Urticarial vasculitis in the childhood with C2 hypocomplementenemia: a rare case.

We report a first case of hypocomplementemic urticarial vasculitis of C2 fraction in a child, with cutaneous manifestation only, with no reports in scientific literature.

Genes influencing coagulation and the risk of aneurysmal subarachnoid hemorrhage, and subsequent complications of secondary cerebral ischemia and rebleeding.

BACKGROUND: We investigated whether genes influencing coagulation are associated with the occurrence of aneurysmal subarachnoid hemorrhage (SAH) and with secondary cerebral ischemia and rebleeding in patients with aneurysmal SAH. METHOD: Genotyping for factor V Leiden (G1691A), prothrombin G20210A, methylenetetetrahydrofolate reductase (MTHFR) C677T, factor XIII subunit A Val34Leu, Tyr204Phe and Pro564Leu, and factor XIII subunit B His95Arg was performed in 208 patients with aneurysmal SAH and in 925 controls. Secondary cerebral ischemia occurred in 49 (24%) patients and rebleeding in 28 (14%) during their clinical course of 3 months after the aneurysmal SAH. The risk of aneurysmal SAH was assessed as odds ratio (OR) with 95% confidence interval (95% CI). The risk of secondary cerebral ischemia and rebleeding was assessed as hazard ratio (HR) with 95% CI using Cox regression. FINDINGS: Carriers of the subunit B His95Arg factor XIII polymorphism had an increased risk of aneurysmal SAH with 23% of the patients homozygous or heterozygous for the variant allele compared to 17% of control subjects (OR 1.5, 95% CI 1.0-2.2). For the remaining genetic variants no effect on the risk of aneurysmal SAH could be demonstrated. A clear relation with the risk of secondary cerebral ischemia and of rebleeding could not be established for any of the genetic variants. CONCLUSIONS: We found that aneurysmal SAH patients are more often carriers of the subunit B His95Arg factor XIII polymorphism compared to controls. This suggests that carriers of the subunit B His95Arg factor XIII polymorphism have an increased risk of aneurysmal SAH. Larger studies should confirm our results. As aneurysmal SAH patients who died soon after admission could not be included in the present study, our results only apply to a population of patients who survived the initial hours after the hemorrhage. For the other studied genetic factors involved in coagulation, no association with the occurrence of aneurysmal SAH or with the occurrence of secondary cerebral ischemia or rebleeding after aneurysmal SAH could be demonstrated.

Further understanding of recombinant activated factor VII mode of action.

Recombinant activated factor VII (rFVIIa) is being increasingly used to treat bleeding associated with a variety of non-hemophilic coagulopathic indications, and its mechanism of action in these areas is under active investigation. Numerous studies have shown that FVIIa binds with low affinity to activated platelets; rFVIIa can subsequently enhance platelet-surface thrombin generation by activating factor (F) X and by contributing additional FIXa to the hemostatic process. This FIXa can rapidly activate additional FX, which may explain why non-hemophilic coagulopathic bleeds respond to lower doses of rFVIIa than do hemophilic bleeds. However, the platelet surface may be able to process only a limited amount of FXa, accounting for the observation that some models of non-hemophilic coagulopathy show a plateau in the effect of rFVIIa.

Venom Protein C Activators as Diagnostic Agents for Defects of Protein C System.

BACKGROUND: Protein C is a vitamin K dependent plasma zymogen. It inhibits clotting by inhibiting clotting by inactivating factor V and factor VIII. Protein C activation pathway involves three steps: (i) Activation of protein C; (ii) Inhibition of coagulation through inactivating factor V and VIII by activated protein C and (iii) Inhibition of activated protein C by plasma protease inhibitors specific for this enzyme. Proteinases converting the zymogen protein C (PC) of vertebrates into activated PC have been detected in several snake venoms. Most PC activators have been purified from venom of snake species belonging to the genera of the Agkistrodon complex. Unlike the physiological thrombin-catalyzed PC activation reaction which requires thrombomodulin as a cofactor, most snake venom activators directly convert the zymogen PC into the catalytically active form which can easily be determined by means of coagulation or chromogenic substrate techniques. CONCLUSION: The fast-acting PC activator Protac® from Agkistrodon contortrix contortrix (Southern copperhead snake) venom has found a broad application in diagnostic practice for the determination of disorders in the PC pathway. Recently, screening assays for the PC pathway have been introduced, based on the observation that the PC pathway is probably the most important physiological barrier against thrombosis.

Mathematical modeling of blood coagulation cascade: kinetics of intrinsic and extrinsic pathways in normal and deficient conditions.

