HGD Hendriks MD, PhD

University Medical Center Groningen

Balanced Transfusion Resuscitation

Transparency in Transfusion Medicine 2013Transparency in Transfusion Medicine 2013

“Balancing”

Preoperative Peroperative Postoperative

1

2

3

BalancedCoagulation management is an understanding of

this balance

Perfect Haemostasis:

No bleedingNo thrombotic events

- Balance the benefits of haemostatic actions against the risks- Haemostasis: platelets, coagulation proteins, fibrinolysis & endothelium- Haemostasis: monitoring

- Balance in Trauma and Obstetrics

Benefit of Prohemostatic Actions balanced with the risk of Adverse Events

Renal insufficiency, Cardiovascular complications, AnaphylaxisAprotinin

AnaphylaxisProtamine sulfate

Anaphylactoid Reaction (IV administration)Vitamin K

Arterial thrombotic eventsrFVIIa

Urinary tract obstruction (Hematuria)Epileptic insult

Lysine Analogs (Tranexamic Acid)

Acute Coronary SyndromeHyponatremia

DDAVP (Desmopressin)

Thrombotic complications4FC

TRALI, fever, allergic reactions, Platelets

TACO,TRALI, Fever,hemolysisRBC

TRALI, TACO, Allergic/anaphylactic reactionsFFP

Adverse EventProcoagulant Action

Panday S, Vyas GN. Adverse effects of plasma transfusion. Transfusion 2012;52:65S-79S

Carson JL et al. Red blood cell transfusion: a clinical practice guideline from the AABB. Ann Intern Med 2012;157:49-58

Refaai et al. Platelet transfusions: impact on haemostasis, thrombosis, inflammation and clinical outcomes. Thromb Res. 2011127: 287-91

M.Levi. Safety of Prohemostatic Interventions. Semin Thromb Hemost 2012;38:292-298

PlateletsNormal range: 150.000 – 350.000 x 109/L

average life span Platelet ~ 10 days each day 15 each day 15 –– 35 x 1035 x 1099/L new platelets/L new platelets

Consensus:Consensus:

Invasive procedures: 50 x 109/L Neurosurgery: 100 x 109/L Neuraxis Blockade: 50 x 109/L

Assumption: all other components of coagulation system are intact

Function of PlateletsNo clinical Test for Platelet Function

Thromboelastography/metry is often used to treat andguide platelet administration

but does not reflect the effect of aspirin/clopidogrel

or a deficient von Willebrand factor function.

Trentalange MJ. Walts LF. A comparision of thromboelastogram and template bleeding time in the evaluation of platelet function after aspirin ingestion. J Clin Anesth 1991;3(5);377-81Mousa et al. Comparison of the effect of different platelet GPIIb/IIIa antagonists on the dynamics of platelet/fibrin-mediated clot strength induced using thromboelastography. Thromb Res 2001;104:49-56

Coagulation Proteins

TF+VIIa

Xa + Va

IIa

Fibrine

XIa

IXa

VIIIa

PlateletPlateletactivationactivation

Concentration

Rea

ctio

nra

te

0 9 20 30 40 0 9 20 30 40 50 60 70 50 60 70 80 90 10080 90 100

INR: 3 1.8 1.2 1.0

Coagulation activity

A level of 1.5 times the upper limit of the PT and aPTT A level of 1.5 times the upper limit of the PT and aPTT is generally considered a risk for bleeding during surgery is generally considered a risk for bleeding during surgery

Assumption: all other components of coagulation system are intact

Classical Coagulation Tests

PT & aPTTProvide

Important, but limited information

Ungoing blood loss: retrospective analysis

These test don’t predict blood lossThese test don’t predict blood lossThey only measure the initial stages of fibrin formationThey only measure the initial stages of fibrin formation

Haemostasis in end-stage Liver Disease

Mannucci. Abnormal hemostasis test and bleeding in chronic liver disease: are they related? No. J Thromb Haem 2006;4:721-723

