How to approach a patient with bleeding? - cdn.ymaws.com · Hemophilia vWD hyper-fibrinolysis...
Transcript of How to approach a patient with bleeding? - cdn.ymaws.com · Hemophilia vWD hyper-fibrinolysis...
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How to approach
a patient with bleeding?
ISTH Advanced training course, Portugal March 2014
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Differential diagnosis
Platelet disorders
Hemophilia
vWD
hyper-fibrinolysis
factor deficiencies
bleeding
liver failure TIC
anticoagulanttreatment
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suspected bleedingdisorder
w/o acutebleeding
acute bleeding
Clinical situations
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suspected bleedingdisorder
w/o acutebleeding
acute bleeding
Clinical situations
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Initial question
Suspectedbleeding disorder
bleeding disorderlikely or unlikely?
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Initial work-up (I)Suspected bleeding
disorder
bleeding history
bleeding disorderlikely or unlikely?
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Bleeding history
- type and frequency of bleeding
- provoked or unprovoked
- type of treatment
- family history (family tree)
- drug history
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Bleeding history
- usually clear in patients with severe bleeding disorders
- in patients with mild/moderate bleeding symptoms a standardized questionnaire is helpful
- standardized scores to quantitate bleeding symptoms
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Bleeding history: scoring keySymptom 0 1 2 3
Epistaxis no/trivial < 5/y
> 5/y > 10 min
Packing/cauterization
transfusion, replacement, DDAVP
Cutaneous no/trivial < 1 cm
> 1 cm w/h trauma
- -
Minor wounds
no/trivial < 5/y
> 5/y or > 5 min
Surgicalhemostasis
Hemostatic treatment
Oral cavity no Reported at least 1
Surgical hemostasis
Hemostatic treatment
Gastro-intestinal
tract
no Identified cause
Surgical hemostasis
Hemostatictreatment
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Bleeding history: scoring keySymptom -1 0 1 2 3
Tooth extraction
No bleeding in 2
None done or no bleeding in 1
reported Resuturing, repacking or antifibrinolytics
Transfusion, replacement, DDAVP
Surgery No bleeding in 2
None done or no bleeding in 1
reported Surgical hemostasis or antifibrinolytics
Transfusion, replacement, DDAVP
Muscle hematoma
- never Post-trauma, no therapy
Spontaneous, no therapy
Spontaneousrequiring treatment
Hemarthrosis - never Post-trauma, no therapy
Spontaneous
CNS - never - - Subdural, intracerebral
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Validated questionnaire1,2
- includes 13 bleeding symptoms
- provides a summative score
- mean bleeding scores:in healthy individuals: 0.5abnormal: 2
1Biss TT, et al. J Thromb Haemost 2010; 8: 9502Biss TT, et al. J Thromb Haemost 2010; 8: 1416
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Initial work up (II)
Suspectedbleeding disorder
bleedinghistory
physical examination
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Physical examination
- inspection for any bleeding signs
- joint abnormalities
- lymphadenopathy
- organomegalies
- in children: signs of nonaccidental trauma!
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Initial work up (III)
Suspectedbleeding disorder
bleedinghistory
physicalexamination
laboratoryscreening
?
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Decision pathway (I)Suspected bleeding
disorder
bleeding history: normal
physical examination:no signs of bleeding
laboratory screeningnot recommended
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Take home message (I)
- Thorough personal and family histories are the best screening tests for identifying potential hemostatic problems.
- Properly obtained histories eliminate the need for laboratory screening procedures.
