Joost J. van Veen

Guideline on the management of bleeding in patients on antithrombotic agents

The guideline writing group was selected to be representativeof UK-based medical experts. The MEDLINE and EMBASEdatabases were searched systematically for publications in Eng-lish from 1966 to June 2011 and 1980 to June 2011 respec-tively, using the following strategy: Approved and proprietarynames of the antithrombotic agents described in the guidelinewere combined with terms relating to antidote, reversal, haem-orrhage, (activated) prothrombin complex concentrate, factorVIII inhibitor bypass activity (FEIBA), Beriplex, Octaplex,recombinant activated factor VII (rFVIIa), Novoseven, freshfrozen plasma, tranexamic acid, antifibrinolytic, platelet trans-fusion, and desmopressin. Identified papers were also searchedfor additional references. The writing group produced the draftguideline which was subsequently revised by consensus bymembers of the Haemostasis and Thrombosis task Force of theBritish Committee for Standards in Haematology (BCSH).The guideline was then reviewed by a sounding board ofapproximately 50 UK haematologists, the BCSH and theBritish Society for Haematology Committee and commentsincorporated where appropriate. Criteria used to quote levelsand grades of evidence are as outlined in: http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMENDATION/43_GRADE.html.The objective of this document is to guide healthcareprofessionals on the management of patients receivingantithrombotic drugs who experience significant bleeding orwho require emergency surgery or an invasive procedure.Guidance on reversal of vitamin K antagonists (VKAs;warfarin, phenprocoumon, acenocoumarol (sinthrome) andphenindione has been described previously (Keeling et al,2011).Antithrombotic drugs are used increasingly in patientgroups at greater bleeding risk. Although major haemorrhageis infrequent, management can be difficult especially withantithrombotics for which there are no specific reversalagents. Bleeding during antithrombotic therapy is associatedwith high morbidity and mortality (Linkins et al, 2003; Eikel-boom et al, 2006; Mannucci & Levi, 2007). Before any anti-thrombotic treatment is started, the risks and benefits shouldbe carefully considered. In this guideline we consider themanagement of bleeding in patients on the more widely usedantithrombotic agents including heparin, anti-IIa and anti-Xainhibitors, oral VKAs, anti-platelet drugs as well as the fibri-nolytic agents.

The risk of spinal haematoma following neuraxial anaesthesia or lumbar puncture in thrombocytopenic individuals

Neuraxial anaesthesia is increasingly performed in thrombocytopenic patients at the time of delivery of pregnancy. There is a lack of data regarding the optimum platelet count at which spinal procedures can be safely performed. Reports are often confounded by the presence of other risk factors for spinal haematomata, such as anticoagulants, antiplatelet agents and other acquired or congenital coagulopathies/platelet function defects or rapidly falling platelet counts. In the absence of these additional risk factors, a platelet count of 80 × 109/l is a ‘safe’ count for placing an epidural or spinal anaesthetic and 40 × 109/l is a ‘safe’ count for lumbar puncture. It is likely that lower platelet counts may also be safe but there is insufficient published evidence to make recommendations for lower levels at this stage. For patients with platelet counts of 50–80 × 109/l requiring epidural or spinal anaesthesia and patients with a platelet count 20–40 × 109/l requiring a lumbar puncture, an individual decision based on assessment of risks and benefits should be made.

Corn trypsin inhibitor in fluorogenic thrombin-generation measurements is only necessary at low tissue factor concentrations and influences the relationship between factor VIII coagulant activity and thrombogram parameters.

The fluorogenic calibrated automated thrombin-generation assay is influenced by contact pathway activation in platelet-rich and platelet-poor plasma. This influence lessens with increasing tissue factor (TF) concentrations and is inhibited by corn trypsin inhibitor (CTI). CTI is expensive and at what TF concentration its influence becomes irrelevant is unclear. Spiking of factor VIII (FVIII)-depleted plasma with FVIII, in samples without CTI, shows a plateau of thrombin generation at low normal FVIII levels. Given the association with thrombosis at high levels, a continuing increase in thrombin generation would be expected. We studied the effect of CTI on this relation by spiking experiments up to 4.8 IU/ml at 1 pmol/l TF and compared the influence of CTI at 1 and 5 pmol/l in platelet-poor plasma. CTI significantly influences thrombin generation in platelet-poor plasma at 1 pmol/l TF (difference of means for endogenous thrombin potential of 232.5 nmol/l per min, P < 0.0001) and peak of 48 nmol/l (P < 0.0001)) but not at 5 pmol/l. Spiking experiments without CTI confirm the hyperbolic relation between FVIII coagulant activity (FVIII:C) and endogenous thrombin potential with a plateau at 0.70–1.40 IU/ml. With CTI, a near-linear response up to 1.0 IU/ml was found with a plateau at 2.4–4.8 IU/ml. For peak thrombin, no plateau was reached with CTI. The present study confirms and extends previous data on CTI and the relationship between FVIII:C and thrombin generation. CTI is not necessary at 5 pmol/l TF, and thrombin generation remains dependent on FVIII:C up to 4.8 IU/ml at 1 pmol/l with CTI. Higher levels than previously thought may be needed to normalize thrombin generation.

