P. M. Mannucci

Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor

Summary.  von Willebrand disease (VWD) is a bleeding disorder caused by inherited defects in the concentration, structure, or function of von Willebrand factor (VWF). VWD is classified into three primary categories. Type 1 includes partial quantitative deficiency, type 2 includes qualitative defects, and type 3 includes virtually complete deficiency of VWF. VWD type 2 is divided into four secondary categories. Type 2A includes variants with decreased platelet adhesion caused by selective deficiency of high‐molecular‐weight VWF multimers. Type 2B includes variants with increased affinity for platelet glycoprotein Ib. Type 2M includes variants with markedly defective platelet adhesion despite a relatively normal size distribution of VWF multimers. Type 2N includes variants with markedly decreased affinity for factor VIII. These six categories of VWD correlate with important clinical features and therapeutic requirements. Some VWF gene mutations, alone or in combination, have complex effects and give rise to mixed VWD phenotypes. Certain VWD types, especially type 1 and type 2A, encompass several pathophysiologic mechanisms that sometimes can be distinguished by appropriate laboratory studies. The clinical significance of this heterogeneity is under investigation, which may support further subdivision of VWD type 1 or type 2A in the future.

Mechanism of Plasminogen Activator and Factor VIII Increase after Vasoactive Drugs

Summary. Adrenaline, nicotinic acid (NA), vasopressin (LVP) and other drugs affecting vascular motility are known to increase plasminogen activator (PA) and factor‐VIII plasma levels in man. To evaluate the hypothesis that NA, LVP and adrenaline release PA from the endothelial cells of the vessel wall through their common effect on vascular motility, PA has been characterized by means of a histochemical technique on vein biopsies obtained from human volunteers after infusion of the compounds. Furthermore, the effect of single and repeated administration has been compared in order to investigate whether the pattern of PA and factor‐VIII variations in plasma is similar with the three drugs. There was no major difference in the PA content of the veins following the marked and sustained increase of the corresponding plasma activities. A simple explanation is that the intensity and duration of the stimulus may not be sufficient to deplete the large stores of the vessel walls. The magnitude, time course and duration of the plasmatic response after single and repeated infusions was on the whole different and peculiar for each drug. A derivative of LVP which is free of vasoactive actions was more effective than LVP in inducing the responses, which could also be elicited in two anephric subjects. These findings suggest that vasoactivity is unlikely to provide the clue to a common pathway for the fibrinolysis and coagulation response after the compounds, and support the existence of different specific receptors.

Response of factor VIII/von Willebrand factor to DDAVP in healthy subjects and patients with haemophilia A and von Willebrand's disease.

Summary. These studies were designed with the purpose of providing clinico‐pharmacological information relevant to the use of DDAVP in the management of mild haemophilia and von Willebrands disease (VWD). In healthy subjects, intravenous DDAVP produced its maximal response at a dose of 0.3 μg/kg. The extent of the increase in factor VIII coagulant activity (VIII:C) and factor VIII related antigen (VIIIR:Ag) induced by this dose was not significantly different from that observed with the same dose in haemophiliacs and VWD patients. In these, the bleeding time was not shortened. DDAVP given intranasally was followed by a two‐fold increase of VIII:C. This route of administration might be adopted to provide an emergency aid in bleeding patients and to yield higher VIII:C levels in blood donors. In healthy subjects, the half‐disappearance time of autologous VIII:C after increase induced by i.v. DDAVP is similar to that observed in patients with VWD treated in the same conditions, whereas the response appears to be more prolonged in haemophiliacs. This study shows that the consistency of the VIII:C response tends to decrease when repeated doses are given to healthy subjects. Repeatedly‐treated haemophiliacs and VWD patients showed varied patterns, ranging from no change of the response to its early abolishment.

Rare coagulation deficiencies

Summary.  Deficiencies of coagulation factors (other than factor VIII and factor IX) that cause a bleeding disorder are inherited as autosomal recessive traits and are generally rare, with prevalences in the general population varying between 1 : 500 000 and 1 : 2 000 000. In the last few years, the number of patients with recessively transmitted coagulation deficiencies has increased in European countries with a high rate of immigration of Islamic populations, because in these populations, consanguineous marriages are frequent. Owing to the relative rarity of these deficiencies, the type and severity of bleeding symptoms, the underlying molecular defects and the actual management of bleeding episodes are not as well established as for haemophilia A and B. This article reviews these disorders in terms of their clinical manifestations and characterization of the molecular defects involved. The general principles of management are also discussed.Keywords: afibrinogenaemia, autosomal recessive disorders, factor VIII, factor XI, factor XIII.