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Decision pathway (II)Suspected
bleeding disorder
bleeding history:abnormal
physical examination:signs of bleeding
bleeding disorderpossible/likely
laboratory screeningrecommended
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Screening parameters
bleeding disorderpossible/likely
CBC/PBF/PFAPT/APTT
FVIII (males)FXIII
CBC, complete blood count; PBF, peripheral blood film; PFA, platelet functionanalyser; PT, prothrombin time; APTT, activated partial thromboplastin time
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Screening parameters
bleeding disorderpossible/likely
CBC/PBF/PFAPT/APTT
FVIII (male patient)FXIII
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CBC/PBF/PFACBC/PBF:- platelet count, size and morphology
- leukocyte morphology
- other cytopenias
PFA:- axis subendothelium-vWF-platelet
- platelet-platelet interaction
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Platelet function analyser (PFA)
collagencoatedmembrane
flow
capillary
closure time
red cellsplatelets
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CBC/PBF/PFA: pitfalls
CBC:- pseudothrombocytopenia
PFA:- hematocrit < 35
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Pseudothrombocytopenia
- EDTA-inducedagglutinationof platelets
- w/o clinical relevance
- confirmed by platelet counting using citrate anticoagulated blood
ASH et al. Blood 2011;117:4168-4168
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Decision finding (III)
platelet count> 150.000/µl
blood smear: normal
platelet disorder/vWD unlikely
PFA normal
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Decision finding (IV)
abnormalplatelet morphology
platelet disorderlikely
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DD: Platelet disorder
mean platelet volume
micro platelets
Wiskott-Aldrich-syndrome/XLT
giant platelets
< 6 fl > 15 fl
DD: BSS/MYH9-related disorders
DD: granule disorders/
GT
7 - 11 fl
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Confirmatory procedures
abnormalplatelet morphology
platelet disorderlikely
genetictesting
flow cytometry
aggregation/secretion
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Decision finding (V)
platelet count:< 100.000/µl
blood smear/mean platelet volume:
normal
quantitative platelet disorder likely
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synthesis
low platelet count
consumption degradation
Isolated thrombocytopenia
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synthesis
low platelet count
consumption degradation
Isolated thrombocytopenia
BM-failure infection/DIC splenomegalie/immune response
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Additional information
- isolated versus combined
- new onset or chronic
- signs of organomegalie
- drug history
- previous infections
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Additional information- isolated versus combined
- new onset or chronic
- no signs of organomegalie
- no drug intake
- previous infections
immune thrombocytopenia suspected
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Decision finding (VI)
platelet count> 150.000/µl
blood smear: normal
vWD suspected
PFA abnormal
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Confirmatory procedures
vWD suspected
AB0 blood groupvWF antigen
Ristocetin Cofactorcollagen binding assay
FVIII testing
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Confirmatory procedures
vWD suspected
AB0 blood groupvWF antigen
Ristocetin Cofactorcollagen binding assay
FVIII testing
genetic testingvWF-multimeric analysis
propeptide analysis
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Screening parameters
bleeding disorder possible/likely
CBC/PBF/PFAPT/APTT
FVIII (male patient)FXIII
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PT versus APTT
FXa/FVa
FIIa
fibrin
contact factors
FXIa
FIXa/FVIIIaFVIIa/TF
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DD: single factor deficiencies
FVII FX/FV/FIIfibrinogen
APTT APTT
prolonged normal
HK/PK/FXIIFXIFIXFVIII
prolonged
factor deficiency
unlikelyexcept FXIII
normal prolonged normal
PT
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Screening parameters
bleeding disorder possible/likely
CBC/PBF/PFAPT/APTT
FVIII (male patient)FXIII
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Hemophilia A pattern
FVII FX/FV/FIIfibrinogen
APTT APTT: 80s (25-35s)
prolonged normal
HMWKPKKFXIIFXI/FIXFVIII: 3%
prolonged
factor deficiency
unlikelyexcept FXIII
normal prolonged normal
PT: 12 s (10.7-12.9s)
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20
25
30
35
40
45
50
55
60
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140
aPTT
(s)
FVIII activity (%)
healthy volunteers
hemophiliac patients
25,5 - 34,3 s
48 - 124 %
APTT versus FVIII (one stage)
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Screening parameters
bleeding disorder possible/likely
CBC/PBF/PFAPT/APTT
FVIII (male patient)FXIII
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Confirmatory procedures
hemophilia A suspected
amidolytic FVIIItwo-stage FVIII
TGAvWD type N
