Capítulo 4

Diagnóstico del tromboembolismo venoso

Hugo Héctor Ferro

El tromboembolismo venoso es la tercera causa de muerte cardiovascular y ocupa el 10% de la mortalidad hospitalaria, el 22% fallece antes del diagnóstico, y los casos no tratados tienen una alta mortalidad (30%). Las estrategias orientadas a disminuir el tremendo impacto en la salud de esta patología son la prevención, el diagnóstico y el tratamiento adaptado al riesgo.Es fundamental que cada centro se organice su sistemática de estudio de acuerdo a su, disponibilidad de recursos técnicos, humanos y logística.

En la actualidad los “estudios de manejo” han reemplazado a la flebografía en el diagnóstico de la enfermedad tromboembólica, el “goldstandar” pasó a ser la probabilidad que un paciente manejado con reglas de predicción clínica, Dímeros D, y ultrasonografía de compresión (CUS) tenga un TEV luego de tres meses de seguimiento.

Métodos de diagnóstico

Reglas de predicción clínica. Se utilizan para categorizar los casos en probabilidad de padecer un tromboembolismo alta moderada o baja. El score de Wells tiene el mérito de haber sido validado en estudios con gran número de pacientes. En orden de acotar los resultados la versión simplificada es recomendable (Tabla 1).

Tabla 1. Score de Wells para TVP y TEP

Ultrasonografía. Tener en cuenta que la mayoría de los trabajos utilizan la llamada ultrasonografía de compresión (CUS); el diagnóstico de TVP es positivo cuando un segmento venoso no es compresible. En nuestro medio lo más usado es el eco doppler de miembros inferiores, la llamada whole-leg US. Este método combina la exploración por compresión, la presencia o no de flujo y los característicos cambios con el ciclo respiratorio. Al utilizar este método tener en cuenta que estaremos incluyendo un número importante de trombosis de venas distales y, seguramente, sobretratando algunas trombosis distales que nunca progresarían. Es importante recordar que en los casos con CUS negativa, se debe realizar un nuevo estudio en 7 días (CUS serial) para descartar una posible progresión de un trombo distal no visualizado en el primer estudio.

Dímeros D. Provienen de la degradación de fibrina y aumentan consistentemente en cuadros de tromboembolismo venoso, pero también en una variedad de patología como infección, trauma, cirugía, embarazo o simplemente la edad. Los pacientes internados frecuentemente tienen alguna causa que eleva el dímero d, lo que disminuye la especificidad del test. Su utilidad queda limitada a la evaluación del paciente que concurre al servicio de emergencias y la regla de predicción clínica orienta a una baja probabilidad de tromboembolismo, de esta manera un Dímero D negativo hace que un estudio de imágenes sea innecesario. Es preferible realizar el estudio metodología de alta sensibilidad como ELISA, látex cuantitativo o inmunoturbidimétrico, pues definen mejor el punto de corte.Recientemente se describió que aumentando el punto de corte adaptado a la edad se discriminaron mejor los grupos positivo/negativo.

Otros métodos como la venografía por TAC y RNM tienen un rol destacado, especialmente cuando está involucrado el territorio ilíaco o vena cava inferior, o cuando la US es imposible de realizar como en el caso de yesos o pacientes con quemaduras, algunas de las inconveniencias de estos métodos son la radiación y la necesidad de inyectar contraste con la TAC y la falta de amplia disponibilidad de la RNM. La venografía, finalmente, queda relegada a centros de investigación o casos muy específicos.

Diagnóstico de TEV recurrente

La recidiva de síntomas en un miembro previamente afectado por una TVP, no es rara. Como el diagnóstico de recurrencia implica una terapia mas prolongada, es necesario contar con la mayor exactitud posible, sin embargo esto no siempre es posible por limitaciones de los métodos para diferenciar secuelas de trombosis previas de un evento nuevo. La persistencia de imagen de trombo persiste por largo tiempo en un porcentaje de hasta el 50% de los casos, con el paso del tiempo se observa una disminución del diámetro de trombo.

Los criterios más aceptados para el diagnóstico de recurrencia son: un nuevo segmento no compresible y el aumento del diámetro en más de 4 mm. En estos casos, si bien hay menos estudios realizados, también se pueden aplicar las reglas de predicción clínica y el uso de los dímeros D, en casos dudosos como aumento del diámetro entre 2 y 4 mm, la CUS serial es recomendada.

Diagnóstico del TEV en la mujer embarazada

El diagnóstico en la mujer embarazada plantea problemas adicionales, el territorio anatómico mas afectado es el miembro inferior izquierdo y en ocasiones sólo la vena ilíaca esta trombosada, y no es visible en la ultrasonografía. Se han realizado estudios con reglas de predicción clínica y uso de dímeros D, pero aún no están validados.

