A talk by Birgitta Romlin at the 2017 meeting of the Scandinavian Society of Anaestesiology and Intensive Care Medicine. All available content from SSAI2017: https://scanfoam.org/ssai2017/ Delivered in collaboration between scanFOAM, SSAI & SFAI.

1. Birgitta Romlin MD,PhD
Anaesthesia and Intensive Care
Queen Silvia Children’s Hospital,
Gothenburg, Sweden
Bleeding and coagulation,
pediatric case reports
SSAI 2017

2. No disclosure

3. Case 1
Boy 12 years hit by a car, femur fracture and suspected
pelvis fracture.
Arrives at the emergency department after a long transport
time of 3 hours.
Haemoglobin in the ambulance 73 g/L.
The boy is awake but tired, systolic blood pressure 78
Saturation 92 with oxygen
Transported in vacuum mattress
3

4. Case 1
Who wants to start with 4:4:1?
Who wants to give O-neg blood?
Who wants to wait for blood samples?
What kind of blood samples/measurements do you want?
Is there anything else you want to do/give?
4

5. Case 1
The boy left for a trauma CT
What kind of monitoring
do you want during transport and CT?
5
Temperature:
Arterial line:(blood pressure, active bleeding)
Blood gas:
pH, Ca, Hb, BE, Lactate

6. Case 1
CT showed femur fracture with severe bleeding
Lung contusion on the right side
with pleura excudate
Stable pelvis fracture
Some bleeding around the liver
6
Treatment at arrival
0 neg blood 1 unit
Tranexamic acid
(Cyklokapron) 1 g
After TEM
Fibrinogen 2 g
Platelets 300 ml

7. Haemostasis – optimal conditions
Temperature
pH
Ca2+
Coagulation disturbances
(1/3) at arrival
Hb >90 g/l
TPK >100 * 109 /l
APTT Standard value
PK <1.5 INR
Fibrinogen >2 - 2.5 g/l

8. Early/directly use of blood products/procoagulation drugs
E-konc: plasma: Trbc: 4:4:1 (SWE) (1:1:1 US)
Tight collaboration with blood department
Massive Transfusion Protocol
Surgery (Damage control)
Hb, TPK, ROTEM/TEG, Fibrinogen, Blood gas (APTT, INR)
Fibrinogen
Cyklokapron
Temperature-Ca-pH
REEVALUATION
Bleeding treatment

9. The european guideline on management of
major bleeding and coagulopathy following
trauma. Crit Care (2016) 20:100
Monitoring of haemostasis
We recommend that the routine practice includes the early and
repeated monitoring of coagulation, using either a traditional
laboratory determination [prothrombine time (PT), activated partial
thromboplastin time (APTT), platelet counts and fibrinogen (Grade 1A)
and/or a viscoelastic method (Grade 1C).
Recommendations:
1 – Strong
2 - Minor
Evidence:
A – High quality
B – Intermediary
C – Low quality

10. Key points
Trauma care very similar to adult care,
need for calculation of fluid/transfusions and medication
Standard monitoring with thromboelastometry, blood samples
Don’t forget the basics (pH, Ca, Temp, Hb)

11. Case 2
16.20 in the afternoon
In theatre since 8 o´clock this morning
Transposition of the great arteries
Weight 3.1 kg

12. What makes children different
Coagulation factor VII, IX, X, XI, XII and prothrombin are 50% less than adult
levels
Factor VIII, XIII, V, fibrinogen and vWF are somewhat higher than adult levels.
Coagulation inhibitors: antithrombin, protein C and S are also 50% less than
adult levels.
Neonates have hyporeactive platelets (granula release, aggregation)
Under physiological conditions neonatal platelets are at least as efficient as
adult platelets in achieving primary haemostasis.

13. Impact of cardio pulmonary bypass
Hypothermia
Bleeding/
increased
blood loss
Loss/dilution of
clotting
factors
Inflammation
PMN activation
Interaction of blood
with artificial surfaces
(ECC system, oxygenator,
cardiotomy suction)
Intrinsic/Extrinsic
Coagulation
thrombin/TF
Heparin
Fibrinolysis
tPA, PAI-1
platelet
dysfunction

14. Why monitor coagulation?
Can we effect the outcome by
monitoring coagulation?

15. If we are able to
Reduce bleeding
Reduce transfusion rate
There is level I evidence that TEG monitoring reduces blood loss and
transfusion requirements after adult cardiac surgery (Level A Recommendation)
Avoid reoperation
We might influence morbidity and mortality after
paediatric cardiac surgery!

