Bleeding management in organ

transplantation and intensive care

Bleeding Management Course - from theory to clinical practice

János Fazakas MD, PhD
THE COMPLEXITY OF PERIOPERATIVE
COAGULATION DISORDERS
one organ failure  multiorgan dysfunction

dilution consumption
loss supply
endogen
heparinoids hyperfibrinolysis
• Kidney transplantation:
• hemodialysis + anticoagulation
• venous and arterial reperfusion: coagulation disorder
• Pancreas and kidney transplantation:
• hemodialysis + anticoagulation , DM + IHD
• „2 grafts  2 x venous + arterial reperfusions”:
• coagulation disorder, fibrinolysis
• Kidney recipients:
• catheter associated thrombosis and stenosis, atrial fibrillation,
coronary stents, congenital coagulation disorders
• treatment with vitamin K antagonist INR 2.5-5.5

TACO

TRALI ?

CIT + 2-4 hours HDF

PCC

Clinical Practice Guidelines and Clinical Practice Recommendations, 2006 Updates

The perioperative management of
antithrombotic therapy
American College of Chest Physicians, evidence-based clinical practice guideline
(8th edition)
Chest, 2008 Jun; 133 (6 Suppl) : 299S-339S

• In patients who are receiving VKAs and require reversal of the

anticoagulant effect for an urgent surgical or other invasive procedure, the
guideline developers recommend treatment with low-dose (2.5 to 5.0

mg) IV or oral vitamin K (Grade 1C).

• For more immediate reversal of the anticoagulant effect,

the guideline developers suggest treatment with fresh-frozen

plasma or another prothrombin concentrate in addition to

low-dose IV or oral vitamin K (Grade 2C).
 Overview of blood product transfusion
during liver transplantation
Coagulation
patients No RBC RBC FFP PLT
monitoring
Dalmau et al. 2001 122 34 % 2.9 (0-6) 1.6 (0-4) 7.9 (0-15) BT, TEG
Dalmau et al. 2004 127 38 % 2.3 (0-5) 1.25 (0-3) 5 (0-11) BT
Massicote et al. 2005 206 32 % 2.8 (0-7) 4.1 (0-8) 0.4 (0-3) ?
Frasco et al. 2005 69 ? 2.9 (0-6) 2.5 (0-5) 1.2 (0-2) ?

Mangus et al. 2007 526 17.5 % 3 7 6 ?

Boer et al. 2008 236 26 % 2.2 (0-6) 2 (0-7) 0 (0-1) BT, TEG

Massicote et al. 2008 200 81.5 % 0.3 ± 0.8 0 0 ?

 Clear reduction of blood products requirements

 Blood tests (BT) usefulness in bleeding prediction
 20% no bleeding, 20% still serious bleeding

Curr Opin Organ Transplant 14 (2009) 286-290

• Hepatectomy: preop. coagulation profile
– coagulation factors  : dilution + consumption
– blood loss correlate with the degree of surgical difficulty
• adhesion dissection and transection of portocaval shunts
• Hepatectomy: preop. coagulation profile
– coagulation factors  : dilution + consumption
– blood loss correlate with the degree of surgical difficulty
• adhesion dissection and transection of portocaval shunts
• Anhepatic phase :
• „no clearance” of activated coagulation factors and tPA
• „no supply” by synthesis activity but a „continuous consumption”
• failure of homeostasis: pH , Se Ca+ , T°C 
• volume overload in the splanchnic area
• Venous and arterial reperfusion:
• coagulopathy and microvascular diffuse bleeding (30-90 min)
• endogen heparinoids  ; fibrinolitic substances 
• the degree and duration is variable with donor graft quality
Intraoperative hypothermia Limbs: venous blood shift
in the abdominal and thoracic vein

skin
core

relative normovolemia
Warming increased CVP
 Coagulation

• Hypothermia • Normothermia

– fibrinogen – FFP (factor VIII !!!!)

– prothrombin complex
– thrombocyte • Fibrinolysis

– EAC, tranexamic acid

• New possibility:

– rFVIIa, XIIIa
 Coagulation tests
„Y shape modell” - 1960 „cell based modell” - 1980

„initiation„ „amplification” „propagation”

IXa

TF VIIa

PLT
IIa Xa 20 x VIIIa

XIIIa Ia

standard Va
tests 5% 95%
Thrombin production
TEG
 INR kva
• „ WHO etalon” – KVA: K vitamin antagonist blood
• (PT test / PT normal) ISIkva

INRkva
 A-B=0.3
C=0.5
„healthy test”

Tripodi et al. Hepatology, 2007, 46: 520-27; Bellest et al. Hepatology, 2007, 46:528-34
 INR liver
• „etalon” – blood of cirrhotic patient
• (PT test / PT normal) ISIliver

INRliver
 A-B=0.01
 C=0.02

Tripodi et al. Hepatology, 2007, 46: 520-27; Bellest et al. Hepatology, 2007, 46:528-34
Evidence of normal thrombin generation in cirrhosis
despite abnormal conventional coagulation tests

„platelets provided phospholipid surface to complement normal thrombin generation”

Tripodi et al. Hepatology, 2007, 46: 727-733

 Balance of potential risks and benefits of
platelets in liver transplantation
Liver Transpl, 2008, 14: 923-931

Platelets in liver transplantation: Friend or foe?

