Hypercoagulability and Hypofibrinolysis and Risk of Deep Vein Thrombosis and Splanchnic Vein Thrombosis: Similarities and Differences

In this review, we provide an overview of the risk factors for venous thromboembolism, focusing on hypercoagulability and hypofibrinolysis. In the first part of this review, we discuss the risk factors for commonly occurring venous thrombosis, in particular deep vein thrombosis and pulmonary embolism. In the second part, we provide an overview of the risk factors for the Budd-Chiari syndrome and portal vein thrombosis. These are rare, life-threatening forms of venous thromboembolism located in the splanchnic veins. There are many similarities in the risk profiles of patients with common venous thrombosis and splanchnic vein thrombosis. Inherited thrombophilia and hypofibrinolysis increase the risk of both common venous thrombosis and splanchnic vein thrombosis. However, there are also apparent differences. Myeloproliferative neoplasms and paroxysmal nocturnal hemoglobinuria have a remarkably high frequency in patients with thrombosis at these unusual sites but are rarely seen in patients with common venous thrombosis. There are also clear differences in the underlying risk factors for Budd-Chiari syndrome and for portal vein thrombosis, suggesting site specificity of thrombosis even within the splanchnic venous system. These clear differences in underlying risk factors provide leads for further research on the site specificity of venous thrombosis and the development of thrombosis at these distinct sites.

[1]  D. Valla,et al.  Factor V Leiden related Budd-Chiari syndrome , 2001, Gut.

[2]  J. Griffin,et al.  High-Density Lipoprotein Deficiency and Dyslipoproteinemia Associated With Venous Thrombosis in Men , 2005, Circulation.

[3]  A. Folsom,et al.  A prospective study of venous thromboembolism in relation to factor V Leiden and related factors. , 2002, Blood.

[4]  P. Prandoni,et al.  Cancer and venous thromboembolism. , 1996, Seminars in thrombosis and hemostasis.

[5]  Paul Enright,et al.  Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology. , 2004, The American journal of medicine.

[6]  E. Oger.  Incidence of Venous Thromboembolism: A Community-based Study in Western France , 2000, Thrombosis and Haemostasis.

[7]  I. Kushner,et al.  Acute-phase proteins and other systemic responses to inflammation. , 1999, The New England journal of medicine.

[8]  F. Rosendaal,et al.  The effect of genetic variants in the thrombin activatable fibrinolysis inhibitor (TAFI) gene on TAFI‐antigen levels, clot lysis time and the risk of venous thrombosis , 2006, British journal of haematology.

[9]  Paolo Bucciarelli,et al.  High levels of factor VIII and risk of extra-hepatic portal vein obstruction. , 2009, Journal of hepatology.

[10]  A. Falanga,et al.  Thrombosis in myeloproliferative disorders: pathogenetic facts and speculation , 2008, Leukemia.

[11]  D. Valla,et al.  Acute portal vein thrombosis unrelated to cirrhosis: A prospective multicenter follow‐up study , 2010, Hepatology.

[12]  R. Skoda,et al.  Myeloproliferative neoplasms: contemporary diagnosis using histology and genetics , 2009, Nature Reviews Clinical Oncology.

[13]  Clifford W Colwell,et al.  Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. , 2004, Chest.

[14]  D. Valla,et al.  Impaired fibrinolysis as a risk factor for Budd-Chiari syndrome. , 2010, Blood.

[15]  L. Melton,et al.  Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study. , 2002, Archives of internal medicine.

[16]  P. Chiusolo,et al.  Incidence of the JAK2 V617F mutation among patients with splanchnic or cerebral venous thrombosis and without overt chronic myeloproliferative disorders , 2007, Journal of thrombosis and haemostasis : JTH.

[17]  P. Mannucci,et al.  Role of the JAK2 mutation in the diagnosis of chronic myeloproliferative disorders in splanchnic vein thrombosis , 2006, Hepatology.

[18]  H. Janssen,et al.  Vascular liver disorders (II): portal vein thrombosis. , 2009, The Netherlands journal of medicine.

