Emergency reversal of oral anticoagulation through PPSB-SD: the fastest procedure in Belgium.

OBJECTIVE: To corroborate results obtained in The Netherlands with PPSB-SD, showing a safe acute reversal of anticoagulation within 15 minutes of administration. MATERIAL AND METHODS: PPSB-SD is a concentrate prothrombin complex containing a relatively constant high level of vitamin K-dependant coagulation factors II, VII, IX and X. PPSB-SD was administered to 14 patients treated with oral anticoagulants, according the patient's weight, the initial and the target INR (< 2.0 for moderate haemorrhage and abdominal surgery, or < 1.5 for severe haemorrhage and cardio-vascular interventions). INR values were measured with the Coagucheck Pro (Roche Diagnostics) upon admission and at 15 minutes, 1, 3 and 5 hours after treatment, and confirmed by the hospitals' laboratory. RESULTS: Within 15 minutes 11 patients out of 12 reached their INR target (data were missing for 2 patients). INR decreased rapidly, then remained stable for the next 5 hours. All patients had a favourable outcome: bleeding was stopped and no haemorrhage occurred during surgery. Only one adverse event was reported, but it was not related to the PPSB-SD treatment. No sign of disseminated intravascular coagulation was observed during this study. The administration of PPSB-SD along with vitamin K and dosed according to body weight and initial and target INR allowed for optimal reversal of anticoagulation, as no second infusion was necessary. The recommended dosing worked also very well for patients with high initial INR (9.2 to 22.8) who were brought down to normal values (0.9 to 1.1) within 15 minutes. CONCLUSION: PPSB-SD can safely be used for the rapid reversal of anticoagulation as needed in emergency situations.

Safety of low-molecular-weight heparin in pregnancy: a systematic review.

Unfractionated heparin (UFH) remains the anticoagulant of choice during pregnancy. Low-molecular-weight heparins (LMWH) are an attractive alternative to UFH due to their logistic advantages and their association with a lower incidence of osteoporosis and HIT. We reviewed all published clinical reports concerning the use of LMWH during pregnancy. In addition, participants of an international interest group contributed a cohort of pregnant women treated with LMWH. Pregnancies were divided into two groups; those with and those without maternal comorbid conditions. The number of adverse fetal outcomes and the occurrence of maternal complications were evaluated in the two groups. In the group of women with comorbid conditions (n = 290), 13.4% of the pregnancies were associated with an adverse fetal outcome. In contrast, in the group of women without comorbid conditions (n = 196), 3.1% were associated with an adverse outcome, which is comparable to that seen in the normal population. We conclude that LMWH appear to be a safe alternative to unfractionated heparin as an anticoagulant during pregnancy.

Hepatic sickling: an unusual cause of liver allograft dysfunction.

Orthotopic liver transplantation can be performed successfully in thalassemia. In this article, we describe a case of liver transplantation in a patient with sickle cell/beta-thalassemia complicated by liver sickling. Intrahepatic sickling must be considered in case of allograft dysfunction. This condition can easily be diagnosed by biochemical investigation and liver ultrasonography.

Acquired activated protein C resistance in pregnancy.

Pregnancy induces several haemostatic perturbations. Some authors described possible acquired activated protein C resistance (APCR) during normal pregnancy. We wanted to test this possibility and to evaluate if this acquired APCR might contribute to the known increased tendency to thrombosis associated with pregnancy. To answer the first hypothesis, we tested APCR with standard and with modified (5) APTT assays; to explore the second one, we chose to test some hypercoagulability and hyperfibrinolysis markers, i.e. fibrinopeptide A (FPA), Fragment 1+2 (F1+2) and D-dimers, and to correlate them with APC-ratio.

The treatment of severe or recurrent deep venous thrombosis. Beneficial effect of the co-administration of antiplatelet agents with or without rheological effects, and anticoagulants.

Deep venous thromboses can be divided into two groups according to their pathogenesis, anatomical features and differing responses to therapy. The first and most frequent consists of so-called simple venous thrombosis while the second group, which is less common, comprises severe or recurrent venous thrombosis characterised by a multifactorial pathogenesis, a mixed thrombus rich in platelets and by an incomplete response to both prophylactic and therapeutic treatment with anticoagulants (heparin or vitamin K antagonist). In a randomized, prospective blind study in patients with severe or recurrent venous thrombosis, which included 6 groups each of 100 patients, co-administration of anticoagulants with various types of antiplatelet agent, either with rheological effects (piracetam, buflomedil, pentoxifylline) or without them (dipyridamole), has shown a beneficial potentiating antithrombotic effect with those drugs possessing rheological effects and the absence of this effect with dipyridamole.

Liver transplantation and haemophilia A.