16. Case 2
FIBTEM HEPTEM
A 10 3 mm CT 402 s
MCF 3 mm CFT 406 s
A 10 22 mm
MCF 25 mm

17. Case 2
What are we monitoring with this method?
Do we need further monitoring, can we
assess the platelet function?
Should this patient be transfused?
Is this child bleeding?

18. Monitoring of haemostasis

19. Thromboelastometry (TEM)

20. Case 2
Is this child bleeding?
Should this patient be transfused?
What are we monitoring with this method?
Do we need further monitoring, can we assess platelet function?

21. TEM results
29 of 50 (58%) HEP-tem CT > 240 s
43 of 50 (86%) HEP-tem CFT > 110 s
37 of 50 (74%) HEP-tem MCF < 50 mm
45 of 50 (90%) FIB-tem MCF < 9 mm

22. Teamwork with surgeons
Clinical evaluation of bleeding,
presence of oozing without visible
clots.
Hemodynamic derangements
Hb and Hct
Fibrinogen
1g
Platelets
20 ml/kg

23. Bleeding and thrombosis
Amount of transfusions
Antithrombin
Increased aggregation of
platelets postoperatively
Use of PCC and Activated
FVIIa
Systemic to pulmonary
artery shunts
Modified BT shunt

24. Key points
Small children less than 1 year have a different
setup in the coagulation system
What is my method really measuring
Minimize the risk for postoperative thrombosis
You are able to influence the outcome

25. Case 3
Liver transplantation
Esophagus varicer
Portal hypertension
Platelets 30, INR 1.6, AT 0.65, ASAT 0.7, ALAT 0.8
Weight 48 kg
Fibrinogen?
26

26. Preoperativ TEM
27
Key point
Measure coagulation
capacity preoperatively
in selected cases

27. The effects on coagulation in liver diseases
The liver plays a central role in the haemostasis as it synthesizes
coagulation factors, coagulation inhibitors and fibrinolytic proteins.
In liver diseases the most common interference in coagulation are low
platelets and effected plasma coagulation.
Note that the goal is not to correct the lab values but to acheive
haemostasis.
Plasma mainly to correct INR prior to procedures or surgery.
Take caution with prothrombin-complex as there is a high risk of thrombotic
complications.
28

28. In summary
What kind of patient?
Which main bleeding/coagulation problems
may I expect?
Combine clinical evaluation, an algorithm
and monitoring
Make a decision regarding treatment
Reevaluate

29. Thank you!

33. Anemi
Trombocytfunktion
–Adhesion/aggregation
• Minskar
–”Marginalisering”
• Minskar
Valeri CR et al: Transfusion 2001:41:977-983

34. Marginalisering

35. Hypotermi
Fibrinbildning
–<35° C
• PT ökar
–<33° C
• APTT ökar
• Trombinbildning minskar
Trombocyter
• Antalet minskar
• TxA2 minskar
Wohlberg AS et al: J Trauma 2004:56:1221-1228

36. Hypotermi
The Effects of Temperature on Clot
Microstructure and Strength in Healthy
Volunteers.
Lawrence MJ1, Marsden N, Mothukuri R, Morris RH, Davies G, Hawkins K, Curtis DJ, Brown MR, Williams
PR, Evans PA
Anaest Analg 2016;122:21-6
Slower forming clots with less structural complexity as
temperature is decreased.
We also found that significant changes in clot
microstructure occurred when the temperature was
<32°C
37

37. Acidos
pH 7.4  7.0
– TF/FVIIa minskar 55 %
– FXa/FVa minskar 70 %
Meng ZH: J Trauma 2003:55:886-891

38. Hypotermi och acidos
Martini WZ etal.: J Traum: 2005:58:1002-10010

40. Tromboelastometri (TEM)

41. Measurements from packed red blood
cells
3d 3d 4d 5d 6d 9d
pH 6.8 6.9 6.9 6.9 6.9 6.7
BE -22 -24 -29 -28 -28 -32
Hb 188 184 225 193 192 182
Lac 6.2 4.9 7.7 8.2 9.1 12.0
Glu 27 27 25 27 26 24
Potassium 9.0 9.1 13.0 13.4 14.4 19.6