genetic testing
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DD: single factor deficiencies
APTT: prolonged
FXI/FIX/FVIII: normal
PT: normal
contact factor deficiency suspected
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Confirmatory procedurescontact factor deficiency
suspected
single factor analysis:HK/PK/FXII
contact factor deficiency:clinically not relevant
except ACT-/APTT-monitoring
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Patients : initial screens
Patient Platelet count (/µl)
PT (s) APTT (s) FXIII (%)
#1 234,000 61 > 150 89
#2 172,000 11 > 150 91
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DD: single factor deficiencies
FVII FX/FV/FIIfibrinogen
APTT APTT
prolonged normal
HMWKPKK
FXIIFXI/FIX/FVIII
prolonged
factor deficiency
unlikelyexcept FXIII
normal prolonged normal
PT
patient #1 patient #2
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Patients: single factor analysis
Patient FII (%)
FX (%)
FV (%)
FIX (%)
FVIII (%)
FXI (%)
#1 87 2 89 - - -
#2 - - - 83 < 1 91
Suspected diagnosis:Patient #1: FX deficiencyPatient #2: FVIII deficiency (severe hemophilia)
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Patient #1: 68-y old male
- severe hematoma after minimal trauma
- he reported no personal or familial history of bleeding
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Patient #2: 56-y old male- severe postoperative bleeding
after hernia operation
- haematothorax after centralvenous support
- massive transfusion24 RBC, 32 FFP4 platelet conc.
- referred to Bonn via helicopter
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- large hematomas
- extensive ecchymoses
- severe mucosal bleeding
- gastrointestinal bleeding
- gross hematuria
- w/o a bleeding history
Acquired hemophilia
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Laboratory approach
inhibitor suspected
inhibitor screen(mixing test)
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- patient plasma is mixed with increasingconcentrations of normal human plasma
- clotting factor activity measured afterincubation for 1 and 2 hours at 37°C
Inhibitor screen
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0
20
40
60
80
100
0 25 50 75 100
Normal human plasma (%)
FVIII
-act
ivity
(%)
Inhibitor screen: negative
1 hour
2 hours
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0
20
40
60
80
100
0 25 50 75 100 125
normal human plasma (%)
FVIII
-act
ivity
(%)
Inhibitor screen: positive
2 hours
1 hour
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Patients: inhibitor screen
Patient FX (%)
FV (%)
FVIII (%)
Mixing test
#1 2 89 - neg
#2 - - < 1 pos
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Laboratory approach
inhibitor screen(mixing test)
positive
inhibitor quantification
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- serial dilutions of patient plasma are incubated for two hours at 37°C with normalhuman plasma
- factor activity is then measured using aclotting assay
- 1 Bethesda unit (BU) is defined to reducethe activity of a clotting factor in normalhuman plasma to 50%
Bethesda assay
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Bethesda units (BU)
0
25
50
75
100
0 25 50 75 100 125 150
FVIII
-act
ivity
(%)
Dilution factor 1/n
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Patients: Bethesda units (BU)
Patient FX (%)
FV (%)
FVIII (%)
Mixing test
BU
#1 2 89 - neg -
#2 - - < 1 pos 37
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Patient #2: 56-y old male- severe postoperative bleeding
after hernia operation
- haematothorax after centralvenous support
acquired hemophilia A caused byhigh titer FVIII-autoantibodies
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Acquired inhibitors: frequencies
Molecular target Estimated frequency
Factor VIII 1 – 1.5 x 106 in non-hemophiliacs
Factor II few case reports only
Factor V 105 cases described
Factors VII, IX, X, XI few case reports only
Factor XIII 20 cases described
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Patients: inhibitor screen
Patient FX (%)
FV (%)
FVIII (%)
Mixing test
#1 2 89 - neg
#2 - - < 1 pos
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Acquired inhibitors
- The majority of acquired inhibitors are
antibodies that either inhibit the activity or
increase the clearance of a clotting factor.
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Laboratory approach
inhibitor suspected
screen forprecipitating antibodies
inhibitor screennegative
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Acquired inhibitor: ELISA
purified clottingfactor
microtiter plate
*-IgG/M
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Patients: laboratory data
Patient FX (%)
FV (%)
Mixing test
BU APA ELISA
#1 2 89 neg - neg neg
#2 - - pos 37 neg -
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Patient #1: 68-y old male
- severe hematoma after minimal trauma
- skin biopsy reveals amyloidosis
amyloid-associated FX-deficiency
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Screening parameters
bleeding disorder possible/likely
CBC/PBF/PFAPT/APTT
FVIII (male patient)FXIII
normal?
