Assessment of perioperative bleeding risk When to look further

A critical balance Bleeding risk ? Widespread preoperative screening Type of operation Consequences of excessive bleeding ? Widespread preoperative screening Expense False positives Procedures delayed

Conditions not to miss Haemophilia A Haemophilia B Von Willebrands disease Deficiency of Factor VII, VIII, IX, X, XI Factor specific inhibitors Platelet dysfunction Hypofibrinoginemia/dysfribrinoginemia

Operations not to miss Intrtacranial Spinal Tonsillectomy Cancer related surgery

History is absolutely critical Guides the need for laboratory investigations

Clinical Clues Previous surgical bleeding Transfusion Return to theatre Readmission for haematoma/bleeding History of significant spontaneous bleeding Recurrent epistaxis , recurrent GIT bleeding Haemarthrosis, retroperitoneal bleeding, muscle bleeds

Clinical clues Menorrahgia Floods, clots, period> 7 days, home from school/work Iron deficiency Hysterectomy for menorrhagia Post partum bleeding not due to obstetric causes Petechia, easy bruising

Family history Bleeding disorder Deaths from ICH Surgical Bleeding – Transfusion, return to theatre Detailed history Prompts- circumcision Tonsillectomy, appendicectomy fractures

Drugs Antiplatelet agents Anticoagulants Drugs associated with thrombocytopenia Herbal medications Garlic Ginseng Ginko biloba

Laboratory screen FBE PT/APTT/fibrinogen vWF Ag Platelet aggregometry

Abnormal coagulation tests Prolonged APTT Any prolongation ? Corrects on mixing – factor deficiency ? Fails to correct- factor specific inhibitor or non specific inhibitor Liver function tests heparin like drugs DIC

Prolonged APPT Mixing studies Corrected mix Non corrected mix Factor assays VIII, IX, X, XI XII Liver function Vit K Non corrected mix Lupus anticoagulant Factor specific inhibitors

Abnormal coagulation tests Prolonged PT Any prolongation ? Corrects on mixing – factor deficiency ? Fails to correct- factor specific inhibitor LFTS, Warfarin, DIC Vit K defcifiency

Prolonged PT Mixing studies Corrected mix Non corrected mix Factor assays VII Liver function tests Vit K Non corrected mix Factor specific inhibitors Lupus anticoagulant unlikely

Controversy re the role of routine preop screening for U/L bleeding disorder Bolger et al found 6 coagulation disorders in 52 pts undergoing preop screening for adenotonsillectomy. recommended preop screening in all patients In a retrospective review of 994 patients, Manning et al found that preop PT/PTT failed to identify any patients with occult coagulopathies. Burk et al performed a retrospective review of 1603 patients undergoing adenotonsillectomy. Preoperative screening , a careful bleeding history is used to identify any potential bleeding disorders and guide further laboratory disorders.

Hutchinson revised a questionnaire originally written by Rappaport Hutchinson revised a questionnaire originally written by Rappaport. Reviewing these questions with each patient or parent will identify many bleeding disorders. Has the patient ever bled for a prolonged period of time after biting the tongue, cheek, or lip? Does the patient develop spontaneous bruises larger than 4 to 5 cm in diameter? Has the patient experienced prolonged bleeding following minor surgical procedures such as circumcision, skin biopsies, or dental extractions? Has bleeding recurred 24 hours after the cessation of hemorrhage? What medications has the patient been taking during the last 10 days? Has the patient ingested any antiplatelet agents such as aspirin? Does the patient have any blood relatives with any known bleeding disorder? Have any other these relatives had prolonged bleeding requiring the use of blood transfusions? Does the patient have any systemic medical disorders that might result in excessive bleeding (Lupus, liver or renal disease)?

Use of Recombinant factor VIIa in massive bleeding Novo Seven

Definition Massive Blood Loss Commonly defined as replacement of patient’s total blood volume or transfusion of >10 units of blood within 24 hours eg in a 70kg adult - translates to an estimated replacement of 4-5L of blood lost, or the transfusion of 16-20 units of packed RBC 2nd definition: replacement of 50% of circulating blood volume in <3hrs or bleeding >150ml/min (Normal blood volume approximately 7% of ideal body weight in adults) 70 ml X Kg

Issues in massive transfusion settings Haemostatic defects “Unknown” patients Appropriateness of usage - especially of non-red cell support Stocks / Inventory management Communication Rapid performance of investigations & compatibility tests Rapid issue of blood products Haematological advice/consultation Documentation

Impaired Haemostasis Impaired haemostasis is a frequent finding in trauma & may be multifactorial dilutional coagulopathy dilutional thrombocytopenia disseminated intravascular coagulation hypothermia acidosis platelet dysfunction volume expanders