Benefits
Component of primary hemostasis
Involvement in tissue repair
Involvement in liver generation
Risk
Contribution to ischemia reperfusion
injury
Involvement in postoperative thrombosis
Association with adverse outcome of
transplantation

• For patients receiving aspirin, clopidogrel, or both, are undergoing surgery

and have excessive or life-threatening perioperative bleeding, the guideline
developers suggest transfusion of platelets or administration of other
prohemostatic agents (Grade 2C).
The perioperative management of antithrombotic therapy. American College of Chest
Physicians evidence-based clinical practice guidelines (8th edition).
Chest, 2008 Jun; 133 (6 Suppl) : 299S-339S
 Fibrinogen < 1g/l V < 20% VII < 20% PLT < 50.000

„initiation – amplification - propagation”

1) factor dilution
Female, HLA DR
2) VIII , vonW syndr.
XIIIa TRALI / TACO
3) G 2a/3b receptor number
VII a
4) fibrin polymerization
trouble
PLT

normothermia ?
FFP
PCC , FFP
hypothermia ?
fibrinogen
TEG, fibrinolysis, aprotinin ?
pH>7,2 SeCa> 1 HGB>100g/l T> 35

surgical hemostasis
Antibody against fathers leukocyte HLA
75% of female blood donors were pregnant

• Appearance of HLA antibody :

– in all female donors: 15 %
– in never pregnant donors: 1.6 %
– after 1 pregnancy: 10.5 %
– after 2 pregnancies: 15.8 %
– after 3 pregnancies: 25 %
– after 4 pregnancies: 36 %

• Odds ratio of TRALI

– all plasma 3.4 (1.2-10.2)
– male plasma 2.7 (0.7-10.1)
– female plasma 25.6 (1.3- 49.9)

Massicote, 2008: „ The avoidance of plasma transfusion was associated

with a decrease in RBC transfusions during liver transplantation. „
Massicote et al: Transplantation 2008 Apr 15;85(7):956-962 Rana et al. Transfusion 2006; 46:1478-83
 healthy 4 - 6 hours

Nature Medicine 2007,13: 463 – 469

12 - 18 hours > 24 hours

MINOR TRALI
SPIROMETRY TESTING AFTER LTX

O2 supply
CPAP mask
 HLA antibodies in blood components
Unappreciated risk factors for transplant patients

 no published data: HLA antibodies promote allograft dysfunction ?!?

 transfusion mediated rejection: HLA-Ag graft + antibodies HLA-Ab

Class I Class II Class I & II Total

Components (n) n (%) n (%) n (%) n (%)

RBCs (106) 7 (6.6%) 8 (7.5%) 3 (2.8%) 18 (16.9%)

Cryo (66) 3 (4.5%) 3 (4.5%) 10 (15.1%) 16 (24.2%)

9
FFP (77) 4 (5.2%) 9 (11.6%) 22 (28.5%)
(11.6%)

Platelets (59) 7 (12%) 5 (9%) 1 (2%) 13 (22%)

Human Immunology 65 (2004) 240-244

 Responsiveness !
6 10
AT III

2 Endogeneous
fibrinolysis
heparinoids

Prepare for anhepatic phase Optimize all function

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 The two tales of coagulation in transplantation:
the rebalancing story
Normal patient Patient with liver disease

„Delicate rebalance”
Promoting bleeding Promoting thrombosis
Primary hemostasis
• thrombocytopenia + function defects • elevated levels of VWF
• enhanced NO + PGI2 production • decreased levels of ADAMTS
(VWF protease)

• low level of II, V, VII, IX, X, XI factors Secondary hemostasis • elevated levels of VIII factor
• dysfibrinogenemia • decreased levels of prot C, prot S, AT III
• decreased levels of heparin cofactors

• low levels of α2antiplasmin,XIII factor Fibrinolysis • low levels of plasminogen

• elevated tPA levels

Current Opinion in Organ Transplantation 2008, 13: 298-303

Hypercoagulability based on TEG
• short R time < 4 min, increased  angle (> 75°), increased MA > 75 mm

Hypercoagulable Normal
 ESDL etiology and coagulation profile
PLT, INR, APTI, coagulation factors ATIII, protein S, protein C
Plasminogen, t PA, PAI 1, PAI 2 2-antiplasmin, 2 -macroglobulin

Risk of thrombosis Risk of bleeding

Budd Chiari syndr., POPH, Wilson’s d., HCV, HBV,
glycogen storage disease, ALD, hemochromatosis
AIH, PSC, PBC
NASH
Yes GRAFT quality TEG Yes
TEG

R, K time ↓
MA / MCF ↑ Normothermia Hypothermia
„volume restriction”
fibrinogen, PCC,
Reperfusion platelets, FFP fibrinogen, PCC,
More AT III (±Na Heparin) than platelets, FFP
fibrinogen, PCC, platelets, FFP
TEG
„Good” quality graft „Poor” quality graft

Fibrinolysis Fibrinolysis
Heparin like effect Heparin like effect
15-30 min Diffuse bleeding
 Anticoagulation
”gylcocalyx the endothelial gatekeeper”

• Physiologic factors: protein C, protein S, AT III

– Level must be measured and corrected
– Graft glycocalyx is burned out after reperfusion
• AT III, Na Heparin, LMWH, platelet inhibitors /adv. vs disadv./
– According to vascular anastomosis
– According to surgical field (wet or dry) Patient tailored
– According to patient comorbidities coagulation profile
– According to coagulation parameters measured
– National and local protocols
• pediatric pts. more vulnerable

AT III