Werner Streif

Direct thrombin and factor Xa inhibitors in children: a quest for new anticoagulants for children.

Direct thrombin and factor Xa inhibitors in children: a quest for new anticoagulants for children.

Wien Med Wochenschr. 2011 Feb;161(3-4):73-9

Authors: Streif W, Ageno W

Abstract
Venous thrombosis and pulmonary embolism rarely occur in children but are associated with significant morbidity and mortality. Venous thromboembolism (VTE) mostly affects children with severe underlying conditions and multiple risk factors. Newborns and adolescents are at the highest risk. Standard and low molecular weight heparins and vitamin K antagonists are routinely used for the prevention and treatment of VTE. The new anticoagulants, both parenteral such as argatroban, bivalirudin and fondaparinux and oral such as dabigatran and rivaroxaban, have favourable pharmacological properties, all are approved for clinical use in adults and are currently being investigated in children. Argatroban is the only new anticoagulant licensed for use in children so far. The role of these new anticoagulants as alternative anticoagulants for children remains to be defined. This review focuses on the characteristics of VTE in children and reviews current knowledge on the use of the new thrombin and factor Xa inhibitors in this population.

PMID: 21404143 [PubMed - indexed for MEDLINE]

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Prothrombin complex concentrate and recombinant prothrombin alone or in combination with recombinant factor X and FVIIa in dilutional coagulopathy: a porcine model.

Prothrombin complex concentrate and recombinant prothrombin alone or in combination with recombinant factor X and FVIIa in dilutional coagulopathy: a porcine model.

J Thromb Haemost. 2011 Apr;9(4):729-37

Authors: Mitterlechner T, Innerhofer P, Streif W, Lödl M, Danninger T, Klima G, Hansson K, Fries D

Abstract
BACKGROUND: This study was conducted to assess whether newly developed recombinant clotting factor concentrates enable the reversal of dilutional coagulopathy.
METHODS: In 50 anesthetized pigs, ~60% of the blood volume was withdrawn and replaced with hydroxyethyl starch. Pigs were randomized to receive either 200 mg kg(-1) fibrinogen (n = 10), fibrinogen and 35 IU kg(-1) prothrombin complex concentrate (PCC) (n = 10), fibrinogen and 4 mg kg(-1) recombinant human factor II (rhFII) concentrate (n = 10), fibrinogen and a three-factor combination (3F) of 4 mg kg(-1) rhFII, 0.006 mg kg(-1) recombinant human FVIIa and 0.32 mg kg(-1) recombinant human FX (n = 10), or saline (n = 10). Thereafter, a standardized liver laceration was performed to induce uncontrolled hemorrhage. Survival time and blood loss were determined, and standard coagulation tests and thrombelastometry were performed.
RESULTS: Fibrinogen combined with rhFII or PCC improved survival. Blood loss was significantly decreased in all groups as compared with the animals receiving saline. Clotting time was significantly shortened in the animals treated with fibrinogen and PCC, as well as in those treated with fibrinogen and 3F. One animal died after administration of fibrinogen and PCC.
CONCLUSION: Following hemodilution, a combination of fibrinogen and PCC, rhFII or 3F enhances coagulation and final clot strength. Mortality was reduced statistically significantly only in the animals treated with fibrinogen and rhFII or PCC, whereas administration of the combination of fibrinogen and PCC caused a fatal thromboembolic complication. The combination of fibrinogen and rhFII might be effective in reversing dilutional coagulopathy and may reduce blood loss in cases of dilutional coagulopathy.

PMID: 21255250 [PubMed - indexed for MEDLINE]

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Real-Time Live Confocal Fluorescence Microscopy as a New Tool for Assessing Platelet Vitality.

Real-Time Live Confocal Fluorescence Microscopy as a New Tool for Assessing Platelet Vitality.

Transfus Med Hemother. 2010;37(5):299-305

Authors: Hermann M, Nussbaumer O, Knöfler R, Hengster P, Nussbaumer W, Streif W

Abstract
BACKGROUND: Assessment of platelet vitality is important for patients presenting with inherited or acquired disorders of platelet function and for quality assessment of platelet concentrates. METHODS: Herein we combined live stains with intra-vital confocal fluorescence microscopy in order to obtain an imaging method that allows fast and accurate assessment of platelet vitality. Three fluorescent dyes, FITC-coupled wheat germ agglutinin (WGA), tetramethylrhodamine methyl ester perchlorate (TMRM) and acetoxymethylester (Rhod-2), were used to assess platelet morphology, mitochondrial activity and intra-platelet calcium levels. Microscopy was performed with a microlens-enhanced Nipkow spinning disk-based system allowing live confocal imaging. RESULTS: Comparison of ten samples of donor platelets collected before apheresis and platelets collected on days 5 and 7 of storage showed an increase in the percentage of Rhod-2-positive platelets from 3.6 to 47 and finally to 71%. Mitochondrial potential was demonstrated in 95.4% of donor platelets and in 92.5% of platelets stored for 7 days. CONCLUSION: Such fast and accurate visualization of known key parameters of platelet function could be of relevance for studies addressing the quality of platelets after storage and additional manipulation, such as pathogen inactivation, as well as for the analysis of inherited platelet function disorders.

