Pregnancy-associated acquired haemophilia A: results from the European Acquired Haemophilia (EACH2) registry.

OBJECTIVE: The European Acquired Haemophilia registry (EACH2) collected data on the demographics, diagnosis, underlying disorders, bleeding characteristics, treatment, and outcome of women with acquired haemophilia A (AHA), a rare and often severe bleeding disorder caused by autoantibodies directed against coagulation factor VIII. DESIGN: Prospective, multi-centre, large-scale, pan-European registry. SETTING: A total of 117 haemophilia centres in 13 European countries. POPULATION: Pregnancy-associated AHA. METHODS: Data were reported using a web-based electronic case report form. Diagnosis was based on the presence of a prolonged activated partial thromboplastin time, reduced coagulation Factor VIII level and positive inhibitor assay. MAIN OUTCOME MEASURES: Presenting characteristics, time to diagnosis, haemostatic treatment and outcome, immunosuppressive treatment and outcome. RESULTS: The EACH2 registry (n = 501) documented 42 (8.4%) cases of AHA associated with the peripartum period, a median Factor VIII level at diagnosis of 2.5 (range 0-25) IU/dl and inhibitor titre of 7.8 (range 0.7-348) BU/ml. Antepartum inhibitors were evident in eight women. Time to diagnosis of AHA after delivery was 89 (range 21-120) days. First-line haemostatic treatment was successful in 20/23 (87%) women treated. Bleeding episodes resolved in 17/18 (94%) women treated with a bypassing agent and 29/39 (74%) women achieved complete remission with first-line immunosuppressive treatment. Two babies experienced postnatal bleeding, suggesting transplacental transfer of the antibody. All women were alive at last follow-up. CONCLUSIONS: Although rare, pregnancy-associated AHA may cause severe bleeding-related morbidity. Once diagnosed, women respond well to haemostatic treatment with bypassing agents and immunosuppression. Awareness of peripartum AHA requires improvement to facilitate rapid and appropriate management.

Demographic and clinical data in acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2).

BACKGROUND: Acquired hemophilia A (AHA) is a rare autoimmune disease caused by autoantibodies against coagulation factor VIII and characterized by spontaneous hemorrhage in patients with no previous family or personal history of bleeding. Although data on several AHA cohorts have been collected, limited information is available on the optimal management of AHA. OBJECTIVES: The European Acquired Hemophilia Registry (EACH2) was established to generate a prospective, large-scale, pan-European database on demographics, diagnosis, underlying disorders, bleeding characteristics, treatment and outcome of AHA patients. RESULTS: Five hundred and one (266 male, 235 female) patients from 117 centers and 13 European countries were included in the registry between 2003 and 2008. In 467 cases, hemostasis investigations and AHA diagnosis were triggered by a bleeding event. At diagnosis, patients were a median of 73.9 years. AHA was idiopathic in 51.9%; malignancy or autoimmune diseases were associated with 11.8% and 11.6% of cases. Fifty-seven per cent of the non-pregnancy-related cases were male. Four hundred and seventy-four bleeding episodes were reported at presentation, and hemostatic therapy initiated in 70.5% of patients. Delayed diagnosis significantly impacted treatment initiation in 33.5%. Four hundred and seventy-seven patients underwent immunosuppression, and 72.6% achieved complete remission. CONCLUSIONS: Representing the largest collection of consecutive AHA cases to date, EACH2 facilitates the analysis of a variety of open questions in AHA.

Diagnosis and treatment of acquired haemophilia.

Acquired haemophilia (AH) is an autoimmune syndrome characterized by acute bleeding in patients with negative family and personal history, and factor VIII depletion. Its incidence is 1.6 x 106 population per year. AH is associated with autoimmune diseases, solid tumours, lymphoprolipherative diseases, pregnancy; 50% of the cases idiopathic. Spontaneous or after minor trauma severe bleeding associated with a prolonged activated partial thromboplastin time, not corrected by incubation with normal plasma, with a normal prothrombin time are the diagnostic hallmarks. The goals of management are the control of bleeding and the suppression of inhibitor. First-line haemostatic treatment includes recombinant factor VIIa and activated prothrombin complex concentrate. Prednisone +/- cyclophosphamide and other immunosuppressive agents are the standard intervention for inhibitor eradication.