[19]  D. Valla,et al.  Current outcome of portal vein thrombosis in adults: risk and benefit of anticoagulant therapy. , 2001, Gastroenterology.

[20]  D. Valla,et al.  Portal vein thrombosis in adults: pathophysiology, pathogenesis and management. , 2000, Journal of hepatology.

[21]  G. Tiscia,et al.  Occurrence of the JAK2 V617F mutation in the Budd–Chiari syndrome , 2008, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[22]  F. Leebeek,et al.  JAK2 mutation: The best diagnostic tool for myeloproliferative disease in splanchnic vein thrombosis? , 2006, Hepatology.

[23]  W. Aird.  Vascular bed‐specific thrombosis , 2007, Journal of thrombosis and haemostasis : JTH.

[24]  S. Middeldorp,et al.  Does thrombophilia testing help in the clinical management of patients? , 2008, British journal of haematology.

[25]  D. Valla,et al.  Cause of portal or hepatic venous thrombosis in adults: The role of multiple concurrent factors , 2000, Hepatology.

[26]  J. Vandenbroucke,et al.  Oral contraceptives and the risk of venous thrombosis. , 2001, The New England journal of medicine.

[27]  M. Prins,et al.  Co-segregation of thrombophilic disorders in factor V Leiden carriers; the contributions of factor VIII, factor XI, thrombin activatable fibrinolysis inhibitor and lipoprotein(a) to the absolute risk of venous thromboembolism. , 2002, Haematologica.

[28]  A A Connolly,et al.  Deep vein thrombosis. , 1988, BMJ.

[29]  G. Mufti,et al.  The prevalence of the activating JAK2 tyrosine kinase mutation in chronic porto‐splenomesenteric venous thrombosis , 2010, Alimentary pharmacology & therapeutics.

[30]  E. Minar,et al.  The Risk of Recurrent Venous Thromboembolism in Patients with and without Factor V Leiden , 1997, Thrombosis and Haemostasis.

[31]  C. Gartung,et al.  Elevated levels of factor VIII:C as a possible risk factor for portal, splenic, and mesenteric vein thrombosis. , 2001, Gastroenterology.

[32]  R. Favier,et al.  Congenital α2‐plasmin inhibitor deficiencies: a review , 2001 .

[33]  F. Rosendaal,et al.  Mechanisms of the Factor V Leiden Paradox , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[34]  J. Kline,et al.  Risk of thromboembolism varies, depending on category of immobility in outpatients. , 2009, Annals of emergency medicine.

[35]  P. Mannucci,et al.  Risk factors for thrombophilia in extrahepatic portal vein obstruction , 2005, Hepatology.

[36]  D. Valla,et al.  Budd-Chiari syndrome: a review by an expert panel. , 2003, Journal of hepatology.

[37]  S. Chevret,et al.  The impact of JAK2 and MPL mutations on diagnosis and prognosis of splanchnic vein thrombosis: a report on 241 cases. , 2008, Blood.

[38]  M. Cushman.  Epidemiology and risk factors for venous thrombosis. , 2007, Seminars in hematology.

[39]  T. Baglin,et al.  High rate of unprovoked recurrent venous thrombosis is associated with high thrombin‐generating potential in a prospective cohort study , 2008, Journal of thrombosis and haemostasis : JTH.

[40]  J. Brandt.  Plasminogen and tissue-type plasminogen activator deficiency as risk factors for thromboembolic disease. , 2002, Archives of pathology & laboratory medicine.

[41]  F. Rosendaal,et al.  Genetic variation in thrombin-activatable fibrinolysis inhibitor (TAFI) is associated with the risk of splanchnic vein thrombosis , 2007, Thrombosis and Haemostasis.

[42]  B. Brenner,et al.  Thrombophilia and Cancer , 2007, Pathophysiology of Haemostasis and Thrombosis.

[43]  A. Folsom,et al.  Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. , 2002, Archives of internal medicine.