PMID: 21113254 [PubMed - as supplied by publisher]

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Testing for inherited platelet defects in clinical laboratories in Germany, Austria and Switzerland. Results of a survey carried out by the Permanent Paediatric Group of the German Thrombosis and Haemostasis Research Society (GTH).

Testing for inherited platelet defects in clinical laboratories in Germany, Austria and Switzerland. Results of a survey carried out by the Permanent Paediatric Group of the German Thrombosis and Haemostasis Research Society (GTH).

Platelets. 2010;21(6):470-8

Authors: Streif W, Streif W, Oliveri M, Martin O, Weickardt S, Stefan W, Eberl W, Wolfgang E, Knoefler R, Ralf K,

Abstract
Inherited platelet defects are a rare and heterogeneous group of disorders. The majority of affected patients present with mild to moderate bleeding tendencies. However, in trauma and surgery, bleeding may be difficult to control. Laboratory tests for diagnosis are necessary for the prevention and treatment of critical bleeding. The aim of the THROMKID study was to obtain information on the means of investigating platelet function employed by clinical centres in German-speaking countries. For this purpose a patterns-of-practice survey was conducted from 2005 to 2007, the results of which are reported here. A total of 37 out of 41 identified clinical centers serving 98 million people completed the survey questionnaire. The number of tests offered for assessment of platelet function varied between 1 and 11, median 4. Aggregometry continued to be the most popular and helpful technique for evaluation of suspected platelet function disorders (100%). The PFA-100(R) CT (76%) and in vivo bleeding time (54%) were used to screen patients with suspected platelet function disorders. Selection of tests was based on a case-by-case decision at most centres (82%). The majority of centres performed specific platelet function tests less than 50 times per month. This survey illustrates the preferences of clinical centres in the selection, performance and interpretation of platelet function tests. These practices may considerably influence the detection and diagnosis of platelet function disorders. There is an urgent need for existing tests to be improved and new, fast and reliable tests of platelet function to be developed.

PMID: 20635849 [PubMed - indexed for MEDLINE]

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Inherited disorders of platelet function in pediatric clinical practice: a diagnostic challenge.

Inherited disorders of platelet function in pediatric clinical practice: a diagnostic challenge.

Klin Padiatr. 2010 May;222(3):203-8

Authors: Streif W, Knöfler R, Eberl W

Abstract
Hereditary disorders of platelet function are a heterogeneous group of diseases that are often complex and tend to go undetected until clinically relevant bleeding occurs. Hallmarks are epistaxis, easy bruising, mucous membrane bleeding, perioperative bleeding and menorrhagia. Bleeding may be intermittent and unpredictable. After decades of successful research on platelet biology and genetics, research findings have not been satisfactorily translated to clinical practice. The lack of robust and well- standardized test systems continues to make the diagnosis of platelet defects cumbersome for the practising clinician. Patient history and description of clinical bleeding symptoms are essential. Exclusion of von Willebrand disease, platelet count and investigation of blood smears may provide a tentative diagnosis. Light transmission aggregometry is still considered the gold standard for assessing platelet function. Due to the wide range of possible genetic defects molecular biological analyses can complement but do not substitute for other tests. The true incidence of inherited disorders of platelet function is unknown. A survey in Germany revealed that receptor-defects including Glanzmann's thrombasthenia and Bernard-Soulier syndrome and aspirin-like defects were the most frequently diagnosed platelet disorders. Of affected children 60% presented with mild and 40% with moderate to severe bleeding tendency. Epistaxis, cutaneous and mucous membrane bleeding were the most frequent symptoms. The paediatric competence network of the GTH e.V. comprises 44 collaborating centres that are caregivers to over 150 children with well-defined inherited platelet defects. A major goal of this network is to promote diagnosis of children with inherited disorders of platelet function.

PMID: 20514633 [PubMed - indexed for MEDLINE]

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[Prevention of perioperative venous thromboembolism in children].

[Prevention of perioperative venous thromboembolism in children].

Wien Med Wochenschr. 2009 Oct;159(19-20):481-6

Authors: Streif W

Abstract
Venous thromboembolic events (VTE) occur in children at the time of surgery. Few guidelines about how to assess the risk and provide prophylaxis have been developed and published so far. It is uncertain if any of these guidelines have been adopted into clinical practice. The article discusses the specific differences of the haemostatic system throughout childhood, risk assessment, choice and dosing of antithrombotic agents, difficulties in drug monitoring and side effects of treatment including HIT. Current available recommendations and guidelines are summarized. Current evidence on which to base risk stratification and prevention of VTE for children undergoing surgery consists mainly of cohort studies, case series, case reports and expert opinion. Many suggestions are merely extrapolated from results from clinical trials in adults. Primary healthy children who undergo minor surgery including circumcision, herniotomy and appendectomy do not need antithrombotic prophylaxis. Children with multiple risk factors for VTE including severe underlying conditions and long-term immobilization, children with central venous lines and children with a history of VTE should be considered to receive VTE prophylaxis. Older children (Tanner II+) should be treated following adult guidelines. Standard unfractionated heparin and low molecular heparin are the most frequently recommended antithrombotic drugs. Decision for VTE prophylaxis must widely be based on individual risk assessment by experienced physicians. Newly developed scores and guidelines may provide assistance. Well designed clinical studies in children that provide proper evidence on risk assessment for VTE at the time of surgery and investigate safety and efficacy of antithrombotic prophylaxis/treatment are urgently needed.

