Von Willebrand factor (VWF) as a risk factor for bleeding and thrombosis.

The von Willebrand factor (VWF) is analysed as a bleeding and thrombotic risk marker. When the VWF level is increased, it predicts a thrombotic phenotype and when VWF level is low in plasma, the phenotype varies to bleeding disorder. But it is quite challenging to define when the level is low, normal or high taking into account that these values are capricious and overlap. This matter should be solved by extensive epidemiologic studies. VWD is a hereditary disorder with several described mutations. VWF is a major acute-phase reactant, besides the physiological conditions such as blood group and pregnancy that affect plasmatic VWF levels. Subjects with O blood group have 25% less VWF than those of non O blood groups, and the latter show higher thrombus burden. VWF would be sensitive though not specific diagnostic marker of myocardial infarction. For the assessment of bleeding severity there are special surveys, scores and pictorial charts. The identification of VWF as a thrombotic risk marker has not been clearly established yet, but it has been involved in stroke and coronary disease. We only have the specific replacement therapy for the bleeding phenotype and we can speculate that enoxaparin and PEG-hirudin are able to blunt the VWF rise in patients with unstable angina pectoris and it is associated with a more favourable clinical outcome. Only two questions remain: does VWF as a bleeding risk marker have the same value as a thrombotic risk marker? Will successful treatments like those achieved for bleeding be also possible in the future for thrombosis?

C1272F: a novel type 2A von Willebrand's disease mutation in A1 domain; its clinical significance.

Most mutations identified in 2A VWD patients are localized in the A2 domain, although missense substitutions have also been recognized in the A1 domain. We describe a novel heterozygous missense mutation in the A1 domain of VWF gene responsible for type 2A phenotype. Analysis of the complete exon 28 was carried out in a patient and his mother with life-long histories of moderate to severe bleeding and laboratory data of type 2A VWD. The analysis of exon 28 of VWF gene showed a 3815 G → T transversion resulting in C1272F mutation. It is probably associated with a group I mechanism according to patients' clinical symptoms, and, in the case of the propositus, the lack of clinical response to treatment with desmopressin. The mutation was not found in 100 normal alleles. This substitution affected the normal S-S bound between C1272 and C1458, which is involved in A1 loop structure, altering the normal multimerization and function of VWF. The VWFpp/VWF:Ag ratio in the propositus and his mother was >3, suggesting a shortened survival of VWF. We believe it is important to report the complete clinical phenotype corresponding to the new mutation to increase the knowledge in the clinical field.

von Willebrand's disease diagnosis and laboratory issues.

SUMMARY: In this paper, the recent developments in the diagnosis and laboratory issues of von Willebrand's disease (VWD) are presented. Dr. Castaman reviews the functional tests available for the diagnosis of VWD and their pathophysiological significance, focusing on which tests are best used in the diagnosis and classification of VWD. Dr Montgomery reviews an emerging issue that is accelerated clearance of von Willebrand factor (VWF) occurring in some variants of VWD. This phenotype can be suspected by the presence of an increased ratio between the VWF propeptide and the VWF antigen. These patients have typically a robust, but short-lived increase of FVIII and VWF after desmopressin. Dr Meschengieser reviews the determinants of bleeding after surgery in patients with VWD, emphasizing the role of bleeding history in predicting this risk.

Patients' perceptions regarding oral anticoagulation therapy and its effect on quality of life.

