Management of Challenging Bleeding: Patients with Coagulopathy

Transcription

1 Management of Challenging Bleeding: Patients with Coagulopathy Joanne E Joseph Department of Haematology, SydPath St Vincent s Hospital University of NSW Sydney

2 First and foremost..

3 It helps to know which coagulopathy you are dealing with Inherited disorder usually single coagulation factor deficiencies, eg FVIII, FIX, FXI, FVII, FX, FXIII, etc Acquired disorder often multiple coagulation factors are deficient, may also be associated with other haemostatic defects including thrombocytopenia, hyperfibrinolysis, concomitant use of antiplatelet and anticoagulant drugs Know your patient population cardiothoracic surgery, liver disease, sepsis, patients with implantable left ventricular assist devices, etc There will always be the unknowns!!

4 What is the best test for detecting a coagulopathy? APTT, PT, TT, Fibrinogen & D- dimer are helpful for the detection of coagulation factor deficiencies, the diagnosis of DIC, UH or VKA effect, etc

5 Limitations of standard coagulation testing Defects which won t be detected: FXIII deficiency Fibrinolytic defects Altered levels of natural anticoagulants Prolonged coagulation times bleeding defect: Lupus anticoagulant FXII deficiency Other contact factor deficiencies Can prove a hindrance in urgent work-up of otherwise asymptomatic patient

6 Classical coagulation cascade

7 Cell based model of coagulation

8 Fibrinolysis

9 Standard coagulation testing

10 Viscoelastic testing First described in 1948 even before APTT and ACT were developed! Utilises the elastic properties of clotting blood Principle of testing Whole blood is placed into a sample cup heated at 37 C in which a pin suspended by a torsion wire is lowered Either the cup (TEG ) or the pin (ROTEM ) is alternately rotated clockwise and counter clockwise As the blood clots, bridges of platelets and fibrin form between the cup and the pin transmitting the torque of the cup to the torsion wire from which it is continuously recorded

11 Schematic representation of ROTEM Hans et al, British Journal of Haematology, 2016, 173, 37 48

12 Typical trace Clevenger et al, Br J Hosp Med (Lond) May;75(5):C71-4.

13 Parameters and traces of TEG and ROTEM Clevenger et al, Br J Hosp Med (Lond) May;75(5):C71-4.

14 Assays available for TEG and ROTEM Hans et al, British Journal of Haematology, 2016, 173, 37 48

15 Assays available for TEG and ROTEM Hans et al, British Journal of Haematology, 2016, 173, 37 48

16 Assays available for TEG and ROTEM Hans et al, British Journal of Haematology, 2016, 173, 37 48

17 Assays available for TEG and ROTEM Hans et al, British Journal of Haematology, 2016, 173, 37 48

18 Assays available for TEG and ROTEM Hans et al, British Journal of Haematology, 2016, 173, 37 48

19 Assays available for TEG and ROTEM Hans et al, British Journal of Haematology, 2016, 173, 37 48

20 Assays available for TEG and ROTEM Hans et al, British Journal of Haematology, 2016, 173, 37 48

21 Assays available for TEG and ROTEM Hans et al, British Journal of Haematology, 2016, 173, 37 48

22 TEG traces in different clinical scenarios Clevenger et al, Br J Hosp Med (Lond) May;75(5):C71-4.

23 Inherited coagulopathy Important to confirm diagnosis patients can be mislabelled as having bleeding disorder, particularly vwd Generally managed through Haemophilia Treatment Centres (HTC) but may present anywhere, anytime Australian Bleeding Disorders Registry (ABDR) National Blood Service Australian Haemophilia Centre Directors Organisation (AHCDO) Guidelines for the Management of Haemophilia in Australia due to be published in June 2016

24 How to manage those with known coagulation disorders NSW Health Policy Directive PD2013_027

25 General policy All patients in NSWACT with haemophilia or a related bleeding disorder that may or may not require treatment must be registered with a HTC and their details should be entered on the ABDR Factor concentrates may be given on demand for bleeding episodes Factor prophylaxis is recommended for all patients with severe Haemophilia and vwd who are at risk of (i.e. factor level < 5%), or who have experienced, joint and other serious bleeding Mandatory that all patients receiving prophylaxis have their treatment co-ordinated and monitored by a designated NSW/ACT HTC Patients with inhibitors should be treated at an HTC NSW Health Policy Directive PD2013_027

