[Haemostatic abnormalities and thyroid disorders: the prospective observational MITH study]. / Alterazioni emostatiche e patologia tiroidea: lo studio prospettico osservazionale MITH.

Haemostatic abnormalities are a common phenomenon in patients with thyroid diseases. On one hand the condition of hyperthyroidism is associated with an increased risk of thrombotic events, on the other in severe hypothyroidism can be found a haemorrhagic tendency, as opposed to the subclinical hypothyroidism seems to correlate with increased thrombotic risk. The prospective, single center, observational MITH study (Mantua Investigation on Thyroid and Haemostasis), whose results are presented, aims to evaluate coagulation parameters in patients with thyroid disease, to establish the prevalence of haemostatic abnormalities in various conditions, to analyse the implications and clinical response to therapy established.

[Clinical use of virally inactived plasma. The experience of Blood Transfusion Unit in Mantova, Italy]. / Utilizzo clinico di plasma virus-inattivato. Esperienza del Servizio Trasfusionale di Mantova.

BACKGROUND: Fresh Frozen Plasma (FFP) is a blood component whose clinical use is widespread worldwide. Transfusion safety of this product is ensured by legally obligatory tests. Although these tests are carried out on each plasma donation, safety levels can be further improved by using some technical procedures, such as, among others, methylene blue (MB) and solvent-detergent (SD) viral inactivation methods. The DMTE (Blood Transfusion Unit) in Mantova has used the pharmaceutical-like SD virally inactivated plasma since 2007 (Plasmasafe, Kedrion) as replacement of the PFC by each single donor. Guidelines for the usage of both products are the same. MATERIALS AND METHODS: With the main aim of assessing the therapeutic effectiveness and safety of Plasmasafe, we decided to clinically monitor transfusions performed with this product on patients of the Intensive Care Unit at the city hospital in Mantova. In addition, we controlled some coagulation parameters (PT, aPTT, ATIII, Fibrinogen, PC, PS, FV, FVII, FVIII) before and 24 hours after the Plasmasafe infusion. RESULTS: From a clinical point of view, the use of Plasmasafe always led to a significant reduction, or complete stop, of the bleeding. No transfusion-related adverse events were recorded. As regards, the most relevant laboratory results, a marked increase in the above mentioned hemostatic parameters was detected. Furthermore, patients transfused with this product received a mean volume significantly lower than an historical cohort of patients treated with FFP (503 mL with Plasmasafe versus 1549 mL with FFP, P<0.001). CONCLUSIONS: The results of our study clearly document that Plasmasafe, a virally inactivated pharmaceutical-like product with a standardized content of coagulation factors, is a safe and cost-effective treatment, able to rapidly correct hemostatic abnormalities, for critical patients.

The spectrum of coagulation abnormalities in thyroid disorders.

The hemostatic balance is a complex system where the delicate equilibrium is regulated by several factors including hormones. A variety of endocrine disorders have been reported to be associated with coagulation abnormalities, ranging from mild laboratory changes to clinically relevant thrombotic or bleeding manifestations. In this review, we summarize the current knowledge on the main abnormalities of the coagulation and fibrinolytic systems associated with thyroid dysfunctions. Overall, although mostly based on uncontrolled studies, data in the literature suggest that patients with hyperthyroidism or subclinical hypothyroidism have a hypercoagulative state, whereas patients with overt hypothyroidism have a bleeding tendency.

Thyroid-associated autoimmune coagulation disorders.

Abnormalities of blood coagulation are not rarely observed in patients with thyroid dysfunctions and may range from subclinical laboratory abnormalities to clinically significant hemorrhagic or thrombotic complications. In this review, we summarize the current knowledge on thyroid-associated autoimmune coagulation disorders (i.e., autoimmune thrombocytopenic purpura, antiphospholipid syndrome, and autoantibodies against coagulation factor VIII) and discuss their laboratory characteristics, clinical impact, and recent progresses in the understanding of pathogenesis. Finally, we conclude that the prompt recognition of possible concomitant autoimmune coagulation disorders is important for the correct management of these patients.