La sugerencia es comenzar con ultrasonografía y si la sospecha clínica de trombo ilíaco es alta (dolor sacro, edema de todo el miembro) se impone confirmarlo con una RNM.

Diagnóstico de tromboembolismo de pulmón

El enfoque inicial es similar, se debe tener en cuenta que en estos casos es importante determinar el riesgo de muerte en TEP (Tabla 2).

Tabla 2. Score de riesgo de la Sociedad Europea de cardiología

La clasificación de la Sociedad Europea de Cardiología es simple y categoriza los pacientes en riesgos alto, mediano y bajo, con una mortalidad de 15%, 1 a 3%, y < de 1%, esto permite adaptar el tratamiento según riesgo desde trombolísis a tratamiento anticoagulante ambulatorio.

Reglas de predicción clínica para TEP. El Score de Wells para TEP simplificado, permite de forma similar que en el caso de TVP, categorizar los pacientes en probabilidades alta y baja de tener un tromboembolismo.

En los casos de baja probabilidad, el dímero D, tiene la misma utilidad que para TVP, en casos de probabilidad alta los estudios de imágenes disponibles son la Angio TAC y el centellograma V/Q.

La angio TAC se considera positiva para el diagnóstico de TEP cuando se observa trombosis de una rama segmentaria o mayor. En los pacientes evaluados con probabilidad pretest baja o con imágenes en ramas subsegmentarias la posibilidad de un falso positivo es mayor y se aconseja evaluar cuidadosamente cada caso antes de decidir la conducta terapéutica.

El centellograma V/Q produce resultados similares a la TAC, con la salvedad que un número importante de pacientes se clasifican en la categoría llamada no diagnóstica. Si el V/Q fue la primera opción de imágenes, estos casos deben ser estudiados mediante angioTAC.

Metodología sugerida

Aplicar las reglas de predicción clínica (Tablas 1 y 2) preferentemente en pacientes ambulatorios o que realizan la consulta con el servicio de emergencias, si la probabilidad de TEV es baja, la determinación del dímero D permitirá la externación del paciente en forma segura, si la probabilidad de TEV es alta, se confirmará el diagnóstico con alguno de los métodos de imágenes. Para los casos con probabilidad pretest alta, hospitalizados con enfermedades intercurrentes, post quirúrgicos o cáncer activo, el paso siguiente es algunos de los métodos de imágenes que se recomienda en el algoritmo.

Bibliografía

  1. Bates SM, Jaeschke R, Stevens SM, Goodacre S, et al. Diagnosis of DVT: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e351S-418S.
  2. Wells P, Anderson D.The diagnosis and treatment of venous thromboembolism. Hematology Am Soc Hematol Educ Program 2013; 2013:457-63.
  3. Cohen AT, Dobromirski M, Gurwith MM. Managing pulmonary embolism from presentation to extended treatment. Thromb Res 2014; 133:139-48

Esmon CT.
Basic mechanisms and pathogenesis of venous thrombosis. Blood Reviews 2009; 23:225-229.

Myers DD, Hawley AG, Farris DM, et al.
P-selectin and leukocyte microparticles are associated with venous thrombogenesis. J Vasc Surg 2003; 38: 1075-1089.

López JA & Chen J.
Pathophysiology of venous thrombosis. Thromb Res 2009; 123 suppl 4: 530-534.

Ohira T. Cushman M, Tsai MY et al.
ABO blood group, other risk factors and incidence of venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology (LITE). J Thromb Haemost 2007; 5:1455-1461.

Silverstein RL, Bauer KA, Cushman M. et al.
Venous thrombosis in the elderly: more questions than answers. Blood 2007; 110: 3097-3101.

Lim W, Eikelboom JW, Ginsberg JS.
Inherited thrombophilia and pregnancy associated venous thromboembolism. BMJ 2007; 334: 1318-1321.

Cushman M.
Epidemiology and risk factors for venous thrombosis. Semin Hematol 2007: 44 (2):62-9.

Lijfering WM, Rosendaal FR, Cannegieter SC.
Risk factors for venous thrombosis - current understanding from an epidemiological point of view. British Journal of Haematology 2010; 149: 824–33.

Martinelli I, De Stefano V, Mannucci PM.
Inherited risk factors for venous thromboembolism. Nat. Rev. Cardiol. 2014; 11: 140–56.

Baglin T, Gray E, Greaves M, et al.
Clinical guidelines for testing for heritable thrombophilia. British Journal of Haematology. 2010; 149: 209–20.

Falck-Ytter Y, Francis CW, Johanson NA, et al.
Prevention of VTE in Orthopedic Surgery Patients Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines CHEST 2012; 141(2)(Suppl): e278S–e325S.

Gould MK, Garcia DA, Wren SM et al.
Prevention of VTE in Non-orthopedic Surgical Patients Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST 2012; 141(2)(Suppl): e227S–e277S.