Liver transplantation has become the standard treatment for a variety of inherited metabolic disorders. We report on two patients who underwent successful transplantation for posthepatitis viral cirrhosis, which developed following blood factor replacement for haemophilia A. The second patient was transplanted before the occurrence of major complications of either his liver or haemophilic disease. We propose early liver transplantation to achieve metabolic cure of haemophilia.

Treatment of the Raynaud's phenomenon with piracetam.

Piracetam (Nootropil, CAS 7491-74-9) has been investigated in the treatment of primary and secondary Raynaud's phenomenon in three sequential and complementary studies. The first study in 20 patients with primary Raynaud's phenomenon, utilising clinical and ultrasound examination, capillaroscopy and laboratory tests established a daily dose of 8 g as most effective. The second study in 58 patients (47 primary, 11 secondary) confirmed the therapeutic efficacy of piracetam in both primary and secondary Raynaud's phenomenon. The third study, of crossover design, in 30 patients with severe Raynaud's syndrome, examined various agents given singly or in combination. The results not only confirmed the efficacy of piracetam but in addition allowed comparison of the efficacy of the principal therapeutic agents or regimens used in the treatment of Raynaud's syndrome and the formulation of a list of these therapies in decreasing order of efficacy, thus: piracetam 4 g/d + buflomedil 600 mg/d; piracetam 8 g/d; buflomedil 600 mg/d; piracetam 4 g/d + acetylsalicylic acid 100 mg/d; pentoxifylline 1200 mg/d; calcium antagonists; ketanserin 120 mg/d. The particular efficacy of 8 g piracetam daily in 3 divided doses at 8-hourly intervals can be attributed to its unique dual mode of action; inhibition of platelet function by inhibition of thromboxane A2 synthetase or antagonism of thromboxane A2 and increased formation of prostaglandin I2, together with a rheological effect involving reduction in blood and plasma viscosity through an increase in cell membrane deformability and a reduction of 30-40% in the plasma concentrations of fibrinogen and von Willebrand's factor. In addition, the administration of piracetam appears to be devoided of adverse effects.

Platelet anti-aggregant and rheological properties of piracetam. A pharmacodynamic study in normal subjects.

The random administration of four different single oral doses of piracetam (Nootropil, CAS 7491-74-9)--1.6 g, 3.2 g, 4.8 g and 9.6 g--at fixed intervals of 2 weeks to 5 healthy subjects has confirmed and explicited its platelet anti-aggregant and rheological properties after doses of 4.8 g and 9.6 g. The effect on platelet aggregation occurs through inhibition of thromboxane synthetase or anti-thromboxane A2 activity together with a reduction in the plasma level of von Willebrand's factor (F.VIIIR:vW). The rheological effect is related to the action of piracetam on cell membrane deformability (red cells, white cells and platelets) and to its simultaneous effect in reducing by 30-40% plasma levels of fibrinogen and von Willebrand's factor. In addition, it exerts a direct stimulant effect on prostacyclin synthesis in healthy endothelium. These effects are greatest between 1 and 4 h after dosage, and then diminish progressively to disappear between 8 and 12 h after administration. This explains the need to divide the total daily dose into 3 intakes at 8-hourly intervals. This study confirms the presence of four sites of action of piracetam: the vessel wall, platelets, plasma and cell membranes (RBC, WBC), which provide the basis for the potentially important antithrombotic activity of piracetam.

Hemostasis in children undergoing liver transplantation.

We reviewed the records of 200 children who underwent 238 orthotopic liver transplantations in order to determine which preoperative factors could predict intraoperative blood loss. A coagulation abnormality score (CAS) was calculated by allowing one point for each abnormality in six preoperative coagulation tests. The mean CAS values were significantly greater in children suffering from fulminant hepatic failure (Fulm) or post-necrotic cirrhosis (PNC) and those having retransplantation (ReTx) than in those with disease of other etiologies. No correlation was found between the CAS and the mean blood requirements in the different etiology groups. According to the amount of blood transfused, children could be divided in two groups. Group 1 were those with biliary atresia and ReTx, who received more than 200 ml/kg. Group 2 included those with PNC, Fulm, metabolic diseases, and Alagille syndrome and Byler disease, who received less than 140 ml/kg. The mean CAS was significantly lower and the PT significantly better in Group 1. We conclude that preoperative coagulation tests were weak predictors of intraoperative bleeding. The etiology of the underlying liver disease and previous abdominal surgery play an important role in the occurrence of severe bleeding. Intraoperatively, children presented the same hemostatic changes as adults.

Viability of long-term cryopreserved human saphenous veins.