Thyroid dysfunction and hemostasis: an issue still unresolved.

Thyroid hormones exert various effects on the hemostatic system, as documented by the fact that subclinical or overt thyroid dysfunctions may be associated with hypocoagulable or hypercoagulable states. In this review, the hemostatic balance (primary hemostasis, coagulation factors, and fibrinolytic system) in different thyroid disorders is analyzed from a laboratory, pathogenic, and clinical point of view. Although limited, the published studies suggest that patients with hyperthyroidism or subclinical hypothyroidism have an increased thrombotic risk, whereas patients with overt hypothyroidism have a bleeding tendency. Further trials on larger series of patients are needed to confirm these preliminary findings and to elucidate the pathogenic mechanisms regulating the complex interaction between thyroid disorders and hemostasis.

Prophylaxis in congenital hemophilia with inhibitors: the role of recombinant activated factor VII.

The development of inhibitors against therapeutically administered factors VIII or IX is actually the most challenging complication of hemophilia patients with inhibitors. The introduction of bypassing agents (i.e., activated prothrombin complex concentrates and recombinant activated factor VII [rFVIIa]) has dramatically improved the management of bleeding episodes in such patients. Over the last decade, there have been increasing reports on the ability of bypassing agents to prevent surgical, joint, or other bleeds in inhibitor patients. The published data on the use of rFVIIa as a prophylactic treatment in hemophilia patients with inhibitors are reviewed in this article.

Interpatient phenotypic inconsistency in severe congenital hemophilia: a systematic review of the role of inherited thrombophilia.

It is well known that the clinical phenotype of hemophilia may vary greatly among patients with the same apparent level of coagulation factor and the same genetic mutation. Thus, patients with severe hemophilia may experience a severe phenotype or only a milder bleeding tendency, suggesting some other moderating influence. To elucidate the mechanism of this heterogeneity, some investigators have recently suggested that inherited thrombophilic factors may play a role in the milder clinical presentation of severe hemophilia. In this review, we summarize current knowledge with respect to the modulation of the clinical phenotype of severe hemophilia by prothrombotic genetic risk factors. Although the published literature seems to indicate a protective effect for the coinheritance of factor V Leiden, the limited data available do not permit any firm conclusions. Further trials on a large population of patients are needed to establish the role of genetic thrombophilia in the phenotypic expression of severe hemophilia.

Extracorporeal immunoadsorption for the treatment of coagulation inhibitors.

Extracorporeal immunoadsorption is a widely used technique for the removal of pathogenic antibodies in a variety of immunologic disorders. This procedure has been used in patients with high-titer inhibitors against coagulation factors for the temporary removal of antibodies before initiating replacement therapy to achieve hemostasis and stop acute bleeding or to cover a surgical procedure. Inhibitor removal by immunoadsorption has also been included at the onset of immune tolerance protocols in both acquired and congenital hemophilia. This article summarizes the current knowledge on the use of this technique in patients with inhibitors against coagulation factors. Overall, the published literature documents that extracorporeal immunoadsorption is a safe and useful technique for the elimination of coagulation inhibitors. However, further randomized clinical trials are needed to better assess the cost-effectiveness of such procedures.

The use of desmopressin in congenital factor XI deficiency: a systematic review.

Factor XI (FXI) deficiency is a rare inherited coagulation disorder characterized by infrequent spontaneous bleeding, but increased risk of hemorrhagic complications especially after trauma or surgery. Treatment options for FXI-deficient patients include virus-inactivated fresh frozen plasma, plasma-derived FXI concentrates, and activated recombinant FVII. Inhibitors of fibrinolysis, such as tranexamic acid, and desmopressin (DDAVP) have also been used in these patients, especially in mild cases. The current knowledge on the use of the latter agent in this congenital bleeding condition is systematically reviewed here. Although limited, the available literature data suggest the potential role of DDAVP for either treatment of bleeding episodes or the prevention of postoperative bleeding in patients with milder FXI defects. However, these findings need to be supported by further trials on large population of patients.