Thrombin generation assays are superior to traditional tests in assessing anticoagulation reversal in vitro

Even though new anticoagulants are being devised with the notion that they do not require regular monitoring, when bleeding occurs, it is important to have an antidote and a reliable test to confirm whether the anticoagulant effects are persisting. We examined the effects of five heparinoids, unfractionated heparin (UFH), tinzaparin, enoxaparin, danaparoid and fondaparinux on the traditional APTT and anti-Xa assays as well as on the calibrated automated thrombogram (CAT). We also studied the ability of protamine sulphate (PS), NovoSeven, FEIBA and FFP to reverse maximum anticoagulation induced by the different heparinoids. The CAT was the only test to detect the coagulopathy of all the anticoagulants. PS produced complete reversal of UFH, and this could be monitored with all three tests. Tinzaparin can also be completely neutralised in vitro with high doses of PS, but the maximum enoxaparin reversal achieved with PS is only approximately 60%. Fondaparinux does not significantly affect the APTT and PS has no significant effect on its reversal. Only NovoSeven was able to correct the fondaparinux induced CAT abnormalities whilst having no effect on the anti-Xa level. None of the reversal agents was very effective in danaparoid spiked plasma but NovoSeven, at high dose, increased the ETP by 40% and reduced the anti-Xa level from 0.93 to 0.78 IU/ml. We conclude that the CAT is superior to the traditional coagulation tests in that it not only detects the coagulopathy of all the heparinoids but can be also be used to monitor their reversal.

Protamine reversal of low molecular weight heparin: clinically effective?

Low molecular weight heparins (LMWHs) are frequently used in the prophylaxis or treatment of venous thrombosis, acute coronary syndromes and peri-operative bridging. Major bleeding occurs in 1–4% depending on dose and underlying condition. Protamine is recommended for reversal but only partially reverses the anti-Xa activity and there are very limited data on clinical effectiveness. We retrospectively studied the effect of emergency reversal of LMWH with protamine in actively bleeding patients and patients requiring emergency surgery in our institution. Eighteen patients were identified through haematology referral/pharmacy records of protamine prescriptions between 1998 and 2009. Case notes were checked for the reversal indication, type/dose of LMWH, dose and clinical response to protamine, timing in relation to the last dose of LMWH and anti-Xa levels before and after protamine. All but one patient received enoxaparin. Fourteen were actively bleeding, three required emergency surgery without active bleeding and one had an accidental overdose without bleeding. The three patients requiring surgery had an uneventful procedure. In 12 of 14 patients with active bleeding, protamine could be evaluated. Bleeding stopped in eight. In the four with continuing bleeding, one had an additional coagulopathy. Protamine only partially affected anti-Xa levels. Protamine may be of use in reversing bleeding associated with LMWH but not in all patients. Anti-Xa levels were useful to assess the amount of anticoagulation before protamine administration but unhelpful in assessing its effect. Better reversal agents and methods to monitor LMWH therapy are required.

Management dilemmas in acute pulmonary embolism

Background Physicians treating acute pulmonary embolism (PE) are faced with difficult management decisions while specific guidance from recent guidelines may be absent. Methods Fourteen clinical dilemmas were identified by physicians and haematologists with specific interests in acute and chronic PE. Current evidence was reviewed and a practical approach suggested. Results Management dilemmas discussed include: sub-massive PE, PE following recent stroke or surgery, thrombolysis dosing and use in cardiac arrest, surgical or catheter-based therapy, failure to respond to initial thrombolysis, PE in pregnancy, right atrial thrombus, role of caval filter insertion, incidental and sub-segmental PE, differentiating acute from chronic PE, early discharge and novel oral anticoagulants. Conclusion The suggested approaches are based on a review of the available evidence and guidelines and on our clinical experience. Management in an individual patient requires clinical assessment of risks and benefits and also depends on local availability of therapeutic interventions.

Calibrated automated thrombin generation and modified thromboelastometry in haemophilia A