Effects of exposure to air pollution on blood coagulation

Summary.  Background: Consistent evidence has indicated that air pollution increases the risk of cardiovascular diseases. The underlying mechanisms linking air pollutants to increased cardiovascular risk are unclear. Objectives: We investigated the association between the pollution levels and changes in such global coagulation tests as the prothrombin time (PT) and the activated partial thromboplastin time (APTT) in 1218 normal subjects from the Lombardia Region, Italy. Plasma fibrinogen and naturally occurring anticoagulant proteins were also evaluated. Methods: Hourly concentrations of particulate (PM10) and gaseous pollutants (CO, NO2, SO2, and O3) were obtained from 53 monitoring sites covering the study area. Generalized additive models were applied to compute standardized regression coefficients controlled for age, gender, body mass index, smoking, alcohol, hormone use, temperature, day of the year, and long‐term trends. Results: The PT became shorter with higher ambient air concentrations at the time of the study of PM10 (coefficient = −0.06; P < 0.05), CO (coefficient = −0.11; P < 0.001) and NO2 (coefficient =−0.06; P < 0.05). In the 30 days before blood sampling, the PT was also negatively associated with the average PM10 (coefficient = −0.08; P < 0.05) and NO2 (coefficient = −0.08; P < 0.05). No association was found between the APTT and air pollutant levels. In addition, no consistent relations with air pollution were found for fibrinogen, antithrombin, protein C and protein S. Conclusions: This investigation shows that air pollution is associated with changes in the global coagulation function, suggesting a tendency towards hypercoagulability after short‐term exposure to air pollution. Whether these changes contribute to trigger cardiovascular events remains to be established.

A prospective randomized trial of high and standard dosages of recombinant factor VIIa for treatment of hemarthroses in hemophiliacs with inhibitors.

Summary.  Aim: A multicenter randomized open‐label crossover prospective trial was designed to compare the efficacy, safety, and cost of standard and high dosages of recombinant factor VIIa (rFVIIa) for home treatment of hemarthroses in hemophiliacs with inhibitors. Methods: Patients were instructed to treat, within 6 h from the onset of bleeding, four consecutive hemarthroses of ankles, knees, or elbows, either with the rFVIIa standard dose of 90 μg kg−1 (repeated as necessary every 3 h) or with a single high dose of 270 μg kg−1. Patients who did not achieve a clinical success within 9 h continued rFVIIa treatment with repeated standard doses. Response to treatment was assessed for up to 48 h by patients/caregivers, who reported on a Visual Analogue Scale (VAS) graded from 0 to 100 the improvement in symptoms and also rated the responses as effective, partially effective or ineffective. Success was defined a treatment course rated as effective and with a VAS score ≥70 and failure a treatment course rated as ineffective and VAS score ≤30, whereas treatment courses that did not fulfill these criteria were considered partial responses. Results: Twenty hemophiliacs with inhibitors were originally enrolled (median age: 27 years), 18 of them treated 32 hemarthroses assigned to the standard‐dosage and 36 to the high‐dosage regimen, during the study period of 18 months. Forty‐eight hemarthroses (71%) occurred in target joints. Success rates for standard‐ and high‐dosage regimens were similar: 31% and 25% at 9 h, 53% and 50% at 24 h, 66% and 64% at 48 h, the end point for outcome assessment. The median number of rFVIIa infusions needed to achieve a successful course was significantly greater for the standard‐dosage (n = 3) than for the high‐dosage regimen (n = 1), and the median amount of rFVIIa ultimately used per successful course was identical (270 μg kg−1). Conclusion: Our results indicate that a high‐dosage regimen with rFVIIa for home treatment of hemarthroses is effective, safe, does not imply an increased consumption of rFVIIa and requires the infusion of a smaller number of rFVIIa doses. Its convenience is particularly relevant in cases with difficult venous access and in hemorrhages into target joints.

Guidelines for the diagnosis and management of von Willebrand disease in Italy

Summary.  von Willebrand disease (vWD) is a bleeding disorder caused by quantitative (type 1 and 3) or qualitative (type 2) defects of von Willebrand factor (vWF). The molecular basis of type 2And 3 vWD are now known and those of type 1 vWD are being understood. Phenotypic diagnosis is based on the measurements of plasma and platelet vWF, of the ability of vWF to interact with platelet receptors and the analysis of the multimeric structure of vWF. Due to the heterogeneity of vWF defects and the variables that interfere with vWF levels, a correct diagnosis of types and subtypes may sometimes be difficult but is very important for therapy. The aim of treatment is to correct the dual defects of haemostasis, i.e. abnormal intrinsic coagulation expressed by low levels of factor VIII (FVIII) and abnormal platelet adhesion. Desmopressin is the treatment of choice in patients with type 1 vWD, who account for approximately 70% of cases, because it corrects FVIII–vWF levels and the prolonged bleeding time (BT) in the majority of these patients. In type 3 and in severe forms of type 1 and 2 vWD patients, desmopressin is not effective and it is necessary to resort to plasma concentrates containing FVIII and vWF. Treated with virucidal methods, these concentrates are effective and safe, but they cannot always correct BT defect. Platelet concentrates or desmopressin can be used as adjunctive treatments when poor correction of BT after plasma concentrate treatment is associated with continued bleeding.

