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Introduction: The final events of the activated clotting cascade include the conversion of fibrinogen to fibrin and stabilization of the growing fibrin clot by factor XIII (FXIII). A missense variant in the alpha chain of fibrinogen, α-fibrinogen (FGA) Thr312Ala (rs6050, NM_000508.3:c.991A>G, NP_000499.1:p.[Thr331Ala]), has been previously shown to interfere with FXIII-dependent cross-linking, leading to stiffer blood clots. It is believed this pathophysiology underlies the increased risk of venous thromboembolism (VTE) associated with the variant. The Thr312Ala variant has been shown to be significantly associated with VTE among White, Non-Hispanic populations. The only investigation of the variant in a Black population (Rasmussen-Torvik et al 2007) found no significant relationship between Thr312Ala and VTE, but the authors cite the relatively small number of participants included in the analysis as a possible reason for a null finding. We investigated the association between FGA Thr312Ala and VTE in a case-control study enrolling a relatively large racially diverse study population. Methods: Conditional logistic regression was used to assess the association between FGA Thr312Ala and VTE among enrollees in the Genetic Attributes and Thrombosis Epidemiology (GATE) study, a case-control study enrolling 1,042 VTE cases and 1,213 controls with no history of VTE, frequency-matched on age, sex, and race. Crude models conditioned on the matching factors, and adjusted models conditioned on the matching factors and controlled for patient characteristics found to be associated with both case/control status and FGA Thr312Ala genotype. Among all patient characteristics evaluated, the β-fibrinogen (FGB) promoter region variant -455 G>A (rs1800790, NM_001184741.1:c.-463G>A) was the only patient characteristic associated with both case/control status and FGA Thr312Ala genotype. Potential effect modification was assessed using likelihood ratio tests. Results: Among 660 White controls and 528 White cases in the GATE study, carrying at least one FGA rs6050 G (Ala) allele was associated with increased odds of VTE compared to not carrying a G allele (odds ratio (OR) and 95% confidence interval (CI) 1.2 [1.0-1.5]) in a crude model. This association was strongest when restricting to n=205 idiopathic (unprovoked) cases, n=125 recurrent cases, or n=112 cases exhibiting both deep vein thrombosis (DVT) and pulmonary embolism (PE) (Table 1). This association was modified by obesity status, with the effect among obese enrollees being multiplicative (Table 2). In contrast, there was no association between carrying at least one FGA rs6050 G (Ala) allele and VTE among 553 Black controls and 514 Black cases in the GATE study (OR and 95% CI 1.0 [0.8-1.2]) when assessing the association among all cases (Table 1). However, the odds of VTE was higher among Black participants carrying the G allele compared to those not carrying the allele when restricting to n=103 PE only cases (OR and 95% CI 1.5 [1.0-2.4]). The association between FGA Thr312Ala and VTE did not appear to be modified by obesity status among Black participants (Table 2). Conclusions: These results indicate that the FGA Thr312Ala (rs6050, NM_000508.3:c.991A>G, NP_000499.1:p.[Thr331Ala]) polymorphism is associated with VTE among White participants in the GATE study, with the strongest effect seen in participants exhibiting both DVT and PE. However, the association among Black participants appears limited to PE, indicating further exploration of genetic risk factors for VTE in Black populations is warranted in order to better understand genetic risk factors for all types of VTE in this population. Disclosures Payne: Bayer: Other: treatment product donation; Bioverativ: Other: treatment product donation; Novo Nordisk: Other: treatment product donation; Shire: Other: treatment product donation; Genentech: Membership on an entity's Board of Directors or advisory committees. Patel:Daiichi Sankyo: Other: DSMB member.

Whether or not vertebrate blood clotting has a major role in defending against microbial infection has long been a matter of debate. Apart from the mere physical barrier that a fibrin clot presents against external invaders when plugging a wound, is there a strategy specifically targeted against the pathogen?

In this issue of Blood, Haling and colleagues demonstrate that in addition to talin-dependent integrin activation, talin is required for platelet fibrin clot retraction by physically linking integrins to the actin cytoskeleton.

Авторы исследовали венозную кровь трех добровольцев и определили время формирования (45-60 мин) фибрин-кровяного сгустка в замкнутом пространстве in vitro, а также изучили влияние на скорость его формирования механических факторов (сдавливания и перемешивания). Установлена зависимость структуры и механических свойств сформированного фибрина от указанных факторов. Изучены гистоморфологические особенности фибрин-кровяных сгустков, полученных из околоотломковых зон 12 пострадавших с закрытыми переломами конечностей, в сроки от 2 ч до 12 суток после травмы. Выявлено, что через 2–4 ч после перелома в сформированную фибриновую сеть по периферии проникают малодифференцированные клетки и фибробласты, начинается врастание кровеносных капилляров. Через 6–12 суток отмечена реорганизация сгустка., The authors examined venous blood of three volunteers and determined the time of the formation (45-60 minutes) of a fibrin-blood clot in closed space in vitro, as well as they studied the effects of mechanical factors (pressure and mixing) on the rate of this formation. Dependence of the structure and mechanical properties of the formed fibrin upon the above factors was revealed. Histomorphological peculiarities of fibrin-blood clots, obtained from perifragmental regions in 12 cases with closed fractures of their extremities from 2 hours to 12 days after the injury, were studied. It was found out that poorly differentiated cells and fibroblasts entered the formed fibrin mesh on its periphery 2-4 hours after the fracture, and ingrowth of blood capillaries began. Reorganization of the clot was observed after 6-12 days., Автори дослідили венозну кров трьох добровольців та визначили час утворення (45–60 хв) фібрин-кров’яного згустку в замкненому просторі in vitro, а також вивчили вплив на швидкість його формування механічних факторів (тиску та перемішування). Встановлено залежність структури та механічних властивостей сформованого фібрину від зазначених факторів. Вивчені гістоморфологічні особливості фібрин-кров’яних згустків, отриманих із навколовідламкових зон 12 постраждалих із закритими переломами кінцівок, у терміни від 2 год до 12 діб після травми. Виявлено, що через 2–4 год після перелому в утворену фібринову сітку по периферії проникають малодиференційовані клітини і фібробласти, починається вростання кровоносних капілярів. Через 6–12 діб відмічена реорганізація згустку.

We have demonstrated that under specific conditions the maximal rate of change in optical density (Vmax∆OD) of plasma resulting from addition of thrombin with subsequent conversion of fibrinogen to fibrin is directly related to the concentration of clottable fibrinogen. Plasma fibrinogen concentration determined in seconds by this thrombokinetic analysis correlated significantly (r > 0.95, p < 0.001) with fibrinogen quantitation measured by desiccated clot weight and by biuret digestion of a thrombin-induced fibrin clot.

An experimental automatic lysis sensor has been designed to measure accurately the time required for fibrinolytic agents to lyse a standardized fibrin clot. New assay procedures for the determination of plasminogen activators, their inhibitors, and other fibrinolytic agents are reported. Procedures for the establishment of calibration curves and the reliability limits of these assays are presented.