Management of patients on long-term oral anticoagulant therapy undergoing elective surgery: survey of the clinical practice in the Italian anticoagulation clinics.

In the perioperative management of patients on long-term oral anticoagulant (OAC) therapy the problem is balancing the thromboembolic (TER) and the haemorrhagic risk (HR) in the perioperative period. The Federazione Centri per la diagnosi della trombosi e la Sorveglianza delle terapie Antitrombotiche (FCSA) activated an online registry from November 2001 to August 2003 in order to collect information on the management of these patients in Italy. Four hundred and eleven patients, undergoing elective major (18%) and minor surgery (82%), from 7 centres, were registered. Three hundred and ninety-nine out of 411 patients received LMWH either once a day (310 patients) or twice a day (89 patients) during OAC therapy discontinuation. Two thromboembolic (0.48%) and 16 bleeding events (7 major; 1.7%) were reported. Notwithstanding the lower doses of heparin (54.3 U/kg o.d. and 64.4 U/kg b.i.d.), the thromboembolic complications are in line with those reported in the literature. The data of this study suggest that the intervention with LMWH may be relevant only in the high-risk patients as already proposed by others.

Hemorrhagic symptoms and bleeding risk in obligatory carriers of type 3 von Willebrand disease: an international, multicenter study.

OBJECTIVES: We undertook an international, multicenter study to describe the clinical picture and to estimate the bleeding risk in a group of obligatory carriers of type 3 von Willebrand disease (VWD). PATIENTS AND METHODS: Obligatory carriers (OC) of type 3 VWD were identified by the presence of offspring with type 3 VWD or by being an offspring of a type 3 patient. Normal controls were age- and sex-matched with the obligatory carriers. A physician-administered standardized questionnaire was used to evaluate hemorrhagic symptoms at presentation. A score system ranging from 0 (no symptom) to 3 (hospitalization, replacement therapy, blood transfusion) was used to quantitate bleeding manifestations. Odds ratios were computed for each symptom. RESULTS: Ten centers participated to the study, enrolling a total of 35 type 3 VWD families, with 70 OC. A total of 215 normal controls and 42 OC for type 1 VWD were also included. About 40% of type 3 OC had at least one bleeding symptom compared to 23% of normal controls and 81.8% of type 1 OC (P < 0.0001 by chi-squared test), showing that type 3 OC clearly represent a distinct population from type 1 OC. The clinical situations associated with an increase of bleeding risk in type 3 OC were epistaxis [odds ratio 3.6; 90% confidence intervals (CI) 1.84-21.5], cutaneous bleeding (odds ratio 5.5; 90% CI 2.5-14.1) and postsurgical bleeding (odds ratio 16.3; 90% CI 4.5-59). The severity of bleeding score correlated with the degree of factor (F) VIII reduction in plasma. CONCLUSIONS: OC for type 3 VWD represent a distinctive population from type 1 OC. These patients, however, present with more frequent bleeding symptoms in comparison to normal controls, especially in case of significantly low FVIII. Desmopressin and/or tranexamic acid might be useful to prevent or treat bleeding in these cases.

Critical bleeding in pregnancy: a novel therapeutic approach to bleeding.

