Management of the Bleeding Patient Dr Management of the Bleeding Patient Dr. Alan Tinmouth, MD, MSc University of Ottawa Centre for Transfusion Research Director, Adult Regional Hemophilia and Bleeding Disorders Clinic

Outline Overview of hemostasis Review common coagulation tests “Coagulopathy Poker”

Breakdown of Hemostasis Processes Primary hemostasis Platelets form temporary hemostatic plug at site of injury Secondary hemostasis Coagulation proteins form insoluble fibrin clot at site of initial platelet plug III. Fibrinolysis Fibrinolytic proteins breakdown fibrin clot after endothelial repair is completed

Overview of Hemostasis

Primary Hemostasis: Platelets Adhesion Platelet glycoprotein Ib/V/IX adheres to subendothelium  binding is primarily to vWF Activation Shape change  formation of pseudopods Anionic phospholipids (phospatidylserine and phosphoethanolamine) exposed on external membrane Glycoprotein IIb/IIIa exposed on surface Secretion of platelet granules Aggregation Platelets bind to each other via Gp IIb/IIIa receptor and soluble fibrinogen and vWF  FORMATION OF HEMOSTATIC PLUG

Platelet Adhesion and Activation

Platelet Aggregation

Current Model of Coagulation Cascade Initiation Phase Exposure of factor VIIa to tissue factor (TF) on subendothelial cell starts coagulation cascade and leads to initial thrombin generation (thrombin “burst”) Amplification Phase Small amount of thrombin then activates platelets and other coagulation factors (factor V, VIII and XI) Propagation Phase Large amounts of thrombin produced on surface of platelets Thrombin converts fibrinogen to fibrin (fibrin deposition) which is cross-linked to form stable thrombus (clot)  Formation of stable thrombus allows for endothelial repair

Initiation Phase Tissue factor is spark initiating coagulation factor cascade Exposed TF activates factor VII Factor VIIa:TF activates (i) Factor VII*  VIIa (ii) Factor X*  Xa (iii) Factor IX*  IXa Factor Xa with Va generates a small amount of thrombin II IIa X Xa TF VIIa Va TF-Bearing Cell TF VIIa IX IXa * Vitamin K dependent clotting factors

Amplification Phase II Factor VIIa:TF inactivated by Tissue Factor Pathway Inhibitor (TFPI):Factor Xa complex Thrombin* (II) generated on TF-bearing cell activates platelets and coagulation factors (V, VIII*, XI) II IIa VIII/vWF TFPI Xa Xa TF VIIa VIIIa Va TF-Bearing Cell XI XIa V Va Platelet VIIIa Va XIa Activated Platelet * Vitamin K dependent clotting factors

Propagation Phase Activated platelets serve as phospholipid platform for generation of large amounts of thrombin Factor IXa with VIIIa (+ Ca2+) forms tenase which activates factor X* Factor Xa with Va (+ Ca2+) forms prothrombinase which produces large thrombin burst Thrombin then generates fibrin and fibrin clot TF-Bearing Cell TF VIIa IX II IXa X Xa IIa IXa VIIIa Va XIa Activated Platelet IX

Formation of Fibrin Clot: Fibrin Deposition Thrombin binds to fibrinogen and forms fibrin Cleaves fibrinopeptide A and B to leave fibrin monomer Thrombin activates factor XIII to XIIIa, Factor XIIIa catalyzes cross-linking of fibrin monomers to produce stable clot IIa IIa

Fibrinolysis Fibrin clots are temporary scaffolding that allow for cellular wound healing Dissolution of clots needed to maintain vessel patency Plasmin (converted from plasminogen) is primary agent of fibrinolysis Fibrinolysis is controlled by t-PA - Activator of plasminogen PAI-1 - Inhibitor of plasminogen activation α2 antiplasmin - Inhibitors of plasmin

Fibrinolytic System

Principle of Coagulation Tests Screening tests are based on the addition of thrombogenic stimuli to ex vivo plasma  time to clot generation is used as the end point Other tests of specific coagulation factors can also be performed Screening Tests: Prothrombin time (PT) Commonly reported as International Normalized Ratio (INR) Activated partial thromboplastin time (aPTT) Thrombin Time (TT)

