Diagnosis and management of von Willebrand disease in a single institution of Argentina.

Von Willebrand disease (VWD) is a bleeding disorder with variable clinical expression. In this article we describe types, clinical features, genetic testing when needed, genotype/phenotype relationships, and the response to desmopressin (DDAVP) testing, according to our experience. Our findings are possible type 1, 69.6%; type 1, 13.5%; severe type 1, 0 .35%; type 3, 0.55%; type 2A, 9.5%; probable 2B, 0.6%; type 2M, 2.5%; and probable type 2N, 3.4%. The most frequent symptoms are ecchymoses-hematomas and epistaxis, and, in females >over 13 years also menorrhagia. In pregnant patients, assessment of laboratory parameters in months 7 and 8 is recommended to plan the need for prophylaxis at term. DDAVP merits to be considered as the first-choice therapy, including pregnant women and children, and no patient showed significant unwanted effects. Because this is a safe, effective, and affordable therapy, we hope to encourage clinicians, mainly pediatricians and obstetricians, to a wider use of DDAVP, especially in developing countries. We also report two patients with prophylactic treatment.

Pilot study of homocysteine and cysteine in patients with thrombosis in different vascular sites. Epidemiology and response to folate.

Hyperhomocysteinemia is a risk factor for arterial and venous thrombosis. However, lowering homocysteine (Hcy) with vitamins not only failed to improve outcomes but also may lead to recurrent events. Our objectives were to evaluate Hcy and cysteine (Cys) levels in patients with thrombosis in different vascular sites, and their response to folate. One hundred and sixty four consecutive patients with thrombosis (42.1% arterial (AT), 36% venous (VT), 4.9% both venous and arterial thrombosis (AVT) and 17% unusual site (UST)) were included. Hcy and Cys were highest in patients with AVT and UST (p=0.0006). Ninety-three patients were treated, 70% were followed-up. Hcy levels normalized after therapy in all patients. Cys levels tended to vary after therapy according to the site of thrombosis. We observed a significant correlation between folate and Hcy (r: 0.48; p=0.005) among homozygous for MTHFR. A significant inverse relation was observed between Hcy and folate among homozygous and heterozygous (r: 0.462, p=0.007 and r: 0.267; p=0.04, respectively). No correlation was observed between folate and Cys. In conclusion, our observations suggest that Hcy and Cys might be implicated in thrombosis in different vascular sites, and respond differently to folate.

Antiphospholipid antibodies and hyperhomocysteinaemia in patients with vascular occlusive disease.

Hyperhomocysteinemia (HHcy), lupus anticoagulant (LA) and anticardiolipin antibodies (ACA) are independent risk factors for thrombosis. Even though risks are cumulative, the clinical impact of the association is unknown. Preliminary data suggested that HHcy might be associated with transient LA and ACA, disappearing after lowering HHcy. We prospectively evaluated the association of HHcy and LA/ACA, the effect of lowering HHcy with folic acid in LA behavior, and the correlation of the initial dRVVT with LA behavior after folic acid in 210 patients with thrombosis and adverse pregnancy outcomes. Prevalence of HHcy among patients with LA/ACA was 40%. Thirty-one patients exhibited only HHcy (15%; Group 1), 106 (50%; Group 2) had only LA/ACA, while 73 (35%; Group 3) had both. After therapy, 63% and 64% of LA/ACA remained positive in Group 3 and 2, respectively. We observed a trend towards a more positive dRVVT in persistent LA after lowering HHcy. No differences in clinical presentation or in outcomes after two years of followup were observed among the groups. Even though the association of HHcy and LA/ACA is common in patients with thrombosis, it might have no prognostic implications if Hcy levels are lowered. Currently, no laboratory findings correlate with LA behavior, which is independent of homocysteine levels and vitamin treatment.

Mechanical heart valve prostheses and persistent lupus anticoagulant: is the thrombotic risk increased?

The risk of thrombosis in patients with mechanical heart valve prostheses in spite of life-long adequate anticoagulation is 1-2% per year. Current recommendations for anticoagulation take into account the prosthesis itself and the co-morbid conditions that enhance the thrombotic risk. Lupus anticoagulant is diagnosed in many thrombotic recurrences. We designed an ambispective case-control study to evaluate thrombotic events in patients with mechanical heart valve prostheses and persistent lupus anticoagulant. Our objectives were to determine whether persistent lupus anticoagulant increased the risk of embolism in that population and thus, if a more intense anticoagulation would be recommended, even at the risk of increasing bleeding episodes. We included 16 patients and 16 controls with more than 80 patient-years of follow-up and with other risk factors for embolism. We observed no increased rate of thromboembolic events in patients than in controls, even during high-risk situations (i.e. bacterial endocarditis). Our population spent most of the time within the intended anticoagulation range. We conclude that adequate anticoagulation is the most important issue to prevent events, protecting against thrombosis without increasing the bleeding risk.

von Willebrand factor-cleaving protease (ADAMTS13) activity in normal non-pregnant women, pregnant and post-delivery women.