Quality of life is associated to the orthopaedic status in haemophilic patients with inhibitors

Summary.  Inhibitors represent one major complication of haemophilia treatment, as they increase the risk of bleeding, physical disability and mortality. The Cost Of Care Inhibitors Study (COCIS) showed that modern strategies applied to manage patients with inhibitors adsorb high amounts of resources but provide satisfactory levels of Health‐Related Quality‐of‐Life (HR‐QoL). This paper focuses on determinants of HR‐QoL in inhibitory patients. Fifty adult patients, enrolled by 11 Italian Haemophilia Centres, were clinically assessed and filled in two HR‐QoL generic questionnaires: the EuroQol instrument (EQ‐5D) and the Short Form‐36 (SF‐36). According to our results, bleeding frequency and inhibitor titres were not found associated with HR‐QoL. Global HR‐QoL, and in particular the physical component of wellbeing in these patients was found negatively associated with their orthopaedic condition: the EQ‐5D Visual Analogue Scale (P < 0.001) scores, the SF‐36 domain ‘physical functioning’ and ‘physical component summary’ (P < 0.01) scores were found significantly correlated with the orthopaedic joint score, even after adjusting for patients’ age. These results were confirmed by those from the EQ‐5D profile. To conclude, the COCIS study is the first study showing that HR‐QoL in inhibitory patients is impaired by their orthopedic status, while other aspects do not seem to influence patients’ global wellbeing. Our results suggest that while the management of this complication is satisfactory, the attention has now to be focused on the prevention of the orthopaedic problems in these patients, which nowadays constitute one of the most important aspects to be considered in the haemophilia care.

Home treatment with recombinant activated factor VII in patients with factor VIII inhibitors: the advantages of early intervention.

To evaluate the feasibility, efficacy and safety of home treatment with recombinant activated factor VII (rFVIIa), 10 inhibitor patients (all haemophiliacs except one acquired post‐partum) self‐administered up to four doses of 90 μg/kg rFVIIa every 3 ± 1 h. The response was rated by the patient as effective (haemorrhage stopped or decreased substantially), partially effective (reduced) or ineffective (unchanged or worsened). 45 haemarthroses and eight haematomas were treated within a median time of 1.0 h (range 0.3–11.9) from the onset of bleeding, with a median of two rFVIIa doses per course (range 1–4). rFVIIa was effective in 42 episodes (79%), partially effective in six (11%) and failed in five (10%). Compared with partially effective and ineffective treatments, effective treatments started earlier (median time: 0.6 v 2.7 h, P = 0.02) and required a smaller number of doses (median: 1.5 v 3, P = 0.007). The risk of a partially effective or ineffective treatment was smaller for treatments started within 6 h from the onset of bleeding than for those which started later (OR 0.24, 95% CI 0.09–0.63). Mild side‐effects were reported only after 3/113 self‐infusions (2.6%). Early home treatment with rFVIIa is safe, feasible and effective, inducing and maintaining haemostasis with a small number of doses.

Immunoradiometric Assay of Factor VIII Related Antigen, with Observations in 32 Patients with von Willebrand's Disease

Summary. A solid phase non‐competitive immunoradiometric assay (IRMA) has been developed which allows measurement of factor VIII related antigen (VIIIR: AG) levels in normal plasma as low as 2.5 × 10−4 U/ml. The assay is based on the extraction of VIIIR: AG from test plasma by means of polystyrene tubes coated with a specific unlabelled anti‐VIIIR: AG rabbit antiserum and subsequent labelling of the extracted antigen with 125I‐labelled anti‐VIIIR: AG rabbit IgG. The amount of radioactivity retained by the tubes (percentage bound) is proportional to VIIIR: AG concentration and a linear correlation is observed when logs of plasma dilutions (from 1 in 300 to 1 in 4000) are plotted against logits of percentage bound. The IRMA is technically simple, specific and reproducible. In 32 normal persons there was a highly significant correlation (r= 0.94) between IRMA and rocket electro‐immunodiffusion assay (EIA) of VIIIR: AG plasma levels using the same antibody. IRMA has also been used to investigate 32 patients with von Willebrands disease (vWd) in whom VIIIR: AG plasma levels were below the lowest measurable concentration using EIA (< 0.10 U/ml). In 17 patients with an autosomal recessive mode of inheritance and unusually severe symptoms, the markedly abnormal laboratory findings were consistent with the homozygous state. In 11 of these VIIIR: AG was < 2.5 × 10−4 U/ml and was extremely low in the remaining 6 (1.3 × 10−2 to 4 × 10−3 U/ml). In 15 patients the disease was familial (being transmitted as an autosomal dominant trait) and of moderate clinical severity; the IRMA or VIIIR: AG ranged between 1.2 × 10−1 and 4 × 10−2 U/ml. The assay thus appears a useful tooi in the investigation of vWd and helps to identify two different types of the disease.