42. Transfusions, lifesaving but
also dangerous
Positive effects
Improve tissue oxygen delivery
Autoregulation of tissue blood flow
Increased number of platelets and coagulation factors
Negative effects
Substantial changes in the immune system, immunomodulation
Infections
Storage time (ATP down-RBC shape and rigidity)(2,3DPG down) 1 week
Morbidity, mortality
Guzzetta NA.. Paediatr Anaesth. 2011

43. Risk factors for bleeding
Weight/age are the strongest risk factors for bleeding.
CPB time, type of surgery, aorta clamp time
Reoperations, which have a high risk for fibrinolysis
pH, Ca
Protamin inhibitory effect on recept Gp I/IX/V and interaction with vWF.
High ACT could delay treatment of low platelet/fibrinogen
Most common changes after CPB
Low platelet count and platelet dysfunction
Low levels of fibrinogen
Miller BE Anesth Anal 1997;85:1196-1202
Williams GD Anesth Analg 1999;89:57-64
Lang T Anesth Analg 2009;108:751-8

44. Platelet dysfunction
(ADP-test <30 U)
0
10
20
30
40
50
60
70
Before
surgery
During CPB After CPB ICU Day 1
%

45. Interpretation
Insignificant bleeding Normal TEM
Insignificant bleeding Abnormal TEM
Significant bleeding Normal TEM
Significant bleeding Abnormal TEM
Bleeding is a prerequisite for transfusion

46. Cut off values
Proposal/discussion of cut off values for
transfusion in paediatric cardiac surgery
EXTEM MCF A10<30, FIBTEM<5 mm
Analysis of our ROTEM parameters revealed that clotting time
(CT) ≥ 111 s, MCF A10 ≤ 38 mm measured on the EXTEM and
A10 ≤ 3 mm obtained on the FIBTEM tests were the three relevant
parameters to guide haemostatic therapy.
MCF HEPTEM< 43 mm, CFT HEPTEM > 166 s, showed markedly
increased transfusion prevalence
Nakayama Br J Anaesth 2015
Faraoni Eur J Anaesth 2015
Romlin Submitted Br J Anaesth

47. Algorithm
Preop history
Sampling (HEPTEM, EXTEM,FIBTEM),Platelet test
TEM and clinical evaluation
Decision about transfusion
Reevaluate when still in theatre
Leave patient in ICU without ongoing significant
bleeding
Enriquez and Shore-Lesserson Br J Anaesth 2009

48. Could we interact with the coagulation
system in any other way?
Haemoglobin/Hematocrit during and after bypass
Modified ultrafiltration increases Hct, fibrinogen
and total plasma proteins, influence inflammatory
respons and complement activation
Cellsaver
Optimization of the dose of protamine sulphate

49. Hur kontrollerar vi
hemostasen?

50. Koagulation och ”yttre miljön”
BT: 60/40 mmHg
Puls: 158 min-1
Timdiures: 0 ml/tim
Echo: Tom vä-kammare
Kirurgen: ”Ge NovoSeven, den
stora dosen” för jag
ser inte var det
blöder
Blodcentralen ringer: ”Blodet är snart slut! Behöver vi
beställa mer?”
Narkossköterskan: Pat är sur
och Ca2+ är lågt
Assistenten: Ge Octostim

51. Monitorering av
hemostasen?

52. Monitorering av hemostasen
Laboratorievärden
– Trombocyter
– APTT
– PK(INR)
– Fibrinogen
– Blodgas
Patientnära analyser
– ROTEM
– TEG
– Sonoclot
– Multiplate
Vilken information får jag av mina mätmetoder och vilken
klinisk konsekvens får svaret

53. Hemostas

54. Koagulationssystemet

55. Sampling
At the end of CPB before weaning?
Thromboelastometry(HEPTEM, FIBTEM)
The result will be ready in time for
weaning
pH,temperatur and Ca level should be
normal

56. Vad krävs för bra
hemostas?

57. 2,0 2,5 3,0 3,5 4,0
Fibrinogen (g/L)
0
500
1000
1500
2000
2500
Postoperativebleeding(ml/18h)
Aljassim et al. Scand Cardiovasc J 2006; 40:43-48
r = - 0.76 , p<0.001
Preop fibrinogen och blödning
TF + VIIa Xa + Va Trombin Fibrin
XIa
Xa + Va
IXa+VIIIa