OBJECTIVE: Anticoagulation clinics have improved the time spent within therapeutic range and decreased hemorrhagic complications and costs in chronic oral anticoagulation. Whether these benefits correlate to patients' quality of life (QOL) remains to be determined. The impact of patients' perceptions about anticoagulation on QOL has not been evaluated. The objective of this study was to evaluate prospectively patients' perceptions and quality of life in patients chronically anticoagulated. RESEARCH DESIGN AND METHODS: A cross-sectional study was designed to investigate the prevalence of positive and negative perceptions about oral anticoagulation therapy (OAT) and to identify vulnerable groups. Patients anonymously completed the SF-36 survey and a questionnaire that focused on patients' perceptions of protection from thrombotic complications or fear of haemorrhage due to the anticoagulation. We related those perceptions to the General Health SF-36 score, to the patient's characteristics, the absolute bleeding risk (i.e. intended International Normalized Ratio [INR]), duration of therapy and medical attention. RESULTS: One thousand patients were included and 905 questionnaires evaluated. Most patients felt protected and better since the beginning of therapy (71.5% and 61.5%, respectively). Patient characteristics associated with negative perceptions were; female sex (Odds Ratio [OR] 1.58, 95% Confidence Interval [CI] 1.06-2.36, p = 0.01); patients with less than 1 year of therapy (OR 2.16, 95% CI 1.34-3.48, p = 0.006); those not satisfied with medical attention (OR 2.86, 95% CI 1.53-5.18, p = 0.0001); and those that modified their lifestyle (OR 2.75, 95% CI 1.49-4.91, p = 0.0002). Patients with a lower bleeding risk (INR 2.0-3.0) had more negative perceptions than those with a higher risk. Patients with negative perceptions achieved the lowest score in the SF-36 survey. Haemorrhages did not affect patients' perception or QOL. CONCLUSIONS: Patients' perceptions correlated with QOL. We were able to identify patient characteristics associated with poor QOL and thus the group of patients whose negative perceptions most warranted special attention from their clinicians.

von Willebrand disease: laboratory aspects of diagnosis and treatment.

von Willebrand disease is the most common inherited bleeding disorder in humans. VWD can be classified into three major types, designated Types 1, 2 and 3; Type 2 can be further separated into subtypes 2A, 2B, 2M and 2N. The diagnosis of VWD requires a personal and family history of bleeding and confirmation by laboratory analysis. Although Types 2 and 3 are relatively straightforward to diagnose, there may be a risk of overdiagnosis of Type 1 because of an overlap within the normal range. We also report on the clinical profile and diagnosis of VWD in a South American cohort of patients and on the in vitro characteristics of some factor concentrates available for treatment of VWD.

Recurrent haemoperitoneum in a mild von Willebrand's disease combined with a storage pool deficit.

Haemoperitoneum secondary to haemorrhagic corpus luteum has been described in severe bleeding disorders such as afibrinogenaemia, type 3 von Willebrand's disease and patients under oral anticoagulation. We have studied one patient who presented three episodes of severe bleeding at ovulation, requiring surgery twice, with the diagnosis of mild von Willebrand's disease and mild storage pool deficiency. Mild von Willebrand's disease (associated with other thrombopathies or coagulopathies) should be considered in this pathology, although physicians would prefer to find a severe haemorrhagic disorder as the underlying condition in these cases.

Clinical features and laboratory patterns in a cohort of consecutive Argentinian patients with von Willebrand's disease.

BACKGROUND AND OBJECTIVES: von Willebrand's disease (vWD) is a bleeding disorder with variable clinical expression. Our aim was to classify patients with vWD and to determine the phenotype in their relatives. DESIGN AND METHODS: The types and subtypes, blood group frequency and its relevance, bleeding sites, response to the desmopressin (DDAVP) test, transfusion requirements and clinical features in type 1 and 2A families were determined in 1,885 patients. RESULTS: Our findings were: type 1: 91%, type 2A: 3.1%, severe vWD: 1.3%; type 2N: 1.6%; type low intraplatelet: 2.7%; combined 1+ 2N: 0.3%. Blood group O prevalence was 70.5%. Bleeding and transfusion requirements were not correlated to blood groups. The most frequent symptoms were: ecchymoses-hematomas and epistaxis and, in females over 13 years, also menorrhagia. Normal levels of factor VIII:C were found in 38.4% of the patients. DDAVP was infused in 567 patients with a good response in 80.6%. About 9% of our patients needed transfusion therapy. The diagnosis of von Willebrand's disease is more likely in subjects belonging to families with type 2A disease than in members of families with type 1 vWD in spite of these being symptomatic. INTERPRETATION AND CONCLUSIONS: These observations provide a good strategy to identify, classify and treat vWD patients without performing molecular assays.