AIM: In the developed countries the frequency of life threatening post-partum hemorrhages (PPH) is 1 in 1,000 deliveries with a risk of death of 1-2/100,000 deliveries. Hysterectomies for intractable bleeding are carried out in approximately 50% of the cases. The majority of PPH have obstetrical causes, most frequently atony of the uterus. Hereditary and acquired hemostatic defects are very rare. Guidelines of standard surgical and medical measures are available. In this paper we focus on the use of activated recombinant factor VII (rFVIIa) in PPH. METHODS: A computerized literature search was carried out in PubMed and Ovid for papers published between 2001 and 2005 in the English literature reporting on life-threatening PPH treated with rFVIIa after failure of conventional therapy, including hysterectomy. RESULTS: We identified 11 papers including 39 patients; in 18 of them the laboratory data were indicative for disseminated intravascular coagulation and in 24 hysterectomy was carried out. Controlled or reduced bleeding was reported in 38 out of 39 treated patients. CONCLUSIONS: The bleeding can occur in a series of events conductive to metabolic complications, hypoxia, disseminate intravascular coagulation, organ damage and multiorgan failure, progressively exhaustive. The therapeutic intervention must be instituted as early as possible before successive complications ensue. These preliminary reports in PPH after failure of conventional standard therapy suggest that rFVIIa is an active agent but should be administered as early as possible before the consequences of severe and intractable bleeding.

The discriminant power of bleeding history for the diagnosis of type 1 von Willebrand disease: an international, multicenter study.

OBJECTIVE: The aim of this study was the validation of the criteria defining a significant mucocutaneous-bleeding history in type 1 von Willebrand disease (VWD). SUBJECTS AND METHODS: To avoid selection bias, 42 obligatory carriers (OC) of type 1 VWD were identified from a panel of 42 families with type 1 VWD enrolled by 10 expert centers. OC were identified by the presence of an offspring and another first degree relative with type 1 VWD (affected subjects, AFF). A standardized questionnaire was administered to evaluate hemorrhagic symptoms at the time of first examination, using a bleeding score ranging from 0 (no symptom) to 3 (hospitalization, replacement therapy, blood transfusion). Sensitivity, specificity, diagnostic likelihood ratios, positive and negative predictive values for the diagnosis of type 1 VWD were calculated from the data collected in OC and in 215 controls. RESULTS: Having at least three hemorrhagic symptoms or a bleeding score of 3 in males and 5 in females was very specific (98.6%) for the bleeding history of type 1 VWD, although less sensitive (69.1%). None of the misclassified OC had life-threatening bleeding episodes after diagnosis. CONCLUSIONS: We suggest that the use of a standardized questionnaire and bleeding score may be useful for the identification of subjects requiring laboratory evaluation for VWD.

von Willebrand factor ristocetin cofactor (VWF:RCo) assay: implementation on an automated coagulometer (ACL).

BACKGROUND: VWF:RCo assay is the standard and widely used laboratory test for von Willebrand disease (VWD) diagnosis. It is hampered by high intra- and inter-assay imprecision and is time consuming. Automation may improve the assay performance and allow its routine application. OBJECTIVE: Automation of VWF:RCo on the ACL 7000 coagulometer (Instrumentation Laboratory, Milan, Italy) and its evaluation in VWD diagnosis. METHODS AND MATERIALS: Method performance determination: precision, detection limit (DL), interferences, dose-response curve. Method comparison: analysis of 105 plasma samples from normal subjects (50), VWD type 1 (24), VWD type 2 (24) and VWD type 3 (7) with ACL VWF:RCo and comparison with the reference aggregometric (AGM) method. RESULTS: ACL VWF:RCo: CVs around 10% vs. 19% of AGM method; DL: 0.08 U mL(-1); potential interferences from bilirubin, triglycerides and hemoglobin, avoided by suitable plasma dilution; high correlation with AGM VWF:RCo (Deming regression Y =-0.0277 + 1.0519X) either in normal or VWD plasmas. In VWD types 1 and 2, the VWF:RCo/VWF:Ag ratios are >0.6 or <0.6, respectively, when calculated with both AGM and ACL VWF:RCo values. CONCLUSIONS: The automated VWF:RCo on the ACL 7000 coagulometer shows precision improvement and high correlation with the reference AGM method. The test allows the diagnosis of both quantitative (VWD types 1 and 3) and qualitative (VWD type 2) forms of the disease. These results and the assay feasibility make it a suitable and reliable test for the routine diagnosis of VWD.