A mathematical model has been developed to simulate the generation of thrombin through intrinsic and extrinsic pathways. The time course of clotting factor activation during coagulation was calculated, and the sensitivity of the kinetics due to a decrease or deficiency in the concentrations of coagulation proteins or their activities was studied. The model gives reasonable predictions without the adjustment of any parameter values. The calculated clotting time was approximately 44 s for the intrinsic pathway and approximately 8.6 s for the extrinsic pathway using normal protein concentrations in plasma. Various prolonged clotting times were observed in different factor-deficient disorders using this model.

Amyloidosis and bleeding: pathophysiology, diagnosis, and therapy.

Amyloid diseases can be associated with potentially life-threatening hemorrhage. Pathogenetic factors contributing to the abnormal bleeding tendency in this setting are heterogeneous and depend on the type of amyloidosis and pattern of organ involvement. In patients with light-chain (AL) amyloidosis, acquired hemostatic abnormalities, including coagulation factor deficiencies, hyperfibrinolysis, and platelet dysfunction, can be regarded as the most important pathogenetic factors. In patients with other types of amyloidosis, acquired hemostatic defects are rare, and amyloid deposition has also been reported to be the main cause of abnormal bleeding manifestations. Amyloid angiopathy with increased fragility of blood vessels and impaired vasoconstriction may promote bleeding in this setting. Rupture of solid organs caused by amyloid deposition also was reported. Whereas therapeutic options in bleeding caused by local amyloid deposition are restricted to supportive measures and, in severe cases, surgery, acquired hemostatic defects may be treated according to the causative mechanism. In this review, we focus on bleeding risks in patients with amyloid diseases. Current concepts with regard to pathophysiology, diagnosis, and treatment are summarized and discussed.

Genetic interactions between the coagulation and fibrinolytic systems.

Nearly all of the genes encoding the established coagulation and fibrinolytic factors have been successfully altered or disrupted in transgenic mice. Although comprehensive studies of each of these gene-targeted mouse lines are still ongoing, the initial findings have significantly refined our understanding of the roles of selected hemostatic factors in vivo, and occasionally altered long-standing concepts. This review summarizes some of the progress that has been made in the generation and phenotypic characterization of mice lacking key hemostatic factors, including coagulation, fibrinolytic, platelet and endothelial cell-associated factors. New insights regarding the role(s) and interplay of hemostatic factors that have emerged from detailed studies of mice carrying multiple deficits in coagulation and fibrinolytic system components are highlighted.

Abnormalities in thrombin-antithrombin pathway in AL amyloidosis.

Various pathogenic factors have been proposed to explain the abnormal hemostasis observed in AL amyloidosis. Since imbalance between clotting factors and inhibitors could play a pathogenic role in both hemorrhagic and thrombotic manifestations, we investigated the thrombin-antithrombin pathway in 35 patients with AL amyloidosis. Ten patients suffered from bleeding while 3 patients experienced deep venous thrombosis. Thrombin time was prolonged in 29 subjects, the mean values of antithrombin III activity (ATIII Act) were significantly lower than those of antithrombin III antigen (ATIII Ag) with loss of relationship between these two different techniques of ATIII detection, normally observed in healthy controls. In 19 patients increased levels of thrombin-antithrombin (TAT) complexes were present. Crossed immunoelectrophoresis of ATIII, performed in presence of heparin, evidenced ATIII forms with reduced binding capacity to heparin and TAT complexes of various electrophoretic mobilities. In conclusion, the impairment of the thrombin-antithrombin pathway, in association with the low ATIII biological activity, might play a pathogenic role in the hypercoagulable state reported in AL amyloidosis, despite the higher frequency of bleeding manifestations.

Thrombotic dysfibrinogenemia. Fibrinogen "Caracas V" relation between very tight fibrin network and defective clot degradability.

Fibrinogen Caracas V is a thrombotic dysfibrinogenemia with an Aalpha 532 Ser-->Cys mutation characterized by a tight fibrin network formed of thin fibers responsible for a less porous clot than a normal one. In the present work, fibrinogen Caracas V is further characterized in order to understand the relationship between the structural defect and thrombophilia. This thrombotic disorder has been attributed to a tight fibrin network responsible for a decreased permeation of flow through the clot, leading to defective thrombus lysis due to a diminished availability of fibrinolytic enzymes to the inner fibrin surface. Correction of clot structure anomaly, by addition of dextran 40 to fibrinogen before clotting, induces an improvement in fibrin degradation that was attributed to an increase in porosity. The pulmonary embolism observed in this family has been related to an hyper rigidity of the clot, an anomaly that is also corrected by dextran. Furthermore, this abnormal fibrinogen binds more albumin than does normal fibrinogen, a phenomenon attributed to the mutation of serine in Aalpha-532 by cysteine. Therefore, this fibrinogen shows a striking similarity to the fibrinogen Dusart, allowing us to confirm that the alphaC-terminal part of fibrinogen plays an important role in fibrin structure, and to conclude that the anomaly of fibrin network observed in fibrinogen Caracas V is responsible for a deficient thrombus lysis.

Elevated hemostatic factor levels as potential risk factors for thrombosis.

