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.

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.

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.

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.

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.