Heparin-Induced Thrombocytopenia (HIT)

Transcription

Heparin‐Induced Thrombocytopenia (HIT)
ISTH Advanced Course,
Cascais, Portugal
Sat 15 Mar 2014
Dr. Ted Warkentin
Professor, Depts. of Pathology & Molecular Medicine, and Medicine, McMaster University
Hematologist and Regional Director, Transfusion Medicine, Hamilton, Ontario, Canada
Disclosures
Organization
GlaxoSmithKline
W. L. Gore
Taylor & Francis
Instrumention
Laboratory
Pfizer Canada
Law firms
Description
research funding
consulting, research funding
royalties
lecture honoraria
lecture honoraria
medical‐legal testimony
• Specific therapeutic recommendations that are not FDA‐labeled indications (treatment of HIT: danaparoid & fondaparinux)
Objectives
Learning Objectives‐‐ Review:
THEME #1 Characteristic timing features of HIT
THEME #2 Strong reactivity at buffer control
THEME #3 Treatment of HIT: Indirect Xa inhibitors vs DTIs
FcRγIIa
Warkentin TE & Greinacher A. Heparin-Induced Thrombocytopenia. 5th edn. CRC Press, Boca Raton, FL, USA 2013.
HIT is Prothrombotic
HIT is Prothrombotic
• Both venous and arterial thrombosis
• ~50‐70% of HIT patients develop thrombosis
HIT
Non‐HIT
RR (95%CI)
P_____
Prox DVT 8/18 (44%) 26/647 (4%) 11 (6, 21) <0.0001
Pulm emb 2/18 (11%) 2/647 (0.3%) 36 (5, 241) 0.004
VTE 9/18 (50%) 28/647 (4%) 12 (6, 21)
<0.0001
Data from orthopedic surgery database (N Engl J Med 1995; Arch Intern Med 2003)
VTE = venous thromboembolism (proximal DVT and/or pulmonary embolism)
HIT “Paradox”
Postoperative DVT: UFH vs Placebo
Type of
Surgery
Odds Ratio
(& 95% CI)
Risk Reduction
(± SD)
General
67% ± 4
Orthopedic
65% ± 7
Urologic
75% ± 15
ANY TYPE
68% ± 3
0.0
0.5
1.0
Heparin better Heparin worse
Odds Ratio (heparin : control)
Collins et al. N Engl J Med 1988; 318: 1162-73.
Heparin ↓thrombosis ~68%;
but HIT ↑thrombosis ~12x;
THUS, HIT↑thrombosis ~4x (vs never getting heparin)
Log10 scale
0.1
0.32
1
UFH reduces clots
Baseline risk
3.2
10
HIT ↑clots ~4X
vs no UFH given
(+ unusually
severe clots)
5% limb loss in HIT !
Log10 scale
0.1
0.32
1
UFH reduces clots
Baseline risk
3.2
10
HIT ↑clots ~4X
vs no UFH given
(+ unusually
severe clots)
HIT: a “Clinical‐Pathologic” Syndrome
“Clinical”
“Pathologic”
• Thrombocytopenia
• Thrombosis (>50%, ven > art)
• Timing (proximate heparin)
• oTher cause(s) less likely
The 4 T’s (pre‐test scoring system)
Warkentin, Chong, Greinacher. Thromb Haemost 1998; 79: 1
4T’s
4Ts Scoring System for HIT
2 Points
1 Point
0 Point
>50% fall
(nadir >20)
30-50% fall or
nadir 10-19; or
>50% (surgery)
<30% fall or
nadir <10
Yes (day 5-10); or
<d1 (hep 5-30d)
Yes (>d10); or
<d1 (31-90d)
No (<d4)
Yes
Possible
No
No
Possible
Likely
Thrombocytopenia
Timing c/w HIT
Thrombosis
T
O her Dx
High probability:
Moderate probability:
Low probability:
6 – 8 points
4 – 5 points
0 – 3 points  HIGH NEG PREDICTIVE VALUE
Warkentin & Heddle. Curr Hematol Rep 2003;2:148. Lo et al. J Thromb Haemost 2006;4:759
HIT: a “Clinical‐Pathologic” Syndrome
“Clinical”
“Pathologic”
• Platelet‐activating • Thrombocytopenia
anti‐PF4/heparin IgG • Thrombosis (>50%, ven > art) (“HIT antibodies”)
• Timing (proximate heparin)
– Positive SRA or HIPA
– Strong positive EIA • oTher cause less likely
(surrogate for SRA+)
The 4 T’s (pre‐test scoring system)
Warkentin, Chong, Greinacher. Thromb Haemost 1998; 79: 1
Two Types of Assays
Platelet Activation Assays
SRA
HIPA
PF4‐dependent Immunoassays
EIA (ELISA) PaGIA instrumentation‐based
Serotonin-Release Assay (SRA)
Washed platelet activation assay
Washed with apyrase
(preserves reactivity to ADP)
Resuspended in buffer
(physiological Ca++, Mg++)
↓Inhibitors of HIT Ab-induced plt act’n
(IgG, fibronectin)
Percent Serotonin Release
100
90
80
70
60
50
40
30
20
typical cut-off
10
0
0
0.1 UFH
0.3 UFH
Heparin (U/mL)
100 UFH
PF4/heparin complexes
HIT-IgG antibodies
Sheridan D, Carter C, Kelton JG.