OBJECTIVES: To review the state of the art relating to elevated hemostatic factor levels as a potential risk factor for thrombosis, as reflected by the medical literature and the consensus opinion of recognized experts in the field, and to make recommendations for the use of specific measurements of hemostatic factor levels in the assessment of thrombotic risk in individual patients. DATA SOURCES: Review of the medical literature, primarily from the last 10 years. DATA EXTRACTION AND SYNTHESIS: After an initial assessment of the literature, key points were identified. Experts were assigned to do an in-depth review of the literature and to prepare a summary of their findings and recommendations. A draft manuscript was prepared and circulated to every participant in the College of American Pathologists Conference XXXVI: Diagnostic Issues in Thrombophilia prior to the conference. Each of the key points and associated recommendations was then presented for discussion at the conference. Recommendations were accepted if a consensus of the 27 experts attending the conference was reached. The results of the discussion were used to revise the manuscript into its final form. CONCLUSIONS: Consensus was reached on 8 recommendations concerning the use of hemostatic factor levels in the assessment of thrombotic risk in individual patients. Detailed discussion of the rationale for each of these recommendations is presented in the article. This is an evolving area of research. While routine use of factor level measurements is not recommended, improvements in assay methodology and further clinical studies may change these recommendations in the future.

Spontaneous intracerebral hemorrhage due to coagulation disorders.

Although intracranial hemorrhage accounts for approximately 10 to 15% of all cases of stroke, it is associated with a high mortality rate. Bleeding disorders account for a small but significant risk factor associated with intracranial hemorrhage. In conditions such as hemophilia and acute leukemia associated with thrombocytopenia, massive intracranial hemorrhage is often the cause of death. The authors present a comprehensive review of both the physiology of hemostasis and the pathophysiology underlying spontaneous ICH due to coagulation disorders. These disorders are divided into acquired conditions, including iatrogenic and neoplastic coagulopathies, and congenital problems, including hemophilia and rarer diseases. The authors also discuss clinical features, diagnosis, and management of intracranial hemorrhage resulting from these bleeding disorders.

Atypical hemolytic-uremic syndrome: the interplay between complements and the coagulation system.

Hemolytic-uremic syndrome (HUS) is a rare life-threatening disorder characterized by microangiopathic hemolytic anemia, thrombocytopenia, and impaired renal function. A thrombotic microangiopathy underlies the clinical features of HUS. In the majority of cases, HUS follows an infection with toxin-producing bacteria such as verotoxin-producing Escherichia coli. In some cases, HUS is not preceded by a clinically apparent infection, and therefore, is named atypical HUS. The prognosis of atypical HUS is poor. While mortality approaches 25% during the acute phase, end-stage renal disease develops in nearly half of patients within a year. Evidence is accumulating that complement activation through the alternative pathway is at the heart of the pathophysiology leading to atypical HUS. Genetic abnormalities involving complement regulatory proteins and complement components form the molecular basis for complement activation. Since microvascular thrombosis is a quintessential feature of atypical HUS, complements and the coagulation system must work in tandem to give rise to the pathologic alterations observed in this condition. Here, a brief discussion of clinical and morphologic features of atypical HUS is followed by a concise presentation of the complement and coagulation systems. The interplay between complements and the coagulation system is graphically highlighted. Last but not least, conventional and emerging therapies for atypical HUS are outlined.

Inherited thrombophilia.

Inherited thrombophilia can be defined as a genetically determined predisposition to the development of thromboembolic complications. Since the discovery of activated protein C resistance in 1993, several additional disorders have been described and, at present, it is possible to identify an inherited predisposition in about 60 to 70% of patients with such complications. These inherited prothrombotic risk factors include qualitative or quantitative defects of coagulation factor inhibitors, increased levels or function of coagulation factors, defects of the fibrinolytic system, altered platelet function, and hyperhomocysteinemia. In this review, the main inherited prothrombotic risk factors are analyzed from epidemiological, laboratory, clinical, and therapeutic points of view. Finally, we discuss the synergism between genetic and acquired prothrombotic risk factors in particular conditions such as childhood and pregnancy.

Predicting abnormal coagulation in ischemic stroke: reducing delay in rt-PA use.

Normal prothrombin time (PT) and partial thromboplastin time (PTT) are recommended for administration of recombinant tissue-plasminogen activator (rt-PA) in stroke, but waiting for results can delay use. We examined the charts of 365 stroke patients to assess predetermined risk factors associated with elevated PT/PTT. Elevated PT/PTT can be predicted in patients taking warfarin or heparin/heparinoid or on hemodialysis, according to emergency department triage, with 100% sensitivity and 94.7% specificity. These results could be applied to rt-PA candidates and reduce potential delays.

Coagulopatías graves: diagnóstico clínico y analítico / Serious coagulation disorders: clinical and analytic diagnosis

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