F. Baudo

Natural history and risk factors for thrombosis in 360 patients with antiphospholipid antibodies: A four-year prospective study from the italian registry

PURPOSE To assess the natural history and risk factors for thrombosis in a large cohort of unselected patients with antiphospholipid antibodies. PATIENTS AND METHODS Three hundred sixty consecutive patients (118 males, 242 females, median age 39 years [range 2 to 78]) fulfilling the currently accepted criteria for diagnosis of lupus anticoagulant (LAC) (n = 326) and/or raised immunoglobulin G anticardiolipin antibodies (IgG ACA) (n = 185) were collected from 16 Italian institutions and prospectively observed for a median of 3.9 years (range 0.5 to 5). Main endpoints were the occurrence of arterial or venous thrombosis, the outcome of pregnancies, and any severe complications leading to hospitalization or death. RESULTS Thirty-four patients developed a thrombotic complication, with a total incidence of 2.5% patient-years. Multivariate logistic regression analysis identified two independent risk factors for thrombotic events: a previous thrombosis (RR 4.9; 95% CI, 1.76 to 13.7; P < 0.005) and IgG ACA titer above 40 units (RR 3.66; 95% CI, 1.24 to 10.8; P < 0.01). A total of 28 pregnancies were observed in 25 women and 11 (39%) were abortive. Adverse pregnancy outcomes were significantly more frequent in women with a history of miscarriage or vascular occlusion (9/16, 56%) than in asymptomatic women (2/12, 17%) (P = 0.035). Four patients developed non-Hodgkins lymphoma during the follow-up. Eighteen patients died. Vascular events and hematological malignancies represented the most frequent causes of death (n = 5 for each). CONCLUSIONS The present study shows that: (a) previous thrombosis and ACA titer > 40 U are independent predictors of thrombosis; (b) history of miscarriage or vascular disease is significantly associated with adverse pregnancy outcome; (c) hematological malignancies can develop during follow-up in patients with antiphospholipid antibodies.

Risk of Venous Thromboembolism and Clinical Manifestations in Carriers of Antithrombin, Protein C, Protein S Deficiency, or Activated Protein C Resistance A Multicenter Collaborative Family Study

Deficiencies of antithrombin (AT), protein C (PC) or protein S (PS), and activated protein C resistance (APCR) are very well-established coagulation defects predisposing to venous thromboembolism (VTE). We performed a retrospective cohort family study to assess the risk for VTE in individuals with AT, PC, or PS deficiency, or APCR. Five hundred thirteen relatives from 9 Italian centers were selected from 233 families in which the proband had had at least 1 episode of VTE. We calculated the incidence of VTE in the whole cohort and in the subgroups after stratification by age, sex, and defect. The overall incidence of VTE (per 100 patient-years) in the group of relatives was 0.52. It was 1.07 for AT, 0.54 for PC, 0.50 for PS, 0.30 for APCR, and 0.67 in the group with a double defect. The incidence was associated with age, but not with sex. The mean age at onset was between 30 and 40 years for all the coagulation defects. Women had the peak of incidence in the age range of 21 to 40 years, earlier than men. The lifetime risk for VTE was 4.4 for AT versus APCR, 2.6 for AT versus PS, 2.2 for AT versus PC, 1.9 for PC versus APCR, and 1.6 for PS versus APCR. AT deficiency seems to have a higher risk for VTE than the other genetic defects. There is a relation between age and occurrence of thrombosis for both men and women. The latter had the peak of incidence earlier than the former.

Diagnosis and treatment of disseminated intravascular coagulation: Guidelines of the Italian Society for Haemostasis and Thrombosis (SISET)☆

BACKGROUND The diagnosis and treatment of disseminated intravascular coagulation (DIC) remain extremely controversial. PURPOSE The Italian Society for Thrombosis and Haemostasis commissioned a project to develop clinical practice guidelines for the diagnosis and treatment of DIC. METHODS Key questions about the diagnosis and treatment of DIC were formulated by a multidisciplinary working group consisting of experts in clinical medicine and research. After a systematic review and discussion of the literature, recommendations were formulated and graded according to the supporting evidence. In the absence of evidence, evidence of low quality, or contradictory evidence, a formal consensus method was used to issue clinical recommendations. RESULTS AND CONCLUSIONS In suspected DIC, we suggest the use of the diagnostic scores ISTH (grade C), JMHW (grade C) or JAAM (grade D) over stand alone tests. The cornerstone of the management of DIC remains the treatment of the underlying triggering disease. We do not suggest the use of antithrombin (grade D), dermatan sulphate (grade D), gabexate (grade D), recombinant factor VIIa (grade D), activated protein C (grade D), thrombomodulin (grade B). The use of unfractionated heparin or low-molecular-weight heparin is not suggested except for thromboembombolic prophylaxis in patients a high risk who do not have active bleeding (grade D). In patients with severe sepsis/septic shock and DIC we suggest the use of human recombinant activated protein C (grade D). In patients with DIC and active bleeding we suggest the use of transfusion therapy (platelets, plasma, cryoprecipitate) (grade D).

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.

Summary. 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 1601 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.