The feasibility of maintaining long-term viability of human venous allografts by cryopreservation has been investigated. Segments of vein were obtained from 85 patients undergoing a stripping operation for varicose veins. The venous segments were immersed in a dimethylsulfoxide 15% solution, deep frozen at -196 degrees C in liquid nitrogen and preserved for a duration of 1 week to 24 months. Light microscopy (n = 126) failed to demonstrate striking differences between control veins and any of the cryopreserved veins. The types of damage observed at scanning electron microscopy included endothelial cell separation, endothelial cell loss, exposed basement membrane and exposed fibrillar collagen, which were graded on a scale. The score for short term (less than 3 weeks) stored veins was 8.1 +/- 0.9 (mean +/- SEM) and did not differ from the long-term (greater than 10 weeks) stored veins score (6.3 +/- 1.0, p NS). The tissue enzymes LDH, GOT, GPT, CPK were measured in the frozen vein groups (n = 115) after thawing to room temperature. Cryopreservation did not alter any of the tissue enzymes measured when compared to controls. Endothelial fibrinolytic activity (FA) of 58 venous segments cryopreserved for a mean duration of 20 months was 6136.4 +/- 292.1 Tissue Activator Units (TAU) and did not differ from FA of 11 controls (5989.1 +/- 696.8 TAU). Synthesis of 6-Keto-PGF1-alpha-2, a stable breakdown product of PGI2, measured in 10 venous segments cryopreserved for 10 months, was significantly higher than in 13 veins stored in saline for 12 hours at 4 degrees C (2.8 +/- 0.4 vs 0.4 +/- 0.1 PG ml-1mg-1min-1, respectively; p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

A novel preservation medium protecting prostacyclin production and endothelial integrity of the human saphenous vein graft.

Patency rates of coronary artery saphenous vein bypass grafts can be as low as 50% in the first year after surgery. Of these occlusions, 70% can be attributed to mural thrombus formation. Improvements in surgical handling techniques and in preservation media have improved patency rates, as has the introduction of perioperative antiplatelet therapy. The authors describe a novel preservation medium consisting of heparinized blood from the patient, papaverine and dipyridamole. This medium enhances prostacyclin production and maintains endothelial integrity in preserved saphenous vein segments.

Atrial natriuretic factor, arachidonic acid metabolites and acute renal ischemia: experimental protocol in the rat.

The effects of an atrial natriuretic factor (ANF) infusion upon the production of the arachidonic acid metabolites (thromboxane B2, TxB2; 6-keto-prostaglandin F1 alpha, 6-keto-PGF1 alpha, PGI2, or prostaglandins E2, PGE2) were investigated after acute renal ischemia in the rat. This experimental protocol included a right nephrectomy and a 45-min left renal artery occlusion. Fifteen minutes after declamping, blood samples were collected from the left renal venous effluent for the assay of plasmatic prostanoid concentrations. Three experimental groups were studied: group I (n = 9) sham, no ischemia-group II (n = 9) control group, 45 min of left renal ischemia, followed by a 15-min revascularization, and group III (n = 10) ANF group, a similar ischemic protocol to that in group II was used but, after declamping, synthetic Atriopeptin III was infused (0.5 micrograms/kg/min) during the 15-min of vascular reflow. Fifteen minutes after declamping, TxB2 secretion significantly increased after ischemia in the control and ANF groups: TxB2: 210 +/- 22.4 pg/ml (control group) and 234.8 +/- 25.1 pg/ml (ANF group) versus 135.8 +/- 17.8 pg/ml (sham group) (p less than 0.05 and 0.01, respectively). On the other hand, the 6-keto-PGF1 alpha plasma levels were significantly higher after ischemia in the ANF group (221 +/- 34 pg/ml) in comparison with the sham (124 +/- 24.1 pg/ml) or with the control group (116.7 +/- 12.5 pg/ml). The calculated TxB2/6-keto-PGF1 alpha ratio was therefore higher in the control group, 1.93 +/- 0.27, than in physiological conditions (sham group), 1.2 +/- 0.17.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics, thrombolytic efficacy and hemorrhagic risk of different streptokinase regimens in heparin-treated acute myocardial infarction.