FibrinolysisPlasminogen

FibrinolysistPA TAFI

Coagulation ProteinsFVIIIProteïne C/S, AT

Coagulation ProteinsFactor II, V, VII, IX, X, XI

PlateletsVon WillebrandADAMTS-13

PlateletsThrombopenie/pathie

Liver transplant patients are in balanceLiver transplant patients are in balance

They fly low

Haemostasis in end-stage Liver Disease

FibrinolysisPlasminogen

FibrinolysistPA TAFI

Coagulation ProteinsFVIIIProteïne C/S, AT

Coagulation ProteinsFactor II, V, VII, IX, X, XI

PlateletsVon WillebrandADAMTS-13

PlateletsTrombopenie/pathiePlatelet count

PT, aPTT

Fibrinogen

Fibrinolysis

Anti-Coagulants

Interactions

Liver Transplantation

Hepatitis Cirrhosis Primary Biliary Cirrhosis

PT = 21 sec aPTT 42 sec

Platelet count 78

Fibrinolysis

Plasminogen Plasmin

FIBRIN

Hyperfibrinolysis:CPBOLTTraumaObstetricsOrthopaedic surgery

ADP-ase b b b b

Intact vessel wall

NO

FVIIa

FVIIa

PGI2

Collagen (subendothelial)

Endothelial cell

Platelet Activated platelet

Breached vessel wall

Vasoconstriction

Von Willebrand Factor (Intermediary between collagen & platelet)

Tissue factor

FVIIa

Thrombin

FVIIa

FVIIa = activated FVII

GPIIb/IIIa – fibrinogen - GPIIb/IIIa

ADP-aseNO PGI2

PlateletPlatelet activationactivation

Thrombomodulin

TFPI

AT

Heparan sulfate

AT = antithrombin

TFPI = tissue factor pathway inhibitor

APC = activated protein C

tPA = tissue Plasminogen activator

Thrombomodulin

Blood flow

Intact vessel wall

TFPI

APC APC

ATAT

APC tPA

tPA

ADP-ase b b b b

Intact vessel wall

NO

FVIIa

FVIIa

PGI2

Collagen (subendothelial)

Endothelial cell

Platelet Activated platelet

Breached vessel wall

Vasoconstriction

Von Willebrand Factor (Intermediary between collagen & platelet)

Tissue factor

FVIIa

Thrombin

FVIIa

FVIIa = activated FVII

GPIIb/IIIa – fibrinogen - GPIIb/IIIa

ADP-aseNO PGI2

PlateletPlatelet activationactivation

Thrombomodulin

TFPI

AT

Heparan sulfate

AT = antithrombin

TFPI = tissue factor pathway inhibitor

APC = activated protein C

tPA = tissue Plasminogen activator

Thrombomodulin

Blood flow

Intact vessel wall

TFPI

APC APC

ATAT

APC tPA

tPA

ADP-ase b b b b

Intact vessel wall

NO

FVIIa

FVIIa

PGI2

Collagen (subendothelial)

Endothelial cell

Platelet Activated platelet

Breached vessel wall

Vasoconstriction

Von Willebrand Factor (Intermediary between collagen & platelet)

Tissue factor

FVIIa

Thrombin

FVIIa

FVIIa = activated FVII

GPIIb/IIIa – fibrinogen - GPIIb/IIIa

ADP-aseNO PGI2

PlateletPlatelet activationactivation

Thrombomodulin

TFPI

AT

Heparan sulfate

AT = antithrombin

TFPI = tissue factor pathway inhibitor

APC = activated protein C

tPA = tissue Plasminogen activator

Thrombomodulin

Blood flow

Intact vessel wall

TFPI

APC APC

ATAT

APC tPA

tPA

ADP-ase b b b b

Intact vessel wall

NO

FVIIa

FVIIa

PGI2

Collagen (subendothelial)

Endothelial cell

Platelet Activated platelet

Breached vessel wall

Vasoconstriction

Von Willebrand Factor (Intermediary between collagen & platelet)

