 12 and spans approximately 178 kb, comprising of 52 exons. The mRNA has a length of 8.7 kb coding for precursor protein of 2813 amino acids that includes a 22 amino acid signal peptide, a pro-peptide of 741 amino acids and a mature subunit of 2050 amino acids [1]. The gene is highly polymorphic with more than 2000 polymorphisms reported in different ethnic populations [2]. Single nucleotide variations (SNVs) contribute to normal phenotypic variations and diseases as well. A chance combination of two SNVs in a single codon changing the nature of the mutation though uncommon, yet higher prevalence of the variant alleles across populations, makes such a deleterious combination possible resulting in the disease phenotype. We report here a severe VWD patient (VWF TGA) by the presence of two heterozygous changes (c.2878C>T, rs370984712; c.2880G>A, rs1800380) in the same codon. The single change c.2878C>T results in a variant (p.R960W), while c.2880G>A results in a synonymous change (p.R960=). The effect of SNV c.2878C>T on the function of VWF is unclear though it has been reported as a polymorphism in the single nucleotide polymorphism database (NCBI dbSNP. NM_000552.3); the prediction softwares however showed the effect of this change as deleterious. Only one such case has been reported earlier wherein the patient was found to have two mutations, i.e., a partial deletion extending the whole gene, i.e., exons 1–52 in heterozygous condition and R960* in homozygous condition, though the details of the second mutation are not discussed in this report [4]. The allelic frequencies of c.2880G>A are quite high varying between 0 and 32 % in different populations, while the frequency of c.2878C>T has been reported to be quite low, i.e., 0.05 % (http://asia.ensembl.org/Homo_sapiens/Info/ Index). One limitation here is that the parents were unavailable for mutation studies, but it is logical to presume that both the variants were in cis position, as the whole gene was sequenced and the patient was found to carry only two single nucleotide variations in heterozygous state. In conclusion, we report an interesting mechanism of two single nucleotide variations occurring together in cis in a single codon changing the nature of the pathogenic mutation. In the presence of the first variant, it would have been a missense variant, probably pathogenic, but the coexistence of a second SNV has changed the nature of the mutation, i.e., from a missense to a premature termination codon mutation. The two SNVs are mutually * Shrimati Shetty shrimatishetty@yahoo.com