A diagnostic test for HIT.
Blood 1986; 67: 27-30.
Radiolabeled 14C-serotonin released
released from normal donor platelets
PF4/heparin-EIA
Add substrate
COLOR
Polyspecific
EIAs detect
all 3 classes:
IgG, IgA, IgM
(IgG-specific
EIAs higher
specificity
heparin
PF4
PF4/heparin
complex
HIT-IgG
(from serum or plasma)
Alkaline phosphataseconjugated goat
antihuman IgG
Adapted from: Lee & Warkentin. In: Warkentin & Greinacher, eds. Heparin-Induced Thrombocytopenia, 4th edn . New York: Informa, 2007
Iceberg Model
HIT-T
HIT SRA EIA- EIAHIPA IgG IgG/A/M
Higher ODs in the EIAs
increase the probability
of SRA+ (or HIPA+) status
EIA-IgG/A/M result (OD units): <0.4 0.4-1.0 1.0-1.5 1.5-2.0 >2.0
Probability of SRA+ status: <1% ~5% ~25% ~50% ~90%
EIA Optical Density (OD) Levels Strongly Predict for Platelet‐
activating Antibodies
OD range
<0.4
1.0-1.4
1.4-2.0
36:1
3%
9:2
18%
5:5
50%
304:0
0%
SRA <50:>50
HIT likelihood%
200
150
0.4-1.0
4:33
89%
198:0
106:0
OD = 1.4-2.0
100
50
20
Number of patients
>2.0
OD >2.0
RISK ~50:50
RISK ~90% OR MORE
15:0
15
1:15
13:1
10
8:0
7:2
0:6
5
2:0
1:2
3:2
1:4
0:5
2:3
1:1
0
0
0.2
0.4
0.6
0.8
EIA-GTI
- SRA
Warkentin et al. J Thromb Haemost 2008
1.0
1.2
1.4
1.6
1.8
2.0
2.2
2.4
range (0.2 OD increments)
+ SRA
2.6
2.8
3.0
Clinical Picture of HIT
Clinical Picture of HIT
VENOUS
DVT
MICROVASCULAR
Warfarin necrosis
Venous limb gangrene
lower limb
upper limb (CVC)
Central skin necrosis
DIC
PE
Adrenal vein (hemorrh.)
ANAPHYLACTOID Rx
Cerebral venous
Post-iv UFH bolus
(dural sinus)
Post-sc LMWH
Without
Chills/rigors/fever
thrombosis
ARTERIAL
Number
of cases
(arbitrary
scale)
Limb > CVA > MI
SKIN NECROSIS
at sc injection
sites
3
5
10
Thrombosis
20
50
100
Dyspnea/chest pain
Flushing
Transient global
amnesia
200
Nadir platelet count (x 10-9/µL)
500
1000
Upper‐limb DVT:
role of vascular injury
Upper-limb DVT Frequency in HIT
Patient
population
Thrombosis
Patients with
central line
Upper-limb
DVT
14/145
(9.7%)
Patients
without
central line
Upper-limb
DVT
0/145
(0%)
Thrombosis Rate in:
Controls
HIT
3/484
(0.6%)
P
Odds Ratio
Odds Ratio
Value
(95% CI)(95% CI)
17.1
(4.9-60.5)
<0.001
<0.001
All 14 upper-limb DVTs occurred at site of central venous catheter:
Right, n=12
Left, n=2
P = 0.011
“We conclude that a localizing vascular injury (catheter use)
and a systemic hypercoagulability state (HIT) interact to explain
upper-limb DVT complicating HIT.”