PMID: 19898787 [PubMed - indexed for MEDLINE]

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Intraoperatively salvaged red blood cells contain nearly no functionally active platelets, but exhibit formation of microparticles: results of a pilot study in orthopedic patients.

Intraoperatively salvaged red blood cells contain nearly no functionally active platelets, but exhibit formation of microparticles: results of a pilot study in orthopedic patients.

Transfusion. 2010 Feb;50(2):400-6

Authors: Oswald E, Streif W, Hermann M, Hengster P, Mittermayr M, Innerhofer P

Abstract
BACKGROUND: Previous data show improved clot formation after retransfusion of salvaged red blood cells (RBCs). This study was conducted to explore whether such RBCs contain clinically relevant numbers of active residual platelets (PLTs) or exhibit formation of microparticles (MPs).
STUDY DESIGN AND METHODS: Thirteen patients undergoing major orthopedic surgery were included in the study, and arterial blood samples from patients and samples from the retransfusion bag were analyzed with various PLT function tests and flow cytometry.
RESULTS: With commercial blood cell counters, the numbers of PLTs in the RBC unit were reduced to approximately 25% compared to patients' blood. In contrast, results from flow cytometry showed an 11- to 945-fold reduction in median counts referring to total PLTs and free PLTs. Interestingly, smaller quantities of PLT-derived MPs were found in samples from the retransfusion bag than in patients' arterial blood. Conversely, RBC- and white blood cell-derived MP counts were increased in the retransfusion bag compared to the patient. Rotational thrombelastometry and the Impact-R system (DiaMed) showed a pronounced impairment of PLT ability with regard to adhesion, aggregation, and clot formation. With the use of confocal microscopy, only a few free thrombocytes were detectable among the huge numbers of RBCs.
CONCLUSION: Only few free and thus active PLTs are detectable in processed RBCs. It seems very unlikely that these few PLTs can improve clot strength. Nevertheless, the impact of the detected MPs on thrombin generation needs to be clarified in further studies.

PMID: 19804574 [PubMed - indexed for MEDLINE]

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An assessment of cardiopulmonary bypass-induced changes in platelet function using whole blood and classical light transmission aggregometry: the results of a pilot study.

An assessment of cardiopulmonary bypass-induced changes in platelet function using whole blood and classical light transmission aggregometry: the results of a pilot study.

Anesth Analg. 2009 Jun;108(6):1747-54

Authors: Velik-Salchner C, Maier S, Innerhofer P, Kolbitsch C, Streif W, Mittermayr M, Praxmarer M, Fries D

Abstract
BACKGROUND: In this study, we explored whether antiplatelet medications impair whole blood impedance aggregometry after cardiac surgery and cardiopulmonary bypass (CPB) compared with classical light transmission aggregometry (LTA).
METHODS: Multiplate (M) assays measuring changes in electrical resistance as aggregation units over time, and LTA assays (% aggregation) induced by collagen (COL), adenosine diphosphate (ADP), or arachidonic acid were performed simultaneously using arterial blood samples obtained before induction of anesthesia, 15 min and 3 h after neutralization of heparin in 70 consecutive patients scheduled for elective coronary artery bypass grafting. Patients in Group A (n = 48) discontinued intake of antiplatelet drugs for at least 7 days and served as controls, patients in Group B (n = 11) received aspirin 100 mg/d and those in Group C (n = 11) aspirin 100 mg/d and clopidogrel 75 mg/d (dual antiplatelet therapy) until the day before surgery.
RESULTS: In patients without antiplatelet therapy, 15 min and 3 h after protamine a significant decrease in platelet aggregation was observed with all three agonists and both aggregation methods. In patients receiving aspirin alone, LTA-COL, LTA-ADP and M-ADP changed significantly over time, and ADP assays of both aggregation methods showed a significant decrease in platelet aggregation 15 min after protamine in patients receiving dual antiplatelet therapy. When calculating the areas under the receiver-operating characteristic curves for discrimination of antiplatelet agents, LTA-COL was able to discriminate between controls and patients receiving aspirin or dual antiplatelet therapy 15 min and 3 h after CPB and the M-ADP assay was able to discriminate between controls and patients receiving dual antiplatelet therapy 3 h after protamine.
CONCLUSION: Whole blood and classical LTA performed with all commonly used agonists enable detection of CPB-induced changes in platelet aggregation in patients not taking antiplatelet medication, whereas in patients receiving antiplatelet therapy, ADP-induced antiplatelet assays are preferable for detecting CPB-induced impairment of platelet aggregation.

PMID: 19448196 [PubMed - indexed for MEDLINE]

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Inhibitor treatment by rituximab in congenital haemophilia A - Two case reports.

Inhibitor treatment by rituximab in congenital haemophilia A - Two case reports.