Diagnosis and treatment of acquired haemophilia

Summary.  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 × 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.

Use of recombinant factor VIIa during orthotopic liver transplantation

In spite of 2 large, well-conducted, randomized studies, the definite conclusions on the use of recombinant factor VIIa (rFVIIa) during orthotopic liver transplantation (OLT) have yet to be drawn. These studies were long awaited, but answers are far from being available. In a small single-center experience we published last February in Intensive Care Medicine, at variance with the first preliminary study published by Hendriks et al., we were not able to find any difference in blood loss and transfusion requirements whether or not the drug was administered. We used rFVIIa (20 /kg at the start of operation plus 20 /kg 30-40 minutes after reperfusion in case of significant bleeding) in 6 patients with end-stage liver disease (Child-Turcotte-Pugh, 9 2.5; range, 9-11) who underwent OLT in February 2003. Three out of 6 patients included in the study group underwent split liver transplantation (mean blood loss, 2,500 1,300 mL; range, 1,000-6,000 mL). Perioperative blood loss and transfusion requirements were compared with those recorded in the 6 patients who underwent OLT in January 2003 without rFVIIa (control group; Child-Turcotte-Pugh, 8 2.5; range, 7-12). All the procedures were performed by the same surgeon with standardized intraoperative anesthesiological approach and transfusion triggers. Blood loss and transfusion requirements did not statistically differ in the treated group (blood loss, 3,500 1,300 mL; range, 1,600-5,000 mL; packed red cells, 9 4 units; range, 4-11 units) mL and in controls (blood loss, 1,800 1,200 mL; range, 500-4,000 mL; packed red cells, 7 2.5; range, 4-10. On the contrary, according to the data reported by Hendriks et al., we found improvements in the following thromboelastographic parameters: r (reduced, P 0.05), alpha angle (increased, P 0.05), maximum amplitude (tendency toward larger maximum amplitude, not statistically significant). All the patients were discharged in good conditions and are alive (follow-up 16 months). As we acknowledged in our paper, the small size of our sample and the obvious methodological biases introduced (dose and number of patients included in the preliminary trial) did not allow us to draw any firm conclusion; universal prophylactic administration of rFVIIa was, of course, stopped. In our opinion, the problem of bleeding during OLT, as quoted by Porte and Caldwell in the editorial accompanying the articles by Planinsic and Lodge, is substantial; however, further work has to be done to find the best way to intervene in this specific setting. As we suggested in commenting on our data, we are strongly convinced (and in this hypothesis we are now heavily supported by the definitive data by Planinsic and Lodge) that rFVIIa should not be recommended per se as a universal prophylaxis to reduce transfusion requirements during OLT. This is particularly true in settings in which good surgical technique and expertise in the pharmacological manipulation of coagulation are available. The improved surgical techniques, the judicious patient selection, the extensive intraoperative monitoring available today, and skillful manipulation of hemostasis are making major liver surgery (both resective and transplantation surgery) more widely performed, safer, and often reported as bloodless, in spite of its potentially high-risk profile. Indications of rFVIIa are rapidly expanding. However, in an era of economical constraints, the high cost of the drug has to be balanced against its cost-effectiveness or its cost benefit. In fact, despite the high dose used in the Lodge study, the only significant result was that 7-10% of the treated patients were able to avoid red blood cell transfusion; however, not different were or other blood products needs, when compared to the needs in the controls. We think the use of rFVIIa should be studied in a randomized fashion in very selective subgroups of OLT candidates at known risk of surgical or nonsurgical bleeding. Split-liver transplants, retransplantation procedures performed years after the first procedure, or liver transplantation in candidates with previous major abdominal surgery, frequent spontaneous bacterial peritonitis, or renal failure might constitute examples of subgroups of patients in which randomized trials could be performed for the correct definition of the role of rFVIIa in significantly reducing blood loss and transfusion requirements during OLT. In such a setting, rFVIIa administration could be defined as a “pre-emptive” ther-

Haemostatic Effect of Fibrin Sealant in Patients with Congenital and Acquired Bleeding Disorders

Fibrin sealant was used for local hemostasis in 405 patients with various hemostatic disorders (thrombocytopenia, chronic liver disease, hemophilia A and B, von Willebrand’s disease and oral anticoagulants) undergoing tooth extraction. Prophylactic replacement therapy (platelets or plasma concentrates) and antifibrinolytic agents were not administered. Oral anticoagulants were not discontinued. Minor postextraction bleeding occurred only in severe hemophilia A and occasionally in the oral anticoagulant group.

Treatment of DIC with Antithrombin III in Patients Admitted to Intensive Care Units

Disseminated intravascular coagulation (DIC) is a syndrome associated with many clinical conditions and may complicate the clinical course and the prognosis of the underlying disease [1, 2]. The clinical picture is characterized by hemorrhagic and/or thrombotic manifestations and sometime by signs and symptoms of organ failure that may complicate the outcome itself [2–4]; the laboratory data are indicative of activation of coagulation and fibrinolytic system and by consumption of the physiological inhibitors (mainly antithrombin III [ATIII]. The clinical conditions frequently associated with DIC are reported in Table 1.