Coagulation in a test tube aPTT XII XIIa PT XI XIa VIIa VII IX IXa +VIIIa X Xa +Va II IIa Fibrinogen Fibrin TT

Coagulopathy Poker

One of Kind Prolonged aPTT Factor Deficiency (VIII, IX, XI, XII) Inhibitor (factor VIII) Heparin Lupus anticoagulant / Antiphospholipid antibody von Willebrand Disease

Three cases of an elevated aPTT 68 year old male lower GI bleed & coagulation factor deficiency INR 0.93 aPTT 46 sec Case 2: 70 year old with SOB and hemoptysis INR 1.02 aPTT 65 Case 3: 51 year old with no bleeding INR 1.1 aPTT 120 secs Mild factor VIII deficiency – 5% Antiphospholipid antibody Factor XII deficiency – 1%

Evaluation of Prolonged aPTT Repeat aPTT (peripheral) ANTIPHOSPHOLIPID ANTIBODY positive Mixing Study (50:50 mix with normal plasma) correction > 3 secs of normal Antiphoslipid Antibody Testing INHIBITOR negative corrects SPECIFIC INHIBITOR FACTOR DEFICIENCY Individual Factor Levels Factor VIII, IX, XI, XII, vWF Specific Factor Levels and Inhibitor Testing

One of Kind Prolonged INR(PT) Factor Deficiency (VII) Warfarin Liver Disease

Fresh Frozen Plasma or Frozen Plasma FFP frozen within 8 hrs of collection FP frozen within 24 hrs of collection Contains all coagulation factors FFP has minimum factor VIII level of 0.7 IU/ml FP has factor VIII > 0.5 IU/ml 200-250 mls / unit Effect may only last 4 hrs (t1/2 of factor VII) Indications: INR / PTT > 1.5 x normal and Bleeding or Emergency procedure or operation

Fresh Frozen Plasma / Frozen Plasma Dose: 10-15 ml/kg for bleeding patients Sufficient to increase all individual coagulation factors by 30% (minimum hemostatic level) Alternatives Vitamin K 2 mg will correct INR in 12 -24 hrs No effect on PTT (factors VIII, IX, XI) Oral dose more effective than subcutaneous Intravenous associated with anaphylactic reactions

One of Kind Thrombocytopenia Decreased production Increased Destruction ► physiologic consumption ► immune mediated clearance Hypersplenism ► 1/3 of platelets normally in spleen ► minimum platelet count ~ 50 x 109/l

Indications for Platelet Transfusions Thrombocytopenia Platelet Dysfunction Congenital Acquired Therapeutic Plat ct < 50x109/L Plat dysfunction Prophylactic Prior to invasive procedures Plat ct < 50-100x109/L Prevent spontaneous bleeding Plat ct  10x109/L

Platelet Dysfunction Congenital Bernard-Soulier Syndrome (GP Ib/IX) ► abnormal adhesion Glanzmann Thrombasthenia (GP IIb/IIIa) ► abnormal aggregation Gray Platelet Syndrome (α granule deficiency) ► abnormal secondary aggregation δ storage pool density

Platelet Dysfunction Acquired Renal Failure Cardiopulmonary Bypass Myoproliferative Disorders Drugs ► ASA ► NSAIDs ► Ticlopidine

Immune Thrombocytopenic Purpura (ITP) Contraindications to Platelet Transfusions in Thrombocytopenic Patients Immune Thrombocytopenic Purpura (ITP) ► Poor platelet recovery ► Only for patients with ongoing bleeding ► IVIG and steroids should be give concurrently Thrombotic Thrombocytopenic Purpura (TTP / HUS) ► Platelet transfusions may aggravate thrombosis ► Only in life threatening bleeding Heparin Induced Thrombocytopenia

167 surgical or invasive procedure in 95 patients with acute leukemia Prophylactic Platelet Transfusion Threshold: Surgical / Invasive Procedures 167 surgical or invasive procedure in 95 patients with acute leukemia 29 major surgeries 52 Hickman line insertions Results: Transfused of pre-op platelet count < 50 x 109/l 93% no bleeding or minor bleeding All bleeding episodes easily controlled with further transfusion or pressure dressing Conclusion: Minimum platelet count of 40 – 50 x 109/l safe Bishop. Am J Hematology 1987; 26: 147