Hamostaseologie. 2009 May;29(2):151-4

Authors: Streif W, Escuriola Ettingshausen C, Linde R, Kropshofer G, Zimmerhackl LB, Kreuz W

Abstract
The development of neutralizing alloantibodies (inhibitors) to factor VIII (FVIII) is one of the most serious complications in the treatment of haemophiliacs. Inhibitors occur in approximately 20 to 30% of previously untreated patients (PUPs), predominantly children, with severe haemophilia A within the first 50 exposure days (ED). Immune tolerance induction (ITI) leads to complete elimination of the inhibitor in up to 80% of the patients and offers the possibility to restore regular FVIII prophylaxis. However, patients with high titre inhibitors, in whom standard ITI fails, usually impose with high morbidity and mortality and therefore prompting physicians to alternate therapy regimens. Rituximab, an anti-CD 20 monoclonal antibody has been successfully used in children and adults for the management of B-cell mediated disorders. We report on the use of a new protocol including rituximab in two adolescents with severe haemophilia A and high titre inhibitors, severe bleeding tendency and high clotting factor consumption after failing standard ITI. Both patients received a concomitant treatment with FVIII according to the Bonn protocol, cyclosporine A and immunoglobulin. Treatment with rituximab resulted in a temporary B-cell depletion leading to the disappearance of the inhibitor. FVIII recovery and half-life turned towards normal ranges. In patient 1 the inhibitor reappeared 14 months after the last rituximab administration. In patient 2 complete immune tolerance could be achieved for 60 months. Bleeding frequency diminished significantly and clinical joint status improved in both patients. In patient 1 the treatment course was complicated by aspergillosis and hepatitis B infection. CONCLUSION: Rituximab may be favourable for patients with congenital haemophilia, high-titre inhibitors and a severe clinical course in whom standard ITI has failed. Prospective studies are required to determine safety, efficacy and predictors of success.

PMID: 19404522 [PubMed - indexed for MEDLINE]

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Detection of protamine and heparin after termination of cardiopulmonary bypass by thrombelastometry (ROTEM): results of a pilot study.

Detection of protamine and heparin after termination of cardiopulmonary bypass by thrombelastometry (ROTEM): results of a pilot study.

Anesth Analg. 2009 Mar;108(3):743-50

Authors: Mittermayr M, Velik-Salchner C, Stalzer B, Margreiter J, Klingler A, Streif W, Fries D, Innerhofer P

Abstract
BACKGROUND: Our goal of this study was to determine whether protamine's effects on coagulation can be detected and differentiated from those of heparin when using thrombelastometry (ROTEM).
METHODS: To reverse the effects of heparin after cardiopulmonary bypass (CPB), 22 consecutive patients undergoing aortocoronary bypass graft surgery were included. According to clinical routine, all patients received a first dose of protamine calculated from the total amount of heparin given; additional protamine (70 U/kg) was administered to patients with activated clotting time (ACT) above baseline and clinical signs of diffuse bleeding. Simultaneously, routine ACT measurements, ROTEM assays (heparin-sensitive INTEM, and heparinase-containing HEPTEM test) and standard coagulation tests were performed, and the activity of coagulation factors as well as antifactor Xa activity measured.
RESULTS: Administration of additional protamine (n = 16) resulted in a statistically significant increase in coagulation times on the intrinsically activated test (INTEM-CT), namely from (mean [+/-SD]) 219.8 (+/-19.1) s to 241.1 (+/-21.7) s (P < 0.001), and on the heparinase-containing test (HEPTEM-CT), namely from 210.2 (+/-19.9) s to 226.8 (+/-21.8) s (P < 0.001). These changes were not observed in patients receiving a single protamine dose (n = 6). The INTEM-CT:HEPTEM-CT ratio correctly identified 56 of the 58 samples as not containing residual heparin and correctly detected residual heparin in 3 of the only 6 samples showing elevated antifactor Xa values after CPB.
CONCLUSION: Our preliminary data show that at termination of CPB administration of additional protamine results in a brief prolongation of coagulation times on the INTEM and HEPTEM test and that ROTEM might be useful in excluding residual heparin in cases showing prolonged ACT.

PMID: 19224778 [PubMed - indexed for MEDLINE]

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Endotoxinemia-induced changes in coagulation as measured by rotation thrombelastometry technique and conventional laboratory tests: results of a pilot study on pigs.

Endotoxinemia-induced changes in coagulation as measured by rotation thrombelastometry technique and conventional laboratory tests: results of a pilot study on pigs.

Blood Coagul Fibrinolysis. 2009 Jan;20(1):41-6

Authors: Velik-Salchner C, Streif W, Innerhofer P, Maier S, Knotzer H, Pajk W, Klingler A, Mittermayr M, Haas T