58. Fibrinogennivå vid kirurgi
Hiippala ST et al.: Anesth Analg 1995;81:360

59. Catastrophic hemorrhage
Airway maintenance with cervical spine protection
Breathing and ventilation
Circulation with hemorrhage control
Disability: Neurologic status
Exposure
Emerg Med J 2006 23: 745-746

60. Management of bleeding and coagulopathy following major
trauma: an updated European guideline
Användning av fibrinogen
“We recommend treatment with fibrinogen concentrate or cryoprecipitate if significant
bleeding is accompanied by thrombelastometric signs of a functional fibrinogen deficit
or a plasma fibrinogen level of less than 1.5 to 2.0 g/l (Grade 1C). We suggest an
initial fibrinogen concentrate dose of 3 to 4 g or 50 mg/kg of cryoprecipitate, which is
approximately equivalent to 15 to 20 units in a 70 kg adult. Repeat doses may be
guided by thrombelastometric monitoring and laboratory assessment of fibrinogen
levels (Grade 2C).”
Management of bleeding and coagulopathy following major trauma: an updated European guideline, Crit Care. 2013; 17(2): R76.

61. Management of bleeding and coagulopathy following major
trauma: an updated European guideline
Hämning av fibrinolys
We recommend that tranexamic acid be administered as early as possible to the trauma
patient who is bleeding or at risk of significant hemorrhage at a loading dose of 1 g
infused over 10 minutes, followed by an intravenous infusion of 1 g over 8 h. (Grade
1A)
We recommend that tranexamic acid be administered to the bleeding trauma patient
within 3 h after injury. (Grade 1B)
We suggest that protocols for the management of bleeding patients consider
administration of the first dose of tranexamic acid en route to the hospital.(Grade 2C)
” We suggest that antifibrinolytic agents be considered in the bleeding trauma patient (Grade 2C). We recommend
monitoring of fibrinolysis in all patients and administration of antifibrinolytic agents in patients with established
hyperfibrinolysis (Grade 1B). Suggested dosages are tranexamic acid 10 to 15 mg/kg followed by an infusion of 1 to
5 mg/kg per hour or ε-aminocaproic acid 100 to 150 mg/kg followed by 15 mg/kg/h. Antifibrinolytic therapy should
be guided by thrombelastometric monitoring if possible and stopped once bleeding has been adequately controlled
(Grade 2C).”
Management of bleeding and coagulopathy following major trauma:
an updated European guideline, Crit Care. 2013; 17(2): R76.

62. Tillbaka till vårat fall
Vad avgör vidare transfusioner
64

63. Vad avgör vidare transfusioner
Blödning eller ej
Vital parametrar
Provsvar/ROTEM
65

64. Övriga koagulations läkemedel
Octostim
NovoSeven
PCC

65. Management of bleeding and coagulopathy following major
trauma: an updated European guideline
Användning av Octostim®
We suggest that desmopressin (0.3
μg/kg) be administered in patients
treated with platelet-inhibiting drugs or
with von Willebrand disease.
(Grade 2C)
We do not suggest that desmopressin
be used routinely in the bleeding

66. Management of bleeding and coagulopathy following major
trauma: an updated European guideline
NovoSeven
We suggest that the use of recombinant activated coagulation factor VII (rFVIIa) be considered if major
bleeding and traumatic coagulopathy persist despite standard attempts to control bleeding and best-
practice use of conventional haemostatic measures. (Grade 2C)
We do not suggest the use of rFVIIa in patients with intracerebral hemorrhage caused by isolated head
trauma. (Grade 2C)
PCC
We suggest the measurement of
substrate-specific anti-factor Xa activity in patients
treated or suspected of being treated with oral antifactor
Xa agents such as rivaroxaban, apixaban or
endoxaban. (Grade 2C)
If bleeding is life-threatening, we suggest reversal
of rivaroxaban, apixaban and endoxaban with highdose
(25 to 50 U/kg) PCC. (Grade 2C)
We do not suggest the administration of PCC in
patients treated or suspected of being treated with
oral direct thrombin inhibitors, such as dabigatran.

