Response to desmopressin of factors XI, X and V in patients with factor VIII deficiency and von Willebrand disease.

Desmopressin [1-deamino-8-d-arginine vasopressin (DDAVP)] has been successfully used in the treatment of type 1 von Willebrand disease (VWD) and mild haemophilia A (MHA). Data suggest that DDAVP can increase factor XI (FXI) plasma levels and may represent an effective treatment for mild FXI deficiency. We assessed the DDAVP response of FXI coagulant activity (FXI:C), FXI antigen (FXI:Ag), factor V coagulant activity (FV:C), and factor X coagulant activity (FX:C) in 33 individuals with VWD or MHA. DDAVP did not produce a clinically significant increase in FXI:C, FXI:Ag, FX:C or FV:C in any patient. The mean +/- SD FXI:C pre-DDAVP (time 0) and at 1 h post-DDAVP was 90.7 (+/-22.9) U/dl and 92.1 (+/-20.9) U/dl, respectively. The mean (+/-SD) FXI:Ag at time 0 and 1 h was 92.2 (+/-20.1) U/dl and 89.9 (+/-21.3) U/dl, respectively. There was a small reduction at 1 h post-DDAVP in both FV:C, from 101.8 (+/-20.9) U/dl to 97.2 (+/-21.4) U/dl (P < 0.001), and FX:C from 103 (+/-19.5) U/dl to 98.8 (+/-18.7) U/dl (P < 0.001). No significant increase in FXI:C, FXI:Ag, FV:C or FX:C levels was seen at 4 h post-DDAVP. This study failed to demonstrate a clinically significant increase in the levels of FXI, FX or FV following administration of DDAVP.

Stem cell transplantation after salvage therapy with high-dose cytarabine and amsacrine in adults with high-risk leukaemia.

Stem cell transplantation (SCT) may be the only curative option for patients with relapsed or refractory leukaemia, that is, high-risk (HR) leukaemia. Several salvage regimens have been used to cytoreduce disease before SCT, but disease progression or treatment toxicity limits numbers of patients receiving SCT. Here, we report our experience with high-dose cytarabine and amsacrine (Ara-amsa) to salvage patients with HR-leukaemia in the context of SCT. A total of 34 patients with HR-leukaemia (20 AML, 12 ALL, two advanced CML) received 3 g/m(2)/day cytarabine for 5 days and amsacrine 200 mg/m(2)/day for 3 days. Disease response was observed in 62% of patients. Toxicity was limited to neutropenic fever, one patient developed cerebellar toxicity and there was one treatment-related death. A total of 17 patients proceeded to SCT (12 allografts and five autografts). Median survival (OS) of all patients was 10.8 months (95% CI 7.8-21). Patients who were consolidated with SCT after salvage therapy had a superior median OS of 29.4 months (95% CI 12.5-upper limit not reached, n=17) than those who did not receive SCT (6.7 months, CI 1.5-8.6, P<0.0001). Median disease-free survival with SCT (23 months) was higher than after treatment with salvage chemotherapy alone (6.7 months, P=0.0002). Thus Ara-amsa can be used effectively to salvage HR-leukaemia, enabling further consolidation with SCT.

The role of the platelet function analyser (PFA-100) in the characterization of patients with von Willebrand's disease and its relationships with von Willebrand factor and the ABO blood group.

Determination of the closure time (CT) with the platelet function analyser (PFA-100) is a useful screening test for von Willebrand's disease (VWD) but its role in the characterization of VWD is not well established. We studied the relationship between the prolongation of the CT with adenosine diphosphate (ADP) (CT-ADP) and epinephrine (CT-EPI) cartridges and the von Willebrand factor (VWF) in 53 patients with VWD. We found that a relatively small percentage of the prolongation of the CT-ADR and CT-ADP (16 and 29%, respectively) was determined by a reduction in VWF levels. The CT-ADP was significantly more prolonged in the presence of qualitative defects in VWF but could not discriminate between the VWD subtypes. The ABO blood group had no effect on the prolongation of the CT or the bleeding time. In conclusion, the PFA-100 appears of little use in the characterization of severity and subtype of VWD.

Inverse relationship between plasma von Willebrand factor and soluble P selectin in patients with type 1 but not type 2 von Willebrand disease.