Abstract
Modified rotation thrombelastometry (ROTEM) is widely used in near-patient assessment of hemostasis, but data on functional consequences initiated by acute endotoxinemia are rare. To test the hypothesis that the ROTEM technique allows detection of endotoxinemia-induced changes in hemostasis, we conducted a pilot study on pigs. Fifteen healthy pigs were anesthetized and instrumented for invasive hemodynamic monitoring. Several coagulation tests and the ROTEM assay were performed at baseline and 60 min after administration of a bolus of 200 microg of Escherichia coli lipopolysaccharide followed by a continuous infusion of 0.1 microg/kg per min. After induction of acute endotoxinemia, clot formation time increased (P = 0.001), and alpha angle (P = 0.001) and maximum clot firmness decreased significantly (P = 0.001) in intrinsically and extrinsically activated ROTEM assays. Moreover, fibrinogen/fibrin polymerization showed significantly lower values during endotoxinemia (P = 0.001), and coagulation time shortened for the intrinsically activated assay (P = 0.017). Simultaneously, a significant decrease in platelet count (P = 0.001), fibrinogen (P = 0.001), antithrombin and protein C (P = 0.001) was registered, whereas results of standard coagulation tests and D-dimers showed no significant changes although thrombin-antithrombin complex increased (P = 0.001). Wilcoxon Z score analysis showed that changes in ROTEM variables were comparable to changes in antithrombin, protein C, platelet count, white blood cells and fibrinogen concentrations. The ROTEM assays were able to reflect endotoxinemia-dependent changes in the hemostatic system in pigs early by showing not only activation but also signs of consumption, whereas results of routine coagulation tests remained unchanged.

PMID: 19129727 [PubMed - indexed for MEDLINE]

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Point-of-care whole blood impedance aggregometry versus classical light transmission aggregometry for detecting aspirin and clopidogrel: the results of a pilot study.

Point-of-care whole blood impedance aggregometry versus classical light transmission aggregometry for detecting aspirin and clopidogrel: the results of a pilot study.

Anesth Analg. 2008 Dec;107(6):1798-806

Authors: Velik-Salchner C, Maier S, Innerhofer P, Streif W, Klingler A, Kolbitsch C, Fries D

Abstract
BACKGROUND: We determined whether whole blood impedance aggregometry using the Multiplate detects the effects of antiplatelet drugs as reliably as does classical light transmission aggregometry (LTA) or the platelet function analyzer PFA-100(R).
METHODS: Multiplate (M) assays, measuring changes in electrical resistance as aggregation units over time (AU*min), and LTA assays induced by collagen (COL), adenosine diphosphate (ADP) or arachidonic acid (AA) and PFA-100 testing, using epinephrine (PFA100-EPI) or ADP (PFA100-ADP) cartridges, were performed simultaneously using arterial blood samples obtained before induction of anesthesia in 70 consecutive patients scheduled for elective coronary artery bypass grafting. Patients in group A (n = 48) served as controls, patients in group B (n = 11) received aspirin 100 mg/d and those in group C (n = 11) aspirin 100 mg/d and clopidogrel 75 mg/d until the day before surgery.
RESULTS: In controls the median (1st, 3rd quartiles) change in impedance AU*min for M-COL (374 [231-469]) was significantly greater than in patients receiving aspirin (164 [86-211], P = 0.0009) or receiving aspirin and clopidogrel (118 [101-244], P = 0.004). M-ADP values in controls were 258 (158-389), in patients receiving aspirin 261 (159-393), and in patients receiving aspirin and clopidogrel 88 (48-231, P = 0.054). M-AA values were significantly lower in patients receiving aspirin alone (45 [28-60], P = 0.0004) or aspirin and clopidogrel (44 [26-221], P = 0.008) than in controls (200 [86-345]). The areas under the receiver operating characteristic curves indicating the ability to discriminate patients taking aspirin from those not taking aspirin were comparable for COL and AA assays using whole blood impedance aggregometry or classical LTA (M-COL 0.84 [P = 0.001], LTA-COL 0.85 [P = < .001], M-AA 0.84 [P = < .001] and LTA-AA 0.87 [P = < .001]), but only 0.74 for PFA-100-EPI (P = 0.03). Similarly, for discrimination of patients not taking antiplatelet drugs from patients taking clopidogrel and aspirin the areas under the receiver operating characteristic curve were also comparable for both aggregometry methods M-COL 0.77 (P = 0.006), LTA-COL 0.78 (P = 0.004), M-ADP 0.74 (P = 0.015), LTA-ADP 0.73 (P = 0.018).
CONCLUSION: Results achieved with the bedside Multiplate assays were not different than those obtained with classical aggregometry for detecting the effects of aspirin and clopidogrel in preoperative patients scheduled for elective cardiac surgery.

PMID: 19020120 [PubMed - indexed for MEDLINE]

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Acquired von Willebrand syndrome in cardiac patients.

Acquired von Willebrand syndrome in cardiac patients.

J Cardiothorac Vasc Anesth. 2008 Oct;22(5):719-24

Authors: Velik-Salchner C, Eschertzhuber S, Streif W, Hangler H, Budde U, Fries D

PMID: 18922429 [PubMed - indexed for MEDLINE]

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Less impairment of hemostasis and reduced blood loss in pigs after resuscitation from hemorrhagic shock using the small-volume concept with hypertonic saline/hydroxyethyl starch as compared to administration of 4% gelatin or 6% hydroxyethyl starch solutio

Less impairment of hemostasis and reduced blood loss in pigs after resuscitation from hemorrhagic shock using the small-volume concept with hypertonic saline/hydroxyethyl starch as compared to administration of 4% gelatin or 6% hydroxyethyl starch solution.