[44]  F. Rosendaal,et al.  Hypofibrinolysis as a risk factor for recurrent venous thrombosis; results of the LETS follow‐up study , 2010, Journal of thrombosis and haemostasis : JTH.

[45]  W. Ageno,et al.  JAK2V617F mutation for the early diagnosis of Ph- myeloproliferative neoplasms in patients with venous thromboembolism: a meta-analysis. , 2009, Blood.

[46]  M. Bonamino,et al.  JAK2V617F Mutation in Patients with Splanchnic Vein Thrombosis , 2010, Digestive Diseases and Sciences.

[47]  A. Taher,et al.  A closer look at paroxysmal nocturnal hemoglobinuria. , 2010, European journal of internal medicine.

[48]  T. Schiano,et al.  The presence of JAK2V617F mutation in the liver endothelial cells of patients with Budd-Chiari syndrome. , 2009, Blood.

[49]  A. Khorana,et al.  Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy , 2007, Journal of thrombosis and haemostasis : JTH.

[50]  S. Eichinger,et al.  Prediction of recurrent venous thromboembolism by endogenous thrombin potential and D-dimer. , 2008, Clinical chemistry.

[51]  Pieter H. Reitsma,et al.  Mutation in blood coagulation factor V associated with resistance to activated protein C , 1994, Nature.

[52]  P. Romundstad,et al.  Incidence and mortality of venous thrombosis: a population‐based study , 2007, Journal of thrombosis and haemostasis : JTH.

[53]  H. Pati,et al.  Tissue plasminogen activator and plasminogen activator inhibitor status in Budd-Chiari syndrome. , 1996, Haemostasis.

[54]  A. Folsom,et al.  High-density lipoprotein cholesterol and venous thromboembolism in the Longitudinal Investigation of Thromboembolism Etiology (LITE). , 2008, Blood.

[55]  A. Folsom,et al.  Peak thrombin generation and subsequent venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology (LITE) study , 2009, Journal of thrombosis and haemostasis : JTH.

[56]  J. Heit.  Venous thromboembolism: disease burden, outcomes and risk factors , 2005, Journal of thrombosis and haemostasis : JTH.

[57]  H. Bounameaux.  Factor V Leiden paradox: risk of deepvein thrombosis but not of pulmonary embolism , 2000, The Lancet.

[58]  S. Goldhaber,et al.  A prospective registry of 5,451 patients with ultrasound-confirmed deep vein thrombosis. , 2004, The American journal of cardiology.

[59]  F. Rosendaal,et al.  Thrombin activatable fibrinolysis inhibitor and the risk for deep vein thrombosis. , 2000, Blood.

[60]  J. Deckers,et al.  Hypofibrinolysis is a risk factor for arterial thrombosis at young age , 2009, British journal of haematology.

[61]  R. Bertina,et al.  A new functional assay of thrombin activatable fibrinolysis inhibitor , 2005, Journal of thrombosis and haemostasis : JTH.

[62]  A. Tefferi,et al.  Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia , 2005, British journal of haematology.

[63]  M. Schemper,et al.  High-Density Lipoprotein and the Risk of Recurrent Venous Thromboembolism , 2007, Circulation.

[64]  G. Tiscia,et al.  The JAK2 V617F mutation frequently occurs in patients with portal and mesenteric venous thrombosis , 2007, Journal of thrombosis and haemostasis : JTH.

[65]  A. Dasgupta,et al.  Thrombophilic conditions in non-cirrhotic portal vein thrombosis. , 2005, Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology.

[66]  F. Rosendaal,et al.  Minor injuries as a risk factor for venous thrombosis. , 2008, Archives of internal medicine.

[67]  D. Tregouet,et al.  Fine mapping of quantitative trait nucleotides underlying thrombin-activatable fibrinolysis inhibitor antigen levels by a transethnic study. , 2006, Blood.

[68]  M. Prins,et al.  Absolute risk of venous and arterial thromboembolism in thrombophilic families is not increased by high thrombin-activatable fibrinolysis inhibitor (TAFI) levels , 2008, Thrombosis and Haemostasis.