Tissue factor

FVIIa

Thrombin

FVIIa

FVIIa = activated FVII

GPIIb/IIIa – fibrinogen - GPIIb/IIIa

ADP-aseNO PGI2

Platelet activationPlatelet activation

Thrombomodulin

TFPI

AT

Heparan sulfate

AT = antithrombin

TFPI = tissue factor pathway inhibitor

APC = activated protein C

tPA = tissue Plasminogen activator

Thrombomodulin

Blood flow

Intact vessel wall

TFPI

APC APC

ATAT

APC tPA

tPA

Endothelium

Role Endothelium is Crucial

There are no (clinical) tests to evaluate the function of the Endothelium

“Is a promising and necessary target for affecting haemostasis”

Jerrold H Levy et al: Multidisciplinary approach to the challenge of hemostasis. A&A 2010;110:354-364

Haemostasis

• Platelets • Coagulation Proteins• Fibrinolysis• Endothelium

Preconditions:Preconditions:

Preconditions of HaemostasisCalcium Ca++ : ≥ 0.9 mmol/LpH: 7.4 (Activity 50% at pH7.1)Anemia: Ht ≥ 30%Temperature: 37°C

- Coagulation Protein Activity 10%/ 1°C)- Platelet function *

Lier et al: Preconditions of hemostasis in trauma: a review. J Trauma 2008;65:951-960

* Kermode et al: Marked temperature dependence of the platelet calcium signal induced by human vWF. Blood 1999;94:199-207

TemperatureMJ Rohrer. Crit Care Med 1992;20:1402-1405

PT & aPTT

at

37 0C

Platelets, Coagulation Proteins, Endothelium

Fibrinolysis, pH, Temperature

Temperature

37°C vs 32° C

pH7.4 vs 7.1

Ramaker et al. Blood Coagul Fibrinolysis. 2009 Sep;20(6):436-9.Effects of acidosis, alkalosis, hyperthermia and hypothermia on haemostasis: results of point-of-care testing with the thromboelastography analyser.

Interactions: Crucial

“Hypothermia is synergistic with acidosis and dilution

resulting in greater clinical coagulopathy than can be

explained by in vitro experimentation”

Howard et al: Prohemostatic interventions in trauma: resuscitation-associated coagulopathy, acute traumatic coagulopathy, hemostatic resuscitation, and other hemostatic interventions. Siminars in Thrombosis and Hemostasis 2012;38:250-258

Finding the Balance in a bleeding patient:difficult

• Haemostasis: not entirely understood

• Coagulation Tests: limited value

• Preconditions of Haemostasis: important

• Influence of Interactions: crucial

Evidence from Trials?

Trials• Difficult to do research in bleeding patients• Evidence from Trials are often not suitable on patients in our Clinic• Lack of Standardized guidelines for administration:

- Blood Products - Pharmacological Agents

• The balance in a patient is strongly influenced by the clinical situation::

Not all massive haemorrhage is the same

Balance in Trauma and Obstetrics

Haemorrhage

Trauma: haemorrhage is the most common cause of death

Obstetrics: haemorrhage is the most important cause of maternal death

Balance in Trauma

Prior to trauma normal coagulation profile

Blood loss: Haemodilution, Hypothermia, Acidosis (lethal triad)

(fibrinolysis, Inflammation, infections)

Trauma-Induced CoagulopathyLarge amounts of crystalloids (and RBC’s):

iatrogenic coagulopathy, resuscitation-associated coagulopathy

Trauma-Induced CoagulopathyDilution: strong correlation between fluid volume and

coagulopathy

25 – 33% of severely trauma patients are coagulopathic upon arrival in hospital*

50% who received > 3 L prehospital fluid were coagulopathic10% who received 500 ml showed also coagulopathy**

InteractionsInteractions with hypothermia and acidosis are crucial

*Frith et al. The acute coagulopathy of trauma shock: clinical relevance. Surgeon2010;8:159-163

**Maegele et al. AG Polytrauma of the German Trauma Society (DGU). Injury 2007;38:298-304

20th century: FFP administration was guided by PT and aPTT, PLT < 50

Trauma-Induced CoagulopathyRBC : FFP = 4 : <1 65% mortalityRBC : FFP = 3 : >2 19% mortality

Borgman et al. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J of Trauma 2007;63:805-813

RBC : Platelet = 2 : >1 30-d survival compared to low ratios

Holcomb et al. Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients Ann. Of Surgery 2008;248:447-458

Trauma-Induced Coagulopathy

Shift toward balanced ratio of blood components

RBC : FFP : PLT = 1 : 1 : 1

Mortality :correction coagulation?