ADAMTS13 dysfunction has been involved in the pathogenesis of Thrombotic Thrombocytopenic Purpura. This disorder occurs more frequently in women and, in 13% of them, is associated with pregnancy. However, there is little information on the protease behaviour in normal pregnancy. We studied von Willebrand factor and ADAMTS13 activity changes in normal non-pregnant, pregnant and post-delivery women. Fifty-five non-pregnant women, normal blood bank donors, who were not taking contraceptive pills were included as controls. A prospective cross-sectional study of 270 normal pregnant and post-delivery women was carried out. ADAMTS13 activity decreased progressively as from the period of 12-16 weeks up to the end of early puerperium (mean 52%, range 22-89, p < 0.0001), to increase slightly thereafter. Nulliparous presented mildly lower levels of ADAMTS13 activity than parous women (65% vs. 83 %, p = 0.0003), and primigravidae than multigravidae between 6-11 weeks up to 17-23 weeks of pregnancy (69% vs. 80%, p = 0.005). Although in all women the protease levels were the same by blood groups, the O blood group non-pregnant women showed a higher mean of ADAMTS13 activity than those non-O (78% vs. 69%, p = 0.064). Our results suggest that the changing levels of protease activity during pregnancy and puerperium, induced by unidentified mechanisms, could render the peripartum time more vulnerable to developed thrombotic microangiopathies.

Anticoagulation in the antiphospholipid syndrome.

Our objectives were to evaluate thrombotic complications in patients with lupus anticoagulant fulfilling Sapporo criteria, anticoagulated with an intended INR 2.0-3.0 due to venous and arterial thrombosis. In our series standard anticoagulation was safe and efficacious in preventing recurrences in patients with systemic lupus erythematosus, with other thrombophilia and with arterial thrombosis.

Morbidity of lupus anticoagulants in children: a single institution experience.

INTRODUCTION: The lupus anticoagulant (LA) and the anticardiolipin antibodies (ACA) are the antiphospholipid antibodies more relevant clinically. Their clinical manifestations are diverse with most patients being asymptomatic while others present venous or arterial thrombosis, and more rarely, bleeding. Our objectives were to evaluate clinical presentation of LA in children and to correlate it to LA behavior. PATIENTS AND METHODS: A retrospective cohort of patients (under 18 years old) who had a positive determination of LA followed by at least another determination of LA at a variable period was evaluated. Personal and family history, including infectious diseases temporally related to the event, were recorded. The screening of other coagulation disorders was performed according to symptoms, family history or laboratory results. RESULTS: Thirty-six patients were evaluated, median age was 10.8 years old, and 52.8% were female. Asymptomatic patients were 19.4% (7/36) of study population. Bleeding and thrombosis were found in 52.8% and 27.8%, respectively. Median LA determinations per patient were 3. von Willebrand disease was diagnosed in 66.7% of patients consulting for bleeding. A concomitant hemostatic defect was found in 8/10 patients with thrombosis (p = 0.003). LA behavior was not uniform and not correlated to symptoms. CONCLUSIONS: Most LA found in children is incidental and asymptomatic. In children with bleeding, LA might be a fortuitous finding associated with VWD. The persistence of LA does not imply a higher risk of thrombosis.

Assessment of platelet activation in myeloproliferative disorders with complementary techniques.

Bleeding and thrombosis in myeloproliferative disorders (MPD) are common events, sometimes both are present in the same patient during the course of the disease. Platelet activation in patients with MPD is often suggested. The present study analyses the presence of circulating activated platelets, using simultaneously flow cytometry and aggregometric studies in MPD. We studied 28 patients: 13 with polycythaemia vera, seven with essential thrombocythaemia, and eight chronic myeloid leukaemia. We performed functional tests, aggregation and adenosine triphosphate (ATP) release and flow cytometric assays (mepacrine staining and platelet activation markers CD62, CD63 and fibrinogen binding (B-FG)). Twenty-one MPD samples (75%) had reduced aggregation and ATP release. Acquired delta-SPD was detected in 11 of 28 MPD patients (39%), and we found no association between reduced mepacrine labelling and abnormal ATP release. High levels of activation markers were obtained: CD62 in 19 of 28 patients (68%), CD63 in 13 of 28 patients (46%) and B-FG in 19 of 28 patients (68%). The most prevalent abnormality was a reduced aggregation and ATP release. The lack of association between ATP release and mepacrine labelling suggests that other mechanisms, besides the deficit of intraplatelet ATP/adenosine diphosphate, might occur. High levels of activation markers were also observed. We conclude that both tests are complementary and necessary to understand the functional status of platelets in MPD.