P selectin is a component of endothelial Wiebel-Palade body membrane and platelet alpha granule membrane. Patients with von Willebrand disease (VWD) have low plasma von Willebrand factor (VWF). To examine the relationship between plasma P selectin and VWF, both were measured by ELISA in 38 patients with VWD and 40 controls. The patient had lower VWF (P < 0.001) but similar P selectin levels (P = 0.458). In 24 type 1 VWD patients, VWF and P selectin correlated inversely (P = 0.005) but in 14 type 2 VWD patients there was no correlation (P = 0.997). These data imply major differences in VWF/P-selectin regulation between types 1 and 2 VWD.

Retrospective review of the management of elective surgery with desmopressin and clotting factor concentrates in patients with von Willebrand disease.

Limited data are available regarding optimal treatment with desmopressin (DDAVP) or intermediate-purity FVIII concentrates rich in VWF (CFCs) in patients with von Willebrand disease (VWD) who undergo planned surgery. We undertook a retrospective review over 10 years (1988-1997) and identified 27 patients treated with DDAVP for 35 surgical events and 38 patients who received CFCs for 68 elective surgical events. Tranexamic acid was usually added for mucosal surgery. The FVIII:C levels and the severity of surgery were used to determine the frequency and the doses of postoperative treatment. For major surgery the median pre- and post-operative doses of CFCs were 54 and 43 IU/kg, respectively, and for minor surgery the median doses varied between 34 and 52 IU/kg preoperatively and between 23 and 37 IU/kg postoperatively. The effectiveness of haemostasis was excellent in 32 events (91%) treated with DDAVP and in 56 events (82%) treated with CFCs. It is concluded that patients with VWD do not carry an increased operative risk if appropriate therapy is given.

Type 1 von Willebrand disease - a clinical retrospective study of the diagnosis, the influence of the ABO blood group and the role of the bleeding history.

This clinical retrospective study investigated the difficulties in diagnosing type 1 von Willebrand disease (VWD). A total of 246 patients previously diagnosed with type 1 VWD were reclassified into 'possible' type 1 VWD (patients with low levels of VWF adjusted for the blood group and either a significant bleeding history or family history) and 'definite' type 1 VWD, requiring low levels of von Willebrand factor (VWF), a bleeding history and inheritance. On reclassification, only 144/246 (59%) patients had low VWF levels adjusted for blood group, 88/246 (36%) patients met all the criteria for 'definite' type 1 VWD and 51/246 (21%) patients were 'possible' type 1 VWD. A significant proportion of patients, 102/246 (42%), remained an indeterminate group with blood type O, VWF levels between 35 and 50 U/dl and personal and/or family bleeding history. This subgroup might require reclassification as 'not VWD'. However, a similar bleeding tendency was found in two matched groups of patients of blood groups O and non-O and VWF levels between 35 and 50 U/dl. These results suggest that the use of ABO adjusted ranges for VWF levels might not be essential for diagnosis, because bleeding symptoms may depend on the VWF level regardless of the ABO type. Of the diagnostic criteria, the bleeding history was of prime importance in the clinical decision to diagnose and treat type 1 VWD. These observations could help in the reconsideration of how the criteria for diagnosing type 1 VWD could be adjusted in order to maximize their clinical relevance.

Identification of type 2 von Willebrand disease in previously diagnosed type 1 patients: a reappraisal using phenotypes, genotypes and molecular modelling.

In order to investigate the possibility that qualitative type 2 defects in von Willebrand factor (VWF) occurred in patients previously diagnosed with quantitative type 1 von Willebrand disease (VWD), the phenotypes and genotypes were reanalysed in 30 patients who exhibited discrepant VWF activity/VWF:Ag ratios of less than 0.7. The capacity of VWF to bind to glycoprotein Ib (GpIb) was reassessed using the ristocetin co-factor activity (VWF:RiCo) assay compared to an in-house and a commercial ELISA assay (based on a mAb directed against the GpIb binding site on VWF). This was supplemented by multimeric analysis and the amplification and sequencing of a 936 bp fragment of exon 28 of the VWF gene with the aim of identifying mutations in the A1 domain. On reappraisal, using the VWF:RiCo assay all patients demonstrated a disproportionately reduced VWF:RiCo/VWF:Ag ratio, indicative of a qualitative defect, while abnormal ratios were detected in only seven kindreds using the in-house ELISA assay and in only one kindred with the commercial ELISA assay. Eight single amino acid substitutions were found in nine kindreds, four of which were novel candidate VWF mutations and four previously described in association with type 2 VWD. In agreement with the phenotype, the novel VWF mutations were located in the VWF-A1 crystal structure at positions that corresponded to potential type 2M defects. This study underlines the difficulties of correct diagnosis of the subtype of VWD and emphasises the importance of using sensitive phenotypic assays, the relevance of the VWF:RiCo/ VWF:Ag ratio, multimeric analysis and molecular modelling analysis.

