Trombolisis endovenosa post reversión de acenocumarol con complejo de protrombina: caso clínico / Intravenous thrombolysis after reversion of acenocoumarol anticoagulation: report of one case

We report an 89-year-old male under oral anticoagulant therapy with a therapeutic international normalized ratio, presenting at the emergency room with right side hemiparesis and aphasia. Neuroimaging was compatible with an acute middle cerebral artery ischemic stroke. Anticoagulation was reverted with the use of four factor prothrombin complex, followed by thrombolysis with alteplase, with a favorable evolution, returning to his basal functional status.

Efecto de las variantes de VKORC1 y CYP2C9 sobre la dosis de anticoagulantes orales en individuos chilenos / Effect of VKORC1 and CYP2C9 variants on dosage of oral anticoagulants in Chilean individuals

Background: The dose of oral anticoagulants (OAC) shows great variability among patients. Pharmacogenetic studies have shown that common variants in genes CYP2C9 (*2 and *3) and VKORC1 (-1639G>A) are associated with lower requirements of OAC. Aim: To study the association between average maintenance doses of oral anticoagulant therapy required to maintain a stable INR and CYP2C9 and VKORC1 gene variants in Chilean adults. Material and Methods: Prospective study of patients on anticoagulant treatment and with a stable international normalized ratio (INR) for prothrombin time for at least three months. Patients were classified as having high or low acenocoumarol or warfarin requirements. Peripheral blood DNA genotyping was performed by polymerase chain reaction and restriction fragment polymorphism or sequencing and electrophoresis. Results: The study included 185 patients, 125 on acenocoumarol and 60 on warfarin. Patients with VKORC1-1639A allele were more likely to require lower doses of both drugs than patients with the G allele (Odds ratio [OR] for acenocoumarol 9.06, and OR for warfarin = 18.7). There was no association between CYP2C9*2 and*3 and acenocoumarol or warfarin requirements. Conclusions: There is an association between VKORC1-1639A variant and anticoagulant doses.

Calidad de las tromboplastinas utilizadas en el laboratorio clínico y en los equipos POCT y su impacto en la dosificación de acenocumarol en pacientes con terapia anticoagulante oral / Types of thromplastin used for INR determination in patients under chronic oral anticoagulant treatment: discrepancies that may affect the dose of coumarin derivatives needed for treatment safety

Antecedentes: El monitoreo del tratamiento con anticoagulantes cumarínicos se realiza a través del INR (International Normalized Ratio) que es el parámetro estandarizado del Tiempo de Protrombina. Las recomendaciones de la OMS indican que la precisión en el cálculo del INR puede ser mejorada usando reactivo de tromboplastina con Indice de Sensibilidad Internacional (ISI) bajo, considerándose como ISI de referencia internacional el valor 1,0. Debido a incongruencias observadas en los INR de pacientes controlados en el Servicio de Salud Metropolitano Occidente, comparando valores de muestra venosa con resultados de INR capilar obtenidos en el mismo paciente el mismo día y hora (con reactivos Tromboplastina de distinto ISI), se efectuó un ensayo clínico cruzado entre los distintos métodos. Materiales y métodos: En 100 pacientes se comparó INR venoso con dos tromboplastinas de diferente ISI (1,3 y 1,0) vs aquel efectuado con muestra capilar (ISI 1,0). Resultados: Los resultados del estudio muestran que a partir de valores de INR 3,0 las determinaciones obtenidas usando Tromboplastina de cerebro de conejo ISI=1,3 subestiman el valor de INR para un mismo paciente y una misma muestra. Conclusiones: El uso de Tromboplastina recombinante humana ISI 1,0 permite evitar la subestimación del INR en pacientes con mayor riesgo tromboembóli-co (indicación de INR objetivo más alto). Por ello, este método se adoptó en el control del TACO en pacientes controlados en el Servicio de Salud Occidente.

Background: INR (International Normalized Ratio) is the standard Prothrombin Time parameter for monitoring anticoagulant treatment with coumarin derivatives Recommendations of WHO indicate that precision in the calculation of the INR can be improved using thromboplastins with a low Index of International Sensibility (ISI=1,0). Discrepancies in INR obtained using either this technique or conventional rabbit brain derived reagents in the same sample in patients attending the Servicio de Salud Metropolitano Occidente (West Metropolitan Health Service) were observed. Our objective was to evaluate these discrepancies in a systematic way. Materials and methods: A comparative study was conducted using two thromboplastins of different ISI (1.0 and 1.3) for the calculation of venous INR in comparison with capillary INR in 100 patients. Results: The study showed that INR values may differ significantly according to the method used. In particular, rabbit brain thromboplastin ISI = 1.3 underestimates the value of INR in the range of INR ≥3.0. Conclusions: The use of human recombinant thromboplastin ISI= 1.0. for determination of INR may significantly decrease the risk of hemorrhagic complications in patients requiring higher levels of anticoagulation.