26 Elective surgery Elective surgery must take place in consultation with a NSW/ACT HTC Applications for supply of coagulation factor for surgery must be approved by the Haemophilia Advisory Council Clinical Committee (HACC). Once approval has been given, factor concentrates will be made available by the ARCBS. Patients with: Factor VIII < 30%, Factor IX < 30%, Factor XI < 30%, Von Willebrand Factor activity < 30%; and other rare bleeding disorders should have elective surgery performed in a designated NSW/ACT Haemophilia Treatment Centre since they are high risk patients with an increased tendency to bleed, both early and late, and they require management by clinicians experienced in managing haemophilia and related bleeding disorders NSW Health Policy Directive PD2013_027

27 Elective surgery If a patient has a factor level that is > 30% and there is a specific reason for a procedure to be conducted at a hospital that is not a designated NSW/ACT HTC, the patient/parent(s) or carer MUST be made aware of the potential risks attached to having surgery in a hospital that is not a designated or affiliated NSW/ACT HTC and the NSW/ACT Haemophilia Advisory Council Clinical Committee MUST be advised. The NSW/ACT Haemophilia Advisory Council Clinical Committee will review such requests on a case by case basis to ensure that the following requirements are met: Appropriate blood bank, ICU and laboratory facilties Clinical haematologist to supervise treatment after consultation with HTC Director Approved treatment plan NSW Health Policy Directive PD2013_027

28 Application form for factor concentrates NSW Health Policy Directive PD2013_027

29 Acquired coagulopathy More commonly seen by most outside HTC setting Usually under the care of another specialist/team (exceptions include acquired FVIII inhibitor) Relatively frequent occurrences within hospital setting Not all coagulopathies require intervention: Is the patient bleeding and if so, is bleeding related to the coagulopathy? Is the patient at high risk of bleeding or requiring urgent surgery? What is the cause of the coagulopathy? Focus on: Anticoagulant related bleeding Coagulopathy of liver disease

30 Warfarin reversal Tran et al, Med J Aust Mar 4;198(4):198-9

31 Reversing warfarin - bleeding Tran et al, Med J Aust Mar 4;198(4):198-9

32 Dose of Prothrombinex-VF according to INR Tran et al, Med J Aust Mar 4;198(4):198-9

33 Managing high INR and no bleeding Tran et al, Med J Aust Mar 4;198(4):198-9

34 DOAC/NOAC reversal Reversal can refer to: Direct antidote that inactivates the drug Replacement of deficient coagulation factors with haemostatic agents/clotting factor concentrates First establish if NOAC needs reversal depends on severity of bleeding, need for urgent surgery, etc, cessation of NOAC alone may be sufficient

35 ASTH Guidelines Tran et al, Intern Med J Jun;44(6):525-36

36 ASH Education Book 2015 Cuker et al, Hematology Am Soc Hematol Educ Program. 2015;2015:117-24

37 ISTH SSC Guidance Levy et al, J Thromb Haemost 2016;14: 623-7

38 Suggestions for laboratory measurements of NOAC Cuker et al, Hematology Am Soc Hematol Educ Program. 2015;2015:117-24

39 Expected drug levels (this is NOT a therapeutic range) Cuker et al, Hematology Am Soc Hematol Educ Program. 2015;2015:117-24

40 Management of NOAC related bleeding general principles Drug discontinuation Baseline laboratory assessment Hb, APTT, PT and TT, specific drug levels (if available), creatinine General supportive care measures identify bleeding source and limit bleeding (if possible); hydration, optimise Hb and platelet count Activated charcoal in patients with moderate and severe bleeding who present within 4 hours of last dose Dialysis may be considered in patients on dabigatran with lifethreatening bleeding, particularly if renal dysfunction and high dabigatran level Consider haemostatic agents in uncontrollable or life-threatening bleeding (Consider use of antidote if available)* Tran et al, Intern Med J Jun;44(6):525-36

