Management of the Bleeding Patient

Dr. Alan TinmouthDirector, Adult Regional Hemophilia and Bleeding

Disorders ClinicFebruary 1st, 2005

Outline

Review the mechanism of blood coagulation Understand the tests used in the investigation

of bleeding disorders Understand the therapeutic options in the

management of bleeding patients “Hemostasis” Poker

Overview of Hemostasis

Primary Hemostasis: Platelets

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

subendothelium binding is primarily to vWFII. 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

Secondary Hemostasis: Coagulation Factors

Coagulation factors are proteins that circulate primarily in inactive state (proenzyme), which are converted to active enzyme

Activation of coagulation factors is a stepwise process of one activated factor activating subsequent factor(s)

Historically separated into the intrinsic pathway and extrinsic pathway Intrinsic and extrinsic pathways believed to act

independently and lead to formation of fibrin clot through separate “coagulation cascades”

Model fails to explain many coagulation abnormalities seen clinically

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

Initiation Phase

Tissue factor is spark initiating coagulation cascade Exposed TF activates factor VII Factor VIIa:TF activates Factor VII*, Factor X*, Factor IX*

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, VII*, XI)

TF-Bearing CellTF-Bearing Cell

Activated PlateletActivated Platelet

PlateletPlateletVIIIaVIIIa VaVa

VaVaTFTF VIIaVIIaXaXa

VV VaVa

VIII/vWFVIII/vWF

VIIIaVIIIa

TFPITFPI

XaXa

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+) [tenase] activates factor X

Factor Xa with Va (+ Ca2+) [pro-thrombinase] 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 clot IIaIIa

IIaIIa

Coagulation Factor Pathway in Vivo

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

Activators of plasminogen activation Inhibitors of plasminogen activation Inhibitors of plasmin

Fibrinolysis and Plasmin Inhibition

Fibrinolysis Plasminogen and t-PA bind to fibrin lysine sites

Activated plasmin protected from degradation by alpha2-antiplasmin

Plasmin optimally positioned to degrade fibrin

Plasmin Inhibition Circulating plasmin is rapidly inactivated by alpha2-

antiplasmin Prevents systemic (widespread) fibrinolysis

Thrombin activated fibrinolytic inhibitor (TAFI) removes lysine sites from fibrin to downregulates fibrinolysis during initial clot formation

Fibrinolytic System

Laboratory Investigations

Platelet Disorders

Platelet Count Platelet Morphology (blood film) Platelet Aggregation / Release von Willebrand Studies

von Willebrand Antigen Ristocetin Cofactor von Willebrand Multimers

Bleeding Time

Coagulation Factor Disorders

Prothrombin Time / International Normalized Ratio

Activated Partial Thromboplastin Time Thrombin Time 50:50 Mixing Studies Coagulation Factor Assays

Activated Partial Thromboplastin Time

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

Activated Partial Thromboplastin Time

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

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

Thrombin Time (TT)

Fibrinolytic System

Euglobulin Lysis Alpha 2 Antiplasmin Factor XIII levels

Therapy

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)

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

Fresh Frozen Plasma

Made from whole blood within 8 hrs of collection Contains all coagulation factors

Minimum factor VIII level of 0.7 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

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

by 30% (minimum hemostatic level) 5-7 ml/kg may be sufficient for warfarin reversal

AlternativesAlternatives 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

Cryoprecipitate

Precipitate collected from plasma thawed at 40C 10-15 mls/unit Contains specific clotting factors from plasma

Factor VIII Fibrinogen von Willebrand’s Factor Factor XIII

IndicationsIndications1. Fibrinogen < 1.0 g/L2. Dysfibrinogenemia

Cryoprecipitate

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

AlternativesAlternatives Factor VIII or IX Deficiency

recombinant factor VIII or IX Von Willebrand’s Disease

virally inactivated plasma derived factor concentrates Other factor deficiencies

recombinant factor concentrates virally inactivated plasma derived factor concentrates

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

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

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

“Hemostasis” Poker

One-of-a-Kind

DisordersINR aPTT TT/Fib Platelets

N N N

N N N

N N N

N N N

Liver diseaseVit K defCoumadinFactor VII

Heparin Antiphospholipid AbFactor VIII, IX, XIvon Willebrand’s(Factor XII)

HypofibrinogenemiaDysfibrinogenemiaThrombin InhibitorsHeparin

ITPTTP/HUSDrugsBone MarrowSplenomegaly

Pair

DisordersINR aPTT TT/Fib Platelets

N N

Factor II, V, X, Coumadin Overdose

Three-of-a-Kind

DisordersINR aPTT TT/Fib Platelets

N

Liver disease (acute)

Full House

DisordersINR aPTT TT/Fib Platelets

Liver disease (chronic)DIC

Nothing

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