[Present and future of oral anticoagulants]. / Presente y futuro de los anticoagulantes orales.

The number of patients under oral anticoagulant therapy has markedly increased lately, mainly due to those with chronic atrial fibrillation. Progress has been made in the control of oral anticoagulation because sensitive and calibrated commercial reagents for prothrombin time have become available. But bleeding is still a problem in these patients. In our experience, the intensity and the duration of the anticoagulant therapy are the most important risk factors for bleeding. The deviation of INR (International Normalized Ratio) can also be associated with higher risk for bleeding. The limitations of oral anticoagulant therapy include frequent laboratory controls for dose adjustment, drug interactions, narrow therapeutic range and the high variability in patient response. These limitations prompted the development of new antithrombotic agents. A number of low molecular weight active site inhibitors of thrombin are being developed and one of them is orally bioavailable, and could become an alternative to vitamin K antagonists.

Bleeding risk factors in chronic oral anticoagulation with acenocoumarol.

We studied major bleeding complications, death related to hemorrhage, and tried to identify predisposing factors for bleeding in outpatients treated with acenocoumarol. We evaluated 811 outpatients attending a specialized anticoagulant therapy unit. The intended INR range was 3.5-4.5 for mechanical heart valve replacement (N= 384) and 2.0-3.0 for other indications (N= 427). The variability of INR for the total follow-up and the 2 months before the hemorrhage was calculated. The total follow-up was 1,963.26 years with 27,321 control tests. We observed 47 major bleeding episodes, including 2 fatal (central nervous system hemorrhages), in 37 patients. 49.5% of the patients had underlying diseases. The rate of major and fatal hemorrhage was 2.39 and 0.10 episodes per 100 patients year, respectively. Hemorrhagic complications were more frequently observed in patients with a more intense intended range (8.2% in the INR 3.5-4.5 group vs. 1.5% in the 2.0-3.0 INR group). The risk of major bleeding increased in patients with an achieved INR higher than 6 and in those with higher INR variability during follow-up. The estimated probability of bleeding also increased with time: it was 0.102% at 78 months, and at the beginning of therapy it was 0.006% and 0.007% at 1 and 4 months, respectively. The intensity of anticoagulation and the deviation of the INR from the target are the most important risk factors for bleeding in patients taking acenocoumarol. Monitoring the variability of INR can help identifying patients predisposed to bleeding. However, the screening for underlying disease should always be performed.

Presente y futuro de los anticoagulantes orales. / [Present and future of oral anticoagulants]

The number of patients under oral anticoagulant therapy has markedly increased lately, mainly due to those with chronic atrial fibrillation. Progress has been made in the control of oral anticoagulation because sensitive and calibrated commercial reagents for prothrombin time have become available. But bleeding is still a problem in these patients. In our experience, the intensity and the duration of the anticoagulant therapy are the most important risk factors for bleeding. The deviation of INR (International Normalized Ratio) can also be associated with higher risk for bleeding. The limitations of oral anticoagulant therapy include frequent laboratory controls for dose adjustment, drug interactions, narrow therapeutic range and the high variability in patient response. These limitations prompted the development of new antithrombotic agents. A number of low molecular weight active site inhibitors of thrombin are being developed and one of them is orally bioavailable, and could become an alternative to vitamin K antagonists.

Anticoagulation in pregnant women with mechanical heart valve prostheses.

