a systematic approach to a low platelet count in icu patients · 2016. 4. 1. · thrombotic...
TRANSCRIPT
S. Felix
1456 1856
Medizinische Klinik der königlichen Universität Greifswald
Andreas Greinacher
Institut für Immunologie und Transfusionsmedizin Universitätsmedizin Greifswald
Numbers, Patterns, and Timing a systematic approach to a low platelet
count in ICU patients
Disclosures for Andreas Greinacher
Research Support/P.I. Boehringer-Ingelheim; Bayer Healthcare
Employee No relevant conflicts of interest to declare
Consultant Schering-Plough; Mitsubishi Pharma; Instrumentation Laboratories
Major Stockholder No relevant conflicts of interest to declare
Speakers Bureau No relevant conflicts of interest to declare
Honoraria Merck, Schering-Plough, Mitsubishi Pharma, GSK, Bayer
Scientific Advisory Board
0
10
20
30
40
50
60
70
<150,000/µL <50,000/µL <150 ,000/µL
Incidence of TP in ICU patients
during ICU stay during ICU stay at admission
12 studies 3162 patients
5 studies 3104 patients
8 studies 2188 patients
medical and surgical ICU patients combined
% o
f p
atie
nts
Patient 1
• 67 year old man
• 110 kg, diabetes
• acute coronary syndrome, admission at 10.00 am
• Hb 9.5 g/dL; WBC 7,500/µL; platelet count 270,000/µL
• PCI several stents including main stem artery with heparin,
clopidogrel, aspirin, and eptifibatide (all standard dose)
Patient 1
• 4.00 pm = 6 hours after intervention transfer to
ICU because of a platelet count of 8,000/µL
• No bleeding
• Eptifibatide perfusor still running
Patient 1: What are the appropriate measures?
a. Stop all antiplatelet drugs, especially the integrilin
perfusor.
b. Stop the next LMWH injection scheduled for 6.00 pm.
c. Transfuse platelets until a platelet count >15-20,000/µL
is reached;
d. Give tranexamic acid to prevent bleeding.
e. Control the platelet count in citrated blood.
Patient 1: The platelet count in citrated blood is 6,000/µL. What is the
appropriate management?
a. Stop all antiplatelet drugs, especially the integrilin
perfusor.
b. Stop the next LMWH injection scheduled for 6.00 pm.
c. Transfuse platelets until a platelet count >10-15,000/µL
is reached;
d. Give tranexamic acid to prevent bleeding.
e. Control for aggregates in the blood smear.
Pseudothrombocytopenia
Frequent in patients receiving GP IIbIIIa inhibitors! GP IIbIIIa inhibitor induced pseudo-TP also occurs in citrated blood.
Review the blood smear!
Treatment: educate the team
CLASSIFICATION • Pseudothrombocytopenia • Hemodilu5on • Consump5on • Destruc5on • Sequestra5on • Decreased Produc5on
• Impaired platelet func5on
trauma, severe bleeding
Thrombocytopenia in the bleeding patient
massive and severe hemorrhage <100,000/μl 2 C
transfusion dependent bleeding <100,000/μl
2 C
German Guidelines 2008 http://www.bundesaerztekammer.de/downloads/LeitCrossBloodComponents4ed.pdf
We suggest maintenance of platelet count above 100,000/µL in patients with multiple trauma who are severely bleeding or have traumatic brain injury.
Grade 2 C Management of bleeding following major trauma, Crit Care 2007
Platelet transfusion trigger in acute bleeding
Treatment: platelet transfusion
Do not forget the hematocrit shear stress
shear stress
platelet red blood cell leukocyte
Hct -15%, bleeding time prolongation by 60% Valeri et al. Transfusion 2001;41:977-83
In acute bleeding aim for Hct >30%
Cines DB et al. Blood 2014; 123:1596-1603
Admission due to symptomatic TP
Blood smear + differential blood count
Yes No
Thrombotic thrombocytopenic
purpura (TTP)
Immune mediated ITP, drug dependent TP,
OR Non-immune causes
bone marrow failure sepsis
Plasmatransfusion Plasmapheresis
“diagnostic“ platelet transfusion
?
Leukemia
Emergency: isolated symptomatic TP
Transfusion of 2 platelet concentrates
Platelet count increase 0.5 - 1h after transfusion
Increased platelet turnover
Platelet production defect, continue
transfusion
yes no
Patient 2 • 46 year old man.