41 Bleeding management summary Tran et al, Intern Med J Jun;44(6):525-36

42 Antidotes Three antidotes are under various stages of development: Idarucizumab (Praxbind), the antidote for dabigatran, is now licensed in the US and Europe with SAS access in Australia Andexanet alfa, the antidote for the oral factor Xa (FXa) inhibitors, is undergoing phase III investigation Ciraparantag (PER977), an agent reported to reverse the anticoagulant effects of all of the DOACs, is at an earlier stage of development Levy et al, J Thromb Haemost 2016;14: 623-7

43 Idarucizumab A humanized monoclonal antibody fragment that binds dabigatran with 350-fold higher affinity than that of dabigatran for thrombin After IV infusion, half-life of idarucizumab is ~ 45 min in subjects with normal renal function Efficacy and safety of idarucizumab evaluated in phase 3 Study of the Reversal Effects of Idarucizumab on Active Dabigatran (REVERSE-AD) in patients who had serious bleeding (group A, n=51) or required an urgent procedure (group B, n=39) Levy et al, J Thromb Haemost 2016;14: 623-7

44 RE-VERSE AD Study dilute TT Pollack et al, N Engl J Med Aug 6;373(6):511-20

45 RE-VERSE AD Study concentration unbound dabigatran Pollack et al, N Engl J Med Aug 6;373(6):511-20

46 Andexanet-alfa A recombinant human FXa variant which serves as a decoy for the oral FXa inhibitors because it binds them with affinities similar to those of native FXa ANNEXA-A and ANNEXA-R were studies of andexanet bolus or bolus plus infusion in healthy older volunteers receiving either 5 mg of apixaban bd or 20 mg of rivaroxaban daily Levy et al, J Thromb Haemost 2016;14: 623-7

47 ANNEXA-A and ANNEXA-R Siegal et al, N Engl J Med Dec 17;373(25):

48 Ciraparantag (PER977) A synthetic, cationic small molecule which binds dabigatran, rivaroxaban, apixaban, and edoxaban via hydrogen bonds Phase 1 study in healthy volunteers given a single 60-mg oral dose of edoxaban an IV bolus of ciraparantag dose-dependently shortened the whole blood clotting time to within 10% of baseline and restored normal clot architecture Studies of ciraparantag in volunteers taking oral FXa inhibitors are under way, but the clinical development program is lagging behind that of andexanet alfa Levy et al, J Thromb Haemost 2016;14: 623-7

49 Potential indications for antidote adminstration Levy et al, J Thromb Haemost 2016;14: 623-7

50 Potential indications for antidote adminstration Levy et al, J Thromb Haemost 2016;14: 623-7

51 Antidote administration general principles Delaying antidote administration until coagulation test results are available may be detrimental in DOACtreated patients with life-threatening bleeding (e.g. ICH, ruptured AAA requiring emergency surgery) Otherwise, decision to give antidote can be guided by time since the last intake of the DOAC, Cr Cl, coagulation test results and plasma drug concentrations If an antidote is given, blood testing is helpful to assess the extent of reversal Levy et al, J Thromb Haemost 2016;14: 623-7

52 Antidote administration general principles Antidote unlikely to be necessary if last dose of DOAC taken >24 hr previously and normal renal function (half-lives of the DOACs will be no longer than 12 h) However, half-lives are prolonged when Cr Cl < 30 ml min, and delayed clearance may be an indication for reversal if the patient has ongoing bleeding In patients with serious bleeding, a drug concentration exceeding 50 ng/ml is likely sufficiently high to warrant antidote administration In patients requiring an urgent intervention associated with a high risk of bleeding, antidote administration should be considered if the drug concentration exceeds 30 ng/ml Levy et al, J Thromb Haemost 2016;14: 623-7