Caprini JA, Risk assessment as a guide to thrombosis prophylaxis.
Current Opinion in Pulmonary Medicine 2010; 16:448–52.

Bahl V, Hu HM, Henke PK, et al.
A validation study of a retrospective venous thromboembolism risk scoring method. Ann Surg. 2010; 251 (2): 344-50.

Baglin T.
Inherited and Acquired Risk Factors for Venous Thromboembolism. Semin Respir Crit Care Med 2012; 33: 127–37.

Jacobsen AF, Sandset PM.
Venous thromboembolism associated with pregnancy and hormonal therapy. Best Practice & Research Clinical Haematology 2012; 25: 319–32.

Watson HG, Baglin TP.
Guidelines on travel-related venous thrombosis. British Journal of Haematology 2010; 152: 31–4.

Gomes M, Khorana AA.
Risk Assessment for Thrombosis in Cancer. Semin Thromb Hemost 2014; 40: 319–24.

Nicolaides AN, Fareed J, Kakkar AK, et al.
Prevention and treatment of venous thromboembolism. International consensus statement (guidelines according to scientific evidence). Thromb Haemost 2013; 19: 116-225.

Hill J, Trasure T.
Reducing the risk of Venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital: summary of the NICE guideline. Heart 2010. 879-882.

Gould MK, Garcia DA, Wren SM, et al.
Prevention of VTE in nonorthopedic surgical patients: antithrombotic therapy and prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: 227-77.

Khan SR, Lim W, Dunn AS. et al.
Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: 195-226.

Vázquez FJ, Watman R, Vilaseca AB, et al.
Guía de recomendaciones para la profilaxis de la enfermedad tromboembolítica venosa en adultos en la Argentina. MEDICINA (Buenos Aires) 2013; 73: 1-26.

Henke PK, Pannucci CJ.
Venous Thromboembolism Risk Factor Assessment and Prophylaxis. Phlebology 2010; 25:219-223.

Guyatt GH, Norris SL, Schulman S, et al.
Methodology for the Development of antithrombotic therapy and prevention of Thrombosis guidelines: Antithrombotic therapy and prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 53-70.

Falck-Yetter Y, Francis CW , Johanson NA, et al.
Prevention of VTE in orthopedic surgery patients: Antithrombotic therapy and prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practical Guidelines. Chest 2012; 141: 278-325.

Barbar S, Noventa F, Rossetto V, et al.
A risk assessment model for the identification of hospitalized medical patients at risk for Venous Thromboembolism: the Padua Prediction Score. J Thromb Haemost. 2010; 8: 2450-2457.

Touqmatchi D, Cotzias C, Girling J.
Venous Thromboprophylaxis in pregnancy: The implications of changing to the 2010 RCOG guidelines. J Obst Gynecol 2012; 32: 743-746.

Bates SM, Jaeschke R, Stevens SM, Goodacre S, et al.
Diagnosis of DVT: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e351S-418S.

Wells P, Anderson D.The diagnosis and treatment of venous thromboembolism.
Hematology Am Soc Hematol Educ Program 2013; 2013:457-63.

Cohen AT, Dobromirski M, Gurwith MM.
Managing pulmonary embolism from presentation to extended treatment. Thromb Res 2014 Feb; 133:139-48

Dentali F, Ageno W.
Cerebral vein thrombosis. Intern Emerg Med 2010; 5: 27-32.

Stam J.
Thrombosis of the Cerebral Veins and Sinuses. N Engl J Med 2005; 352: 1791-98.

Tait C,Baglin T,Watson H et al.
Guidelines on the investigation and management of venous thrombosis at unusual sites. Br J Haematol 2012; 159: 28-38.

Einhaupl K, Stam J, Bousser MG et al.
EFNS guideline on the treatment of cerebral venous and sinus thrombosis in adult patients. Eur J Neurol 2010; 17: 1229-35.

Martinelli I, De Stefano V.
Rare thromboses of cerebral, splanchnic and upper-extremity veins: A narrative review. Thromb Haemost 2010; 103: 1136-44.

Parikh S, Shah R, Kapoor P.
Portal Vein Thrombosis. Am J Med 2010; 123: 111-19.

Janssen M, den Heijer M, Cruysberg J et al.
Retinal vein occlusion: a form of venous thrombosis or a complication of atherosclerosis? A meta-analysis of thrombophilic factors. Thromb Haemost. 2005; 93:1021-26.

Kuhli-Hattenbach C, Scharrer I, Lüchtenberg M et al.
Coagulation disorders and the risk of retinal vein occlusion. ThrombHaemost 2010;103:299-305.

Hayreh S, Podhajsky P, Zimmerman M.
Central and hemicentral retinal vein occlusion: role of anti-platelet aggregation agents and anticoagulants. Ophthalmology 2011;118:1603-11.