Haemostatic effects of colloids all semi-synthetic colloid solutions produce some impairment of haemostasis Primarily due to haemodilution of clotting factors Gelatins (e.g. Haemaccel & Gelofusin) - least impact on haemostasis Dextrans - more significant haemostatic derangements - max dose 1.5g/kg to avoid risk bleeding lowMW dextrans increase microvascular flow & have specific effects - FVIII activity reduced, plasminogen activation and fibrinolysis increased, clot strength reduced & platelet function impaired

Dilutional Coagulopathy 72 kg Adult trauma victim 5 litre whole blood volume Pre-trauma haematocrit 45% Initial plasma volume 5000 ml x (100-45) = 2750 ml plasma Haemorrhage of 60% of whole blood volume Represents loss of: 5000 x 0.6 x (100-45) plasma = 1650 ml plasma = 8 units of FFP - but...

Dilutional Coagulopathy On-going losses Do not always need 100% activity of clotting factors for haemostasis - e.g. Factor V need only 30% Factor X need only 30% Factor XI need only 20% Fibrinogen need only 40%

Dilutional Thrombocytopenia thrombocytopenia is the most common haemostatic abnormality during and after massive transfusion microvascular bleeding eg oozing from mucosa, wounds & puncture sites platelet count of 50 x 109/L during active bleeding should be sufficient for normal haemostasis provided platelet function intact. count of 50 x 109/L expected when red cell concentrates equivalent to 2 blood volumes transfused. However, marked individual variation.

Pharmacological techniques/agents Antifibrinolytic agents Aprotinin tranexamic acid EACA (epsilon-aminocaproic acid) Desmospressin (DDAVP) Fibrin sealants rVIIa (NovoSeven)

Massive Blood Loss/Transfusion Episodes

Practice Guidelines for component therapy in Massive Blood Loss FFP: if APTT,INR >1.5 x normal 2 or more units of FFP 10 -15 mL/kg Platelets: Platelet count < 50 - 100 x10*9/L if platelets < 100 then 1platelet pool if platelets <50 then 2 platelet pools Cryoprecipitate: Fibrinogen < 1.0 g/L 10 units cryoprecipate

NovoSeven given

Activated Platelets Activated by small amount of thrombin generated by TF-VIIa complex Activation leads to negatively charged phospholipids being exposed on platelet surface Forms the platform for augmentation of coagulation IXa generated binds to platelet surface and with VIIIa forms Xase complex Xase complex leads to generation of increased thrombin “Thrombin Burst”

rFVIIa production hFVII Gene Amplification hFVII gene Multiple copies of hFVII gene rFVIIa production Incorporate into BHK cells hFVII gene Expression of rFVII in culture medium

Only approved funded indication in Australia Control of bleeding and surgery prophylaxis in patients with inhibitors to coagulation factors FVIII or FIX

Impaired Haemostasis in Massive Bleeding Multifactorial Dilution of platelets and coagulation factors following transfusion and volume expanders Loss of haemostatic factors Consumption in clot formation Disseminated intravascular coagulation (DIC) Hypothermia Acidosis Platelet dysfunction Haemostatic impairment due to semisynthetic colloids All these lead to impaired thrombin generation

Potential benefit of rFVIIa : Bleeding in : Coagulopathy associated with trauma or surgery thrombocytopenia platelet-function disorders liver failure/ transplantation intracerebral haemorrhage BMT

Contraindications hypersensitivity to mouse, hamster or bovine proteins

Current cost of one dose of NovoSeven: (as at 1/7/2005) e.g. dose in massive blood loss setting e.g. 70 kg patient (round up weight to 72 kg) give 100 μg per kg = 7200 μg = 7.2 mg = 6 vials each of 1.2 mg = 6 x ($1208.26 for each 1.2 mg vial) = $7249.56 (without GST)

Recombinant Factor VIIa (NovoSeven)

Dose/Presentation/ Administration powder for reconstitution, stored at 2-8C sterile water for injection for reconstitution (2.2mL with 1.2mgvial) vials 1.2mg, 2.4mg, 4.8mg - usual stock 1.2mg dose recommended 100mcg/kg rounded to nearest whole vial administered as IV bolus over 2-5minutes time to peak concentration 15 minutes elimination half life 2-3 hour

The Lancet Vol 354 July 10, 1999

Recombinant activated factor VII for adjunctive hemorrhage control in trauma Uri Martinowitz et al J Trauma 51(3) 431-439 2001 7 Massively bleeding trauma pts Average of 40 units of blood each Rx NovoSeven Bleeding almost stopped in all cases Reduction of APTT/PT