Factor VIII and von Willebrand factor changes during normal pregnancy and puerperium.

Gestation is a challenge to haemostasis and it is associated with significant haemostatic changes. Several studies have evaluated von Willebrand factor in normal pregnancy, but none considered the personal history of bleeding. We studied a group of healthy non-bleeding women (184 pregnant, 64 puerperium, 37 non-pregnant) to evaluate normal ranges and their relationship to blood group and parity. The von Willebrand factor increased markedly from non-pregnant values up to the end of early puerperium (P < 0.0001), while factor VIII only showed a slight increase. Factor VIII and von Willebrand factor activity remained within the normal range for non-pregnant women. The return to non-pregnant factor levels occurred in late puerperium, later than previously reported. Only factor VIII was significantly lower in the O blood group (P = 0.035). As regards parity, there were no differences in factor VIII, von Willebrand factor antigen and von Willebrand factor ristocetin cofactor between primigravidae and multigravidae for any period studied (P = 0.888, 0.999, and 0.237, respectively). Our results provide reference ranges that may help to design a study in von Willebrand factor disease in pregnancy.

Biological and clinical response to desmopressin (DDAVP) in a retrospective cohort study of children with low von Willebrand factor levels and bleeding history.

The diagnosis and management of von Willebrand disease (VWD) in paediatrics is challenging. Our aim was to review patient's characteristics related to biological and clinical response to DDAVP in children with low von Willebrand factor (VWF) levels and bleeding history from a single institution. We included a retrospective cohort of 221 children (median age 11 years; 137 females): 27 type 1 (VWF levels within 15-30 IU dL-1) and 194 possible type 1 (VWF levels within 31-49 IU dL-1). The DDAVP infusion-test was performed in 214/221 children, 93.4% of whom showed good response. Patients with type 1 were at higher risk of DDAVP-test failure: 9/26 (34.6%) vs. 18/188 (9.6%) with possible type 1 (RR 3.44, 1.75-6.79; p= 0.002, Fisher's exact test). In 68 children, the clinical response to DDAVP was evaluated 87 times: i) to stop bleeding: menorrhagia (13), mucocutaneous (12), haemarthrosis (1); and ii) to prevent surgical bleeding: adenotonsillectomy (17), major (15) and minor surgery (10); and dental procedures (19). No major adverse events or bleeding were observed. The treatment was effective with one single dose of DDAVP in almost all patients, without antifibrinolytic or local therapy, except in a girl with severe haemorrhage during menarche who required replacement therapy. In conclusion, patients with VWD type 1 were at higher risk of no response to DDAVP infusion-test. In this series, one dose of DDAVP proved effective and safe for children with VWD. Since this is a safe, effective and affordable therapy, we consider that a wider use should be promoted, especially in developing countries.

Effect of low-dose aspirin on the international normalized ratio variability in patients with mechanical heart valve prostheses.

An increased risk of bleeding is associated with a more intense oral anticoagulation, a greater international normalized ratio (INR) variability and the use of aspirin. We studied the INR variability of patients (n = 121) with modern heart valves who had been prospectively randomized to receive acenocoumarol at a targeted INR of 2.4-3.6 plus aspirin 100 mg/day or acenocoumarol alone at the same dosage, to evaluate whether aspirin influences variability and thus the risk of bleeding. Variability was similar in patients with no events regardless of the use of aspirin. A statistically significantly higher variability was observed in patients with bleeding events independently of the use of aspirin. Nevertheless, the concomitant use of aspirin in patients with a high variability should be monitored closely and thoroughly.

Acquired von Willebrand factor abnormalities in myeloproliferative disorders and other hematologic diseases: a retrospective analysis by a single institution.

BACKGROUND AND OBJECTIVES: Acquired von Willebrand syndrome (AVWS) is a rare acquired disorder. In most cases it is associated with lymphoproliferative disorders and monoclonal gammopathies, while less frequently myeloproliferative disorders (MPD) are involved. Although bleeding is the most important symptom, thrombotic complications have also been observed in cases associated with MPD. Our aim was to review the clinical and laboratory findings in AVWS patients from a single institution. DESIGN AND METHODS: The records of 99 patients with AVWS were reviewed to identify the underlying diseases, the symptoms and the laboratory parameters. RESULTS: In 75% of cases the AVWS was associated with MPD. The most frequent pattern was type 2 (67.7%). Abnormalities of bleeding time, factor VIII levels or platelet retention to glass beads were observed in 83.8% of cases. Bleeding was present in 38.4% of patients, more frequently in the not-MPD-associated (58.3%) vs. MPD-associated cases (32%) (p=0.022), with a significant predominance in females, irrespective of the underlying disease (p=0.0007). In 32% of patients with MPD, thrombotic manifestations, mostly microvascular and arterial episodes, were observed. INTERPRETATION AND CONCLUSIONS: AVWS in MPD seems to be mainly a laboratory diagnosis, without clinical symptoms in most cases, although bleeding as well as ischemic events can be present. In contrast, AVWS in not-MPD-associated cases is most frequently associated with severe bleeding symptoms. Performing appropriate laboratory tests may be useful for screening for AVWS.