Anesth Analg. 2008 Apr;106(4):1078-86, table of contents

Authors: Haas T, Fries D, Holz C, Innerhofer P, Streif W, Klingler A, Hanke A, Velik-Salchner C

Abstract
BACKGROUND: Small-volume resuscitation using hypertonic saline/hydroxyethyl starch 200/0.62 (HS-HES) has been shown to be an effective alternative to the administration of crystalloids or colloids in trauma patients. All i.v. fluids cause dose-related dilutional coagulopathy and show intrinsic effects on the hemostatic system, but only few data refer to functional consequences after small-volume resuscitation.
METHODS: Using thrombelastometry (ROTEM), we studied 30 pigs (weighing 35-45 kg) after withdrawal of 60% of blood volume [1484 mL (1369-1624 mL)] and receiving 4 mL/kg HS-HES for compensation of blood loss or 4% gelatin or 6% HES 130/0.4 in a 1:1 ratio to lost blood volume. To compare the ROTEM variables (coagulation time, clot formation time, alpha angle, clot firmness, and fibrinogen polymerization) with bleeding tendency, a hepatic incision was made and blood loss was measured.
RESULTS: Median (25th, 75th percentile) fibrinogen polymerization was significantly higher after HS-HES infusion [11 mm (10, 11), P = 0.0034] when compared with administration of 4% gelatin [4.5 mm (3.0, 5.8)] or HES 130/0.4 [3.5 mm (2.3, 4.0)]. Median blood loss after liver incision was 725 mL (900, 375) after HS-HES, 1625 mL (1275, 1950) after 4% gelatin, and 1600 mL (1500, 1800) after 6% HES 130/0.4 (P = 0.004). Hemodynamic stabilization was traceable in all groups but showed differences regarding filling pressures.
CONCLUSIONS: Resuscitation from hemorrhagic shock with HS-HES 200/0.62 results in less impairment of clot formation when compared with compensation of blood loss by administering 6% HES 130/0.4 or 4% gelatin.

PMID: 18349176 [PubMed - indexed for MEDLINE]

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Re-transfusion of salvaged washed red cells improves clot formation in pigs as measured by rotational thrombelastometry (ROTEM).

Re-transfusion of salvaged washed red cells improves clot formation in pigs as measured by rotational thrombelastometry (ROTEM).

Eur J Anaesthesiol. 2008 Jun;25(6):473-8

Authors: Haas T, Innerhofer P, Klingler A, Wagner-Berger H, Velik-Salchner C, Streif W, Fries D

Abstract
BACKGROUND AND OBJECTIVE: Patients exhibiting considerable blood loss are prone to develop dilutional coagulopathy following volume supply. In such patients, in addition to transfusing stored blood components, cell saver systems are used to minimize allogeneic transfusion. Since red cell transfusion might influence the haemostatic system by further dilution, we investigated the effects of re-transfusion of salvaged washed red blood cells on the haemostatic process in an animal model of controlled haemorrhage using rotational thrombelastometry (ROTEM; Pentapharm Co., Munich, Germany).
METHODS: Anaesthetized pigs (n = 20) developed coagulopathy following haemorrhagic shock (withdrawal of 66% of estimated blood volume) and volume resuscitation with 6% hydroxyethyl starch 130/0.4. The shed blood was processed in a Cellsaver device (CATS; Fresenius AG, Bad Homburg, Germany), and the resulting salvaged red blood cells were re-transfused. ROTEM assays were performed at baseline, after blood loss, after volume resuscitation and following re-transfusion of salvaged red blood cells.
RESULTS: As compared with baseline, blood loss and subsequent volume resuscitation resulted in significantly increased median values of clotting time (CT: 47.0, 5 .3 and 103.5 s), and clot formation time (CFT: 36.0, 40.0 and 186.0 s), whiggle maximum clot firmness decreased (MCF: 72.0, 68.5 and 39.5 mm). After re-transfusion of salvaged red blood cells (805 +/- 175 mL) all these parameters improved (CT: 80.5 s; P = 0.05, CFT: 144.0 s; P = 0.0008, MCF: 42.0 mm; P = 0.0019) although baseline values were not reached.
CONCLUSION: In the case of extreme isovolaemic haemodilution, increasing the circulating red cell mass by re-transfusing salvaged red blood cells did not worsen the findings of dilutional coagulopathy but interestingly, at least partially, improves the clot formation process.

PMID: 18298874 [PubMed - indexed for MEDLINE]

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Effects of colloid and crystalloid solutions on endogenous activation of fibrinolysis and resistance of polymerized fibrin to recombinant tissue plasminogen activator added ex vivo.

Effects of colloid and crystalloid solutions on endogenous activation of fibrinolysis and resistance of polymerized fibrin to recombinant tissue plasminogen activator added ex vivo.

