Budd-Chiari Syndrome and Portal Vein Thrombosis: Etiology and Treatment

Venous thrombosis is a common disorder with an annual incidence of around 1-2 cases per 1.000 individuals and is the third leading cause of cardiovascular morbidity and mortality in developed countries.1-4 Thrombosis may arise in any section of the venous system, but it typically occurs in the deep veins of the lower extremities. The major concern in these patients is pulmonary embolism, which can be fatal. A more common, but often disabling, complication of deep vein thrombosis and its sequelae is the post-thrombotic syndrome.5 Rarely, thrombosis may involve other venous sites. One of these uncommon manifestations of thrombosis is located in the splanchnic veins, which is accompanied by a considerable morbidity and mortality

Safety and efficacy of ruxolitinib in splanchnic vein thrombosis associated with myeloproliferative neoplasms

Splanchnic vein thrombosis (SVT) is one of the vascular complications of myeloproliferative neoplasms (MPN). We designed a phase 2 clinical trial to evaluate safety and efficacy of ruxolitinib in reducing splenomegaly and improving disease-related symptoms in patients with MPN-associated SVT. Patients diagnosed with myelofibrosis (12 cases), polycythemia vera (5 cases) and essential thrombocythemia (4 cases) received ruxolitinib for 24 weeks in the core study period. Spleen volume was assessed by magnetic resonance imaging (MRI) and splanchnic vein circulation by echo-Doppler analysis. Nineteen patients carried JAK2V617F, one had MPLW515L, and one CALRL367fs*46 mutation. Eighteen patients had spleno-portal-mesenteric thrombosis, two had Budd\u2013Chiari syndrome, and one had both sites involved; 16 patients had esophageal varices. Ruxolitinib was well tolerated with hematological toxicities consistent with those of patients without SVT and no hemorrhagic adverse events were recorded. After 24 weeks of treatment, spleen volume reduction 6535% by MRI was achieved by 6/21 (29%) patients, and a 6550% spleen length reduction by palpation at any time up to week 24 was obtained by 13/21 (62%) patients. At week 72, 8 of the 13 (62%) patients maintained the spleen response by palpation. No significant effect of treatment on esophageal varices or in splanchnic circulation was observed. MPN-related symptoms, evaluated by MPN-symptom assessment form (SAF) TSS questionnaire, improved significantly during the first 4 weeks and remained stable up to week 24. In conclusion, this trial shows that ruxolitinib is safe in patients with MPN-associated SVT, and effective in reducing spleen size and disease-related symptoms

The C allele of JAK2 rs4495487 is an additional candidate locus that contributes to myeloproliferative neoplasm predisposition in the Japanese population

<p>Abstract</p> <p>Background</p> <p>Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are myeloproliferative neoplasms (MPNs) characterized in most cases by a unique somatic mutation, <it>JAK2 </it>V617F. Recent studies revealed that <it>JAK2 </it>V617F occurs more frequently in a specific <it>JAK2 </it>haplotype, named <it>JAK2 </it>46/1 or GGCC haplotype, which is tagged by rs10974944 (C/G) and/or rs12343867 (T/C). This study examined the impact of single nucleotide polymorphisms (SNPs) of the <it>JAK2 </it>locus on MPNs in a Japanese population.</p> <p>Methods</p> <p>We sequenced 24 <it>JAK2 </it>SNPs in Japanese patients with PV. We then genotyped 138 MPN patients (33 PV, 96 ET, and 9 PMF) with known <it>JAK2 </it>mutational status and 107 controls for a novel SNP, in addition to two SNPs known to be part of the 46/1 haplotype (rs10974944 and rs12343867). Associations with risk of MPN were estimated by odds ratios and their 95% confidence intervals using logistic regression.</p> <p>Results</p> <p>A novel locus, rs4495487 (T/C), with a mutated T allele was significantly associated with PV. Similar to rs10974944 and rs12343867, rs4495487 in the <it>JAK2 </it>locus is significantly associated with <it>JAK2</it>-positive MPN. Based on the results of SNP analysis of the three <it>JAK2 </it>locus, we defined the "GCC genotype" as having at least one minor allele in each SNP (G allele in rs10974944, C allele in rs4495487, and C allele in rs12343867). The GCC genotype was associated with increased risk of both <it>JAK2 </it>V617F-positive and <it>JAK2 </it>V617F-negative MPN. In ET patients, leukocyte count and hemoglobin were significantly associated with <it>JAK2 </it>V617F, rather than the GCC genotype. In contrast, none of the <it>JAK2 </it>V617F-negative ET patients without the GCC genotype had thrombosis, and splenomegaly was frequently seen in this subset of ET patients. PV patients without the GCC genotype were significantly associated with high platelet count.</p> <p>Conclusions</p> <p>Our results indicate that the C allele of <it>JAK2 </it>rs4495487, in addition to the 46/1 haplotype, contributes significantly to the occurrence of <it>JAK2 </it>V617F-positive and <it>JAK2 </it>V617F-negative MPNs in the Japanese population. Because lack of the GCC genotype represents a distinct clinical-hematological subset of MPN, analyzing <it>JAK2 </it>SNPs and quantifying <it>JAK2 </it>V617F mutations will provide further insights into the molecular pathogenesis of MPN.</p

Relevance of the JAK2V617F mutation in patients with deep vein thrombosis of the leg

Venous thromboembolism (VTE) can be the first presenting symptom in myeloproliferative neoplasms (MPN). Studies have demonstrated a high prevalence of the JAK2V617F mutation in patients with splanchnic vein thrombosis. Fewer studies have been done in patients with thrombosis outside the splanchnic area, showing a lower prevalence although the clinical relevance of the mutation in these patients, e.g., progression to overt MPN, remains unknown. The objective of this study was to determine the effect size of JAK2V617F in prospectively collected DNA samples of patients objectively diagnosed with deep vein thrombosis (DVT) of the leg and controls without DVT, with follow-up on JAK2V617F-positive patients to assess clinical relevance. Presence of JAK2V617F was determined in DNA samples from 187 patients with DVT and 201 controls, using quantitative RT-PCR. Hematological parameters were also analyzed. All initially JAK2V617F-positive patients were reassessed. Of 187 patients with DVT, 178 were analyzed for JAK2V617F, and in four (2.3%; 95% CI 0.1–4.4), JAK2V617F was present. Of 201 controls, 198 were analyzed; one was JAK2V617F positive (0.5%; 95% CI −0.5–1.5, OR 4.5; 95% CI 0.5–40.9). None had MPN features, nor upon reassessment after a median follow-up of 68.5 months. Four JAK2V617F-positive patients with DVT and one control without DVT did not develop overt MPN after a median follow-up of nearly 6 years. Thus, in patients with non-splanchnic venous thrombosis, JAK2V617F appears not to be clinically relevant

Superimposed Coagulopathic Conditions in Cirrhosis: Infection and Endogenous Heparinoids, Renal Failure, and Endothelial Dysfunction

In this article, the authors discuss three pathophysiologic mechanisms that influence the coagulation system in patients who have liver disease. First, bacterial infections may play an important role in the cause of variceal bleeding in patients who have liver cirrhosis, affecting coagulation through multiple pathways. One of the pathways through which this occurs is dependent on endogenous heparinoids, on which the authors focus in this article. Secondly, the authors discuss renal failure, a condition that is frequently encountered in patients who have liver cirrhosis. Finally, they review dysfunction of the endothelial system. The role of markers of endothelial function in cirrhotic patients, such as von Willebrand factor and endothelin-1, is discussed