Acquired factor VIII inhibitors in oncohematology: a systematic review.

Acquired hemophilia A is an uncommon but potentially life-threatening hemorrhagic disorder caused by the onset of autoantibodies against coagulation factor VIII. Acquired hemophilia A is most frequently associated with autoimmune diseases, neoplasia, pregnancy and drug reactions but in approximately 50% of the cases no underlying disorder can be identified. A prompt diagnosis of this acquired bleeding disorder is essential for the appropriate management which is aimed to the control of hemorrhage and the suppression of inhibitor. Based on electronic and hand searches of the published literature, this systematic review examines the current knowledge on factor VIII autoantibodies associated with oncohematological disorders.

Potential role of recombinant activated factor VII for the treatment of severe bleeding associated with disseminated intravascular coagulation: a systematic review.

Recombinant activated factor VII (rFVIIa) is a novel hemostatic agent, originally developed for the treatment of hemorrhage in hemophiliacs with inhibitors, which has been successfully used recently in an increasing number of nonhemophilic bleeding conditions. In the present systematic review we report the existing literature data on the use of this hemostatic agent in severe bleeding, unresponsive to standard treatment, associated with disseminated intravascular coagulation. A total of 99 disseminated intravascular coagulation-associated bleeding episodes treated with rFVIIa were collected from 27 published articles: in the majority of the cases, the underlying disorder complicated by disseminated intravascular coagulation was a postpartum hemorrhage, while in the remaining cases it was a cancer, trauma, sepsis or liver failure. Although limited, the data available suggest that rFVIIa could have a potential role in this clinical setting. Large randomized trials are needed, however, to confirm the preliminary results and to assess the safety and dosing regimens of this agent in refractory bleeding associated with disseminated intravascular coagulation.

Influence of the centrifuge time of primary plasma tubes on routine coagulation testing.

Preparation of blood specimens is a major bottleneck in the laboratory throughput. Reliable strategies for reducing the time required for specimen processing without affecting quality should be acknowledged, especially for laboratories performing stat analyses. The present investigation was planned to establish a minimal suitable centrifuge time for primary samples collected for routine coagulation testing. Five sequential primary vacuum tubes containing 0.109 mol/l buffered trisodium citrate were collected from 10 volunteers and were immediately centrifuged on a conventional centrifuge at 1500 x g, at room temperature for 1, 2, 5, 10 and 15 min, respectively. Hematological and routine coagulation testing, including prothrombin time, activated partial thromboplastin time and fibrinogen, were performed. The centrifugation time was inversely associated with residual blood cell elements in plasma, especially platelets. Statistically significant variations from the reference 15-min centrifuge specimens were observed for fibrinogen in samples centrifuged for 5 min at most and for the activated partial thromboplastin time in samples centrifuged for 2 min at most. Meaningful biases related to the desirable bias were observed for fibrinogen in samples centrifuged for 2 min at most, and for the activated partial thromboplastin time in samples centrifuged for 1 min at most. According to our experimental conditions, a 5-10 min centrifuge time at 1500 x g may be suitable for primary tubes collected for routine coagulation testing.

Increased factor VIII coagulant activity levels in male carriers of the factor V R2 polymorphism.