• 10 year history of ITP: platelet count 20-40,000/µL; no major bleeding.
• wait and watch strategy, short courses of prednisone in case of increased bleeding symptoms. Good response documented.
• Admitted to ICU after bicycle accident with intracranial hemorrhage. Platelet count 11,000/µL.
Male 46 ys
Chronic ITP ~20-40,000/µL, bicycle accident
Patient 2: What is the appropriate initial management
Platelet count 11.000/µL
a. Platelet transfusions until bleeding stops?
b. i.v. IgG 1g/kg bw
c. Prednisone i.v.
d. No drugs which inhibit platelet funtion
e. No heparin
All answers are correct
48h after admission: platelet count 40,000 µL. CT scan no increase in bleeding. Which is the appropriate management?
a. Platelet transfusions until platelet counts are >50,000/µL?
b. Third course of i.v. IgG 1g/kg bw c. Prednisone i.v. d. No drugs which inhibit platelet function e. No heparin
What did we do? • Day 1 five platelet concentrates transfused until
plt count increased to 35,000/µL
• i.v. IgG 1g/kg bw, day 1 and 2
• Prednisone 100 mg/day
• No heparin
• Antiepileptic drug to prevent seizures: levetiracetam (Keppra)
• Day 5: pulmonary embolism
Patients with thrombocytopenia require thrombosis prophylaxis in risk
situations for DVT
Prevent thrombosis – PE!
CLASSIFICATION
• Pseudothrombocytopenia • Hemodilu5on • Consump5on • Destruc5on • Sequestra5on • Decreased Produc5on
postopera5ve thrombocytopenia
0
100
200
300
400
500
0 1 2 3 4 5 6 7 8 9 10
Postoperative day (day 0 = day of surgery)
Pla
tele
t co
un
t (x
10
9/L
)
Greinacher A & Selleng K; Hematology 2010
Early platelet count nadir:
information about magnitude of platelet consumption/severity
of trauma
Recovery of plt. count:
information about intact physiologic
response
0
100
200
300
400
500
0 1 2 3 4 5 6 7 8 9 10
Postoperative day (day 0 = day of surgery)
Pla
tele
t co
un
t (x
10
9/L
)
rebound of the platelet count after day 4
cardiac surgery
orthopedic surgery
platelet count nadir
Greinacher A & Selleng K; Hematology 2010
0
100
200
300
400
500
0 1 2 3 4 5 6 7 8 9 10
Postoperative day (day 0 = day of surgery)
Pla
tele
t co
un
t (x
10
9/L
)
rebound of the platelet count after day 4
trauma
cardiac surgery
vascular surgery
abdominal surgery
orthopedic surgery
platelet count nadir
Greinacher A & Selleng K; Hematology 2010
Nijsten et al. Crit Care Med. 2000;28:3843-3846 Akca et al. Crit Care Med. 2002;30:753-756
Constant production of thrombopoietin in the liver
Bone marrow megakaryocytopoiesis
(free thrombopoietin) free thrombopoietin
Wang B, et al. Clin Pharmacol Ther. 2004;76:628-38
romiplostim
An early fall in platelet counts to
60,000 – 100,000/µL
until day 4 after major surgery
is normal
CLASSIFICATION
• Pseudothrombocytopenia • Hemodilu5on • Consump5on • Destruc5on • Sequestra5on • Decreased Produc5on
immune disorders ITP, HIT, TTP extracorporeal circuits
Pre-Op
CPB
Day 3 Day 4 Day 5-6 Day 7-8 Day 9-11
0
100
200
300
400
Pla
tele
ts (
x 1
09/L
) Platelet fall in first 4 days is
USUALLY NOT HIT
Pouplard C et al. Br J Haematol. 2005;128:837-41
Pre-Op CPB Day 3 Day 4 Day 5-6 Day 7-8 Day 9-11
0
100
200
300
400
Pla
tele
ts (
x 1
09/L
) Platelet fall on day 5-10 = HIT
unless proven otherwise
CPB
Pouplard C et al. Br J Haematol. 2005;128:837-41
Platelet Count Monitoring
P. Hinz et al. Unfallchirurg 2009
50% 30%
platelet count monitoring
monitoring unnecessary
DVT Pla
tele
t co
un
t
Days
Incidence of HIT in ICU
26732 1
26133 0
3559
143 170
500
1000
1500
2000
2500
3000
3500
4000
Verma et al. (1) Cook et al. (2) University ofGreifswald (3)
patients
clinically suspectedHITserologicallyconfirmed HIT
(1) Verma AK, Levine M et al.: Pharmacotherapy 2003;23:745-753. (2) Cook DJ, Crowther MA et al.: Crit Care 2003; 7(suppl. 2):S54.[abstract] (3) Selleng et al. Crit Care Med, 2007;35:1165-76
0.39%(1) (95%CI, 0.01-2.1%)
0.48%(3)
(95%CI, 0.25-0.7%).
