DMB March 2010

March 2010 Newsletter

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TARGETED RESEARCH

Coagulation- and Thrombosis-Related Research

Blood Coagulation as an Intrinsic Pathway for Proinflammation:
A Mini Review

Abstract: Blood coagulation could be recognized as intrinsic inflammation. The coagulant mediators (FVIIa, FXa, thrombin (FIIa), FXIIa) and fibrin(ogen) activate cellular signaling, eliciting the production of cytokines, chemokines, growth factors, and other proinflammatory mediators.

Hypercoagulability with elevated coagulant mediators would certainly trigger hyper-inflammatory state not to mention about the direct hypercoagulable actions on thrombosis, and platelet and complement activations, all of which contribute to inflammatory events. Furthermore, anticoagulant’s anti-inflammatory effects readily reinforce the proposal that blood coagulation results in inflammation. The observations on protease activated receptor (PAR) activation and PAR antagonists modulating inflammation are also in line with the concept of coagulation-dependent
inflammation.

Inflamm Allergy Drug Targets. 2009 Sep 1. [Epub ahead of print]

Effects of Cigarette Smoke Exposure on Clot Dynamics and Fibrin Structure. An Ex Vivo Investigation.

Objective: The purpose of this study was to examine the effect of cigarette smoke exposure (CSE) on clot dynamics and fibrin architecture and to isolate the relative contribution of platelets and fibrinogen to clot dynamics.

Methods and Results: From young healthy males smokers (n=34) and non-smokers (n=34) a baseline blood was drawn, and smokers had another blood draw after smoking two2 regular cigarettes. Using thromboelastography (TEG) the degree of platelet-fibrin interaction was measured. In additional experiments, abciximab (20 mug/mL) was added to the smokers samples (n=27) to reduce the effects of platelet function from the TEG parameters. The maximum clot strength (G) obtained with abciximab measured mainly the contribution
of fibrinogen to clot strength (GF). By subtracting GF from G, the contribution of platelets to clot strength (GP) was presumed.

A significant difference was found for all TEG parameters between non-smokers versus post-smoking and pre- versus post-smoking samples. Post-smoking both GF and GP were significantly higher as compared to pre-smoking. On electron microscopy and turbidity analysis, post-smoking fibrin clots were significantly different compared to pre-smoking and non-smoking samples.

Conclusions: Acute CSE changes clot dynamics and alters fibrin architecture. Both functional changes in fibrinogen and platelets appear to contribute to heightened thrombogenicity after acute CSE.

Arterioscler Thromb Vasc Biol. 2010 Jan;30(1):75-9.

Hypercoagulable State and Methylenetetra-hydrofolate Reductase (MTHFR) C677T Mutation in Patients with Beta-Thalassemia Major in Kuwait

Introduction: Patients with thalassemia major often present with a hypercoagulable state, the pathogenesis of which is still not understood.

Materials and Methods: This study evaluates the risk factors for hypercoagulability in 50 b-thalassemia major patients and 50 healthy controls. Fasting total homocysteine, protein C (PC), protein S (PS), antithrombin (AT), activated protein C resistance (APCR) and lupus anticoagulant (LA) were assessed. MTHFR C677T mutation was determined.

Results: Significant reductions in PC, PS and AT were noted in patients. Only 4% of the patients had hyperhomocysteinemia. Thirty-two percent of the patients were heterozygous and 4% were homozygous for MTHFR C677T mutation.

Conclusion: The natural coagulation inhibitors PC, PS and AT were significantly reduced in patients with b-thalassemia major and were thus important risk factors for the hypercoagulable state, but hyperhomocysteinemia and MTHFR mutation do not seem to be significant risk factors for thromboembolic events.

Acta Haematol 2010;123:37- 42

Impaired fibrinolysis as a risk factor for Budd-Chiari syndrome

Abstract: In Budd-Chiari syndrome (BCS), thrombosis develops in the hepatic veins or inferior vena cava. To study the relationship between hypofibrinolysis and BCS, we measured plasma levels of fibrinolysis proteins in 101 BCS patients and 101 healthy controls and performed a plasma-based clot lysis assay. In BCS patients, plasminogen activator inhibitor 1 (PAI-1) levels were significantly higher than in controls (median, 6.3 vs 1.4 IU/mL, P < .001).

