Purpura fulminans (PF) is a haematological emergency in which there is skin necrosis and disseminated intravascular coagulation. This may progress rapidly to multi-organ failure caused by thrombotic ...occlusion of small and medium-sized blood vessels. PF may complicate severe sepsis or may occur as an autoimmune response to otherwise benign childhood infections. PF may also be the presenting symptom of severe heritable deficiency of the natural anticoagulants protein C or protein S. Early recognition and treatment of PF is essential to reduce mortality and to prevent major long-term health sequelae. However, management strategies require accurate identification of the underlying cause. This review focuses on the clinical features, differential diagnosis and laboratory features of the range of PF disorders and includes expert consensus opinion about immediate and on-going management.
Summary
Background
Diagnosis of inherited platelet function disorders (IPFDs) is important for appropriate management and to improve epidemiologic and clinical knowledge. However, there remains a ...lack of consensus on the diagnostic approach.
Objectives
To gain knowledge on the current practices for the diagnosis of IPFD worldwide.
Methods
A 67‐item questionnaire was distributed to the ISTH members and to the members of several national hemostasis and thrombosis societies.
Results
A total of 202 laboratories from 37 countries participated in the survey. The most frequent criterion to define patients with a suspected IPFD was a history of mucocutaneous bleeding and no acquired cause, but heterogeneity on the identification criteria was evident. Only 64.5% of respondents performed a direct clinical interview. On average, each laboratory studied 72 patients per year. The most commonly used laboratory equipment were the light‐transmission aggregometer, the Platelet Function Analyzer‐100, and the flow cytometer. Screening tests were platelet count, peripheral blood smear, light‐transmission aggregometry, and Platelet Function Analyzer‐100. Second‐step tests were flow cytometry, molecular genetic analysis, and electron microscopy. Methodologies varied widely. In total, ~ 14 000 patients were investigated yearly and 60% turned out to not have a defect. Of the remaining 40%, only 8.7% received a diagnosis at a molecular level.
Conclusions
Many laboratories worldwide are involved in the diagnosis of IPFD. A large fraction of the patients studied remain without a diagnosis. A high variability in the diagnostic approaches is evident.
Recent literature has suggested a role for elevated FVIII:C in venous thromboembolic disease (VTED). However since FVIII:C is known to rise in response to an acute phase reaction, it is difficult to ...determine whether the increased FVIII:C precedes the thrombosis or represents a secondary reactive phenomenon. In an attempt to address this question, we followed 35 patients with confirmed VTED, raised FVIII:C level (>1.5 iu/ml) and no other thrombotic tendency. Serial measurements of FVIII:C, vWF:Ag, C-reactive protein and fibrinogen were performed. We hypothesized that a persistent increase in FVIII:C in the absence of any other measures of ongoing acute phase response, would support the idea that elevation of FVIII:C is a constitutional phenomenon. Of this initial group, 94% continued to have an elevated FVIII:C level throughout the period of follow up (median 8 months; range 3 to 39 months), with no significant difference between the FVIII:C levels determined at first estimation and those obtained during follow up (p = 0.58). Conversely, only 18% had evidence of an acute phase reaction when first assessed, and nonparametric ranking analysis demonstrated no correlation between FVIII:C and either C-reactive protein or fibrinogen (p = 0.315 and 0.425 respectively).We conclude that increased FVIII:C levels following VTED are persistent, independent of the acute phase reaction, and thus may represent a constitutional risk factor for VTED.
The rare coagulation disorders are heritable abnormalities of haemostasis that may present significant difficulties in diagnosis and management. This review summarizes the current literature for ...disorders of fibrinogen, and deficiencies of prothrombin, factor V, FV + VIII, FVII, FX, the combined vitamin K‐dependent factors, FXI and FXIII. Based on both collective clinical experience and the literature, guidelines for management of bleeding complications are suggested with specific advice for surgery, spontaneous bleeding, management of pregnancy and the neonate. We have chosen to include a section on Ehlers‐Danlos Syndrome because haematologists may be consulted about bleeding manifestations in such patients.
The European Non‐native Species in Aquaculture Risk Analysis Scheme (ENSARS) was developed in response to European ‘Council Regulation No. 708/2007 of 11 June 2007 concerning use of alien and locally ...absent species in aquaculture’ to provide protocols for identifying and evaluating the potential risks of using non‐native species in aquaculture. ENSARS is modular in structure and adapted from non‐native species risk assessment schemes developed by the European and Mediterranean Plant Protection Organisation and for the UK. Seven of the eight ENSARS modules contain protocols for evaluating the risks of escape, introduction to and establishment in open waters, of any non‐native aquatic organism being used (or associated with those used) in aquaculture, that is, transport pathways, rearing facilities, infectious agents, and the potential organism, ecosystem and socio‐economic impacts. A concluding module is designed to summarise the risks and consider management options. During the assessments, each question requires the assessor to provide a response and confidence ranking for that response based on expert opinion. Each module can also be used individually, and each requires a specific form of expertise. Therefore, a multidisciplinary assessment team is recommended for its completion.