HIT in the ICU
• Of 200 ICU patients
– 100 will be thrombocytopenic
– In 1 HIT will be the underlying cause
HIT very likely (score > 6) or confirmed?
Danaparoid 750 U t.i.d. s.c.
No
Yes
Therapeutic dose anticoaguation
Therapeutic dose anticoagulation necessary due to underlying disease?
No
Selleng K. et al. Crit Care Med 2007; 35:1165-76
Suspected HIT
Fondaparinux?
0
100
200
300
400
500
600
700
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46
days
plat
elet
s (x
10
9 /l)
LMWH dalteparin
Danaparoid
Piperacillin/tazobactam Piperacillin
Hip surgery
Pla
tele
ts x
10
9/L
Pneumonia HIT antigen test positive
Lubenow N, Hron G, Greinacher A, unpublished
0
0,5
1
1,5
2
2,5
extinction
donor platelets 1-4 without piperacillin
0
0,5
1
1,5
2
2,5
extinction
normal serum
patient serum
donor platelets 1-4 without piperacillin
donor platelets 1-4 with piperacillin
donor platelets 1-4 with piperacillin
Richard H. Aster and Daniel W. Bougie N Engl J Med 2007; 357:580-587
Drug dependent TP: clinical management `The Friday evening Consultant Call´
• female 67 years old, diabetic coma, renal failure, rhabdomyolysis, platelet count < 5000/µl
• Multiple blood transfusions during the last 2 weeks, 2 pregnancies
• DD: HIT? drug-dependent TP? post transfusion purpura? • Intrafusin, structolipid, glucose, voluven, paspertin,
sufenta, actrapid, liquemin, lasix, tracutil, cernevit, antra, acetylcystein, konakion, ebrantil, nitro, ciprobay, vancomycin, aterenol, vicogant, glucerna, decortin
• Stop all drugs but electrolytes, vitamins, hormons • Start alternative antibiotics • Start i.v. IgG and exclude PTP as soon as possible • Reintroduce drugs sequentially after platelet counts
raised
Immune Thrombocytopenias
ITP PTP Drug dependent TP
GP IIb/IIIa inhibitor
TP
HIT TTP
Platelet count
variable <20.000
<10.000 <10.000 <10.000 40-80.000
10-30.000
Bleeding symptoms
(+) - +++ ++++
++++ (+) - - - --
Onset chronic day 7-14 after
transfusion
day 7-14 after start of drug
(day 1 in case of reexposure)
day 1 of GPIIb/IIIa treatment (delayed onset)
day 5-14 acute deteriorating
Thrombosis -- (+) -- -- -+ depends
on treatment
++++ ++
0
100
200
300
400
500
0 1 2 3 4 5 6 7 8 9 10
Postoperative day (day 0 = day of surgery)
Pla
tele
t co
un
t (x
10
9/L
)
bacteria contaminated transfusion
transfusion of blood product
passive alloantibody TP
10 1000 3 150 100 20 30 50 70 15 5 300 500 200 1
10
20
30
40
0
Num
ber o
f pa5
ents with
HIT
Platelet count nadir (x109/L), log scale
HIT
TTP
No thrombosis
HIT-‐associated thrombosis
Quinine
2
Median Platelet Counts: Q-‐ITP, TTP, HIT
<5
~10
~60
Warken5n. Hematol ASH Educ Program 2006
(ADAMTS13↓)
• 31 year old female admitted with severe head ache.
• Upper respiratory tract infection that began 10 days earlier.
• Otherwise healthy, no medications. • INR 1.4, aPTT 34s, fibrinogen 0.6 g/L, D-dimer
>35mg/L (<0.5), platelets 31,000/µL, no bleeding, no signs of infection
• normal CT head scan (to exclude sinus vein thrombosis).
Greinacher A, BLOOD 2014
Patient 3: for the specialists
• 4 g fibrinogen and LMWH thrombosis prophylaxis.