Br J Anaesth. 2008 Mar;100(3):307-14

Authors: Mittermayr M, Streif W, Haas T, Fries D, Velik-Salchner C, Klingler A, Innerhofer P

Abstract
BACKGROUND: The study was conducted to explore the effects of colloid and crystalloid solutions on activation of fibrinolysis during orthopaedic surgery and to determine whether fluids facilitate clot dissolution at a particular fibrinolytic activity.
METHODS: Tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) were measured in plasma samples of 66 orthopaedic patients randomly receiving gelatin solution, hydroxyethyl starch (HES) (130/0.4), or exclusively Ringer's lactate solution. Plasma obtained before induction of anaesthesia (undiluted) and at the end of surgery (diluted) was exposed to recombinant tissue plasminogen activator (r-tPA) in vitro and analysed by modified thrombelastography (ROTEM).
RESULTS: There were similar changes in t-PA and PAI-1 concentrations in the gelatin, HES, and Ringer's lactate groups. When compared with the effect of r-tPA on undiluted plasma samples, the presence of colloids prompted faster clot dissolution than did Ringer's lactate solution. Lysis index at 30 min decreased significantly [median (min/max); P vs Ringer's lactate solution] to 43 (1/82)% (P=0.007), 14 (3/70)% (P<0.001), and 91 (34/97)%, lysis onset time decreased to 1269 (1054/1743) s (P=0.007), 972 (490/1565) s (P<0.001), and 1970 (1260/2165) s, and lysis time to 2469 (1586/3303) s (P=0.019), 2002 (1569/3600) s (P=0.006), and 3012 (2017/3600) s in the gelatin, HES, and Ringer's lactate groups, respectively.
CONCLUSIONS: The type of i.v. fluid used does not influence endogenously occurring fibrinolytic activity in patients undergoing major orthopaedic surgery. However, during hyperfibrinolysis, the presence of HES or gelatin solution facilitates clot disintegration to a greater extent than Ringer's lactate solution, because the weaker clots formed with colloids dissolve faster.

PMID: 18158312 [PubMed - indexed for MEDLINE]

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Hemostatic changes after crystalloid or colloid fluid administration during major orthopedic surgery: the role of fibrinogen administration.

Hemostatic changes after crystalloid or colloid fluid administration during major orthopedic surgery: the role of fibrinogen administration.

Anesth Analg. 2007 Oct;105(4):905-17, table of contents

Authors: Mittermayr M, Streif W, Haas T, Fries D, Velik-Salchner C, Klingler A, Oswald E, Bach C, Schnapka-Koepf M, Innerhofer P

Abstract
BACKGROUND: To explore whether disturbed fibrin polymerization is the main problem underlying dilutional coagulopathy and can be reversed by fibrinogen administration, we conducted a prospective study using modified thrombelastography (ROTEM).
METHODS: Sixty-six orthopedic patients randomly received modified gelatin solution, hydroxyethyl starch 130/0.4, or exclusively Ringer lactate solution. ROTEM analysis was performed, concentrations of coagulation factors and markers of thrombin generation were measured. Fibrinogen concentrate (Hemocomplettan) was administered (30 mg/kg) when thrombelastographically measured fibrinogen polymerization was critically decreased.
RESULTS: The alpha angle, clot firmness, and fibrinogen polymerization (median [min to max]) significantly decreased in the patients receiving hydroxyethyl starch (area under the curve minus baseline (-5 [-9 to -2]), followed by gelatin solution (-3 [-8 to 0]), with the least reductions seen for Ringer lactate solution (-2 [- 4 to 1]) (colloids versus Ringer lactate P < 0.0001). Thirteen patients in the colloid groups but none in the Ringer lactate group needed fibrinogen concentrate to maintain borderline clot firmness. Activity of FVII, FVIII, FIX, and von Willebrand ristocetin activity decreased significantly with colloids. Thrombelastographically measured coagulation time, molecular markers of thrombin generation, and activity of all other coagulation factors were comparable in all groups.
CONCLUSION: Disturbance of fibrinogen/fibrin polymerization is the primary problem triggering dilutional coagulopathy during major orthopedic surgery. The magnitude of clot firmness reduction is determined by the type of fluid used, with hydroxyethyl starch showing the most pronounced effects. These undesirable effects of intravascular volume therapy can be reversed by increasing fibrinogen concentration by administering fibrinogen concentrate, even during continuing blood loss and intravascular volume replacement.

PMID: 17898365 [PubMed - indexed for MEDLINE]

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Blood coagulation activation and fibrinolysis during a downhill marathon run.

Blood coagulation activation and fibrinolysis during a downhill marathon run.

Blood Coagul Fibrinolysis. 2007 Jul;18(5):435-40

Authors: Sumann G, Fries D, Griesmacher A, Falkensammer G, Klingler A, Koller A, Streif W, Greie S, Schobersberger B, Schobersberger W

Abstract
Prolonged physical exercise is associated with multiple changes in blood hemostasis. Eccentric muscle activation induces microtrauma of skeletal muscles, inducing an inflammatory response. Since there is a link between inflammation and coagulation we speculated that downhill running strongly activates the coagulation system. Thirteen volunteers participated in the Tyrolean Speed Marathon (42,195 m downhill race, 795 m vertical distance). Venous blood was collected 3 days (T1) and 3 h (T2) before the run, within 30 min after finishing (T3) and 1 day thereafter (T4). We measured the following key parameters: creatine kinase, myoglobin, thrombin-antithrombin complex, prothrombin fragment F1 + 2, D-dimer, plasmin-alpha(2)-antiplasmin complexes, tissue-type plasminogen activator antigen, plasminogen-activator-inhibitor-1 antigen and thrombelastography with ROTEM [intrinsic pathway (InTEM) clotting time, clot formation time, maximum clot firmness, alpha angle]. Thrombin generation was evaluated by the Thrombin Dynamic Test and the Technothrombin TGA test. Creatine kinase and myoglobin were elevated at T3 and further increased at T4. Thrombin-antithrombin complex, prothrombin fragment F1 + 2, D-dimer, plasmin-alpha(2)-antiplasmin complexes, tissue-type plasminogen activator antigen and plasminogen-activator-inhibitor-1 antigen were significantly increased at T3. ROTEM analysis exhibited a shortening of InTEM clotting time and clot formation time after the marathon, and an increase in InTEM maximum clot firmness and alpha angle. Changes in TGA were indicative for thrombin generation after the marathon. We demonstrated that a downhill marathon induces an activation of coagulation, as measured by specific parameters for coagulation, ROTEM and thrombin generation assays. These changes were paralleled by an activation of fibrinolysis indicating a preserved hemostatic balance.