Haemorrhage is a frequent manifestation of amyloidosis. We performed a retrospective clinical analysis of 337 patients with systemic immunoglobulin light‐chain (AL)‐amyloidosis, in whom whole‐body ...serum amyloid P component (SAP) scintigraphy and a clotting screen had been performed. Abnormal bleeding was noted in 94 cases (28%), and the coagulation screen was abnormal in 172 cases (51%). The most common abnormalities were prolongation of the thrombin time (TT; 108 cases, 32%) and the prothrombin time (PT; 82 cases, 24%). In multivariate analysis, a prolonged PT was the only coagulation abnormality associated with abnormal bleeding (P = 0·0012), but this was independent of the whole‐body amyloid load. Prolongation of the TT was associated with hepatic amyloid infiltration (P < 0·00001), with proteinuria (P < 0·001) and low serum albumin (P < 0·00001). In 154 patients who were studied further, subnormal factor X activity (FX:C) was found in 22 cases (14%). In cases with subnormal FX:C, the corresponding factor X antigen (FX:Ag) measurements were consistently higher (median FX:Ag/FX:C 2·5, range 0·81–9·25, n = 16) than cases with normal FX:C (median FX:Ag/FX:C 0·96, range 0·65–1·29, n = 28, P < 0·0001). No evidence was found of an FX inhibitor. Of the 48/154 (31%) cases with a prolonged TT, the reptilase time was also prolonged in 38/48 cases (79%). These data show that haemorrhage and abnormal coagulation are common in AL‐amyloidosis and are multifactorial in origin. We provide evidence suggesting that hepatic amyloid infiltration and nephrotic syndrome are determinants of the TT. In most patients, prolongation of the PT was explained by reduction in FX:C, but this was not wholly explained by a reduction in FX:Ag.
Genomics of platelet disorders Westbury, S. K.; Mumford, A. D.
Haemophilia : the official journal of the World Federation of Hemophilia,
07/2016, Letnik:
22, Številka:
S5
Journal Article
Recenzirano
Odprti dostop
Genetic diagnosis in families with inherited platelet disorders (IPD) is not performed widely because of the genetic heterogeneity of this group of disorders and because in most cases, it is not ...possible to select single candidate genes for analysis using clinical and laboratory phenotypes. Next‐generation sequencing (NGS) technology has revolutionized the scale and cost‐effectiveness of genetic testing, and has emerged as a valuable tool for IPD. This review examines the potential utility of NGS as a diagnostic tool to streamline detection of causal variants in known IPD genes and as a vehicle for new gene discovery.
Background: Vitamin K epoxide reductase subunit 1 (VKORC1) is the molecular target of coumarin anticoagulants and mutations in VKORC1 have been identified previously in individuals who required high ...warfarin doses. Objective: Detailed characterization of the relationship between variation in VKORC1 and the warfarin resistance phenotype. Patients and methods: Serum warfarin concentration and coagulation parameters were determined in 289 subjects who required warfarin doses >20 mg day−1. The VKORC1 sequence was studied in selected study subjects. Results: Twenty‐eight out of 289 (10%) subjects had serum warfarin >2.3 mg L−1 during stable therapeutic anticoagulation indicating pharmacodynamic warfarin resistance. Detailed analysis of 15 subjects from this group showed that eight out of 15 (53%) had nucleotide substitutions in VKORC1 predictive of p.V66M, p.L128R, p.V54L or p.D36Y. VKORC1 was normal in the remaining seven out of 15 (47%) subjects and in nine out of nine (100%) subjects with high warfarin dose requirement not caused by pharmacodynamic resistance. At referral, subjects with VKORC1 mutations received a median warfarin dose of 32 mg day−1 (range 22–55) and had a median serum warfarin concentration of 4.6 mg L−1 (range 2.6–9.0). VKORC1 substitutions were associated with a requirement for high warfarin doses but not with adverse clinical events. Family members with VKORC1 nucleotide substitutions and not receiving warfarin had undetectable PIVKA‐II and K1 epoxide (K1O). Conclusions: Nucleotide variations in VKORC1 are a common cause of pharmacodynamic warfarin resistance but are not associated with adverse outcome during anticoagulation. Mutations associated with warfarin resistance do not cause a discernible defect in VKORC1 reductase function.
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