Eficacia y seguridad del tratamiento anticoagulante oral con antagonistas de vitamina k en pacientes con prótesis valvulares cardíacas / Safety and efficacy of anticoagulation with vitamin k antagonists in patients with prosthetic heart valves

Introducción: Los pacientes con válvulas mecánicas cardíacas (VMC) representan una proporción significativa del total de pacientes que requieren anticoagulación. Sin embargo, hay pocos estudios que comparen la efectividad de la anticoagulación con distintos antagonistas de vitamina K (AVK). Objetivo: Comparar la efectividad y seguridad del tratamiento con warfarina y acenocumarol en pacientes con VMC. Métodos: Estudio observacional de pacientes en po-liclínico de anticoagulación UC sometidos a recambio valvular entre los años 2005 y 2013. Se estandarizó las dosis de AVK con software Isaza Hytwin Biostac 2.0. Se evaluaron registros de hemorragia mayor y menor (seguridad) y accidentes vasculares y embolías sistémicas (efectividad). La efectividad se analizó mediante el tiempo en rango terapéutico (TTR) con método de Ro-sendaal. Resultados: Se incluyó 365 pacientes con edad promedio de 64,1 +/- 13,2 años, 53,9 por ciento de sexo femenino. El seguimiento promedio fue de 33,3 +/- 18 meses; La mortalidad registrada fue 2,1 por ciento. El promedio de TTR fue 68 +/- 13,3 por ciento (recambio aórtico TTR 66,1 +/- 12,6 por ciento, recambio mitral TTR 65,8 +/- 13,8 por ciento y recambio mitro-aórtico TTR 61,2 +/- 12 por ciento). Acenocumarol presentó un TTR menor que warfarina (65,1 +/- 13,1 vs. 71,2 +/- 13,6, p = 0,001), sin aumento del riesgo de complicaciones. Conclusión: Aunque warfarina ofrece un mejor perfil de TTR, no existen diferencias significativas en la eficacia o seguridad al compararla con acenocumarol.

Background: Patients with cardiac mechanical valves (MHV) represent a significant proportion of all patients requiring anticoagulation. However, there are few studies comparing safety and efficacy of different vitamin K antagonists (VKA). Aim: To compare the efficacy and safety of warfarin and acenocoumarol in patients with MHV. Methods: Observational study of patients who had a mitral and /or aortic valve replacement between 2005 and 2013, followed at the Catholic University anticoagulation clinics. VKA dose adjustments were performed using the Isaza Hytwin Biostac 2.0 software. Major and minor bleeding (safety) and stroke and systemic embolism (effectiveness) were evaluated. The efficacy was estimated by the time in therapeutic range (TTR) with the Rosendaal method. Results: 365 patients were included with a mean age of 64.1 +/- 13.2 years, 53.9 percent of them were females. Mean follow-up was 33.3 +/- 18 months Overall mortality rate was 2.1 percent, which is similar to that of patients treated with VKA for other reasons. The average TTR was 68 +/- 13.3 percent (66,1 +/- 12,6 percent for aortic valves, 65,8 +/- 13,8 percent for mitral valves and 61,2 +/- 12 percent for aortic and mitral valves). TTR was lower with acenocoumarol compared to warfarin (65.1 +/- 13.1 vs. 71.2 +/- 13.6 , p = 0.001 ), However, the risk of complications was not different between groups. Conclusions: Although warfarin provides a better profile of TTR , there were no significant differences in efficacy or safety when compared with acenocoumarol.

Necrosis cutánea por tratamiento anticoagulante oral: caso clínico / Cutaneous necrosis caused by acenocumarol: case report

Cutaneous necrosis is a rare but serious complication, among patients treated with warfarin or acenocumarol derivatives. We report a 71 years old female with a history of deep venous thrombosis, receiving acenocumarol for three months. The treatment was discontinued, but had to be restarted, due to a new episode of thrombosis. Three days after restarting acenocumarol, the patient consulted for ecchymosis and pain of the right foot. At physical examination, there was distal cyanosis and absence of distal pulses. The patient was subjected to an embolectomy with the suspicion of an acute arterial occlusion, but no emboli were found. Due to the possibility of a cutaneous necrosis caused by Acenocumarol, the medication is discontinued. The cutaneous lesions progressed and eight days after the failed embolectomy, a gangrene of the right foot was diagnosed. The patient did not accept amputation dying fourteen days after the first intervention.