53 Antidote administration general principles Every hospital/lhd should develop a protocol for management of bleeding in patients taking anticoagulants, including DOACs Antidotes are likely to be expensive, so should only be used when benefits outweigh their disadvantages, which include cost, potential risks directly attributable to the antidote, and other adverse effects such as the risk of thrombosis once the patient is no longer anticoagulated Logistics of availability, storage, indications, and prescribers are important considerations for timely administration of the antidotes Need for refrigeration will impact storage; time-consuming preparation may delay their administration. Andexanet and idarucizumab require refrigeration, whereas ciraparantag may not Levy et al, J Thromb Haemost 2016;14: 623-7

54 Coagulopathy of liver disease a balancing act Kujovich. Hematology Am Soc Hematol Educ Program. 2015;2015:243-9

55 Rebalanced haemostasis in chronic liver disease Kujovich. Hematology Am Soc Hematol Educ Program. 2015;2015:243-9

56 Limitations of laboratory testing in patients with liver disease Kujovich. Hematology Am Soc Hematol Educ Program. 2015;2015:243-9

57 Potential triggers of bleeding in chronic liver disease Kujovich. Hematology Am Soc Hematol Educ Program. 2015;2015:243-9

58 Management of active bleeding in liver disease Bleeding complications in chronic liver disease are infrequently related to abnormal haemostasis Majority of clinically significant bleeding episodes are due to increased portal pressure rather than deranged haemostasis, however it may affect severity of bleeding in some cases Standard treatment for acute variceal haemorrhage includes a combination of a vasoconstrictor and endoscopic therapy Kujovich. Hematology Am Soc Hematol Educ Program. 2015;2015:243-9

59 Transfusion Resuscitation with red cell transfusion should aim for a target Hb of 70 80: restrictive transfusion protocol improves control of variceal bleeding Over transfusion of RBC or large volumes of FFP carries a risk of increased portal pressure and re-bleeding No evidence-based guidelines for treatment of abnormal haemostasis during acute bleeding Platelet transfusion recommended for patients with thrombocytopenia and active bleeding maintain platelet count at 50 during acute bleeding (level shown to ensure adequate thrombin generation) Platelet increment may be poor if hypersplenism, active bleeding and/or coexistent infection Cryoprecipitate to maintain a fibrinogen level > 1 is usually recommended (however a threshold haemostatic fibrinogen level is also not well defined) No evidence that prophylactic plasma or platelet transfusions reduce the risk of re-bleeding in patients with varices Kujovich. Hematology Am Soc Hematol Educ Program. 2015;2015:243-9

60 Other possible agents rviia: Although it normalizes a prolonged PT/INR, there is no evidence it reduces bleeding, including Cochrane systematic analysis Not approved for use in liver disease and off-label use is associated with an increased risk of arterial thromboembolism PCC: Potential advantage over FFP including delivery of a smaller volume with a 25-fold higher concentration of coagulation factors and more rapid correction of haemostatic parameters However no evidence that administration of PCC as adjunctive or rescue therapy in cirrhotic patients with active bleeding improves outcome and PCC may increase thrombotic risk in patients with liver disease In absence of evidence confirming benefit, the routine use of PCC for bleeding complications of chronic liver disease is not recommended Kujovich. Hematology Am Soc Hematol Educ Program. 2015;2015:243-9

61 Other possible agents Desmopressin: No evidence that desmopressin improves control of bleeding or clinical outcome in patients with variceal bleeding Several studies found that desmopressin did not reduce blood loss in patients with acute variceal haemorrhage or undergoing hepatectomy or liver transplant May have minimal haemostatic benefit in cirrhotic patients with elevated baseline VWF and FVIII levels Antifibrinolytic agents: Although antifibrinolytic agents such as tranexamic acid have been shown to reduce blood loss during liver transplantation, there is inadequate evidence of benefit outside of the transplant setting. Ongoing RCT HALT-IT (hemorrhagic alleviation with tranexamic acid-intestinal system) is investigating the effectiveness and safety of TXA in patients with GI bleeding Currently insufficient evidence to support routine use of TXA acid in the setting of acute variceal haemorrhage or other bleeding Kujovich. Hematology Am Soc Hematol Educ Program. 2015;2015:243-9

62 If all else fails in the bleeding, coagulopathic patient.