Platelet Transfusions - Products Random Donor Platelets Separated from whole blood donations Dose = 5 units (250-300 mls) ABO matched preferable but not mandatory Increases platelet ct by 5-10 x 109/L per unit Single Donor Platelets Collected from 1 donor by apheresis Equivalent to 5-6 random donor platelets Decrease donor exposure Can be matched if patient has identified antibodies to platelets (alloimmune platelet refractoriness)

Pair 45 year old male (105 kg) with recurrent nose bleeds INR 4.8 aPTT 120 secs Diagnosis: Factor Deficiency (II, V, X) Warfarin overdose Liver Disease

Coagulation in a Test Tube XII XIIa XI XIa VIIa VII IX IXa +TF INTRINSIC +VIIIa EXTRINSIC X Xa +Va II IIa Fibrinogen Fibrin COMMON

Three of a kind Increased INR, aPTT and decreased Fibrinogen Diagnosis Fibrinogen deficiency Liver disease

Cryoprecipitate Precipitate collected from plasma thawed at 40C 10-15 mls/unit Contains specific clotting factors from plasma Factor VIII & von Willebrand’s Factor Fibrinogen Factor XIII Indications Fibrinogen < 1.0 g/L Dysfibrinogenemia Dose 1 unit / 5-10 kg body weight (total 8-10 units) t ½ of 3-5 days

Four of a kind Increased INR and PTT Decreased Fibrinogen and Platelets Diagnosis: Liver Disease Massive Transfusion

Massive Transfusion Replacement of blood volume or transfusion 10+ units of RBCs in less than 24 hrs Complications Thrombocytopenia Replacement > 1.5 plasma volume* Coagulopathy Hypothermia Hypocalcemia/citrate toxicity Hyperkalemia * May occur earlier in trauma patients

Recombinant Factor VIIa Initiates coagulation by interaction with TF Only approved for treatment of hemophilia with inhibitors Treat/prevent bleeding in other patient groups? Efficacy not proven Risk of thrombosis? Primary use is bleeding patients refractory to other treatments Dose for hemophilia 90 ug/kg q2-3h Lower dose often effective in other patients 30-40 ug/kg Vials of 1.2 mg, 2.4mg, 4.8mg Cost ~ $1000/mg

Multicentre RCT of rVIIa in Trauma 280 pts with blunt or penetrating trauma All patients receive 3 doses 200 ug/kg followed by 100ug/kg 1h and 3h later Arrive at ER rVIIa 48h 30d trauma randomize 6 8 placebo Units of RBCs 48h 30d Transfusion ICU/Hosp LOS Survival Adverse Events

Multicentre RCT of rVIIa in Trauma 287 patients with blunt and penetrating trauma Non significant reduction in RBC units transfused Significant only in blunt trauma if early deaths excluded (within 48h) Similar overall survival - 25% vs 30% Composite outcome incl organ dysfunction showed increased trend favouring rVIIa (29 vs. 43%) No difference in adverse events

Bleeding with normal tests Von Willebrand’s Disease Mild Hemophilia A or B Mild Factor XI deficiency Platelet Function Disorder Factor XIII deficiency Alpha 2 antiplasmin deficiency Plasminogen Activator Inhibitor deficiency

DDAVP Synthetic vasopressin Release of VIII and vWF from endothelium May also help with platelet dysfunction 2-3 fold rise in levels Dose – 0.3 ug/kg q 12-24 hours Tachyphylaxis may occur after 2-3 doses Uses Mild hemophilia A Von Willebrand Disease Platelet dysfunction

Antifibrinolytics Tranexamic acid (Cyclokapron) 20-25 mg/kg po or 10 mg/kg IV q8h Epsilon aminocaproic acid (Amicar) 50-60 mg/kg po q6h Competitive inhibition with plaminogen activator (t-PA) Prevents fibrinolysis (clot breakdown) Promotes thrombosis Relative contraindication in renal bleeding Uses Mucosal bleeding Fibrinolytic disorders