Antibodies to factor XII: a possible predictive marker for recurrent foetal loss.

Antibodies to factor XII (FXIIabs) have been demonstrated in some patients with the anti-phospholipid syndrome (APS). The presence of these antibodies were shown to lead to statistically significantly reduced levels of FXII (p = 0.02). In an extension to this study forty female patients with either primary APS (n = 26) or systemic lupus erythematosus (APS positive) (n = 14) were investigated for levels of factor XII, the presence of lupus anticoagulant and antibodies to cardiolipin, beta 2-glycoprotein I and factor XII. Twenty one of the forty patients had a history of foetal loss (> 2, mean = 2.6). Lupus anticoagulant positivity showed a weak association with foetal loss (odds ratio = 1.1). While there was no association between the presence of antibodies to cardiolipin or beta 2-glycoprotein I with foetal loss, antibodies to factor XII showed a strong and statistically significant association (odds ratio = 5.4, p = 0.025).

Plasma levels of factor XII, prekallikrein and high molecular weight kininogen in normal blood donors and patients having suffered venous thrombosis.

INTRODUCTION: The contact system proteins factor XII (FXII), prekallikrein (PK) and high molecular weight kininogen (HK) have roles in coagulation, fibrinolysis, thrombin-induced platelet activation, cell adhesion and angeogenisis. It has been suggested that inherited or acquired deficiencies of these proteins may be risk factors for thrombosis. Studies on the levels of FXII in plasma from normal and thrombotic patient populations have been reported, to our knowledge however, no systematic study on plasma levels of PK and HK in large populations of normal blood donors and patients having had venous thrombotic events has been performed. MATERIALS AND METHODS: Chromogenic substrate assays were used to measure plasma levels of FXII, PK and HK in 300 normal blood donors (ND) and 300 patients attending our anticoagulant clinic who had a history of venous thrombosis (deep vein thrombosis or pulmonary embolism [VT]). All subjects were Caucasian, antiphospholipid antibody negative and had normal liver function. RESULTS: Mean values +/- SD were: FXII: ND 99.4 +/- 26.7%: VT 91.0 +/- 27.2%: PKK: ND 99.7 +/- 19.8%: VT 99.1 +/- 21.2%: HK: ND 101.0 +/- 20.5%: VT 110.7 +/- 32.3%. Statistical analysis of the data revealed significantly lower (p< or =0.001) mean values for FXII and significantly higher (p< or =0.001) mean values for HK in the VT group. Calculated lower limits of normal for each parameter were: FXII: 49.1%, PKK: 66.8%, HK: 63.4%. The prevalence of values below the lower limit of normal were FXII-ND 2.3%: FXII-VT 8.0%, PKK-ND 3.0%: PKK-VT 4.7%, HK-ND 2.3%: HK-VT 5.0%. No homozygous deficiency patients were found for any parameter. One VT patient had combined FXII and HK deficiency and one ND and two VT patients had combined PK and HK deficiency. CONCLUSIONS: FXII levels were lower and HK levels and the prevalence of FXII, PK and HK deficiency higher in a population of patients with a history of VT than in a population of healthy blood donors.

Thrombin generation: a comparison of assays using platelet-poor and -rich plasma and whole blood samples from healthy controls and patients with a history of venous thromboembolism.

We have developed a whole blood thrombin generation (TG) assay whereby TG is initiated with a low-tissue factor concentration and monitored using a fluorogenic thrombin substrate. Significantly higher values were found in blood samples from 50 patients with a history of venous thromboembolism (VTE) compared with 31 healthy controls (HC), for peak height (P = 0.0034) and endogenous thrombin potential (ETP) (P = 0.0027). Results from 31 VTE patients and the 31 controls in the absence of corn trypsin inhibitor (CTI) showed significantly higher values in the VTE group for peak height (P = 0.0013) and ETP (P = 0.002). In the presence of CTI, significantly higher values were only seen in ETP (P = 0.024). No significant increases in TG were found using platelet poor (PPP) or -rich (PRP) plasma with or without CTI. The whole blood TG assay in the absence or presence of CTI showed a higher proportion (25/50 and 12/31, respectively) of raised peak height and/or ETP values than plasma assays (PPP 9/50 and 5/31 respectively and PRP 13/50 and 6/31, respectively). Our results show the whole blood TG assay is more sensitive for determining the increases in TG in patients with a history of VTE than PPP and PRP TG assays.