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Extended screeningbleeding disorder possible/likely
initial screen:normal
α2-antiplasminplatelet function testing/vWF-testing
vascular bleeding disorderrepeat testing during active bleeding
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Clinical decision finding
bleeding disorder possible/likely
extended screeningw/o abnormal results
suspected diagnosis:bleeding disorder of unknown reason
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Take home message (II)
- If relatively simple screening procedures are used, the vast majority of hemorrhagic problems can be identified.
- Confirmatory tests are subsequently usedto establish an appropriate differential dia-gnosis.
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suspected bleedingdisorder
w/o acutebleeding
acute bleeding
Clinical situations
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Acute Bleeding: Grading
- Life-threatening (WHO grade 4)Trauma or critical organ bleeding
- Severe (WHO grade 3)gross blood loss, requires transfusion
- Mild blood loss but clinically significant (WHO grade 2)
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severe trauma
massive blood loss
loss of clottingfactors/platelets
coagulopathy
TIC-cascade (I)
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severe trauma
consumption ofclotting factors/platelets
massive blood loss
activation of thecoagulation system
loss of clottingfactors/platelets
coagulopathy
TIC-cascade (II)
thrombin burst
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severe trauma
generation of APC
consumption ofclotting factors/platelets
massive blood loss
activation of thecoagulation system
loss of clottingfactors/platelets
systemic anticoagulation
coagulopathy
TIC-cascade (III)
thrombin burst
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TIC: APC-formation
Chesebro BB, et al. Shock 2009; 32: 659-665
C = control, T = trauma, H = hemorrhage, TH = trauma + hemorrhage
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severe trauma
hypoperfusion/anoxia
generation of APC
consumption ofclotting factors/platelets
massive blood loss
activation of thecoagulation system
loss of clottingfactors/platelets
systemic anticoagulation
coagulopathy
TIC-cascade (IV)
thrombin burst
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Ca2+ cAMP
PAR? V2-R ?
epinephrinprostacyclinevasopressin
thrombinacidosis
t-PA-secretion
t-PA: tissue-type plasminogen activator
t-PA/PAI
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severe trauma
hypoperfusion/anoxia
generation of APC
consumption ofclotting factors/platelets
massive blood loss
activation of thecoagulation system
loss of clottingfactors/platelets
PA-release from ECs
hyperfibrinolysis systemic anticoagulation
coagulopathy
TIC-cascade (V)
thrombin burst
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severe trauma
hypoperfusion/anoxia
generation of APC
consumption ofclotting factors/platelets
massive blood loss
activation of thecoagulation system
loss of clottingfactors/platelets
PA-release from ECs
hyperfibrinolysis systemic anticoagulation
coagulopathy
TIC: treatment options
thrombin burst
surgery
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severe trauma
hypoperfusion/anoxia
generation of APC
consumption ofclotting factors/platelets
massive blood loss
activation of thecoagulation system
loss of clottingfactors/platelets
PA-release from ECs
hyperfibrinolysis systemic anticoagulation
coagulopathy
TIC: treatment options
thrombin burst
surgery
transfusion transfusionTXA FFP?
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Tranexamic acid (TXA)
plasminogen plasmin
t-PA
fibrin
TXA
fibrin
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CRASH-2 trial
Study population: 20,211 trauma patients
Treatment group: 1 g TXA bolus/1 g over 8 h
Control group: Placebo
All-cause mortality: 14.5% vs. 16% (p = 0.0035)
Bleeding relatedmortality: 4.9% vs. 5.7%
1CRASH-2 trial. Lancet 2010; 376: 23-32, TXA: tranexamic acid
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TIC: treatment triggers
1. Clinical probability of TIC
1. Laboratory values
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High TIC risk: indicators*- hemorrhagic shock on admission
- pelvic fracture/multiple bone fractures
- rupture of liver/spleen/positive FAST
- brain damage
- BE < -6
- use of antithrombotic drugs
* TASH-Score, German Society of Trauma Surgeons
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TIC: hemostatic support (I)
severetrauma
hemostasis screen:CBC/PT/APTT/
fibrinogen
TXA 1g Bolusfollowed by
1g/h1
TIC-risk: high
1CRASH-2 trial. Lancet 2010; 376: 23-32, TXA: tranexamic acid
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TIC: hemostatic support (II)
3g fibrinogenFFP/PRC 1:1
parameter-adjustedtreatment
High TIC risk?