67. Blödning vid
leversjukdom/kirurgi

68. Koagulationsprofil
APTT 63 s
PK 3.3 INR
Fibrinogen 1.6 g/l
AT ~ 0.1 kIE/l
Trombocyter 143*109 /l
NATEM Värde Range
CT (s) 980 300-1000
CFT (s) 441 150-700
α (°) 32 30-70
A20 (mm) 34 35-60
MCF (mm) 36 40-65
Klassisk bild vid leversvikt

69. Tillbaka till fallet
Kraftigt sivande blödning från början då man
dissekerar ut levern, kontinuerliga transfusioner
av blod, plasma och trombocyter
Inotropt stöd för att upprätthålla blodtryck
Buffer och kalk upprepas
Följs med ROTEM och Multiplate
Operationen får avbrytas för att stabilisera vitala
parametrar71

70. TEM : 01.30
72

71. TEM : 04.30
73
pH 7.30
BE -6.9
Sat 98
Hb 111
EVF 34
Na 130
K 6.4
Ca 1.15
Glu 8.0
Lakt 3.0

72. Sammanfattning
Struktur-Organisation-Eftertanke
Vad är mitt huvudproblem ur blödningssynpunkt
Basala kunskaper om koagulation
Läkemedel och doseringar74

73. Kostnad och dosering
Ocplex,=protrombinkomplex, F II, VII, IX, X, prot C, prot S
OBS Tänk på att detta läkemedel kan doseras I både Enheter och ml, kontrollera noga.
500E späds i 20 ml = 25 E/ml
Engångsdosen får ej överstiga 3000 E=120 ml för vuxna.
INR 2-2.5 ge 0.9-1.3 ml ocplex/kg kroppsvikt,
INR 2.5-3.0 ge 1.3-1.6 ml ocplex/kg kroppsvikt,
INR 3.0-3.5 ge 1.6-1.9 ml ocplex/kg kroppsvikt,
INR>3.5 ge >1.9 ml ocplex/kg kroppsvikt.
Dosering till barn
INR över 3.0 ge 25E/kg
INR 2.0-3.0 ge 15E/kg
INR 1.5-1.9 ge 10E/kg
500E kostar 3500 kr
Hemate= F VIII, vWF, vid allvarli/livshotande blödning 0.6-1 E/kg, profylax eller liten blödning 0.3-0.6 E/kg
1000E kostar 6937 kr
Novo Seven= aktiverat FVIIa, doseras 90-100 ug/kg (1mg=1000 ug)
1 mg kostar 6200 kr, en vuxen behandling på 70 kg patient blir 43 400 kr
Fibrinogen 1g kostar 4100 kr
Mer info på www.SBU.se

74. Impedansaggregometri
Impedansaggregometri
Reaktionskurva & parametrar

75. :
TRAP
ADP
Arachidonic
Acid
Collagen
ArA1
COX
TXA2
TXA2
COLtest
ASPItest
TRAPtest
ADPtest
PGE1 ADPtest HS
(ADP + PGE1)
aktivering
Hämning
GpIIb/IIIa hämmare:
Reopro ® (Abciximab)
Aggrastat ® (Tirofiban)
Integrillin ® (Eptifibatid)
Aspirin ®
Clopidogrel
Prasugrel
Ticagrelor
1 Frisläppande av
arachidonsyra
ASPItest (Arachidonsyra): Aspirin® & övriga
cyklooxygenas blockerare
(79-141U)
ADPtest (ADP)(P2Y12) Plavix ®, & övriga ADP receptor
blockerare
(55-117U)
TRAPtest (trombin receptor aktiverat protein), bl.a. kontroll
av GP IIb/IIIa-blockerare
(87-147U)

76. Paediatric cardiac surgery
Lake Carol L, Booker Peter D. Pediatric cardiac anesthesia. 2005
1% of all children are born with a congenital heart
disease
Annually, 600 children are operated in Sweden
There are about 35 different diagnoses
200 different operation methods
Cardio-pulmonary bypass is necessary in most
cases

77. Case 1
FIBTEM EXTEM
A 10 3 mm CT 57 s
MCF 3 mm CFT 444 s
A 10 23 mm
MCF 35 mm
Just before leaving you got this answer from the TEM (thromboelastogram)