A propósito un caso registrado, se resume la historia clínica y se revisa la literatura, dada la escasa frecuencia de esta complicación derivada del tratamiento por anticoagulantes orales. La necrosis cutánea es un evento adverso raro, pero serio, de la anticoagulación con derivados de acenocumarol o warfarina. Se comunicó por primera vez en 1943. La incidencia de la necrosis cutánea inducida por anticoagulantes orales es de 0,01 al 0,1 por ciento de los pacientes tratados. El número de casos publicados en el mundo es de aproximadamente 300, y menos de 100 en lengua inglesa en las últimas tres décadas. Este trabajo reporta el caso de una paciente que presenta necrosis cutánea en hombro izquierdo y pierna derecha.

Warfarina versus acenocumarol en alcanzar niveles terapéuticos en una población ambulatoria / Comparison of acenocumarol vs. warfarin in achieving oral anticoagulation therapeutic level in ambulatory patients

Introducción: La anticoagulación constituye una terapia farmacológica habitual en la práctica clínica diaria. En Chile, los ACO disponibles y utilizados son warfarina y acenocumarol, no existiendo mayores experiencias nacionales documentadas sobre el mayor beneficio de un fármaco en particular. Objetivo: Analizar y comparar la eficacia terapéutica de warfarina y acenocumarol en una población ambulatoria. Metodología: Estudio retrospectivo, longitudinal. Se analizó 188 pacientes que estuvieron en tratamiento con acenocumarol durante más de un año, y que luego fueron cambiados a warfarina. Se registró: sexo, edad, efectos adversos, diagnóstico y justificación de inicio de ACO. Se obtuvo el promedio del International Normalizad Ratio (INR) de los últimos 3 meses de tratamiento con acenocumarol. Luego, se sustituyó por warfarina, obteniendo luego de un año de tratamiento, el INR promedio de los últimos 3 meses. Los pacientes se agruparon en tres grupos: Bajo rango terapéutico (INR<2.0), en rango terapéutico (INR=2.0-3.0), sobre rango terapéutico (INR>3.0). Resultados: En los pacientes con acenocumarol, se observó 67 (35,64 por ciento) bajo rango terapéutico; 91 (48,4 por ciento) en rango terapéutico; y 30 (15,96 por ciento) sobre rango terapéutico. Luego del cambio a warfarina, 76 (40,43 por ciento) bajo rango terapéutico; 95 (50,53 por ciento) en rango terapéutico; y 17 (9,04 por ciento) sobre rango terapéutico, diferencias no significativas. Bajo el efecto de ambos fármacos no se registraron hemorragias mayores y no hubo diferencia significativa en hemorragias menores. Discusión: La eficacia terapéutica fue similar con ambos fármacos. A pesar de que con acenocumarol se obtuvo mayor porcentaje de pacientes sobre rango terapéutico, no se observaron complicaciones mayores en el periodo de seguimiento.

Background: oral anticoagulation is frequently needed in clinical practice. Warfarin and acenocumarol are available in Chile for this purpose. Locally there is no evidence favoring one over the other Aim: To compare the efficacy of warfarin and acenocumarol in an ambulatory population. Method: A retrospective study compared data on 188 patients with over 1 year of treatment with acenocumarol, before and after being switched over to treatment with warfarin. Demographic data, adverse effects, diagnosis and indication for oral anticoagulation were record. INRs obtained in the last 3 months of treatment with each agent were compared. Patients were classified in 3 groups: insufficient level (INR < 2.0), adequate level (INR 2.0- 3.0) and high level (INR > 3.0) of anticoagulation. Results: With acenocumarol, low level INR was present in 35.6 percent>, adequate INR in 48.4 percent> and high INR in 15.9 percent> of subjects. After switching to warfarin, corresponding levels in each group were 40.4 percent>, 50.3 percent> and 9 percent> (NS). There were no serious bleeding episodes in either group; minor hemorrhages occurred with similar frequency in both groups. Conclusion: There was similar clinical efficacy of oral anticoagulation with acenocumarol compared to warfarin. The slightly higher percentage of acenocumarol treated patients exhibiting a high IRN level did not result in increased risk of hemorrhage.