Audit of clinical management of von Willebrand disease during 1997 at a single institution and review of treatment patterns between 1980 and 1997.

In 1997 the UK Haemophilia Centre Directors Organization published the guidelines for diagnosis and management of von Willebrand disease (vWD). The guidelines stated that desmopressin (DDAVP) should be used in type 1 and type 2N vWD, that it might be useful in other types 2 vWD and that it is ineffective in type 3 vWD. If patients are unresponsive to DDAVP or if it is contraindicated, the treatment of choice is clotting factor concentrates (CFC). In the light of these guidelines, we audited our practice for 1997. Furthermore, we undertook a retrospective review of the changing patterns of treatment of vWD between 1980 and 1997. During 1997, 10 patients with vWD received DDAVP and another 30 patients were treated with CFC (a total of 1.2 million IU): Haemate P (Centeon, Germany) and/or 8Y (BPL, Elstree, UK). Few patients had clear contraindications to DDAVP, but several patients with type 1 and 2 vWD received CFC on the basis of age or reduced levels of von Willebrand factor - where DDAVP was considered suboptimal for adequate haemostasis. However, this assumption was made without a preliminary test dose to assess the response to DDAVP. The analysis of treatment of vWD for the past 17 years showed that cryoprecipitate was discontinued from use in the early 1990s and that both DDAVP and CFC usage has been on the increase. In conclusion, the audit illustrated a general good adherence to guidelines but it highlighted the need for a DDAVP test before using CFC.

Acquired von Willebrand syndrome--report of 10 cases and review of the literature.

Acquired von Willebrand syndrome (AvWS) is a rare bleeding disorder with clinical and laboratory features closely resembling hereditary von Willebrand disease (vWD), arising in previously haemostatically normal individuals. We present a retrospective review of 10 cases with AvWS diagnosed over 17 years. The severity of the bleeding tendency varied from mild to severe forms. Multimers electrophoresis showed that 8/10 patients had a normal pattern similar to type 1 vWD, 1/10 had a type 2A vWD pattern (with absence of high and intermediate molecular weight multimers) and 1/10 had a type 3 vWD pattern. An inhibitor screen was performed in 6/10 patients and autoantibodies against von Willebrand factor were found in only two cases. The underlying cause/associated conditions were identified in 8/10 patients. Treatment of the bleeding diathesis was successfully achieved with desmopressin or clotting factor concentrates. Resolution of underlying hypothyroidism (in two cases) and multiple myeloma (in one case) led to normalization of the coagulation parameters. The report on this cohort of 10 patients with AvWS illustrates the complexity of AvWS and its multifactorial aetiology. A brief review of the recent literature on AvWS is also presented, with emphasis on the current opinions in pathogenesis and treatment. Acquired von Willebrand syndrome (AvWS) is an acquired bleeding disorder, characterized by a phenotype similar to the inherited von Willebrand disease (vWD), with a prolonged bleeding time and low plasma levels of factor VIII - von Willebrand factor (vWF) measurements. It occurs in patients with no family history of vWD, who present with recent onset of bleeding symptoms. AvWS appears to be associated mainly with lymphoproliferative disorders, immunological conditions and neoplasia. AvWS is a rare condition and it is difficult to conduct prospective studies, therefore it is important to document the experience with such cases. The aim of this paper is first, to report 10 cases of AvWS identified at our Haemophilia Centre during the past 17 years. Second, to present a brief review of the recent literature on AvWS - outlining the salient features, associated disorders, mechanisms of acquisition and the available options of treatment.