The role of endogenous kallikrein inhibition in perioperative transfusion and adverse outcome in cardiac surgical patients.

OBJECTIVE: The goal of this study was to explore the relationship among endogenous plasma kallikrein inhibition (KI), perioperative bleeding, and adverse outcomes in cardiac surgery. DESIGN: A prospective, observational study. SETTING: University teaching hospitals. PARTICIPANTS: Cardiac surgical patients. INTERVENTIONS: Endogenous plasma KI levels (%) and kallikrein-like activity (KKA) were measured preoperatively, 30 minutes into cardiopulmonary bypass, and at the end of surgery. Patients were divided into quartiles of preoperative KI. Data including risk factors, blood loss, transfusion requirements, and postoperative outcomes were collected. MEASUREMENTS AND MAIN RESULTS: Preoperative endogenous KI ranged from 40% to 175%, where 100% represents the activity of pooled healthy volunteer plasma. The quartiles of KI levels were as follows: quartile 1, KI = 40% to 83.8% (n = 40); quartile 2, KI = 84% to 101.5% (n = 40); quartile 3, KI = 102% to 120% (n = 42); and quartile 4, KI = 121% to 175% (n = 38). The hematocrits on admission to the intensive care unit were as follows: quartile 1, 28% +/- 4%; quartile 2, 26% +/- 4%; quartile 3, 26% +/- 4%; and quartile 4, 24% +/- 4% (p = 0.009). Blood product use was similar among quartiles in the operating room. Quartiles 3 and 4 received more blood (p = 0.003) and platelet (p = 0.04) transfusions than quartiles 1 and 2 in the first 24 hours after surgery. More patients in quartile 4 were ventilated for more than 24 hours after surgery (p < 0.05). Hospital length of stay was longest in quartile 4 (p = 0.002). CONCLUSION: Contrary to expectation, higher endogenous KI levels were associated with more blood product transfusion, longer postoperative mechanical ventilation, and hospital length of stay. These findings raise questions as to the role of KI in postoperative outcomes.

The significance of heparin-coated veno-venous bypass circuits in liver transplantation.

We studied the effects of veno-venous bypass (VVBP) circuit surface heparinization on the activation of the plasma defence systems (coagulation, fibrinolysis, kallikrein-kinin and complement) and leukocyte activation in a prospective randomized study in 20 patients during and 1 day after liver transplantation (OLT). To our knowledge, this is the first study of this kind where the possible benefits of surface heparinization of the VVBP circuit in OLT have been investigated. Twenty patients were randomized to either heparin-coated (HC) VVBP equipment or to otherwise identical noncoated (NC) circuits. Five blood samples were drawn during the OLT procedure: one just before VVBP, three during VVBP and one 5 min after portal venous reperfusion (PVR). A further sample was taken 1 day after the operation. Components of the blood coagulation, fibrinolytic and kallikrein-kinin systems were analysed using functional assays (chromogenic peptide substrate assays) or enzyme immunoassays (EIA). Complement system factors and granulocyte activation, represented by myeloperoxidase (MPO) release, were analyzed by EIA. Activation of the plasma defence systems occurred in both groups at an early stage during OLT and a further activation occurred 5 min after PVR. MPO levels were slightly elevated 5 min after PVR. However, no significant differences between the two groups were observed. Significant activation of the humoral defense systems was found in both groups during OLT. A considerably larger study, including at least 330 patients, is necessary to fully assess the possible benefits of surface heparinization of the VVBP circuit.