10. Squizzato A, Manfredi E; Bozzato S et al.
Antithrombotic and fibrinolytic drugs for retinal vein occlusion: A systematic review and a call for action. Thromb Haemost 2010; 103: 271-76.

Kucher N.
Deep-vein thrombosis of the upper extremities. N Engl J Med 2011; 364: 861-9.

Mai C, Hunt D.
Upper-extremity deep venous thrombosis: a review. Am J Med 2011; 124: 402-407.

Saseedharan S, Bhargava S.
Upper extremity deep vein thrombosis. Int J Crit Ill Inj Sci 2012; 2: 21-26.

Engelberger R, Kucher N.
Management of deep vein thrombosis of the upper extremity. Circulation 2012; 126: 768-773.

Grant J, Stevens S, Woller S, et al.
Diagnosis and management of upper extremity deep-vein thrombosis. Thromb Haemost 2012; 108: 1097-1108.

Schleyer A, Jarman K, Calver P, et al.
Upper extremity deep vein thrombosis in hospitalized patients: a descriptive study. J Hosp Med 2014; 1: 48-53.

Bates S, Jaeschkes R, Stevens S, et al.
Diagnosis of dvt. Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 141 (2) (suppl): e419S-e494S.

Aguilar Shea A, Gallardo Mayo C.
A case of upper extremity deep vein thrombosis. Semergen 2013; 2: 107-109.

Sadeghi R, Safi M.
Systemic thrombolysis in the upper extremity deep vein thrombosis. ARYA Atherosclerosis 2011; 7(1): 40-46.

Basar N, Cagli K, Basar O, et al.
Upper-extremity deep vein thrombosis and downhill esophageal varices. Tex Heart Inst J 2010; 37(6): 714-6.

Ferrer Galvan M, Jara Palomares L, Caballero Eraso C, et al.
Chronic thromboembolic pulmonary hypertension due to upper extremity deep vein thrombosis caused by thoracic outlet syndrome. Arch Bronconeumol 2012; 48(2): 61-63.

Arnhjort T, Persson LM, Rosfors S, et al.
Primary deep vein thrombosis in the upper limb: a retrospective study with emphasis on pathogenesis and late sequelae. Eur J Intern Med 2007; 18: 304-8.

Baskin JL, Pui C, Reiss U, et al.
Management of occlusion and thrombosis associated with long-term indwelling central venous catheter. Lancet 2009; 374: 159-69.

Cadman A, Lawrance JA, Fitzsimmons L, et al.
To clot or not to clot? That is the question in central venous catheters. Clin Radiol 2004; 59: 349–55.

Debourdeau P, on behalf of the working group of the SOR.
SOR Guidelines for the Prevention and Treatment of Thrombosis Associated with Central Venous Catheters in Patients with Cancer: Report from the Working Group:2008 SOR Guidelines. Ann Oncol 2009; 20: 1459-71.

Geerts WH, Bergqvist D, Pineo GF, et al.Prevention of venous thromboembolism.
ACCP Evicence-Based Clinical Practice Guidelines (8th edition). CHEST 2008; 133: 381S–453S.

Lee AYY, Levine MN, Baker RI, et al.
Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349: 146 – 53.

Vescia S, Baumgartner AK, Jacobs VR, et al.
Management of venous port systems in oncology: a review of current evidence. Ann Oncol 2008; 19: 9–15.

Deitcher SR Fesen MR, Kiproff PM; et al.
Cardiovascular Thrombolytic to Open Occluded Lines-2 Investigators. Safety and efficacy of alteplase for restoring function in occluded central venous catheters: results of the cardiovascular thrombolytic to open occluded lines trial. J Clin Oncol 2002; 20: 317-24.

Randolph AG, Cook DJ, Gonzales CA, et al.
Ultrasound guidance for placement of central venous catheters: a meta-analysis of the literature. Crit Care Med 1996; 24: 2053 – 8.

Young A, Billingham L, Begum G, et al.
Warfarin thromboprophylaxis in cancer patients with central venous catheters (WARP): an open label randomized trial. Lancet 2009; 373: 567 – 74.

Leick J, Szardien S, Liebetrau C et al.
Mobile left ventricular thrombus in left ventricular dysfunction: case report and review of literature. Clin Res Cardiol 2013; 102: 479–84.

Egolum U, Stover D, Anthony R et al.
Intracardiac Thrombus: Diagnosis, Complications and Management. Am J Med Sci 2013; 345(5): 391-5.

Torbicki A, Galie N, Covezzoli A et al.
Right heart thrombi in pulmonary embolism: results from the International Cooperative Pulmonary Embolism Registry. J Am Coll Cardiol 2003; 41: 2245–51.

Warnes C, Williams R, Bashore T et al.
ACC/AHA 2008 guidelines for managment of adults with congenital heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2008; 52: e143-e263.