All data retrospective. Randomized and Prospective data are lacking

Survivorship bias: survivors live longer to receive the treatment

Magnotti et al: improved survival after hemostatic resuscitation: does the emperor have no clothes? J trauma 2011;70:97-102

MTB protocol

RBC FFP PLT Fibrinogen (g)

3 3 1 1 : 1: 0.3

6 3 < 70 2 : 1 : 1

3 3 1 1 : 1: 0.3 <1.5 g/l

3 3 1 1 : 1: 0.3

4 2 1 2 : 1 : 0.5

5 5 1 1 : 1 : 0.2 2-4

3 3 1 1 : 1: 0.3 <1.5 g/l

3 3 1 1 : 1: 0.3

4 2 1 2 : 1: 0.5

3 3 1 1 : 1 : 0.3

5 3 1 2 : 0.6 : 0.2 2

Trauma-Induced CoagulopathyTherapy

Transfusion Ratio: RBC : FFP : PTL = 3 : 3 : 1

• Fibrinogen: ? Critical value of 1 g/L* 1.5 – 2.0 g/L**Fibrinogen: first in line for depletion. Cause? Dilution and Consumption(impaired bioavailability, impaired production, enhanced breakdown, inadequate replacement)

• rFVIIa: wide variability in timing and dosing. Effect?*• Tranexamic acid (CRASH-2 Trial, decrease in mortality, but no difference in

bleeding). Early administration. Dose: 10 -15 mg/kg Guided by TEG/ROTEM**

• No routine use of Desmopressine**

Blood Pressure (MAP 60 mmHg) (Systolic 80-100mmHg)**Hb = 5 mmol/L

* Knudson et al.Trauma, transfusions, and use of rFVIIa. J Am Coll Surg2011;212:87-95

**Rossaint et al. Management of bleeding following major trauma: an updated European guideline. Critical Care 2010;14:R52

Trauma-Induced CoagulopathyTherapy

• Hypothermia: 0C“Hypothermia is a ominous clinical sign accompanied by high mortality”*

• Hypothermia: cold infusion, heat loss on the street (40% in trauma patients)• Mild (<36 °C) and moderate (32 – 36 °C) have already deleterious effect Smith et al: Avoiding hypothermia in the trauma patient. Curr Opin Aenesthesiol 2000;13:167-174

Direct warming up the patient, warming up fluids

• Acidosis: serum lactate (& base deficit)Metabolic dysfunction secondary to hypoperfusion and administration NaCl 0.9%Reversal of Acidosis does not always result in return of clotting functionMechanism? Uncertain (activation Protein C by thrombomodulin?)**

*Rossaint et al. Management of bleeding following major trauma: an updated European guideline. Critical Care 2010;14:R52

** Cohen et al. Critical role of activated protein C in early coagulopathy and later organ failure, infection an death in traumapatients. Ann Surg 2012;255:379-385

PostPartum Hemorrhage

Postpartum HemorrhagePostpartum hemorrhage (PPH) has been defined as:blood loss in excess of 500 ml after a vaginal birth,

1000 ml after a cesarean delivery

No factors predict PPH:every pregnancy is at risk

Fibrinogen: < 2g/L positive predictor of postpartum haemorrhage*

No clinical trials to guide management

*Charbit et al. The decrease of fibrinogen is an early predictor of the severity of postpartum hemorrhage. J Thromb Haemost2007;5:266-73

Balance in Obstetrics

40% increase in Plasma Volume25% increase ErythrocytesHt decrease, Platelet Count drop

