Management of the Bleeding PatientDr. Alan Tinmouth, MD, MScUniversity of Ottawa Centre for Transfusion ResearchDirector, Adult Regional Hemophilia and Bleeding Disorders Clinic

Outline

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

Breakdown of Hemostasis Processes

I. Primary hemostasis– Platelets form temporary hemostatic plug at

site of injury

II. 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

I. Adhesion – Platelet glycoprotein Ib/V/IX adheres to subendothelium

binding is primarily to vWF

II. 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

III. 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

I. Initiation Phase• Exposure of factor VIIa to tissue factor (TF) on subendothelial

cell starts coagulation cascade and leads to initial thrombin generation (thrombin “burst”)

II. Amplification Phase• Small amount of thrombin then activates platelets and other

coagulation factors (factor V, VIII and XI)

III. 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

TF-Bearing CellTF-Bearing Cell

TFTF

VaVa

VIIaVIIa

TFTF VIIaVIIa

XX

XaXa

IIIIIIaIIa

IXIX

IXaIXa

* Vitamin K dependent clotting factors

Amplification Phase• 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)

TF-Bearing CellTF-Bearing Cell

Activated PlateletActivated Platelet

PlateletPlateletVIIIaVIIIa VaVa

VaVaTFTF VIIaVIIaXaXa

VV VaVa

VIII/vWFVIII/vWF

VIIIaVIIIa

TFPITFPIXaXa

IIIIIIaIIa

XIa

* Vitamin K dependent clotting factors

XIXI XIaXIa

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

Activated PlateletActivated Platelet

TF-Bearing CellTF-Bearing Cell

TFTF

VIIIaVIIIa VaVa

VIIaVIIa

IIIIIXaIXa XX

IXaIXa IIaIIaXaXa

IXIX

IXIX

XIaXIa

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 clotIIaIIa

IIaIIa

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 TestsPrinciple 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:1. Prothrombin time (PT)

Commonly reported as International Normalized Ratio (INR)

2. Activated partial thromboplastin time (aPTT)3. Thrombin Time (TT)

Coagulation in a test tube

XII XIIa

XI XIa

IX IXa

X Xa +VIIIa

II IIa

VIIa VII

Fibrinogen Fibrin

+Va

PT

TT

aPTT

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

Case 1:68 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 aPTTRepeat aPTT (peripheral)

Mixing Study(50:50 mix with normal plasma)

corrects

FACTOR DEFICIENCY

Individual Factor LevelsFactor VIII, IX, XI, XII, vWF

correction

> 3 secs of normal

INHIBITOR Antiphoslipid Antibody Testing

negative

positive

SPECIFIC INHIBITOR

Specific Factor Levels and Inhibitor Testing

ANTIPHOSPHOLIPID ANTIBODY

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:Indications:

INR / PTT > 1.5 x normal

andand

1. Bleeding or

2. Emergency procedure or operation

Fresh Frozen Plasma / Frozen Plasma

Dose:Dose:• 10-15 ml/kg for bleeding patients• Sufficient to increase all individual

coagulation factors by 30% (minimum hemostatic level)

AlternativesAlternatives• Vitamin K

2 mg will correct INR in 12 -24 hrsNo effect on PTT (factors VIII, IX, XI)Oral dose more effective than subcutaneous Intravenous associated with anaphylactic reactions

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

ThrombocytopeniaThrombocytopenia

Platelet DysfunctionPlatelet Dysfunction– Congenital– Acquired

TherapeuticTherapeutic–Plat ct < 50x109/L

–Plat dysfunction

ProphylacticProphylactic–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

► abnormal secondary aggregation

Platelet Dysfunction

Acquired– Renal Failure– Cardiopulmonary Bypass– Myoproliferative Disorders– Drugs

► ASA

► NSAIDs

► Ticlopidine

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► Platelet transfusions may aggravate thrombosis► Only in life threatening bleeding

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

Prophylactic Platelet Transfusion Threshold:Surgical / Invasive Procedures

Bishop. Am J Hematology 1987; 26: 147

Platelet Transfusions - Products

Random Donor PlateletsRandom 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 PlateletsSingle 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)

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

IX IXa

X Xa +VIIIa

II IIa

VIIa VII +TF

Fibrinogen Fibrin

INT

RIN

SIC

EX

TR

INS

IC

COMMON

+Va

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

Indications1. Fibrinogen < 1.0 g/L2. Dysfibrinogenemia

Dose• 1 unit / 5-10 kg body weight (total 8-10 units)• t ½ of 3-5 days

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– Replacement > 1.5 plasma volume*

• 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

TransfusionTransfusion

ICU/Hosp LOS

Survival

Adverse Events

traumaArrive at ER randomize

0 6 8

Units of RBCs

rVIIa 48h

48h

30d

30d

placebo

• 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

Multicentre RCT of rVIIa in Trauma

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 dosesUses• 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 bleedingUses• Mucosal bleeding• Fibrinolytic disorders