• Next day: platelet count 15,000/µL • New DVT; persistent headache
• Although HIT seemed implausible, platelet decrease and new thrombosis during LMWH prompted HIT testing
Greinacher A, BLOOD 2014
• Anti-PF4/heparin IgG ELISA strongly positive OD >2.5
• HIPA test strongly positive also in the sample without addition of heparin.
• Pre-LMWH admission sample: same results
• Immediate start of therapeutic-dose danaparoid anticoagulation
• she deteriorated neurologically the same day, and massive sinus vein thrombosis associated with intracerebral bleeding was demonstrated by repeat CT imaging.
Spontaneous HIT or Autoimmune HIT
• 10 patients reported in the literature • 6 after orthopedic surgery (no heparin) • 3 after infection • 1 no obvious trigger • HALLMARK: positive functional assay
without heparin • “HIT“ during fondaparinux, rivaroxaban,
dabigatran
Warkentin et al. BLOOD 2014 Greinacher BLOOD 2014
CLASSIFICATION
Cirrhosis (severe)
• Pseudothrombocytopenia • Hemodilu5on • Consump5on • Destruc5on • Sequestra5on • Decreased Produc5on
Patient 4
• Male 57 years, acute pancreatitis, alcohol induced liver cirrhosis, renal failure.
• PTT 42 sec, INR 1.9, platelet count 58.000/µl.
• Heparin 200 U/h for continuous renal replacement therapy
• After 48h: PTT 55 sec, INR 2.5, plt. 22.000/µl, bleeding at line insertions, mucosal bleeding
clotting factors platelets
renal replacement
artificial surface
100% 100%
Thrombin
fibrinolysis
bleeding
anticoagulation
coagulopathy
antifibrinolytics
Underdosing of heparin for dialysis/CVVH
• Coating of the artifical surface by plasma
proteins
• Loss of contact phase proteins (aPTT-
prolongation)
• Adhesion and activation of platelets
• Thrombin-generation
• Activated fibrinolysis
TP and Mortality
• Persistent low platelet counts are a marker for adverse outcome.
• Successful treatment of the underlying disease results in normalization of platelet counts and improved outcome.
• Does normalization of platelet counts by platelet transfusion improves outcome?
• This is unkown!
PRODUCTION Isolated thrombocytopenia – Alcohol – Hereditary Pancytopenia – Numerous marrow disorders
Acquired platelet function defects
• Myeloproliferative disorders • Myelodysplasia • Liver cirrhosis • Uremia • Enzymatic degradation of platelet membrane
receptors (plasmin, pancreatitis) • Drugs:
– Anti-platelet drugs – Serotonin reuptake inhibitors – Anticonvulsive drugs, valproic acid
Patient 5: 50 y male pacemaker
• Pacemaker generator change 6 months before;
• Treated for pneumonia for 1 week, levofloxacine
• Lower limb edema, 38.5°C; WBC, 22,500/µL, 88% granulocytes, platelets 10,000/µl, no petechia, no bleeding
300
250
200
150
100
50
0
Days after starting antibiotics
Pla
tele
t cou
nt (x
109 /L
)
0 Pre 5 10 15 20 25 30 35 40 45 50 55 60 65
Antibiotics
Cardiac surgery
IV IgG
Plasmapheresis and prednisone
Platelet
Heparin infusion
transfusions
Platelet transfusions
Hospital admission
Selleng K. et al. Am J Hematol. 2007;82:766-71
Blood cultures: S. epidermidis
Pseudothrombocytopenia? Drug dependent thrombocytopenia? Infection associated TTP?
Cardiac echo: large mass engulfing the wire
INR 1.7 Fibrinogen 1.6 g/L D-Dimer 2.0 mg/L
Selleng K. et al. Am J Hematol. 2007;82:766-71
Dilution of the bacterial supernatant (x 102)
Fact
or X
a ge
nera
tion
(%),
log
scal
e
10
100
1000
1
LPS-induced factor Xa generation
0.25 0.5 1 2 4 8 16 32 64 128 256 512 1024
Selleng K. et al. Am J Hematol. 2007;82:766-71
0
100
200
300
400
500
0 1 2 3 4 5 6 7 8 9 10
Postoperative day (day 0 = day of surgery)
Pla
tele
t co
un
t (x
10
9/L
)
initial recovery
drug induced TP PTP
HIT
Greinacher A & Selleng K, Hematology 2010
e.g.: enhanced platelet consumption or multi organ failure, sepsis.
Greifswald