Summary. Background: The plasma kallikrein-kinin system (PKKS) has been implicated in cardiovascular disease, but activation of the PKKS has not been directly probed in individuals at risk of coronary heart disease (CHD) or stroke. Objective: To determine the involvement of the PKKS, including factor XI, in cardiovascular disease occurring in a nested case-control study from the Second Northwick Park Heart Study (NPHS-II). Methods and results: After a median follow-up of 10.7 years, 287 cases of CHD and stroke had been recorded and 542 age-matched controls were selected. When FXIIa-C1 esterase inhibitor (C1-inhibitor) concentrations were divided into tertiles (lowest tertile as reference), the odds ratios (ORs) at 95% CIs for CHD were 0.52 (0.34-0.80) in the middle tertile and 0.73 (0.49-1.09) in the highest tertile (P = 0.01 for the overall difference; P = 0.01 for CHD and stroke combined). For kallikrein-C1-inhibitor complexes, the ORs for stroke were 0.29 (0.12-0.72) and 0.67 (0.30-1.52) in the middle and high tertiles, respectively (P = 0.02). FXIIa-C1-inhibitor and kallikrein-C1-inhibitor complexes were negatively related to smoking and fibrinogen (P < 0.005). FXIa-inhibitor complexes correlated strongly with FXIIa-inhibitor complexes. Conclusions: Lower levels of inhibitory complexes of the PKKS enzymes and particularly of FXIIa contribute to the risk of CHD and stroke in middle-aged men. This observation supports the involvement of the PKKS in atherothrombosis.

To cite this article: Smid M, Dielis AWJH, Winkens M, Spronk HMH, van Oerle R, Hamulyá k K, Prins MH, Rosing J, Waltenberger JL, ten Cate H.Thrombin generation in patients with a first acute myocardial infarction. J Thromb Haemost 2011; 9: 450-6. Summary. Background: Despite improved treatment options, myocardial infarction is still an important cause of morbidity and mortality. One of the contributing mechanisms in the acute myocardial infarction (AMI) is plasma hypercoagulability. Methods: We investigated hypercoagulability in 135 (first) patients with AMI using thrombin generation (TG) testing. TG testing was performed in plasmas, drawn upon admission and before medication administration, and subsequently after 4 days, 3 and 6 months. Further, we evaluated determinants of thrombin generation using multiple regression analysis of major coagulation proteins and inhibitors. Admission TG results were also related to 1-year outcome: cardiovascular death, recurrent myocardial infarction, a second coronary intervention [percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG)] and ischemic stroke. Results: At day 0, the TG parameters peak height, endogenous thrombin potential (ETP) and lag time were increased compared with a reference population. Peak height and lag time stayed persistently increased in patients. The lowest half of the ETP values was statistically not significantly associated with an occurrence of endpoints. The lowest half of the ETP values combined with the upper half of the D-dimer values were associated with endpoints; odds ratio 5.8 (1.1-30.7). Tissue factor pathway inhibitor (TFPI) seems to be an important determinant of TG in AMI and healthy persons. Conclusions: TG reflects acute hypercoagulability during AMI and partly also in the 6-month period after the acute event. TG shows a trend of an inverse association with risk of recurrent ischemic cardiovascular complications. Unraveling mechanisms in TG might improve our understanding of the pathophysiology of AMI and direct future improvements in medical care.

Abstract-Despite increased pulsatile stress, thrombotic rather than hemorrhagic events represent a major complication of hypertension. The pathophysiology of thrombosis in hypertension involves the interaction among vascular endothelium and particularly the renin-angiotensin and kallikrein-kinin systems. Because hypertension is often associated with some degree of inflammation, the combination of chronic inflammation and chronic shear stress may convert the normal anticoagulant endothelium into a procoagulant surface, expressing tissue factor. Activation of the renin-angiotensin system leads to activation of nuclear factor B-dependent proinflammatory genes, also accelerating the expression of tissue factor. Renin-angiotensin and kallikrein-kinin systems interact at several levels to modulate coagulation, fibrinolysis, and vasodilatation in such a way that these 2 systems could have a major influence on the occurrence of thrombotic complications. Treatment with angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists may favorably influence the balance between the renin-angiotensin and kallikrein-kinin axis, regulating blood pressure as well as reducing the risk of thrombosis, which may explain part of the clinical efficacy of these drugs. Key Words: renin-angiotensin system Ⅲ kallikrein-kinin systems Ⅲ blood pressure A lthough hypertension exposes blood vessels to increased pulsatile stress, thrombotic rather than hemorrhagic events represent a major complication in hypertensive patients. This apparent contradiction is known as the thrombotic paradox of hypertension or "Birmingham paradox." 1,2 Nevertheless, in hypertension, several thrombogenic abnormalities occur and evidence is emerging that the condition confers a "prothrombotic state." Just as is the case in venous thrombosis, abnormalities in the vessel wall, blood constituents (such as hemostatic and fibrinolytic factors and platelets), and blood flow can precipitate and explain most thrombotic complications. All of the components of this arterial variant of Virchow's triad are dependent on endothelial function. Indeed, vascular endothelium maintains blood fluidity, modulates blood coagulation, promotes or prevents vascular growth, modulates inflammation, and regulates vasomotor tone. 3 The renin-angiotensin and the kallikrein-kinin systems are powerful regulators of these processes. Therefore, in this brief review, we discuss the possible endothelial origin of the prothrombotic state in hypertension in relation to these 2 regulatory systems. As a PubMed search strategy, we selected relevant articles by entering as key words hypertension, renin-angiotensin, aldosterone, kallikrein, (brady)kinin, coagulation, fibrinolysis, and their various combinations.

ObjectivesFirst, to estimate the added value of a clinical decision support system (CDSS) in the performance of medication reviews in hospitalised elderly. Second, to identify the limitations of the current CDSS by analysing generated drug-related problems (DRPs).MethodsMedication reviews were performed in patients admitted to the geriatric ward of the Zuyderland medical centre. Additionally, electronically available patient information was introduced into a CDSS. The DRP notifications generated by the CDSS were compared with those found in the medication review. The DRP notifications were analysed to learn how to improve the CDSS.ResultsA total of 223 DRP strategies were identified during the medication reviews. The CDSS generated 70 clinically relevant DRP notifications. Of these DRP notifications, 63 % (44) were also found during the medication reviews. The CDSS generated 10 % (26) new DRP notifications and conveyed 28 % (70) of all 249 clinically relevant DRPs that were found. Classification of the CDSS generated DRP notifications related to ‘medication error type’ revealed that ‘contraindications/interactions/side effects’ and ‘indication without medication’ were the main categories not identified during the manual medication review. The error types ‘medication without indication’, ‘double medication’, and ‘wrong medication’ were mostly not identified by the CDSS.ConclusionsThe CDSS used in this study is not yet sufficiently advanced to replace the manual medication review, though it does add value to the manual medication review. The strengths and weaknesses of the current CDSS can be determined according to the medication error types.