A common factor V gene haplotype, the FVR2 haplotype (FVHR2), has been associated with a reduced cofactor activity in activated protein C-mediated activated factor VIII inactivation. Our aim was to investigate the role of FVHR2 as a possible determinant of factor VIII levels in a population study. A total of 516 individuals (401 men, 115 women; mean age 58.4 +/- 10.8 years) were enrolled within the frame of a regional cardiovascular survey, characterized for factor VIII coagulant activity (FVIII:c) and factor V coagulant activity (FV:c) levels, and genotyped for factor V polymorphisms. In men without signs of overt inflammation, FVHR2 carriers had higher levels of FVIII:c than noncarriers (154 IU/dl, 95% confidence interval = 143-166 versus 142 IU/dl, 95% confidence interval = 138-147; P = 0.045) and were more represented in individuals with high (> or = 150 IU/dl) FVIII:c levels (21.2 versus 10.8%; odds ratio = 2.27, 95% confidence interval = 1.17-4.39 after adjustment for age, blood group and high-sensitivity C-reactive protein levels). In conclusion, this clinical report suggests the common FVHR2 as a possible independent determinant of FVIII:c levels. The report concomitantly addresses the relationship between factor V and factor VIII levels and supports the hypothesis of a mild prothrombotic role of FVHR2 by means of increased factor VIII levels.

Recent acquisitions in the pathophysiology, diagnosis and treatment of disseminated intravascular coagulation.

Disseminated intravascular coagulation (DIC) is a disorder characterized by both acute generalized, widespread activation of coagulation, which results in thrombotic complications due to the intravascular formation of fibrin, and diffuse hemorrhages, due to the consumption of platelets and coagulation factors. Systemic activation of coagulation may occur in a variety of disorders, including sepsis, severe infections, malignancies, obstetric or vascular disorders, and severe toxic or immunological reactions. In this review, we briefly report the present knowledge about the pathophysiology and diagnosis of DIC. Particular attention is also given to the current standard and experimental therapies of overt DIC.

Clinical heterogeneity of acquired hemophilia A: a description of 4 cases.

Acquired hemophilia A is a rare but severe auto-immune bleeding disorder characterized by the presence of autoantibodies directed against clotting factor VIII. Acquired hemophilia A may be idiopathic or associated with several conditions, such as postpartum, autoimmune diseases, malignancies or drugs. The treatment modalities of bleeding episodes and eradication of the factor VIII auto-antibody depend on the titer of anti-factor VIII:C and may include desmopressin (DDAVP), prednisolone, prednisolone-cyclophosphamide, high dose intravenous gammaglobulin, FVIII-VWF concentrate and/or recombinant FVIIa (rFVIIa). In this study we report four cases of autoimmune factor VIII inhibitors (2 associated with autoimmune disorders, 2 idiopathic) demonstrating the heterogeneity of this disease from pathogenic, clinical, therapeutic and prognostic points of view.

Influence of polymorphisms in the factor VII gene promoter on activated factor VII levels and on the risk of myocardial infarction in advanced coronary atherosclerosis.

In this study, we investigate the influence of three factor VII (FVII) gene polymorphisms on activated FVII levels (FVIIa), and also on the risk of myocardial infarction (MI) in patients with advanced coronary atherosclerotic disease (CAD). The -323A2 allele in the promoter is known to be associated with low FVII levels, and has been suggested to protect against MI in some studies. The -402GA promoter polymorphism, that in vitro has been associated with having opposite effect, is less well studied clinically. For this study, plasma FVIIa levels and three FVII gene polymorphisms were assessed in 934 subjects of both sexes, all with an angiographic documentation of coronary vessels. Our results show that two promoter polymorphisms, plasma cholesterol, and gender, were significant predictors of FVIIa levels. The -402A allele was associated to a significant increase of FVIIa levels in males (by 19.2%). In a selected clinical model including the patients with severe CAD, with or without a thrombotic complication (MI), male carriers of the -402A had an increased risk of MI (OR=1.79; 95% CI 1.15-2.80). The -323A2 allele was associated to a significant decrease in FVIIa (by 36.02% in males, and 39.7% in females). Male carriers of the -323A2 were protected from MI (OR=0.6; 95% CI 0.39-0.94), but only after correction for the confounding effect of combined heterozygosity for the promoter polymorphisms. We can conclude that FVII gene polymorphisms with an opposite effect on FVIIa levels may modulate the risk of MI in males with advanced CAD. This study highlights a "within-gene" interaction, and the need to explore polymorphisms in candidate gene(s) in detail.