[69]  H. Janssen,et al.  Myeloproliferative disease in the pathogenesis and survival of Budd-Chiari syndrome. , 2006, Haematologica.

[70]  L. V. Van Gaal,et al.  Visceral fat as a determinant of fibrinolysis and hemostasis. , 2005, Seminars in vascular medicine.

[71]  J. Hirsh,et al.  Fibrinolytic Variables in Patients with Recurrent Venous Thrombosis: a Prospective Cohort Study , 2001, Thrombosis and Haemostasis.

[72]  Bradley Flansbaum,et al.  Clinical factors and recurrent venous thrombotic events. , 2005, JAMA.

[73]  W. Aird.  Phenotypic Heterogeneity of the Endothelium: II. Representative Vascular Beds , 2007, Circulation research.

[74]  E. Minar,et al.  Thrombin-activatable fibrinolysis inhibitor and the risk for recurrent venous thromboembolism. , 2004, Blood.

[75]  I. Martinelli,et al.  Rare thromboses of cerebral, splanchnic and upper-extremity veins , 2010, Thrombosis and Haemostasis.

[76]  A. Folsom,et al.  Prospective study of fibrinolytic markers and venous thromboembolism. , 2003, Journal of clinical epidemiology.

[77]  F. Rosendaal.  Venous thrombosis: a multicausal disease , 1999, The Lancet.

[78]  H. Kluin-Nelemans,et al.  A prospective cohort study on the absolute risks of venous thromboembolism and predictive value of screening asymptomatic relatives of patients with hereditary deficiencies of protein S, protein C or antithrombin , 2010, Journal of thrombosis and haemostasis : JTH.

[79]  A. Koshy,et al.  High FVIII level is associated with idiopathic portal vein thrombosis in South India. , 2007, The American journal of medicine.

[80]  P. Ziakas,et al.  Thrombosis in paroxysmal nocturnal hemoglobinuria: sites, risks, outcome. An overview , 2007, Journal of thrombosis and haemostasis : JTH.

[81]  C. Mannhalter,et al.  Probability of Recurrence of Thrombosis in Patients with and without Factor V Leiden , 1996, Thrombosis and Haemostasis.

[82]  M. Prins,et al.  Risk of Recurrent Venous Thrombosis in Homozygous Carriers and Double Heterozygous Carriers of Factor V Leiden and Prothrombin G20210A , 2010, Circulation.

[83]  F. Rosendaal,et al.  Synergistic Effects of Hypofibrinolysis and Genetic and Acquired Risk Factors on the Risk of a First Venous Thrombosis , 2008, PLoS medicine.

[84]  P. Mannucci,et al.  High thrombin generation measured in the presence of thrombomodulin is associated with an increased risk of recurrent venous thromboembolism , 2008, Journal of thrombosis and haemostasis : JTH.

[85]  D. Valla,et al.  Vascular disorders of the liver , 2009, Hepatology.

[86]  B. Psaty,et al.  Serum Lipid Levels and the Risk of Venous Thrombosis , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[87]  P. Ridker,et al.  Factor V Leiden and risks of recurrent idiopathic venous thromboembolism. , 1995, Circulation.

[88]  D. Valla.  Primary Budd-Chiari syndrome. , 2009, Journal of hepatology.

[89]  F R Rosendaal,et al.  Factor V Leiden mutation, prothrombin gene mutation, and deficiencies in coagulation inhibitors associated with Budd-Chiari syndrome and portal vein thrombosis: results of a case-control study. , 2000, Blood.

[90]  M. Gianni,et al.  Inherited thrombophilic abnormalities and risk of portal vein thrombosis , 2008, Thrombosis and Haemostasis.

[91]  R. Roubey,et al.  Venous Thrombosis in the Antiphospholipid Syndrome , 2009, Arteriosclerosis, thrombosis, and vascular biology.

