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.

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.

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.

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 III (ATIII) replacement therapy in patients with sepsis and/or postsurgical complications: a controlled double-blind, randomized, multicenter study.

BACKGROUND: ATIII is decreased in sepsis and/or shock and its baseline value correlates with mortality. The efficacy of ATIII therapy on mortality was assessed in a selected group of patients admitted to the intensive care unit (ICU) in a double-blind, randomized, multicenter study. METHODS: 120 patients admitted to the ICU with an ATIII concentration < 70% were randomized to receive ATIII (total dose 24000 units) or placebo treatment for 5 days; 56 patients had septic shock. RESULTS: ATIII concentrations in the treated group remained constant throughout the treatment period (range 97-102%). The Kaplan-Meier analysis showed no difference in overall survival between the two groups: 50 and 46% for ATIII and placebo, respectively. Septic shock and hemodynamic support were unbalanced in the two groups at admission. Therefore the Cox analysis was carried out after adjusting for these two variables. Treatment with ATIII decreases the risk of death with an odds ratio (OR) of 0.56. Of the covariates analyzed, septic shock and the baseline multiple organ failure score were negatively associated with survival and plasma activity level was positively associated with survival with an OR of 0.97 for each 1% increase in the ATIII plasma concentration at baseline. CONCLUSIONS: The results of ATIII treatment in this population of patients suggests that replacement therapy reduces mortality in the subgroup of septic shock patients only.

Antithrombin III supplementation during orthotopic liver transplantation in cirrhotic patients: a randomized trial.

Severe intraoperative bleeding is one of the main problems during liver transplantation. Acquired hemostatic defects, namely primary or secondary hyperfibrinolysis, are considered significant pathogenetic events. Antithrombin III (ATIII), the main physiological serine protease inhibitor, has a critical role in the regulation of hemostasis. 29 patients with post necrotic cirrhosis undergoing liver transplantation were randomized to receive or not ATIII replacement therapy before the induction of anaesthesia and thereafter throughout surgery. Activation of both coagulation and fibrinolysis (increase of thrombin-antithrombin complexes, fibrin and fibrinogen degradation products) were demonstrated in both groups. Blood loss and transfusion requirements were not affected by ATIII administration.

The multimeric pattern of von Willebrand's factor (vWF) can be demonstrated also in the severe form of the disease.

The multimeric analysis was carried out on the plasma of 18 patients with severe von Willebrand's disease (vWD) using two different types of agarose: Seakem HGT(P) and Seaplaque LGT. No pattern was found in any of the patients using Seakem HGT(P). On the contrary, by Seaplaque LGT, a multimeric pattern was found in four patients belonging to three different families, indicating that it is possible to identify and characterize variable multimeric patterns also in type III vWD.

Emergency treatment with recombinant tissue plasminogen activator of pulmonary embolism in a pregnant woman with antithrombin III deficiency.

Thromboembolic complications during pregnancy are frequent in patients with congenital antithrombin III deficiency. We report on a 29-year-old patient with congenital antithrombin III deficiency and severe pulmonary embolism treated with recombinant tissue plasminogen activator. The diagnosis of antithrombin deficiency is retrospective. This case indicates that the risk of thrombolytic therapy in this clinical setting might have been overemphasized.

Prothrombin-antibody coexistent with lupus anticoagulant (LA): clinical study and immunochemical characterization.

The patient is a 23 y.o. man with acute nephritis and bleeding at presentation. Laboratory data consistent with the diagnosis of systemic lupus erythematosus. A lupus anticoagulant was found: tissue thromboplastin inhibition test (TTIT) ratio 3.4; diluted Russell viper venom (DRVV) ratio 2.6. Hypoprothrombinemia (FII:C less than 1%; FIIR:Ag 5%) was present; prothrombin survival time (FII concentrate infusion 60 U/kg): t1/2 approximately to 9 hours. A prothrombin antibody was identified: it is not neutralizing but forms an immunecomplex with prothrombin. The antibody was characterized as IgG2, IgA, k, lambda. The prothrombin survival time indicates that the hypoprothrombinemia is due to the clearance of the prothrombin-antiprothrombin complex in vivo.

Severe von Willebrand's disease: SDS agarose multimer analysis.

In severe von Willebrand's disease (vWD), the multimeric analysis of von Willebrand factor (vWF) has been hindered by the low content of the protein although different patterns have been observed by radiocrossed immunoelectrophoresis (RCIE). Cryoprecipitate and vWF concentrate were obtained from the plasma of a severe vWD patient, that on RCIE had only the more anodic forms. The sodium dodecylsulfate (SDS) agarose analysis evidences the presence of the main bands, a relative increase of the smaller forms and a lesser definition of some minor bands. These findings suggest the possibility of structural abnormalities in severe vWD. The study of cryoprecipitates could be a means to evidence the presence of multimers and the extent of the eventual pattern variability.