Primary upper-extremity deep vein thrombosis: high prevalence of thrombophilic defects.

Primary deep venous thrombosis of the upper extremity (UEDVT) is an unusual disorder. Limited data are available on the contribution of hypercoagulable status in the pathogenesis of this disease. This study aims to report the prevalence of inherited and acquired thrombophilic risk factors (TF) in patients with primary (effort-related and spontaneous) UEDVT. From 1993 to 2002, 31 patients (17 females, median age 38.8 years, range 16-60 years; and 14 males, median age 31.4 years, range 20-56 years) with primary UEDVT (n = 15 effort-related and n = 16 spontaneous) were referred for screening of hypercoagulable status. Nineteen (61.3%) patients had at least one coagulation abnormality. The most common acquired TF were antiphospholipid antibodies (31% lupus anticoagulant and 12.9% anticardiolipin antibodies). Factor V Leiden (12.9%) and prothrombin G20210A mutation (20%) were the most prevalent genetic risk factors. Five patients (16.1%) had high plasma homocysteine levels, and one patient (4.7%) had protein S deficiency. Effort-related UEDVT was associated with male gender (P = 0.04) and younger age (P = 0.02). There was no significant difference in the prevalence of acquired or inherited TF between patients with effort-related or spontaneous UEDVT. A local anatomic abnormality was detected in seven patients (22.5%), and the prevalence of TF was significantly lower within this group (P = 0.006). The incidence of TF in patients without an anatomic abnormality was 75% (RR 5.25). This study found a high prevalence of an underlying thrombophilic status in spontaneous and effort-related UEDVT. Hypercoagulable status may play a significant role in both groups. Screening for local anatomical abnormalities and thrombophilia should be included in the evaluation of primary UEDVT.

Medicina hoy: presente y futuro de los anticoagulantes orales / Medicine today: present and future of oral anticoagulants

El número de pacientes bajo tratamiento anticoagulante oral se ha incrementado notablemente en los últimos años al incorporarse la población de pacientes con fibrilación auricular crónica. Su manejo se ha facilitado al contar actualmente con reactivos comerciales sensibles y calibrados. No obstante este avance, las complicaciones hemorrágicas siguen siendo uno de los peligros de este tratamiento. En nuestra experiencia, las hemorragias mayores se correlacionan sobre todo con la intensidad de la anticoagulación y la duración del tratamiento. También la variabilidad del RIN (Razón Internacional Normatizada) (la desviación del RIN del rango deseado) puede asociarse con mayor sangrado. La necesidad de ajustar la dosis con pruebas de laboratorio, los controles frecuentes, la interacción con otras medicaciones, la estrecha ventana terapéutica y la alta variación en la relación dosis-respuesta, hacen surgir la necesidad de nuevos agentes antitrombóticos, igualmente eficaces, pero que permitan prescindir del ajuste por el laboratorio. Inhibidores de trombina de bajo peso molecular disponibles por vía oral están actualmente en período de prueba y constituirían una alternativa al tratamiento con antagonistas de vitamina K.

Presente y futuro de los anticoagulantes orales / Present and future of the oral anticoagulants

El número de pacientes bajo tratamiento anticoagulante oral se há incrementado notablemente en los últimos años al incorporarse la población de pacientes con fibrilación auricular crónica. Su manejo se há facilitado al contar actualmente con reactivos comerciales sensibles y calibrados. No obstante este avance, las complicaciones hemorrágicas siguen siendo uno de los peligros de este tratamiento. En nuestra experiencia las hemorragias mayores se correlacionan sobre todo con la intensidad de la anticoagulación y la duración del tratamiento. También la variabilidad del RIN (Razón Internacional Normatizada) (la desviación del RIN del rango deseado) puede asociarse con mayor sangrado. La necesidad de ajustar las dosis con pruebas de laboratorio, los controles frecuentes, la interacción con otras medicaciones, la estrecha ventana terapéutica y la alta variación en la relación dosis-respuesta hacen surgir la necesidad de nuevos agentes antitrombóticos, igualmente eficaces, pero que permitan prescindir del ajuste por el laboratorio, Inhibidores de trombina de bajo peso molecular disponibles por vía oral están actualmente en período de prueba y constituirían una alternativa al tratamiento con antagonistas de vitamina K.