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• W1512978275 abstract "Human clotting factor XII (FXII) deficiency is not associated with bleeding problems, but the assumption that FXII is irrelevant to physiological clotting has been challenged by recent studies with FXII-null mice (Renne et al, 2005; Kleinschnitz et al, 2006; Stoll et al, 2008). Thrombin generation, clot formation and clot stability have been examined in vitro in human blood and plasma where FXII activity has been artificially depleted or inhibited (Luddington & Baglin, 2004; Nielsen et al, 2005; Nielsen, 2009), revealing some technical limitations to simulating FXII deficiency. We have extended these studies using samples from a patient lacking constitutive FXII expression, representing a genuine human FXII-null. The patient was a healthy 18-year-old male with no prior bleeding history, evaluated for an incidental finding of elevated activated partial thromboplastin time (APTT) >180 s. Laboratory testing reported undetectable plasma FXII (<0·01), confirmed by immunoblot analysis. Normal range values were reported for fibrinogen and other plasma proteins, coagulation and Von Willebrand factor (VWF) levels [iu/ml: FVIII 1·52, FIX 1·16, FXI 1·39, VWF antigen (VWF:Ag) 0·73, ristocetin cofactor (VWF:RCo) 1·03; blood group O positive], complete blood count, bleeding time and International Normalized Ratio. Anticoagulated (sodium citrate 3·2%) blood was collected by venepuncture from the FXII-null patient and from normal control subjects with or without the addition of corn trypsin inhibitor (CTI; Haematologic Technologies Inc., Essex Junction, VT, USA) at 20 μg/ml. Plasma was prepared by centrifugation. Thrombin generation was measured via calibrated automated thrombography (CAT) assays performed with a Thrombinoscope system (Synapse BV, Maastricht, Netherlands). Consistent with previous studies (Luddington & Baglin, 2004), assays of normal plasma with and without CTI (Fig 1) using low concentration tissue factor (TF; 1 pmol/l) activation (n = 5) showed significantly decreased (P > 0·01) values for mean (±standard deviation) peak thrombin (165 ± 68 nmol/l. vs. 267 ± 65) and longer time to peak (7·0 ± 1·0 vs. 9·0 ± 1·8 min) for CTI-treated samples. Compared to normal plasma with CTI (Fig 1), CAT assays of FXII-null patient plasma samples (n = 3) showed significantly lower (P > 0·01) peak thrombin (69·5 ± 9·1 nmol/l) and time to peak (11·7 ± 0·7 min). CAT assays of FXII immunodepleted normal plasma gave similar results to CTI-treated normal samples. Addition of purified FXII at a physiological concentration of 50 μg/ml to FXII-null plasma increased thrombin generation to a level equivalent to CTI-treated normal plasma (Fig 1). Assays using high TF (5 pmol/l) activation showed no significant differences among all sample groups, presumably due to rapid induction of FVIIa-mediated thrombin generation. Thrombin generation in normal donor plasma without (Normal) or with corn trypsin inhibitor (Normal + CTI), and FXII-null plasma without (FXII-null) or with added FXII (FXII-null + FXII). The samples were activated with 1 pM TF. Clotting was measured via thromboelastography (TEG) assays performed with Haemoscope 5000 analysers (Haemonetics Corp., Braintree, MA, USA). As expected from clinical laboratory results and previous studies (Nielsen et al, 2005), unactivated FXII-null blood samples did not clot within 120 min. Clotting was observed with kaolin contact-pathway activation but, compared to the mean for normal samples (n = 17), FXII-null blood had a much lower maximum rate of thrombus generation (MRTG; 3·7 mm/min vs. 10·7 ± 1·8 normal mean) and considerably extended time until clotting onset (43·2 min vs. 6·0 ± 1·0). Clotting kinetics were also decreased in kaolin-activated CTI-treated normal blood, but not nearly to the extent observed in FXII-null samples. A similar pattern of clotting kinetics was observed in TEG assays using activation with low concentration TF (140 fmol/l), but at 1·4 pmol/l TF no differences were observed between FXII-null and normal blood. Clot stability was tested via TEG fibrinolysis assays where tissue-type plasminogen activator (tPA; Cathflo Activase®, alteplase, Genentech) was added to samples at a final concentration of 0·56 ng/ml. CTI has been shown to directly inhibit tPA activity in TEG fibrinolytic assays (Nielsen, 2009), thus CTI-treated normal samples cannot be reliably tested for clot stability in vitro. TF activation (≥1·4 pmol/l) was used to produce consistent initial clot formation kinetics in normal and FXII-null samples, and assays were run until the amplitude returned to the baseline value of 2 mm to yield a value for the clot lysis time (CLT, min). We observed that clot stability was notably decreased in FXII-null blood compared to normal (Fig 2), as indicated by a CLT of 47 min versus the normal mean (n = 5) of 83 ± 22·6 min. Similar assays were performed using plasma samples, which also showed significantly lower (P > 0·01) mean CLT for FXII-null samples (63·2 ± 11·2 min; n = 8) compared to normal plasma samples (92·0 ± 17·6; n = 7). Results for FXII-depleted normal plasma were within the normal range. TEG fibrinolysis assays of FXII-null and representative normal donor whole blood. Clotting was activated with TF and fibrinolysis stimulated with tPA. Clot breakdown is demonstrated by the convergence of the amplitude curve back to baseline as indicated by the clot lysis time (CLT). In summary, we observed that using low levels of TF activation in vitro plasma thrombin generation was depressed in FXII-null samples compared to both normal samples and those treated to inactivate FXII (with CTI) or deplete it. FXII-null blood also showed depressed clot formation kinetics at low levels of TF. When sufficient TF was used to produce uniform clotting kinetics in blood and plasma, FXII-null clots were observed to be less stable as assessed by tPA-mediated fibrinolysis than those formed in normal and FXII-depleted samples (CTI-treated samples cannot be reliably tested for clot stability). Clot structure is influenced by thrombin generation (Weisel, 2007; Wolberg & Campbell, 2008) and TF activity in whole blood has been estimated to be 20 fmol/l or less (Butenas et al, 2008). Within this physiological range our results indicate that FXII may positively influence the kinetics of clot formation. Our results are also in line with studies indicating that lack of FXII activity in FXII-null mice (Renne et al, 2005; Kleinschnitz et al, 2006; Stoll et al, 2008) protects mice from arterial and venous thrombosis without affecting bleeding. In humans, decreased levels of FXII have been observed to have a negative effect on survival, but not severe deficiency (Endler et al, 2007). Given the evidence for a physiological role for FXII in clotting and the differences we have observed between assays of genuine human FXII-null samples and those simulating FXII deficiency, it would be worthwhile to extend this analysis to other cases of constitutive lack of FXII expression." @default.
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• W1512978275 date "2010-09-29" @default.
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• W1512978275 title "Decreased in vitro thrombin generation and clot stability in human FXII-null blood and plasma" @default.
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• W1512978275 doi "https://doi.org/10.1111/j.1365-2141.2010.08382.x" @default.
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