A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS).

BACKGROUND: The optimal intensity of oral anticoagulation for the prevention of recurrent thrombosis in patients with antiphospholipid antibody syndrome is uncertain. Retrospective studies show that only high-intensity oral anticoagulation [target international normalized ratio (INR) >3.0] is effective but a recent randomized clinical trial comparing high (INR range 3.0-4.0) vs. moderate (INR 2.0-3.0) intensities of anticoagulation failed to confirm this assumption. METHODS: We conducted a randomized trial in which 109 patients with antiphospholipid syndrome (APS) and previous thrombosis were given either high-intensity warfarin (INR range 3.0-4.5, 54 patients) or standard antithrombotic therapy (warfarin, INR range 2.0-3.0 in 52 patients or aspirin alone, 100 mg day(-1) in three patients) to determine whether intensive anticoagulation is superior to standard treatment in preventing symptomatic thromboembolism without increasing the bleeding risk. RESULTS: The 109 patients enrolled in the trial were followed up for a median time of 3.6 years. Mean INR during follow-up was 3.2 (SD 0.6) in the high-intensity warfarin group and 2.5 (SD 0.3) (P < 0.0001) in the conventional treatment patients given warfarin. Recurrent thrombosis was observed in six of 54 patients (11.1%) assigned to receive high-intensity warfarin and in three of 55 patients (5.5%) assigned to receive conventional treatment [hazard ratio for the high intensity group, 1.97; 95% confidence interval (CI) 0.49-7.89]. Major and minor bleeding occurred in 15 patients (two major) (27.8%) assigned to receive high-intensity warfarin and eight (three major) (14.6%) assigned to receive conventional treatment (hazard ratio 2.18; 95% CI 0.92-5.15). CONCLUSIONS: High-intensity warfarin was not superior to standard treatment in preventing recurrent thrombosis in patients with APS and was associated with an increased rate of minor hemorrhagic complications.

Clinical efficacy of highly purified, doubly virus-inactivated factor VIII/von Willebrand factor concentrate (Fanhdi) in the treatment of von Willebrand disease: a retrospective clinical study.

The goal of therapy in patients with von Willebrand disease (vWD) is to correct the dual defect of primary haemostasis and intrinsic coagulation reflected by low levels of von Willebrand factor (vWF) and factor VIII coagulant activity (FVIII:C). Factor VIII/von Willebrand factor (FVIII/vWF) concentrates are currently the treatment of choice in vWD patients unresponsive to desmopressin (DDAVP). However, only few studies on their clinical use are available so far. The main objective of this study was to retrospectively evaluate the clinical efficacy of a highly purified, doubly virus-inactivated FVIII/vWF concentrate with a high content of FVIII/vWF (Fanhdi). Twenty-two patients with congenital vWD have been treated from 1999 to 2001 at eight specialized centres belonging to the Italian Association of Hemophilia Centers (AICE). Ten males and 12 females, median age 28.5 years, range 5-70 years) had type 3 vWD (six cases), DDAVP-unresponsive type 1 (nine cases) and type 2B (seven cases). The study drug was given to stop or prevent 12 bleeding episodes or to prevent excessive bleeding during 14 surgical or invasive procedures. Overall, replacement therapy with the concentrate showed an excellent to good clinical efficacy in 92% of bleeding episodes and in 93% of surgical procedures. No adverse events occurred during 1,601 infusions, accounting for a total of 304,500 IU of FVIII:C administered. These results confirm the efficacy and safety of this concentrate in the management of bleeding episodes and in the prevention of excessive bleeding during major and minor surgery.

Relationship between factor VII activity and clinical efficacy of recombinant factor VIIa given by continuous infusion to patients with factor VIII inhibitors.