OBJECTIVE: To evaluate the outcome of pregnancy in women with mechanical heart valve prostheses in relation to the anticoagulant treatment used in the first trimester and the incidence of thrombotic and bleeding complications. METHODS: 92 pregnancies in 59 women were followed between 1986 and 1997. In 31 pregnancies, oral anticoagulants were discontinued when pregnancy was diagnosed and subcutaneous heparin was started (12 500 U every 12 hours) adjusted to prolong the adjusted partial thromboplastin time to twice the control level. In the second trimester oral anticoagulants were resumed but changed to heparin again 15 days before the expected delivery date. In 61 pregnancies oral anticoagulants were continued during the first trimester. The same regimen of heparin was used for delivery. RESULTS: Abortion or fetal losses were similar (p = 0. 5717) in women exposed to oral anticoagulants in the first trimester (13/61; 25%) compared with those who received adjusted subcutaneous heparin (6/31; 19%). Embolic episodes were more common (p = 0.0029) in women who received heparin (4.92%) compared with those on oral anticoagulants (0.33%). Embolic episodes were cerebral and transient. No valve thromboses were observed. No malformations appeared in the 71 newborns, except for one case of hydrocephalus. There were no maternal deaths secondary to thrombotic complications. The only death was the result of major bleeding after the delivery of a premature stillborn. CONCLUSIONS: Oral anticoagulants seem to be safer for the mother than adjusted subcutaneous heparin. Heparin does not offer a clear advantage over oral anticoagulation in the pregnancy outcome.

Low-intensity oral anticoagulation plus low-dose aspirin versus high-intensity oral anticoagulation alone: a randomized trial in patients with mechanical prosthetic heart valves.

BACKGROUND: Mechanical heart valve replacement requires lifelong anticoagulant treatment. Aspirin has proved useful in further reducing thromboembolic events when added to oral anticoagulants. However, increased (gastrointestinal) bleeding was observed at the doses previously tested for this combination in heart valve prostheses. METHODS: We performed a prospective randomized trial to compare the combination of low-intensity oral anticoagulants (international normalized ratio 2.5 to 3.5) plus aspirin (100 mg/day) (arm A) versus high-intensity oral anticoagulants alone (arm B) (international normalized ratio 3.5 to 4.5). Arm A included 258 patients and arm B 245 patients. The two groups were comparable for all baseline characteristics. RESULTS: The outcomes of the study were embolism, valve thrombosis, and major hemorrhage. The median follow-up was 23 months. The two treatments offered similar antithrombotic protection. The incidence of embolic episodes was 1.32 per 100 patient-years (95% confidence interval 0.53 to 2.7) for arm A and 1.48 per 100 patient-years (95% confidence interval 0.59 to 3.03) for arm B. Major hemorrhage occurred in 1.13 per 100 patient-years (95% confidence interval 0.41 to 2.45) for arm A and 2.33 per 100 patient-years (95% confidence interval 1.17 to 4.14) for arm B. Gastrointestinal bleeding was not increased by this combined reduced dose of aspirin and coumarin.

Persistence of low platelet adhesiveness in von Willebrand disease during pregnancy.

Platelet adhesiveness (PA) is a valuable measure of ex vivo platelet function. A low PA is a usual feature of von Willebrand disease (vWd). However, PA has rarely been measured during vWd pregnancies. The aim of this work was to observe the behaviour of PA in vWd pregnancies. PA was measured during pregnancy in 33 vWd patients. Intrapregnancy PA remained low without any significant variation compared with non-pregnancy values. Advanced gestation was not accompanied by any increase in PA in spite of the concomitant normalization showed by the other markers of vWd. A low intrapregnancy value was not predictive of an increased risk of bleeding at labour. A low PA could be the only clue for vWd during gestation warranting both a vigilant postpartum attitude and a thorough haemostatic evaluation after pregnancy.

Effect of acenocoumarine on the breast-fed infant.