PMID: 17581317 [PubMed - indexed for MEDLINE]

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The effect of fibrinogen concentrate on thrombocytopenia.

The effect of fibrinogen concentrate on thrombocytopenia.

J Thromb Haemost. 2007 May;5(5):1019-25

Authors: Velik-Salchner C, Haas T, Innerhofer P, Streif W, Nussbaumer W, Klingler A, Klima G, Martinowitz U, Fries D

Abstract
OBJECTIVES: The hypothesis that the administration of fibrinogen concentrate enables restoration of impaired clot formation and increased bleeding in severe thrombocytopenia was tested.
METHODS: Thirty pigs were anesthetized, instrumented for blood sampling (routine coagulation tests, modified thrombelastography ROTEM, hemodynamic monitoring and platelet apheresis to a target below 30 x 10(9) L(-1) after splenectomy. Thereafter 10 each of the animals randomly received two apheresis platelet concentrates, 250 mg kg(-1) fibrinogen concentrate or normal saline solution. A standardized liver injury was subsequently inflicted to induce uncontrolled hemorrhage.
RESULTS: Median (Q1, Q3) clot firmness increased significantly more in thrombocytopenic pigs after fibrinogen administration (42 mm (41, 43) to 60 mm (57, 63)) than following platelet transfusion (40 mm (37, 45) to 52 mm (48, 55), P = 0.0004) or placebo (45 mm (41, 48) to 45 mm (43, 46), P = 0.0002). Median blood loss velocity after liver injury was significantly less with fibrinogen (33 mL min(-1), P = 0.005) than with platelets (62 mL min(-1), P = 0.037) or saline (84 mL min(-1), P = 0.005), and median survival time after liver injury was 55 min in the fibrinogen, 26 min in the platelet (P = 0.035) and 19 min in the saline group (P = < 0.0001).
CONCLUSIONS: These data show for the first time that impaired clot formation during thrombocytopenia improves with administration of fibrinogen concentrate, which results in a slowdown of blood loss and prolonged survival.

PMID: 17461931 [PubMed - indexed for MEDLINE]

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Comparison of low-molecular-weight heparin and antithrombin versus antithrombin alone for the prevention of symptomatic venous thromboembolism in children with acute lymphoblastic leukemia.

Comparison of low-molecular-weight heparin and antithrombin versus antithrombin alone for the prevention of symptomatic venous thromboembolism in children with acute lymphoblastic leukemia.

Pediatr Blood Cancer. 2008 Feb;50(2):298-303

Authors: Meister B, Kropshofer G, Klein-Franke A, Strasak AM, Hager J, Streif W

Abstract
BACKGROUND: Children with acute lymphoblastic leukemia (ALL) have a substantial risk for thromboembolism (TE) that is related to L-asparaginase-induced antithrombin (AT) deficiency and placement of central venous lines. Recent in vitro studies showed that the anticoagulant effects of low-molecular-weight heparin were profoundly affected by endogenous AT levels in children undergoing ALL therapy.
METHODS: A total of 112 consecutively recruited children with newly diagnosed ALL treated according to BFM 95/2000 protocols were enrolled in this trial. This prospective cohort study was carried out to determine the influence of combined low molecular weight heparin-prophylaxis (enoxaparin 1 mg/kg/ per day) and AT supplementation versus AT alone (noncontemporaneous control group) on the incidence of symptomatic TE during a follow-up of 240 days.
RESULTS: To maintain AT plasma levels above 50%, nearly 60% of all children needed at least one, most children two or three AT supplementations during induction therapy. 12.7% of the children that did receive only AT-prophylaxis (n = 71) (95% CI = 6.0-22.7) developed objectively confirmed symptomatic TE, as compared with no TE in children after combined prophylaxis (n = 41) (95% CI = 0.0-8.6, P < 0.05). Thromboses were located in the sinovenous system in the brain (n = 3), the lower deep veins (n = 3), the upper deep veins (n = 2) and in an upper deep vein combined with pulmonary embolism (n = 1).
CONCLUSION: Prophylaxis with enoxaparin was safe and effective in preventing TE. Although our data are encouraging, the in vivo efficacy of combined enoxaparin and AT prophylaxis to prevent symptomatic venous TE in children with ALL should be evaluated in a prospective randomized clinical trial.

PMID: 17443678 [PubMed - indexed for MEDLINE]

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