A multicenter prospective study of recombinant activated factor VII (rFVIIa) given by continuous infusion (CI) to treat severe hemorrhages and to handle surgical procedures was carried out. Relations between clinical efficacy, dosages used and levels of FVII coagulant activity (FVII:C) achieved in plasma were also evaluated. Case material included 25 patients with hemophilia (9 children and 16 adults) with high-responding inhibitors and 3 patients with acquired factor VIII inhibitors. Overall, 35 CI courses were given for 10 spontaneous bleeding episodes, 11 major surgical procedures and 14 minor surgical procedures. Bolus doses of 90 to 150 microg/kg (median: 100) were followed by CI given at median rates of 20 microg/kg/h for major surgery and of 17 and 16 microg/kg/h for minor surgery and spontaneous hemorrhages. Satisfactory hemostasis was obtained in 30 of 35 courses (88%). rFVIIa CI was ineffective in 2 hemophiliacs undergoing surgical operations and in another hemophiliac with hemoperitoneum who had to be switched to other treatments (high doses of porcine or human factor VIII concentrates). rFVIIa CI was partially effective in 2 hemophiliacs who had mild local bleeding after minor surgery. The CI rates and the corresponding FVII:C levels in plasma were similar in effective, partially effective and ineffective courses (median rate: 17, 20 and 20 microg/kg/h, respectively; median FVII:C:14, 18 and 18 IU/ml, respectively). A single adverse event was observed, superficial thrombophlebitis. This study confirms that rFVIIa given by CI is effective in a high proportion of patients with factor VIII inhibitors. It also demonstrates that FVII:C levels attained in plasma do not always predict efficacy because similarly high levels were attained during successful treatments and in those that failed.

Long-term evaluation of a novel surgical approach to the pseudotumour of the ilium in haemophilia: exeresis and transposition of the omentum in the residual cavity.

Pseudotumour of the ilium is a rare but severe complication in haemophiliacs. Excision is often complicated by infections, fistulation and extensive pelvic bone destruction. In 1978, the first author carried out excision of the pseudotumour with transposition of the omentum in the dead cavity to avoid recurrence. This type of surgery has been carried out in three additional patients. The long follow-up of these four patients suggests that this procedure is feasible and curative; local bleeding, infection and fistulation did not recur and the patients remained ambulant with the aid of appropriate devices.

The continuous infusion of recombinant activated factor VIIa (rFVIIa) in patients with factor VIII inhibitors activates the coagulation and fibrinolytic systems without clinical complications.

The standard modality of administration of rFVIIa to patients with FVIII and FIX inhibitors is the intermittent infusion every 2 to 6 hours. No untoward local or systemic effects have been reported; laboratory data of activation of coagulation were reported in the presence of coexistent problems (sepsis, septic shock) or with high doses. We treated four patients with FVIII inhibitor with rFVIIa administered by continuous infusion by a central vein catheter, monitoring the signs of systemic activation of the hemostatic system. The F(1+2) prothrombin fragments and the D-dimer increased after the bolus, and remained above the baseline values throughout the treatment period. These variations observed during the infusion period were not accompanied by clinical events.

[Antithrombin III concentrates in the treatmetn of sepsis and septic shock: indictions, limits and future prospects] . / Concentrati di Antitrombina III nella terapia della sepsi e dello shock settico: indicazioni, limiti e prospettive future.