Apart from teratogenic phenomena and the potential risk of maternal or neonatal peripartum haemorrhage, the use of oral anticoagulants during pregnancy poses an additional hazard: the risk of transferring some anticoagulant activity to the nursing infant through breast milk. We analysed the coagulation status of seven full term breast-fed neonates whose mothers were under chronic anticoagulant therapy with acenocoumarine as thromboembolic prophylaxis following cardiac valve replacement. Prothrombin Times (PT) observed in neonates were significantly higher than the corresponding maternal values. Data were subsequently compared with those obtained from a control group comprising forty-two full term neonates nursed by non-anticoagulated mothers: coagulation profiles again showed no signs of any noticeable antivitamin K effect. Our results indicate that mothers given acenocoumarine at therapeutic doses may safely breast-feed their infants: anticoagulant activity in breast milk seems to be negligible as assessed by neonates PT.

Uso del DDAVP en pacientes con enfermedad de von willebrand y trombocitopatias / DDAVP use in patients with Von Willebrand's disease and thrombocitopathy

Se evaluó la eficacia de la desmopresina (DDAVP) por vía intranasal o endovenosa en 5 pacientes con enfermedad de von Willebrand y en uno con una trombocitopatía tipo déficit del pool de depósito. En 2 casos con 250 microng de DDAVP intransales sde observó aumento en el FVIII, vWFAg y vWFRCo, y la adhesividad plaquetaria. Esto desapreció a las 6 horas y no llegó a duplicar los valores basales. En 3 casos con 500 microng de DDAVP intranasales. La adhesividad plaquetaria se incrementó con una duración breve en 2 casos y sin alcanzar niveles normales en el tercero. El aumento en el FVIII, vWFAg y vWFRCo se observó en 2 de los 32 casos ue partieron de niveles basales normales. El tiempo de sangría se acortó en 2 pacientes. Globalmente se consideró que en los 3 casos con 500 microng, la respuesta fue inadecuada y debería optarse por la vía endovenosa. En el pacietne con trombocitopatía se administraron 4 microng endovenosos de DDAVP (una sexta parte de la dosis teórica). La adhesividad plaquetaria se normalizó y el tiempo de sangría se acortó pero el efecto se agotó a las 2 horas. Estos ensayos sugieren que la vía intranasal puede lograr correción delos parámetros alterados en la enfermedad de von Willebrand de breve duración; pero que como los resultados pueden no ser satisfactorios, siempre debe ser probada previamente a su indicación terapéutica

Uso del DDAVP en pacientes con enfermedad de von willebrand y trombocitopatias / DDAVP use in patients with Von Willebrands disease and thrombocitopathy

Se evaluó la eficacia de la desmopresina (DDAVP) por vía intranasal o endovenosa en 5 pacientes con enfermedad de von Willebrand y en uno con una trombocitopatía tipo déficit del pool de depósito. En 2 casos con 250 microng de DDAVP intransales sde observó aumento en el FVIII, vWFAg y vWFRCo, y la adhesividad plaquetaria. Esto desapreció a las 6 horas y no llegó a duplicar los valores basales. En 3 casos con 500 microng de DDAVP intranasales. La adhesividad plaquetaria se incrementó con una duración breve en 2 casos y sin alcanzar niveles normales en el tercero. El aumento en el FVIII, vWFAg y vWFRCo se observó en 2 de los 32 casos ue partieron de niveles basales normales. El tiempo de sangría se acortó en 2 pacientes. Globalmente se consideró que en los 3 casos con 500 microng, la respuesta fue inadecuada y debería optarse por la vía endovenosa. En el pacietne con trombocitopatía se administraron 4 microng endovenosos de DDAVP (una sexta parte de la dosis teórica). La adhesividad plaquetaria se normalizó y el tiempo de sangría se acortó pero el efecto se agotó a las 2 horas. Estos ensayos sugieren que la vía intranasal puede lograr correción delos parámetros alterados en la enfermedad de von Willebrand de breve duración; pero que como los resultados pueden no ser satisfactorios, siempre debe ser probada previamente a su indicación terapéutica (AU)