[92]  M. Boffa,et al.  Two Naturally Occurring Variants of TAFI (Thr-325 and Ile-325) Differ Substantially with Respect to Thermal Stability and Antifibrinolytic Activity of the Enzyme* , 2002, The Journal of Biological Chemistry.

[93]  F. Rosendaal,et al.  Elevated endogenous thrombin potential is associated with an increased risk of a first deep venous thrombosis but not with the risk of recurrence , 2007, British journal of haematology.

[94]  G. Guyatt,et al.  Antithrombotic and thrombolytic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). , 2008, Chest.

[95]  D. Valla,et al.  Proteomic analysis reveals that apolipoprotein A1 levels are decreased in patients with Budd-Chiari syndrome. , 2011, Journal of hepatology.

[96]  F. Leebeek,et al.  Severe thrombotic tendency associated with a type I plasminogen deficiency , 1989, American journal of hematology.

[97]  F. Rosendaal,et al.  Venous thrombosis risk associated with plasma hypofibrinolysis is explained by elevated plasma levels of TAFI and PAI-1. , 2010, Blood.

[98]  H. Lijnen,et al.  New insights into the molecular mechanisms of the fibrinolytic system , 2009, Journal of thrombosis and haemostasis : JTH.

[99]  F. Rosendaal,et al.  Reduced plasma fibrinolytic potential is a risk factor for venous thrombosis. , 2004, Blood.

[100]  F. Rosendaal,et al.  Etiology, management, and outcome of the Budd-Chiari syndrome. , 2009, Annals of internal medicine.

[101]  C. Chagneau,et al.  Paroxysmal nocturnal hemoglobinuria in Budd-Chiari syndrome: findings from a cohort study. , 2009, Journal of hepatology.

[102]  J. Manson,et al.  Baseline Fibrinolytic State and the Risk of Future Venous Thrombosis: A Prospective Study of Endogenous Tissue‐Type Plasminogen Activator and Plasminogen Activator Inhibitor , 1992, Circulation.

[103]  P. Reitsma,et al.  A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. , 1996, Blood.

[104]  Frits R Rosendaal,et al.  Thrombophilia, clinical factors, and recurrent venous thrombotic events. , 2005, JAMA.

[105]  M. Prins,et al.  The risk of recurrent venous thromboembolism in patients with an Arg506-->Gln mutation in the gene for factor V (factor V Leiden). , 1997, The New England journal of medicine.

[106]  E. Björnsson,et al.  Budd‐Chiari syndrome in Sweden: epidemiology, clinical characteristics and survival – an 18‐year experience , 2009, Liver international : official journal of the International Association for the Study of the Liver.

[107]  R. Brodsky.  Narrative Review: Paroxysmal Nocturnal Hemoglobinuria: The Physiology of Complement-Related Hemolytic Anemia , 2008, Annals of Internal Medicine.

[108]  Cecilia Becattini,et al.  Cardiovascular Risk Factors and Venous Thromboembolism: A Meta-Analysis , 2008, Circulation.

[109]  P. Reitsma,et al.  Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study) , 1995, Blood.

[110]  F. Rosendaal,et al.  The impact of the fibrinolytic system on the risk of venous and arterial thrombosis. , 2009, Seminars in thrombosis and hemostasis.

[111]  H. Janssen,et al.  Vascular liver disorders (I): diagnosis, treatment and prognosis of Budd-Chiari syndrome. , 2008, The Netherlands journal of medicine.

[112]  M. Björck,et al.  Portal vein thrombosis: prevalence, patient characteristics and lifetime risk: a population study based on 23,796 consecutive autopsies. , 2006, World journal of gastroenterology.

[113]  Paul D Stein,et al.  Obesity as a risk factor in venous thromboembolism. , 2005, The American journal of medicine.

[114]  T. Baglin,et al.  Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study , 2003, The Lancet.

[115]  B. Binder,et al.  Identification of patients at low risk for recurrent venous thromboembolism by measuring thrombin generation. , 2006, JAMA.

[116]  Y. Shoenfeld,et al.  International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS) , 2006, Journal of thrombosis and haemostasis : JTH.