INTRODUCTION Global coagulation tests may have a better relation with phenotype in haemophilia than traditional coagulation tests. These include the Calibrated Automated Thrombin generation assay (CAT) and modified thromboelastometry using low tissue factor triggering. Both have shown marked variability in thrombin generation and clot formation profiles respectively despite similar FVIII:C levels and have been suggested as means to monitor treatment. Data with modified thromboelastometry are largely limited to severe and moderate haemophiliacs. CAT measurements in haemophilia are generally performed at low TF concentrations (1 pM) because of a higher sensitivity for the intrinsic pathway at this concentration but is also sensitive for FVIII at higher concentrations (5 pM) and this has the advantage that inhibition of contact factor activation can be avoided. No formal comparison of both TF concentrations has been reported and the data on modified thromboelastometry in mild haemophilia are limited. METHODS In this study we compared thrombin generation at 1 and 5 pM in 57 haemophilia patients without exposure to treatment and 41 patients after treatment. We also assessed the sensitivity of thromboelastometry for haemophilia A in 29 patients. RESULTS AND CONCLUSION We found that CAT discriminates well between normal individuals and haemophilia patients; also FVIII:C correlates well with the ETP/peak. We found no clear advantages of measurements at 1 compared to 5 pM but found increased variation over time at 1 pM. The sensitivity of modified thromboelastometry for haemophilia A was less than CAT with abnormal measurements largely limited to severe and moderate patients. Larger studies correlating both methods with clinical outcome are required.

Normal prothrombin time in the presence of therapeutic levels of rivaroxaban

more, Md.: 1950), 182, 7254–7263. Rosenbauer, F., Wagner, K., Kutok, J.L., Iwasaki, H., Le Beau, M.M., Okuno, Y., Akashi, K., Fiering, S. & Tenen, D.G. (2004) Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1. Nature Genetics, 36, 624–630. Smith, L.T., Hohaus, S., Gonzalez, D.A., Dziennis, S.E. & Tenen, D.G. (1996) PU.1 (Spi-1) and C/ EBP alpha regulate the granulocyte colony-stimulating factor receptor promoter in myeloid cells. Blood, 88, 1234–1247. Wang, K., Wang, P., Shi, J., Zhu, X., He, M., Jia, X., Yang, X., Qiu, F., Jin, W., Qian, M., Fang, H., Mi, J., Yang, X., Xiao, H., Minden, M., Du, Y., Chen, Z. & Zhang, J. (2010) PML/RAR[alpha] Targets Promoter Regions Containing PU.1 Consensus and RARE Half Sites in Acute Promyelocytic Leukemia. Cancer Cell, 17, 186–197.

Specific and global coagulation assays in the diagnosis of discrepant mild hemophilia A

The activity of the factor VIII coagulation protein can be measured by three methods: a one or two-stage clotting assay and a chromogenic assay. The factor VIII activity of most individuals with mild hemophilia A is the same regardless of which method is employed. However, approximately 30% of patients show marked discrepancies in factor VIII activity measured with the different methods. The objective of this study was to investigate the incidence of assay discrepancy in our center, assess the impact of alternative reagents on factor VIII activity assays and determine the usefulness of global assays of hemostasis in mild hemophilia A. Factor VIII activity was measured in 84 individuals with mild hemophilia A using different reagents. Assay discrepancy was defined as a two-fold or greater difference between the results of the one-stage and two-stage clotting assays. Rotational thromboelastometry and calibrated automated thrombography were performed. Assay discrepancy was observed in 31% of individuals; 12% with lower activity in the two-stage assay and 19% with lower activity in the one-stage assay. The phenotype could not always be predicted from the individual’s genotype. Chromogenic assays were shown to be a suitable alternative to the two-stage clotting assay. Thromboelastometry was found to have poor sensitivity in hemophilia. Calibrated automated thrombography supported the results obtained by the two-stage and chromogenic assays. The current international guidelines do not define the type of assay to be used in the diagnosis of mild hemophilia A and some patients could be misclassified as normal. In our study, 4% of patients would not have been diagnosed on the basis of the one-stage factor VIII assay. Laboratories should use both one stage and chromogenic (or two-stage) assays in the diagnosis of patients with possible hemophilia A.

Contact factor deficiencies and cardiopulmonary bypass surgery: detection of the defect and monitoring of heparin

Contact factor pathway deficiencies do not cause surgical bleeding but make heparin monitoring by the activated partial thromboplastin time (APTT) and activated clotting time (ACT) unreliable. Heparin monitoring during cardiopulmonary bypass (CPB) surgery in these patients is particularly challenging. Here we describe heparin monitoring during CPB using the chromogenic anti Xa assay in two patients with severe factor XII deficiency (FXII < 0.01 U/mL) and one patient with severe prekallikrein (PK) deficiency (PK < 0.01 U/mL). Anti Xa levels of the three patients during CPB varied between 3.8 and 4.8 U/mL in keeping with a control group (mean anti Xa 4.5 U/mL and ACT > 480 s). There were no bleeding or thrombotic complications. We also found that detection of severe PK deficiency by the APTT in the PK deficient patient was dependent on the reagent used and discuss the sensitivity of different APTT reagents for contact factor deficiencies. We conclude that the sensitivity of APTT methods for contact pathway deficiencies is highly variable and although insensitivity is not a clinical problem in terms of bleeding, it can be a cause of discrepancy between different APTT reagents and the ACT. This can lead to confusion about a possible haemorrhagic tendency and delays in surgery. If these patients need to undergo cardiac surgery requiring high dose heparin treatment, monitoring by chromogenic anti Xa assay is a good alternative.