FibrinolysisFibrinolysistPA,

Coagulation ProteinsFI, FVII, FVIII, Protein C/S

Coagulation ProteinsUnchanged: FV, FXIIIUnchanged: AT

PlateletsVWF

PlateletsThrombopenie

PT and aPTT:

Unchanged

Platelet Count

TEG/ROTEM:

Hypercoaguable*

Lange et al. Obstetric hemorrhage and coagulation: an update. Thromboelastography, thromboelastometry, and conventional coagulation tests in the diagnosis and prediction of postpartum hemorrhage. Obstet Gynecol Surv 2012;67:426-35

Solomon et al. Haemostatic monitoring during postpartum haemorrhage and implications for management. Br J Anaest 2012;109:851-63

*Sharma et al. Thromboelastographic changes in healthy parturients and postpartum woman. Anest & Analg 1997;85:94-98

Balance in Obstetrics

40% increase in Plasma Volume25% increase ErythrocytesHt decrease, Platelet Count drop

FibrinolysisFibrinolysistPA,

Coagulation ProteinsFI, FVII, FVIII, Protein C/S

Coagulation ProteinsUnchanged: FV, FXIIIUnchanged: AT

PlateletsVWF

PlateletsThrombopenie

PT and aPTT:

Unchanged

Platelet Count

TEG/ROTEM:

Hypercoaguable*

Lange et al. Obstetric hemorrhage and coagulation: an update. Thromboelastography, thromboelastometry, and conventional coagulation tests in the diagnosis and prediction of postpartum hemorrhage. Obstet Gynecol Surv 2012;67:426-35

Solomon et al. Haemostatic monitoring during postpartum haemorrhage and implications for management. Br J Anaest 2012;109:851-63

*Sharma et al. Thromboelastographic changes in healthy parturients and postpartum woman. Anest & Analg 1997;85:94-98

Bleeding & Medication History

Balance in ObstetricsCause of bleedig: uterine atony (oxytocin, ergometrine)

Damage control: balloon tamponade, embolization, hysterectomyDilutionalDilutional CoagulopathyCoagulopathy (and consumptive)

“Recommended in 20th century”:

PT and aPTT ≤ 1.5 normal valuePlasma Fibrinogen ≥ 1 g/L

Platelets ≥ 50 x 109/L

Balance in ObstetricsTherapy

Transfusion Ratio: If If uterotonicsuterotonics and sutures failand sutures failRBC : FFP = 4 : 1 or 1: 1 (extrapolating)James et al. Postpartum Hemorrhage: when uterotonics and sutures fail. Am J Hematol. 2012;87:S16-22

Have a Protocol, EvaluateHave a Protocol, EvaluateTemperature, Ph, CalciumBlood Pressure (MAP 60 mmHg?)• rFVIIa: wide variability in timing and dosing. Effect?• Fibrinogen: Critical value of 1 g/L 1.5 – 2.0 g/L• Tranexamic acid: 1 gr iv *• Desmopressin: (0.3 µg/kg) Small trials**

Peitsidis et al. Antifibrinolytic therapy with tranexamic acid in pregnancy and postpartum. Expert Opin Pharmacother 2011;12:503-16

* Novikova et al. Tranexamic acid for preventing postpartum haemorrhage. Cochrane Database Syst Rev 2010:CD007872

**Trigg et al. A systematic review: the use of desmopressin for treatment and prophylaxis of bleeding disorders in pregnancy. Haemophilia 2012;18:25-33

CONCLUSIONS

Conclusions

• Haemostatic Balance is poorly understood

• Limited Evidence to guide therapy

• PT/aPTT limited value in a bleeding patient

• Not all massive haemorrhage is the same

Conclusions• Treatment is tailored:- Lab:

PT, aPTT, PC, Fibrinogen, lactate, TEG/ROTEM, last but not least: surgical field

• Have a Protocol, Evaluate• Tranexamic acid (recFVIIa)

• Fibrinogen administration (< 1 gr/L ? 4 gr/L?)• INERACTIONS: CRUCIAL• Influence on blood loss of the

surgeon/lab/anaesthetist/haematologist/

TEAM WORKTEAM WORK