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
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