The systemic activator activity of 4 streptokinase (SK) regimens (250,000 IU intracoronary, group A; 500,000 IU, group B; 1.5 X 10(6) IU, group C; and 30 U anisoylated plasminogen streptokinase activator complex (APSAC) intravenously, group D) was tested with the fibrin plate technique. One hour after initiation of treatment, the activator activity was highest after APSAC (3.6 +/- 0.9 U), slightly but not significantly less after SK 1.5 X 10(6) IU (3.0 +/- 0.7), and significantly less after SK 500,000 IU (1.6 +/- 0.5) and 250,000 IU (0.6 +/- 0.5), p less than 0.001. After SK, activator activity half-lives were 184 minutes (group B) and 169 minutes (group C), and after APSAC 188 minutes (group D). These were all in agreement with greater than 12 hour duration of changes in other markers of systemic fibrinolysis (euglobulin lysis time) and substrates depletion (fibrinogen, plasminogen, alpha 2 antiplasmin). In extended pilot clinical groups given identical thrombolytic regimens during full anticoagulation with heparin, angiographic coronary patency was found in 83% (35 of 42) after intracoronary SK (group 1), in 73 and 75%, respectively, after 500,000 IU (31 of 43) and 1.5 X 10(6) IU (30 of 40) (group 2 and 3, difference not significant) and 80% (8 of 10) after the 30-U bolus of APSAC (group 4). The overall hemorrhagic risk was 24%, equally distributed among the 4 regimens and mostly (91%) related to catheters. The incidence of bleeding unrelated to vessel puncture was 4%; no deaths occurred. It is concluded that APSAC is the most fibrinolytic regimen but its potential thrombolytic superiority over SK remains to be demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial protection by intracoronary nicardipine administration during percutaneous transluminal coronary angioplasty.

To determine if the calcium antagonist nicardipine protects the myocardium against ischemia, myocardial lactate, hypoxanthine and prostanoid function was studied in 12 patients during percutaneous transluminal coronary angioplasty (PTCA). Values were obtained before balloon inflation and during 4 minutes after deflation. Intracoronary injection of 0.2 mg of nicardipine distal to the stenosis was done randomly before the first or second inflation; the other inflation served as a control. One minute after deflation, coronary sinus flow levels were similar during the nicardipine and control procedure (161 +/- 61 vs 159 +/- 72 ml/min); lactate (-9 +/- 21% vs -17 +/- 21%, p less than 0.025) and hypoxanthine production (-107 +/- 85% vs -218 +/- 153%, p less than 0.05) were less severe after nicardipine pretreatment than after control. All patients reverted to lactate extraction 4 minutes after inflation plus nicardipine infusion, whereas lactate was still produced 4 minutes after control inflation. No significant changes in thromboxane B2 or prostacyclin levels were observed in the coronary sinus 1 minute after inflation, but higher arterial thromboxane B2 values were observed after control inflation than after inflation with nicardipine infusion (median values 169 vs 78 pg/ml, p less than 0.05). In conclusion, intracoronary infusion of nicardipine reduced signs of ischemia and alterations in prostanoid handling after coronary occlusion. The mechanisms of myocardial protection appeared unrelated to coronary sinus blood flow changes or to a systemic effect of nicardipine.

Analysis of coagulation and fibrinolysis after intravenous anisoylated plasminogen streptokinase activator complex or heparin in patients with acute myocardial infarction. A Belgian multicentre study.

A multicentre randomised trial including 87 patients admitted for acute myocardial infarction compared the effects of a single intravenous bolus of an anisoylated plasminogen streptokinase activator complex (APSAC) 30 units with those of heparin treatment on haemostasis during the first 4 days after treatment. In the APSAC group, a rapid and significant reduction in fibrinogen, plasminogen and alpha 2-antiplasmin was observed, associated with an increase of fibrin(ogen) degradation products, reflecting a strong systemic lytic activity. None of these parameters were significantly modified by heparin, but the anticoagulant effect was apparent as assessed by the activated partial thromboplastin time. The systemic fibrinolysis induced after different regimens of streptokinase infusion demonstrated that an intravenous bolus of APSAC 30U was as potent as streptokinase 500,000 or 1,500,000IU administered intravenously over 45 minutes and definitely more fibrinolytic than intracoronary infusion of streptokinase 250,000IU. Despite the demonstrated fibrin specificity of the drug at a low dose, a high dose of APSAC (30U intravenously) induced an important systemic lytic state for at least 12 hours.

[Treatment of the first episode of pulmonary embolism in the hospital. Anticoagulants, anti-platelet aggregation drugs and thrombolysis stimulants]. / Traitement du premier épisode d'embolie pulmonaire en milieu hospitalier. Anticoagulants, anti-agrégants plaquettaires et stimulants lytiques.

The treatment of the first pulmonary embolic accident in Hospital consist in the administration of anticoagulants. Heparin will be first used intravenously or subcutaneously during 10 to 12 days and will be followed by oral anticoagulants (VKA) during 3 to 12 months. These treatments must be controlled following national or international standardized technics and can be associated with antiplatelet drugs or thrombolytic activators. The most important and frequent complications observed are haemorrhages. They are consecutive to a non conformed administration of the drugs or overdosage bound to a non correct control or drugs interferences or to a misappreciated counterindication. They will be corrected in most of the cases by a simple anticoagulant dosage reduction and exceptionally by the interruption of the therapy with administration of antidotes and plasma substitutes. Other complications are extremely rare and bound to the nature of the drugs used.