yes no
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Parameter-adjusted treatment
Fibrinogen:- < 1.5 g/dl with ongoing blood loss/ICB- < 0.5 g/dl→ 3 g fibrinogen concentrate
Prothrombin time:- > 25s with ongoing blood loss/ICB- < 50s→ 50 IE/kg b.w. PCC
ICB, intracranial bleeding;
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Parameter-adjusted treatment
→ platelet transfusion, if platelet count:
- < 100.000/µl with ongoing bleeding/ICB- < 50.000/µl with coagulopathy- < 30.000/µl
ICB, intracranial bleeding
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Parameter-adjusted treatment
Signs of hyperfibrinolysis
→ bolus injection of 1 g TXA followed by 20 mg/kg b.w./h
→ 3 g fibrinogen concentrate
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time axis
max. amplitude
r-time k-time
TEG: fibrinolysis
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Take home message (III)
- TIC is frequent in severe trauma patients.
- TIC is caused by consumption and loss ofcoagulation factors and platelets and bysecondary hyperfibrinolysis and APC for-mation.
- TIC can be successfully treated by TXA treat-ment and transfusion of blood products including fibrinogen, fresh frozen plasmaand platelets.
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Acute Bleeding: Grading
- Life-threatening (WHO grade 4)Trauma or critical organ bleeding
- Severe (WHO grade 3)gross blood loss, requires transfusion
- Mild blood loss but clinically significant (WHO grade 2)
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Critical organ bleeding
Suspected anticoagulant treatment
antithrombotic screen:APTT/INR/TT/BT/aFXa/TTI
APTT, activated partial thromboplastin time;INR, international normalized ratio; TT, thrombin time;BT, batroxabin time; aFXa, anti-FXa-activity; TTI, thrombininhibition time
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Anticoagulant screen
Parameter Result indicating a clinically relevant anticoagulant activity
Reference range
LMWH/Fonda-parinux
ArgatrobanBivalirudinDabigatran
VKA RivaroxabanApixaban
APTT normal prolonged prolonged prolonged < 35sINR normal increased increased increased < 1,2TT normal prolonged normal normal < 21 sBT normal normal normal normal < 21 s
aFXa detectablenot
detectablenot
detectable detectable < 0,1
TTIno
inhibition inhibitionno
inhibitionno
inhibition
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Anticoagulant screen
Parameter Result indicating a clinically relevant anticoagulant activity
Reference range
LMWH/Fonda-parinux
ArgatrobanBivalirudinDabigatran
VKA RivaroxabanApixaban
APTT normal prolonged prolonged prolonged < 35sINR normal increased increased increased < 1,2TT normal prolonged normal normal < 21 sBT normal normal normal normal < 21 s
aFXa detectablenot
detectablenot
detectable detectable < 0,1
TTIno
inhibition inhibitionno
inhibitionno
inhibition
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Anticoagulant screen
Parameter Result indicating a clinically relevant anticoagulant activity
Reference range
LMWH/Fonda-parinux
ArgatrobanBivalirudinDabigatran
VKA RivaroxabanApixaban
APTT normal prolonged prolonged prolonged < 35sINR normal increased increased increased < 1,2TT normal prolonged normal normal < 21 sBT normal normal normal normal < 21 s
aFXa detectablenot
detectablenot
detectable detectable < 0,1
TTIno
inhibition inhibitionno
inhibitionno
inhibition
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Take home message (IV)
- If six relatively simple screening procedures are used, patients showing clinically relevant plasma levels of anticoagulants can be identified.