a systematic approach to a low platelet count in icu patients · 2016. 4. 1. · thrombotic...

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



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

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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

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200

300

400

500

0 1 2 3 4 5 6 7 8 9 10


Pla

tele

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10

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)

rebound of the platelet count after day 4

cardiac surgery

orthopedic surgery

platelet count nadir


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400

500

0 1 2 3 4 5 6 7 8 9 10


Pla

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)

rebound of the platelet count after day 4

trauma

cardiac surgery

vascular surgery

abdominal surgery

orthopedic surgery

platelet count nadir


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


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?

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700

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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

++++ ++

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Pla

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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)


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

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Days after starting antibiotics

Pla

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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

Dilution of the bacterial supernatant (x 102)

Fact

or X

a ge

nera

tion

(%),

log

scal

e

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1

LPS-induced factor Xa generation

0.25 0.5 1 2 4 8 16 32 64 128 256 512 1024


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Pla

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)

initial recovery

drug induced TP PTP

HIT

Greinacher A & Selleng K, Hematology 2010

e.g.: enhanced platelet consumption or multi organ failure, sepsis.

Greifswald

a systematic approach to a low platelet count in icu patients · 2016. 4. 1. · thrombotic...

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