Thrombin-activatable fibrinolysis inhibitor and plasmin inhibitor levels were lower than in controls (13.8 vs 16.9 μg/mL and 0.91 vs 1.02 U/L, both P < .001). Median plasma clot lysis time (CLT) was 73.9 minutes in cases and 73.0 minutes in controls (P = .329). A subgroup of cases displayed clearly elevated CLTs. A CLT above the 90th or 95th percentile of controls was associated with an increased risk of BCS, with odds ratios of 2.4 (95% confidence interval, 1.1-5.5) and 3.4 (95% confidence interval, 1.2-9.7), respectively. In controls, only PAI-1 activity was significantly associated with CLT.

Analysis of single nucleotide polymorphisms of fibrinolysis proteins revealed no significant differences between cases and controls. This case-control study provides the first evidence that an impaired fibrinolytic potential, at least partially caused by elevated PAI-1 levels, is related to the presence of BCS.

Blood 2010 Jan 14;115(2):388-395

Usefulness of repeated D-dimer testing after stopping anticoagulation for a first episode of unprovoked venous thromboembolism: the PROLONG II prospective study

Abstract: The PROLONG randomized trial showed that a normal D-dimer (D-d) one month after anticoagulation suspension for unprovoked venous thromboembolism (VTE) was associated with a low risk of late recurrences (4.4% patient years). However, it is unknown whether D-d changes subsequently.

The aim of this prospective multicenter study was to assess D-d time course and its relation with late recurrences in patients with normal D-d one month after anticoagulation suspension for a first episode of unprovoked VTE. D-d was measured with a qualitative method (Clearview Simplify D-dimer; Inverness Medical Professional Diagnostics). Patients with a normal D-d one month after stopping anticoagulation repeated D-d testing every two months for one year. D-d was normal in 68% (243/355) of patients one month after anticoagulation suspension.

Patients in whom D-d became abnormal at the third month and remained abnormal afterward had a higher risk of recurrence (7/31; 27% patient years; 95% confidence interval [CI]: 12-48) than patients in whom D-d remained normal at the third month and afterward (4/149; 2.9% patient years; 95% CI: 1-7; adjusted hazard ratio: 7.9; 95% CI: 2.1-30; P = .002). Repeated D-d testing after anticoagulation suspension for a first episode of unprovoked VTE could help tailor the duration of treatment.

Blood 2010 Jan 21;115(3):481-488

Increased Thrombophilic Tendency in Pediatric Cystic Fibrosis Patients

Abstract: Thrombophilia has recently been reported to be increased in patients with cystic fibrosis (CF). We wanted to determine whether this was applicable to our population with CF and how our patients compared to the previously reported groups.

Seventy one pediatric CF patients were assessed for a thrombophilic tendency, using a lupus anticoagulant screen, protein C, protein S, antithrombin assay, and activated protein C resistance (APCR) screen. The incidence of activate protein C resistance (4.2%) was within expected limits for the general population as was the incidence of antithrombin deficiency. However there was a marked increase in the incidence of lupus anticoagulants (18%) and 14% and 19.7% of the patients showed a reduced protein C and protein S, respectively, far in excess of the general population.

This increased incidence of thrombophilia was not related to any specific CF phenotype and while perturbed liver function cannot be entirely ruled out, it appeared unlikely to be responsible for all the abnormal coagulation findings.

Despite the apparent thrombophilic tendency, no clinically evident thrombotic episodes were noted during the study period. Thrombophilia is of concern because of the increasingly frequent placement of indwelling catheters in CF patients. The precise cause for the thrombophilic tendency in CF patients is unknown at this stage.

Clin Appl Thromb Hemost. 2010 Feb;16(1):71-6.

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