Heik S, Kupper W, Hamm C et al.
Efficacy of high dose intravenous heparin for treatment of left ventricular thrombi with high embolic risk. J Am Coll Cardiol 1994; 24: 1305–9.

Meurin P, Tabet J, Renaud N et al.
Treatment of left ventricular thrombi with a low molecular weight heparin. Int J Cardiol 2005; 98:319–23.

Mallory R, Balcezak T et al.
Treatment of mobile left ventricular thrombus with low-molecular-weight heparin. N Engl J Med1999; 341: 1082–3.

Lee J, Park J, Jung H et al.
Left ventricular thrombus and subsequent thromboembolism, comparison of anticoagulation, surgical removal, and antiplatelet agents. J Atheroscler Thromb 2012; 20(1):73–93.

Massie B, Collins J, Ammon S et al.
Randomized trial of warfarin, aspirin, and clopidogrel in patients with chronic heart failure: the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial. Circulation 2009; 119: 1616–24.

Steg P, James S, Atar D et al.
Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC) (2012) ESC. Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012; 33: 2569–619.

O’Gara P, Kushner F, Ascheim D et al.
ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 61: e78 –140.

Giglia T, Massicotte P, Tweddell J et al.
Prevention and Treatment of Thrombosis in Pediatric and Congenital Heart Disease: A Scientific Statement From the American Heart Association. Circulation 2013; 128: 2622-703.

Kajimoto H.
Increased Thrombogenesity in patients with cyanotic congenital heart disease. Circ J 2007; 71: 948-53.

Nishimura R, Otto C et al.
2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014; 63, 22: e57-e185.

Özkan M, Gündüz S, Biteker M et al.
Comparison of Different TEE-Guided Thrombolytic Regimens for Prosthetic Valve Thrombosis The TROIA Trial JACC 2013; 6: 206-16.

Margetic S.
Diagnostic algorithm for thrombophilia screening. Clin Chem Med 2010; 48 (Suppl 1): S27-39.

Baglin T, Gray E, Greaves M, et al.
British Committee for Standards in Haematology. Clinical guidelines for testing for heritable thrombophilia. Br J Haematol 2010; 149: 209-20.

Pengo V, Tripodi A, Reber G, et al.
Update of the guidelines for lupus anticoagulant detection. J Thromb Haemost 2009; 7: 1737-40.

Favaloro E, McDonald D, Lippi G.
Laboratory Investigation of thrombophilia: the good, the bad, and the ugly. Semin Thromb Hemost 2009; 35: 695-710.

Marlar RA, Gausman JN.
Laboratory testing issues for protein C, protein S, and antithrombin. Int Jnl Lab Hem 2014; 36: 289–95.

ME Martinuzzo, LH Barrera, MA D Adamo, et al.
Frecuent False-positive results of lupus anticoagulant test in plasma of patients receiving the new oral anticoagulants and enoxaparin. Int. Jnl. Lab. Hem.2014, 36, 144-150.

Forastiero R, Martinuzzo M.
Investigación en el laboratorio de los estados trombofílicos. Capítulo 13 en Fundamentos para el manejo práctico en el laboratorio de hemostasia. Segunda edición, 2013.

Righini M, Perrier A, de Moerloose P, Bounameaux H.
D-dimer for venous thromboembolism diagnosis: 20 years later. J Thromb Haemost 2008;6: 1059-71.

Adam S, Key N, Greenberg Ch.
D-dimer antigen: current concepts and future prospects. Blood 2009, 113: 2878-87.

Bates S.
D-dimer assays in diagnosis and management of thrombotic and bleeding disorders. Semin Thromb Haemost 2012;38: 673-682.

Olson J, Cunningham T, Russell A et al.
D-dimer. Simple test, tough problem. Arch Path Lab Med.2013; 137:1030-38.

Olson J, Adcock D, Bush T et al.
Quantitative D- dimer for the exclusion of venous thromboembolic disease; Approved Guideline. CLSI document H59-A: vol 31:6.

Huisman MV, Klok FA.
Diagnostic management of acute deep vein thrombosis and pulmonary embolism. J Thromb Haemost 2013; 11: 412–22.

Uresand F, Blanquer J et al.
Guía para el diagnóstico, tratamiento y seguimiento de la tromboembolia pulmonar. .Arch bronconeumonol. 2004; 40(12): 580-94.

Tripodi A.
D-Dimer testing in laboratory practice. Clinical Chemistry. 2011; 57:1256-62.

Ansell J, Hirsch J, Hylek A, et al.
Pharmacology and management of the vitamin K antagonist: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition), Chest 2008; 133: 160S-198S.

Expert WHO.
Committee on Biological Standardization. Guidelines for Thromboplastins and Plasma Used to Control Oral Anticoagulant Therapy. WHO Technical Report Series no. 889 Geneva, Switzerland: WHO; 1999:64–93.

