Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo

Copyright © 2008 Massachusetts Medical Society. A 19-year-old woman presents to the emergency department with light-headedness, severe abdominal pain, and intractable nausea and vomiting that began 12 hours earlier. The patient reports previous episodes of abdominal pain and swelling of her hands and feet that have been attributed possibly to food allergies, which have recently become more frequent. There is no associated urticaria. Her only medication is an oral contraceptive that was started 3 months earlier. She notes a history of similar episodes in her father. She is afebrile, with a blood pressure of 75/40 mm Hg, a pulse of 120 beats per minute, and diffuse abdominal tenderness with guarding and rebound tenderness. How should her case be evaluated and treated?

Clinical practice. Hereditary angioedema.

https://www.cell.com/trends/immunology/pdf/S1471-4906(07)00048-8.pdf

Complement and coagulation: strangers or partners in crime?

Angioedema is defined as localized and self-limiting edema of the subcutaneous and submucosal tissue, due to a temporary increase in vascular permeability caused by the release of vasoactive mediator(s). When angioedema recurs without significant wheals, the patient should be diagnosed to have angioedema as a distinct disease. In the absence of accepted classification, different types of angioedema are not uniquely identified. For this reason, the European Academy of Allergy and Clinical Immunology gave its patronage to a consensus conference aimed at classifying angioedema. Four types of acquired and three types of hereditary angioedema were identified as separate forms from the analysis of the literature and were presented in detail at the meeting. Here, we summarize the analysis of the data and the resulting classification of angioedema.

/pdf/classification-diagnosis-and-approach-to-treatment-for-1cqcj2tgqz.pdf

Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group

Polyphosphate: an ancient molecule that links platelets, coagulation, and inflammation

Hereditary angioedema (HAE) is characterized clinically by recurrent acute skin swelling, abdominal pain, and potentially life-threatening laryngeal edema. Three forms of HAE have been described. The classic forms, HAE types I and II, occur as a consequence of mutations in the C1-inhibitor gene. In contrast to HAE types I and II, HAE type III has been observed exclusively in women, where it appears to be correlated with conditions of high estrogen levels--for example, pregnancy or the use of oral contraceptives. A recent report proposed two missense mutations (c.1032C-->A and c.1032C-->G) in F12, the gene encoding human coagulation factor XII (FXII, or Hageman factor) as a possible cause of HAE type III. Here, we report the occurrence of the c.1032C-->A (p.Thr328Lys) mutation in an HAE type III-affected family of French origin. Investigation of the F12 gene in a large German family did not reveal a coding mutation. Haplotype analysis with use of microsatellite markers is compatible with locus heterogeneity in HAE type III. To shed more light on the pathogenic relevance of the HAE type III-associated p.Thr328Lys mutation, we compared FXII activity and plasma levels in patients carrying the mutation with that of healthy control individuals. Our data strongly suggest that p.Thr328Lys is a gain-of-function mutation that markedly increases FXII amidolytic activity but that does not alter FXII plasma levels. We conclude that enhanced FXII enzymatic plasma activity in female mutation carriers leads to enhanced kinin production, which results in angioedema. Transcription of F12 is positively regulated by estrogens, which may explain why only women are affected with HAE type III. The results of our study represent an important step toward an understanding of the molecular processes involved in HAE type III and provide diagnostic and possibly new therapeutic opportunities.

https://www.cell.com/ajhg/pdf/S0002-9297(07)63472-7.pdf

Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III

Purpose of reviewBlood coagulation is a tightly regulated process, involving vascular endothelium, platelets, and plasma coagulation factors. Formation of fibrin involves a series of sequential proteolytic reactions, initiated by the ‘extrinsic’ and ‘intrinsic’ pathway of coagulation. As hereditary

Novel roles for factor XII-driven plasma contact activation system.

Spliceosomal Uridine-rich small ribonucleo protein (U snRNP) assembly is an active process mediated by the macromolecular survival motor neuron (SMN) complex. This complex contains the SMN protein and six additional proteins, named Gemin2-7, according to their localization to nuclear structures termed gems. Here, we provide biochemical evidence for the existence of another, yet atypical, SMN complex component, termed unr-interacting protein (unrip). This abundant factor has been previously shown to form a complex with unr, a protein implicated in cap-independent translation of cellular and viral mRNA. We show that unrip is integrated into a complex with unr or with the SMN complex in vivo in a mutually exclusive manner. In the latter case, unrip is recruited to the active SMN complex via a stable interaction with Gemin7. However, unlike SMN and Gemins, unrip localizes predominantly to the cytoplasm and is absent from gems/Cajal bodies. Interestingly, RNAi-induced reduction of unrip protein levels leads to enhanced accumulation of SMN in the nucleus as evident by the increased formation of nuclear gems/Cajal bodies. Our data identify unrip as the first component of the U snRNP assembly machinery that associates with the SMN complex in a compartment-specific way. We speculate that unrip plays a crucial role in the intracellular distribution of the SMN complex.

/pdf/unrip-a-factor-implicated-in-cap-independent-translation-3v5d1t56nx.pdf

Felicitas Müller

Papers

Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III

Novel roles for factor XII-driven plasma contact activation system.

Unrip, a factor implicated in cap-independent translation, associates with the cytosolic SMN complex and influences its intracellular localization