Heparina subcutánea durante el primer trimestre del embarazo en mujeres con prótesis valvulares cardíacas / Subcutaneous heparin during the first trimester of pregnancy in women with prosthetic heart valves

Background: Oral anticoagulation therapy in pregnant women with prosthetic heart valves is associated with a greater risk of abortion, fetal malformations and thromboembolic complications. Aim: To assess the use of subcutaneous heparin in women with pregnancies of less than 12 weeks as an alternative to oral anticoagulation therapy. Material and methods: Pregnant women were admitted to the hospital and coumarinics were replaced with not fractionated subcutaneous heparin in a dose of 10,000 IU every 12 hours, aiming at prolonging partial thromboplastin time, 2 or 2 1/2 times. During the hospitalization period, women were taught about the heparin injection technique. Coumarinics were restarted after week 13 of pregnancy until 10 days prior to the delivery date in which women were again admitted to the hospital and intravenous heparin was used until the delivery. Results: Between 1991 and 1997, this protocol was used during ten pregnancies in seven women aged 19 to 36 years old. Five had a Starr-Edwards prosthesis, one had a mitral Bjsrk-Shilley prosthesis and one, a double prosthesis (mitral Starr-Machi and aortic St Jude). Subcutaneous heparin was started in the fifth week of pregnancy in 1 case, in the sixth week in seven and in the seventh week in two. There was no maternal mortality and one transient ischemic attack without sequelae. One non compliant patient had a Bjsrk Shilley prosthetic valve dysfunction that required a valve replacement at the twelfth week of pregnancy and she had a spontaneous abortion at week 15. Other patient had a pneumonia at week 37 and gave birth to a stillbirth. There were no fetal malformations. Conclusions: This therapeutic protocol can be used among Chilean patients, but must be restricted to compliant women and a strict surveillance must be maintained

Hipertensión pulmonar e infección por VIH: comunicación de un caso / Pulmonary hypertension and HIV infection: 1 case report

Pulmonary hypertension associated to HIV infection has been reported in the literature with increased frequency. Apparently, this condition has a faster clinical evolution and a higher mortality than primary pulmonary hypertension. The pathogenic mechanisms of HIV associated pulmonary hypertension and the influence of its treatment on patientÕs evolution are not well known. We report a 32 years old homosexual male that developed a severe dyspnea in a period of 2 months. Echocardiogram demonstrated right ventricular dilatation and a systolic pulmonary artery pressure of 86 mm Hg. No other causes for pulmonary hypertension were found. Antiviral therapy and vasodilator treatment with a calcium channel blocker were started and the patient had an important subjective clinical improvement

Anticoagulación en embarazadas con prótesis valvulares mecánicas / Anticoagulation in pregnant patients with mechanical valve prostheses

La anticoagulación oral durante el embarazo es un tema controvertido y no hay uniformidad de criterios sobre cuál es el tratamiento más adecuado para las pacientes embarazadas con prótesis valvulares mecánicas. Los anticoagulantes orales pueden inducir una embriopatía si son administrados entre la 6ª y 12ª semana del embarazo, sus sustitución por heparina previene esta complicación pero su eficacia en la prevención de complicaciones trombóticas ha sido cuestionada. Ambos anticoagulantes también son responsables del mayor riesgo de abortos o pérdidas fetales. Evaluamos el resultado de 92 embarazos consecutivos en 59 pacientes con prótesis valvulares mecánicas desde 1986 hasta junio de 1997. En 31 embarazos se suspendió la anticoagulación oral durante el 1er. trimestre y se indicó heparina SC ajustada por APTT. En 61 embarazos se continuó con anticoagulación oral. Para el parto se utilizó nuevamente heparina ajustada. Los abortos o pérdidas fetales fueron similares en las que recibieron anticoagulación oral el 1er. trimestre (13/61=25 por ciento) comparado con las que recibieron heparina (6/31=19 por ciento). Los episodios embólicos fueron más frecuentes en el período tratado con heparina (4.92 por ciento) que en el tratado con anticoagulantes orales (0.33 por ciento). Las embolias fueron cerebrales y transitorias. No se observaron malformaciones en los 71 recién nacidos excepto 1 caso de hidrocefalia. La única muerte materna resultó de una hemorragia mayor luego del parto de un feto muerto prematuro. Aunque la anticoagulación oral parece ser más segura para la madre, la heparina ajustada ofrece una protección adecuada de fenómenos tromboembólicos.