Hirsch J, Bauer K, Donati M, et al.
Parenteral anticoagulants. American College of Chest Physicians evidence-based clinical practice Guideline (8th Edition). Chest 2008; 133: 141S-159S.

Baglin T, Barrowcliffe T, Cohen A, et al.
British committee for standards in haematology guidelines on the use of and monitoring of heparin. Br J Haematol 2006; 133: 19-34.

Watson H, Davidson S , Keeling D.
Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology. Guidelines on the diagnosis and management of heparin induced thrombocytopenia: second edition. Br J Haematol 2012; 159: 528-540.

Hirsch J, Warkentin T, Shaughnessy S.
Heparin and low molecular weight heparin. Mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy and safety. Chest 2001; 119: 64S-94S.

Kitchen S, Gray E, Mackie I, et al.
Measurement of non-Coumarin anticoagulants and their effects on tests of Haemostasis: Guidance from the British Committee for Standards in Haematology. Br J Haematol 2014. Jun 14. doi: 10.1111/bjh.12975.

Samama M, Guinet C.
Laboratory assessment of new anticoagulants. Clin Chem Lab Med 2011; 49: 764-772.

Harenberg J, Erdle S, Marx S, et al.
Determination of rivaroxaban in human plasma samples. Semin Thromb Hemost 2012; 38: 178-84.

Castellone D, Van Cott E.
Laboratory monitoring of new anticoagulants. Am J Hematol 2010; 85: 185-187.

Kearon C, Akl E, Comerota A, et al.
Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 141: e419S-e494S.

Keeling D, Baglin T, Tait C et al.
Guidelines on oral anticoagulation with warfarin – fourth edition. British Committee for Standards in Haematology. Br J Haematol 2011; 154: 311-24.

Brandjes D, Heijboer H, Büller H et al.
Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis. N Engl J Med. 1992; 327: 1485-9.

Kearon C, Ginsberg J, Julian J, et al.
Fixed-Dose Heparin (FIDO) Investigators. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA 2006; 296: 935-42.

Boutitie F, Pinede L, Schulman S et al.
Influence of preceding lenght of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants’ data from seven trials. Br Med J 2011; 342: d3036

Baglin T,Palmer C,Luddington R, et al.
Unprovoked recurrent venous thrombosis: prediction by D-dimer and clinical risk factors. J Thromb Haemost 2008; 6: 577-82.

Baglin T, Luddington R, Brown K, et al.
Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet 2003; 362: 523-6

Prandoni P, Noventa F, Milan M.
Aspirin and recurrent venous thromboembolism. Phlebology 2013; 28 Suppl 1: 99-104

Carrier M, Le Gal G, Cho R et al.
Dose escalation of low molecular weight heparin to manage recurrent venous thromboembolic events despite systemic anticoagulation in cancer patients. J Thromb Haemost 2009; 7: 760-5.

Pillai A, Olujohungbe A, Evans M, et al.
The management of recurrent VTE in cancer patients receiving therapeutic anticoagulation: the use of dual anticoagulant therapy combined with an IVC filter. Blood Coagul Fibrinolysis 2010; 21: 766-9.

Masuda E, Kistner R, Musikasinthorn C, et al.
The controversy of managing calf vein thrombosis. J Vasc Surg 2012; 55: 555-61.

Di Nisio M, Wichers I, Middeldorp S.
Treatment for superficial thrombophlebitis of the leg. Cochrane Database Syst Rev 2013 Apr 30; 4: CD004982.

Decousus H, Prandoni P, Mismetti P, et al.
Fondaparinux for the treatment of superficial-vein thrombosis in the legs. CALISTO study Group. N Engl J Med 2010; 363: 1222-32.

Schulman, M.D, Kearon, M.D. Kakkar, et al.
Dabigatran versus Warfarin in the Treatmentof Acute Venous Thromboembolism. NEJM 2009; 361:2342-52.

The EINSTEIN Investigators.
Oral Rivaroxaban for Symptomatic Venous Thromboembolism NEJM 2010; 363: 2499-2510

Schulman S, Kearon C, Kakkar,et al.
Extended Use of Dabigatran, Warfarin or Placebo in Venous Thromboembolism. NEJM 2013; 368:709-18

Agnelli G, for the AMPLIFY Investigators.
Oral Apixaban for the Treatment of Acute Venous Thromboembolism. NEJM 2013; 369: 799-808

Lozano Sánchez FS.
Nuevos anticoagulantes orales en el tratamiento de la trombosis venosa profunda. Angiología 2012; 64: 212-17

Schulman S.
Adherence to anticoagulant treatment with dabigatran in a real-world setting. J Thromb Haemost 2013; 11: 1295-99

Lega J.
Consistency of safety profile of new oral anticoagulants in patients with renal failure. J Thromb Haemost 2013; 12:337-43

Sardar P, Chatterjee S, Chaudhari S, et al.
New oral anticoagulants in elderly adults: evidence from a meta-analysis of randomized trials. J Am Geriatr Soc 2014; 62: 857-64

Agnelli G, for the AMPLIFY-EXT Investigators.
Apixaban for extended treatment of venous thromboembolism. NEJM 2013; 368:699-708.