High prevalence of acquired von Willebrand's syndrome in patients with thyroid diseases undergoing thyroid surgery.

BACKGROUND AND OBJECTIVES: Various coagulation abnormalities occur in patients with thyroid diseases. These abnormalities range from subclinical laboratory findings to hemorrhage or thromboembolism. However, the prevalence of hemostatic abnormalities in patients with thyroid diseases is still unclear. DESIGN AND METHODS: Between January 1999 and December 2003, 1342 consecutive patients with various thyroid diseases who were candidates for thyroid surgery underwent preoperative screening of hemostatic parameters including prothrombin time, activated partial thromboplastin time and platelet-related hemostasis with the PFA-100 platelet-function analyzer. RESULTS: Thirty-nine patients (2.9%) had abnormalities of the coagulation screening tests. Of these, 35 patients had von Willebrand's disease (type 1 in 33 cases and type 2A in 2 cases), 2 patients had decreased platelet aggregability, and 2 patients had coagulation factor XI deficiency. As all patients with coagulation abnormalities responded to subcutaneous desmopressin injection (0.3 microg/Kg BW), this drug was successfully used as surgical prophylaxis. INTERPRETATION AND CONCLUSIONS: Up to 3% of patients with thyroid diseases undergoing thyroid surgery have coagulation abnormalities, in most cases resembling von Willebrand's disease. Coagulation screening tests are needed in order to identify those patients at increased risk of bleeding.

Efficacy and safety of factor VIII/von Willebrand's factor concentrate (Haemate-P) in preventing bleeding during surgery or invasive procedures in patients with von Willebrand disease.

BACKGROUND AND OBJECTIVES: To evaluate the efficacy and safety of the factor VIII/von Willebrand factor concentrate Haemate-P as replacement therapy in patients with von Willebrand's disease (VWD) undergoing surgical or invasive procedures. DESIGN AND METHODS: Between January 1996 and October 2002, 26 patients (12 males and 14 females, median age 41.5 years, range 9-80 years), followed at three Italian Hemophilia Centers (Trento, Verona and Parma), with VWD type 1 (19 cases) and VWD type 2B (7 cases), underwent 43 surgical or invasive procedures: major surgery (14 cases), minor surgery (11 cases), dental extractions (11 cases), invasive diagnostic procedures (7 cases). Replacement therapy with factor VIII/von Willebrand factor concentrate (Haemate-P) was administered in the surgical setting as perioperative prophylaxis against excessive bleeding. RESULTS: The mean total dose (range) of Haemate-P used for major surgery was 284.1 IU VWF:RCo/kg (range 125.0-976.4), for minor surgery it was 120.8 IU VWF:RCo/kg (range 42.9-173.3), for dental extractions it was 38.4 IU VWF:RCo/kg (range 23.5-100.0) and for invasive procedures it was 87.3 VWF:RCo/kg (range 27.3-160.0). We recorded one bleeding episode 3 days after multiple dental extractions in a patient with severe periodontal disease; this bleeding was controlled with 2 further administrations of concentrate. We did not observe thrombotic episodes or other side effects following infusion of the concentrate. INTERPRETATION AND CONCLUSIONS: In conclusion, Haemate-P was effective and safe in preventing excessive bleeding after major and minor surgery or invasive procedures in VWD patients.

[Hepatitis C in hemophiliacs]. / L'epatite C negli emofilici.

Hepatitis C virus (HCV) infection is an important cause of morbidity and mortality in patients with hereditary bleeding disorders treated with non virus inactivated clotting factor concentrates during the 1970s. In this article, we briefly report the actual knowledge about HCV infection in hemophiliacs, by analyzing the prevalence of HCV infection, the genotype distribution, the natural history of the infection and the most important factors involved in the progression of chronic hepatitis into liver cirrhosis, hepatic decompensation and hepatocellular carcinoma. Finally, we describe the main advances in the treatment of HCV infection.