Transcript Management of the Bleeding Patient

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
I.
Primary hemostasis
–
II.
Platelets form temporary hemostatic plug at
site of injury
Secondary hemostasis
–
III.
Coagulation proteins form insoluble fibrin clot
at site of initial platelet plug
Fibrinolysis
–
Fibrinolytic proteins breakdown fibrin clot after
endothelial repair is completed
Overview of Hemostasis
Primary Hemostasis: Platelets
I.
Adhesion
–
II.
Platelet glycoprotein Ib/V/IX adheres to subendothelium
 binding is primarily to vWF
Activation
–
–
–
–
III.
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
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
II
X
TF VIIa
Xa
Va
IIa
TF-Bearing Cell
TF VIIa
IX
IXa
* 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/vWF
II
VIII*, XI)TFPI
Xa TF
VIIa
Xa
Va
IIa
VIIIa
TF-Bearing Cell
XI
V
XIa
Va
Platelet
VIIIa
XIa
Va
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
TF-Bearing Cell
X*
TF VIIa
• Factor Xa with Va
IX
2+
(+ Ca ) forms
IXa
X
II
prothrombinase which
produces large thrombin
Xa
VIIIa
Va
IXa
burst
XIa
Activated Platelet
• Thrombin then
IX
generates fibrin and
fibrin clot
IIa
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
IIa
monomers to produce stable clot
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:
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
aPTT
XII
XIIa
XI
PT
XIa
VIIa
IX
IXa
+VIIIa
X
Xa
+Va
II
Fibrinogen
TT
IIa
Fibrin
VII
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
Mild factor VIII deficiency – 5%
• aPTT 46 sec
Case 2:
70 year old with SOB and hemoptysis
• INR 1.02
• aPTT 65
Antiphospholipid antibody
Case 3:
51 year old with no bleeding
• INR 1.1
• aPTT 120 secs
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
INHIBITOR
Antiphoslipid
Antibody Testing
negative
corrects
FACTOR DEFICIENCY
Individual Factor Levels
Factor VIII, IX, XI, XII, vWF
SPECIFIC INHIBITOR
Specific Factor Levels
and Inhibitor Testing
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
1. Bleeding or
2. 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
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
► 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
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)
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
XIa
INTRINSIC
VIIa
IX
IXa
VII
+TF
+VIIIa
X
Xa
+Va
II
Fibrinogen
COMMON
IIa
Fibrin
EXTRINSIC
XI
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
1. Fibrinogen < 1.0 g/L
2. 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
trauma
Arrive
at ER
randomize
0
6
rVIIa
8
48h
30d
48h
30d
placebo
Units of RBCs
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