Van der Hulle et al.
Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 2013; 12: 320–283

Kearon C, Akl E, Comerota A, et al.
Antithrombotic therapy for VTE Disease. Chest 2012; 141 (2) Suppl: e419S-94S.

Levine M, Gent M, Hirsch J, et al.
A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal-vein thrombosis. N Engl J Med 1996; 334: 677-81.

Koopman M, Prandoni P, Piovella F, et al.
Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med 1996; 334: 682-7.

Chong B, Brighton T, Baker R, et al.
Once-daily enoxaparin in the outpatient setting versus unfractioned heparin in hospital for the treatment of symptomatic deep-vein thrombosis. J Thromb & Thrombolysis 2005; 19: 171-81.

Boccalori H, Elias A, Chale J, et al.
Clinical outcome and cost of hospital vs. home treatment of proximal deep vein thrombosis with a low-molecular-weight heparin: the Vascular Midi-Pyrenees study. Arch Int Med 2000; 160: 1769-73.

Daskalopoulos M, Daskalopoulous S, Tzortzis E, et al.
Long-term treatment of deep venous thrombosis with a low molecular weight heparin (tinzaparin): A prospective randomized trial. Eur J Vasc & Endovasc Surg 2005; 29: 638-50.

Ramacciotti E, Araujo GR, Lastoria S, et al.
An open-label, comparative study of the efficacy and safety of once-daily dose of enoxaparin versus unfractionated heparin in the treatment of proximal lower limb deep-vein thrombosis. Thromb Res 2004; 114: 149-53.

Zidane M, van Hulsteijn L, Brenninkmeijer B, et al.
Out of hospital treatment with subcutaneous low molecular weight heparin in pacients with acute deep-vein thrombosis: a prospective study in daily practice. Haematologica 2006; 91:1052-8.

Lozano F, Trujillo Santos J, Barron M, et al.
Home versus in-hospital treatment of outpatients with acute deep vein thrombosis of the lower limbs. J Vasc Surg 2014; 59: 1362-7.

Zondag W, Mos I, Creemers-Schild D, et al.
Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study. J Thromb Haemost 2011; 9: 1500-7.

Wells P.
Outpatient treatment of patients with deep-vein thrombosis or pulmonary embolism. Curr Op Pulm Med 2001; 7: 360-4.

Vedantham S.
Interventional approaches to deep vein thrombosis. Am J Hematol. 2012; 87 Suppl 1:S113-8

Arko FR, Arko Z, Murphy EH.
Endovascular Intervention for lower extremity deep venous thrombosis. Vascular Disease Management. 2011; 8

Mehrzad H, Freedman J, Harvey JJ, GAneshan A.
The role of interventional radiology in the management of deep vein thrombosis. Postgrad Med J 2013; 89: 157-64

Dumantepe M, Tarhan A, YurdakulI, Özler A.
US-accelerated catheter-directed thrombolysis for the treatment of deep venous thrombosis. Diagn Interv Radiol 2013; 19:251-8

Tsuji A, Yamada N, Ota S, et al.
Early results of rheolytic thrombectomy in patients with proximal deep vein thrombosis. Circ J. 2011; 75: 1742-46

Hillman DE, Pharm D, Razavi M.
Clinical and economic evaluation of the Trellis-8 infusion catheter for deep vein thrombosis. J Vasc Interv Radiol. 2008; 19: 377-83

O'Sullivan GJ, Lohan DG, Gough N, et al.
Pharmacomecanical thrombectomy of acute deep vein thrombosis with the Trellis-8 isolated thrombolysis catheter. J Vasc Interv Radiol 2007; 18: 715-24

Matsuda A, Yamada N, Ogihara Y, et al.
Early and long-term outcomes of venous stent implantation for iliac venousstenosis after catheter-directed thrombolysis for acute deep vein thrombosis. Circ J. 2014; 78:1234-9

Enden T, Haig Y, Kløw NE, et al.; CaVenT Study Group.
Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomized controlled trial. Lancet. 2012; 379:31-8

Meissner MH, Gloviczki P, Comerota AJ, et al; Society for Vascular Surgery; American Venous Forum.
Early thrombus removal strategies for acute deep venous thrombosis: clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum. J Vasc Surg. 2012; 55: 1449-62.