Sepsis and septic shock are the most frequent cause of mortality in non cardiologic intensive care units. Mortality of the severe form is still elevated in spite of the progress in the antibiotic therapy and in the hemodynamic and respiratory support. The most frequent cause of death is the Multi Organ Dysfunction Syndrome (MODS). The excessive inflammatory reaction and the damage of the microvascular bed secondary to the inflammation and to the disseminated intravascular coagulation (DIC) are important pathogenetic factors. In the sepsis a complex system of cellular activation initiates the release and the interaction of activators and inhibitors of the inflammation (cytokines), the activation of the enzymatic cascade systems (coagulation, fibrinolytic and complement systems) and the synthesis of proteases and anti proteases. The activation of the coagulation system, uncontrolled by the fibrinolytic system with formation of fibrin in the micro vascular bed, has an important role in the MODS. Experimental data and clinical observations suggest a possible therapeutic role of antithrombin III (AT) in sepsis; its plasma concentration is constantly decreased in patients with sepsis or septic shock and the entity of the decrease is correlated with the severity of the clinical picture and the outcome. At has a double function: regulation of the coagulation system and anti inflammatory properties. The anti inflammatory properties depend in part on the binding to the glycosaminoglycans of the endothelial cells and the consequent release of prostacyclin (PGI2). The anti inflammatory effect is independent from the anticoagulant one. The preliminary studies on the clinical use of AT were carried out in small groups of patients with DIC associated with pathologies of different etiology and often in very critical conditions. In general the evaluation criteria were the improvement or the normalization of the laboratory data. The interpretation of the therapeutic effect of AT is difficult because the dysomogeneity of these studies. The effect on mortality is controversial. Recently three prospective, randomized, double blind studies have been published in patients with severe sepsis and septic shock. The results of the single studies are inconclusive but the limited number of patients included in each study may explain the results. A meta-analysis of the data referring to the patients with severe sepsis and septic shock evidenced an odd ratio (OR) of 0.43 with 95% confidential interval of 0.20-0.92 (p = 0.029). The preliminary analysis of the results of a phase III study is unconclusive. Time, dosage and duration of treatment are still open to question. In perspective AT may be used in other clinical conditions associated with activation of the hemostatic system (cardiac surgery, stem cell transplantation, burns) even though the preliminary results must be confirmed by prospective studies. All these data suggest severe sepsis and septic shock as main criteria for treatment.

Orthotopic liver transplantation in a patient with severe haemophilia A and with advanced liver cirrhosis.

A patient with severe haemophilia A underwent orthotopic liver transplantation because of changes correlated to end-stage liver cirrhosis due to hepatitis B, C and D infection. Replacement therapy was carried out for 4 days and the clinical course was uneventful. At the time of reporting the patient has a normal working life. FVIII plasma concentration is normal. The indirect hyperbilirubinaemia may be related to the Gilbert's anomaly of the donor.

Antithrombin replacement in patients with sepsis and septic shock.

Sepsis is a frequent complication of critically ill patients and its incidence is increasing. Currently, septic shock is the most common cause of death in non-coronary intensive care units. Over the last 10 to 15 years, new antibiotics and increasingly sophisticated critical care have had little impact on the mortality rate of septic shock. The Italian SEPSIS Study, carried out in 99 intensive care units in 1994, reported mortality rates of 52% and 82% for severe sepsis and septic shock respectively. New therapeutic approaches aimed at neutralizing microbial toxins and modulating host mediators have shown some efficacy in large clinical trials and/or in animal models, but to date, no therapy of sepsis aimed at reversing the effects of bacterial toxins or of harmful endogenous mediators of inflammation has gained widespread clinical acceptance. Because of the strong association of severe sepsis with a state of activation of blood coagulation and of the potential role of capillary thrombosis in the development of the multiple organ dysfunction syndrome, anticoagulant agents have been tested in the setting of septic shock. However, neither administration of heparin nor of active site-blocked factor Xa or of anti-tissue factor antibodies have proven effective in preventing deaths due to septic shock in animal models. In contrast, infusion of antithrombin, protein C, or tissue factor pathway inhibitor all resulted in a significant survival advantage in animals receiving lethal doses of E. Coli. Antithrombin concentrates have been used in a significant number of critically ill patients. A double-blind, placebo controlled study carried out in 3 italian intensive care units has recently shown that the administration of antithrombin aimed to normalize plasma antithrombin activity had a net beneficial effect on 30-day survival of patients requiring respiratory and/or hemodynamic support because of severe sepsis and/or post-surgery complications.