1st USA case report of FVIIa in trauma Successful use of recombinant activated factor VII for trauma-associated hemorrhage in a patient without pre-existing coagulopathy Patricia O’Neill et al J Trauma 52: 400-405 2002 24 yo female stabbed 6 times to right chest / epigastrium / limbs Aggressive volume expansion / surgery / transfusion support Prolonged surgery to hepatic lacerations After 108 units of red cells, 78 units FFP, 18 units cryoprecipitate, eqiv 60 units platelets / further surgery x 2 / gelfoam packing / angiographic embolisation – the bleeding continued One dose of rFVII given – bleeding ceased immediately

Safety profile of recombinant factor VII Harold Roberts et al Seminars in Hematol 41: 101-108 2004 10 years of usage in haemophiliacs with inhibitors & bleeding >400,000 doses Expanding usage in cardiac surgery & trauma setting No increase in thrombosis rate

No of reported thrombotic events in haemophilia patients with inhibitors Total of 1939 treated bleeding episodes 298 separate patients 0.8% event rate CVA 2 AMI 7 DIC 2 DVT 6

Safety profile of rFVIIa Requires tissue factor from injured site for activity – thus effect confined 0.2% thrombosis rate in haemophiliac group Fatal thrombosis rate of 4 in 5522 cases (0.07%) One thrombotic cerebral infarction in 10 patients treated for SAH

NovoSeven / Thrombosis AMI 5 pts of 7 > 70 years 1 AMI occurred 3 days post dose (also on tranexamic acid) 1 AMI following continuous infusion of FVII for dental procedure 6 Cerebral thrombotic events. 3 patients had pre-existing cerebrovascular disease 1 occipital infarct following craniotomy 1 DVT / PE in Glanzmann’s pt

Blood Coag Fibrinolysis 14: 713-717 2003 Recombinant activated factor VII for the treatment of life-threatening haemorrhage John Eikelboom et al. Blood Coag Fibrinolysis 14: 713-717 2003 Use national email-out to gather cases 21 patients (22-79 years) Multi-trauma / cardiac or vascular surgery / liver transplantation Median pre-Factor VIIa usage of 22 units of red cells Median INR 1.6 Median APTT 55s In 24 hours post FVIIa median red cells usage was 2 units 16/21 alive at 30 days No thrombotic complications

Royal Perth Hospital Patient Characteristics 18 massively transfused, coagulopathic patients (no pre-existing coagulopathy) Median age 44 (range 22-79) Females 5 (28%), Males 13 (72%) Cause of bleeding/surgical procedure 7 cardiac/vascular surgery 5 orthoptic liver transplant 2 chronic liver disease with coagulopathy 2 multitrauma 1 fatty liver of pregnancy, caesarian section 1 severe haemorrhagic pancreatitis

Coagulation Profile before and after rVIIa † *Median, range † First result after rVIIa given ‡Paired Wilcoxon signed rank sum test

Transfusion before and 24 hours after rVIIa

Currently at RMH When NovoSeven is requested / recommended Direct consultation with haematology consultant and treating consultant with patient Usually only considered after failure of aggressive non-red cell blood product support to achieve haemostasis MPH: treating consultant advised to contact health fund/ hospital management to get agreement for payment Funding issues/ process: to be resolved Increasing frequency of requests

10/8/8/10 rFVIIa Management of patients with Critical Bleeding and Coagulopathy If bleeding and coagulopathy continue after conventional therapy (usually: 10 units RBC, 8 units FFP, 8 units platelets, 10 units cryoprecipitate) 10/8/8/10 Appropriate Medical interventions prevent and reverse hypothermia prevent and reverse acidosis correct coagulopathy heparin reversal - warfarin reversal - consider antifibrinolytic agents (i.e. surgery, angiographic embolisation) Identify and manage surgical bleeding rFVIIa 100 µg/kg (rounded to whole vial) Laboratory Tests Repeat blood tests after each 4-6 units RBCs PT, APTT > 1.5 X control  4 units FFP Fibrinogen < 1g/L  10 units cryoprecipitate Platelet count < 75 X 109/l  4 units of platelets Consider calcium chloride If no response in 20 minutes Consider 2nd dose of rFVIIa (100 µg/kg) Note: Use of rFVIIa in children and pregnancy requires special consideration of risk/benefits Early use may be considered in high-risk groups e.g. patients with cirrhosis and undergoing liver surgery

Recombinant factor VIIa for life threatening post-partum haemorrhage J Ahonen and R Jokela. Recombinant factor VIIa for life threatening post-partum haemorrhage British Journal of Anaethesia (2005) 1-4

NovoSeven Summary Effective in 90 % of cases (case reports) Not derived from blood Not antigenic Effective when other Rx has failed Unaffected by blood supply shortages Currently off-label for trauma / CT Surgery Incidence of serious adverse events <1% Caution Elderly Those with pre-existing thrombotic risk factors Intra-cranial pathology / surgery DIC / sepsis