Lefevre P, Laliberté F, Nutescu E, et al.
All-Cause and Potentially Disease-Related Health Care Costs Associated with Venous Thromboembolism in Commercial, Medicare, and Medicaid Beneficiaries. J Manag Care Pharm 2012; 18(5): 363-74

Kahn S, et al.
How I Treat Post-Thrombotic Syndrome. Blood 2009; 114 (21): 4624-4631

Kearon C, Akl E, Comerota J, et al.
Antithrombotic Therapy for VTE Disease: Antithrombotic Therapy and prevention of thrombosis, 9th ed American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e419s-e494s

Kahn S, Ginsberg J.
Relationship between deep venous thrombosis and the post thrombotic syndrome. Arch Intern Med 2004; 164(1): 17-26

Soosainathan A, Moore H, Gohel M, et al.
Scoring Systems for The Post-thrombotic Syndrome. J Vasc Surg 2013; 57: 254-61

Gallie N, Hoeper M, Humbert M.
Guidelines for The Diagnosis and Treatment of Pulmonary Hypertension: The Task Force for The Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and The European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009; 30(20): 2493-537

Vulcano N, et al.
Consenso para el Diagnóstico y Tratamiento de la Hipertensión Arterial Pulmonar. Sociedad Argentina de Cardiología-SAC, Asociación Argentina de Medicina Respiratoria-AAMR, Sociedad Argentina de Reumatologia-SAR. Vol 79 Suplemento 2 Mayo-Junio 2011

The Confidential Enquiry into Maternal and Child Health (CEMACH).
Saving mother’s lives: reviewing maternal deaths to make motherhood safer-2003-2005: the seventh report on confidential enquiries into maternal deaths in the United Kingdom. London: CEMACH, 2007.

Grand B, Voto L.
Maternal issues in thrombosis and thrombophilia. In: The Textbook of Perinatal Medicine. Asim Kurjak and Frank Chevernak, editors. Second Edition. Taylor & Francis; 2006 Chapter 191, p 2044-50.

Blanco-Molina A, Rota L, Di Micco P, et al.
Venous thromboembolism during pregnancy, postpartum or during contraceptive use. Thromb Haemost 2010; 103: 306-311.

Chan W, Lee A, Spencer F, et al.
Predicting deep vein thrombosis in pregnancy: out in “LEFt” Field? Ann Int Med 2009;151:85-92.

Righini M, Jobic C, Boehlen F, et al.
EDVIGE study group. Predicting deep venous thrombosis in pregnancy: external validation of the LEFT clinical prediction rule. Haematologica 2013; 98: 545-48.

To MS, Hunt BJ, Nelson-Piercy C.
A negative D-dimer does not exclude venous thromboembolism (VTE) in pregnancy. J Obstet Gynecol 2008; 28:222-3.

Shahir K, Goodman L, Tali A, et al.
Pulmonary embolism in pregnancy: CT pulmonary angiography versus perfusion scanning. AJR 2012; 195:W214-W220.

Bourjeily G, Paidas M, Rosene-Montella et al.
Pulmonary embolism in pregnancy. Lancet 2010; 375:500-12.

Le gal G, Kercret G, Bressollette L, et al.
Diagnostic value of single complete compression ultrasonography in pregnant and postpartum women with suspected deep vein thrombosis: prospective study. BMJ 2012; 344:e2635.

Bates SM, Greer IA, Middeldorp S, et al.
Venous thromboembolism, thrombophilia, antithrombotic therapy and pregnancy. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th Edition) Chest 2012; 141: e691S-e736S.

Marik P, Plante Lauren.
Venous thromboembolic disease and pregnancy . N Eng Med 2008;359:2025-33.

Stefanovic BS, Vasiljevic Z, Mitrovic P y col.
Trombolytic therapy for massive pulmonary embolism 12 hours after cesarean delivery despite contraindication. Am J Med 2006;24:502-4.

Raffini L, Huang YS, Witmer C, et al.
Dramatic increase in venous thromboembolism in children's hospitals in the United States from 2001 to 2007. Pediatrics 2009; 124: 1001-8.

Chalmers E, Ganesen V, Liesner R, et al.
Guidelines on the investigation, management and prevention of venous thrombosis in children. Br J Haematol 2011; 154: 196-207.

Monagle P, Chan AK, Goldenberg NA, et al.
American College of Chest Physicians. Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141: e737S-e801S.

Bonduel M, Sciuccati G, Hepner M, et al.
Acenocoumarol therapy in pediatric patients. J Thromb Haemost. 2003; 1: 1740-3.

Sharley N, Yu A, Williams D.
Stability of Mixtures Formulated from Warfarin Tablets or Powder. J Pharm Pract Res 2007; 37: 95-7.

Bonduel M, Hepner M, Buontempo F, et al.
Use of warfarin oral suspension for antithrombotic therapy and prevention of thrombosis in infants and children. (Abstract). 60th Annual Meeting of the SSC of the ISTH 2014.

Manco-Johnson MJ, Grabowski EF, Hellgreen M, et al.
Recommendations for tPA thrombolysis in children. On behalf of the Scientific Subcommittee on Perinatal and Pediatric Thrombosis of the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis. Thromb Haemost. 2002; 88: 157-8.