Hong et al. Blood 2003;101:3049-51
}
Adrenal hemorrhage (hemorrhagic necrosis)
Adrenal vein thrombosis  secondary hemorrhage
Hematologist 3 causes of adrenal hemorrhage
1. HIT
2. APS
3. Sepsis
2-3% of HIT; 50% are unilateral
50% are bilateral (adrenal failure)
can be a feature of CAPS
Waterhouse-Friderichsen syndrome
Warfarin-induced Venous Limb Gangrene
(HIT→ thrombin; warfarin → ↓↓Protein C)
palpable pulses
X
X
Macrothrombosis (DVT) +
microthrombosis (venules)
Warkentin et al. Ann Intern Med 1997;127:804-812
Profound Disturbance in Procoagulant‐
Anticoagulant Balance
1.
2.
HIT: ↑↑ Thrombin
Warfarin: ↓↓PC
67‐year‐old Female with Respiratory Arrest
Post‐Heparin Bolus
Sternal wound infection
350
Platelet Count ( x 109/L)
PICC line heparin flush followed by
respiratory arrest and bleeding
Aortic valve
replacement
surgery
300
(accidental heparin overdose)
Resp.
arrest
250
200
HIT
Pos
150
100
50
HIT
Pos
HIT
Neg
Nadir = 32 x 109/L
CPB
S.C. UFH
0
HIT
Pos
Danaparoid
5000 U BID
0
2
4
28
30 32
34
36
38 40
60
138
Days after Aortic Valve Replacement
Warkentin. J Crit Illn 2002;17:215.
Acute Systemic (Anaphylactoid)
Reactions to iv Bolus Heparin
•
•
•
•
•
•
•
•
•
Onset within 5 ‐ 30 minutes
Chills, rigors, fever
Tachycardia, hypertension
Tachypnea, dyspnea
Chest pain or tightness
Diaphoresis, flushing
Nausea, vomiting, diarrhea
Sudden death
Transient global amnesia
Warkentin TE. In: Warkentin & Greinacher, eds. Heparin-Induced Thrombocytopenia, 5th ed. Boca Raton, FL: CRC Press, 2013
Death in ICU Trial
15 min interval
Death
Platelet Count (x109/L)
SRA+
DVT
Patient #8
84M
TIMELINE OF POST-UFH BOLUS
CARDIAC ARREST
0518h platelet count = 427
1050h UFH 5000 U i.v. bolus given
1100h UFH 1600 U/hr i.v. given x 30min
1105h Onset bradycardia, severe ↓BP
ECG changes of acute MI;
1126h CPR for cardiac arrest
1131h Death
[No repeat platelet count performed]
[No post-mortem examination performed]
474
400
427
Day 8
?
UFH
5000-U bolus
200
open-label UFH (5000 U b.i.d.)
Study drug: UFH (5000 U b.i.d.)
0
-2
0
2
4
6
8
Days after Start of UFH
Warkentin et al. Chest 2013;144:848-58.
10
12
14
16
18
20
22
“fatal presumed
anaphylactoid reaction”
Interpreting Platelet Counts Post‐Surgery
Interpreting Platelet Counts
400
81 F
Previous Hx of DVT 10y ago
Platelet count (x109/L)
300
Colon resection
Day 3 platelet count ~95
IS THIS HIT?
200
100
Heparin s.c.
5000 U bid
0
0
2
4
6
8
10
Days after surgery
12
14
16
18
Platelet Counts After Surgery
Postoperative thrombocytosis
+2 SD
9
Platelet Count x 10 /L
1000
800
Normal Postoperative
Platelet Counts
(mean + 2 SD)
Early postoperative
thrombocytopenia
600
>50%↓ e.g., d8 500
200
400
Mean
-2 SD
200
0
Pre
1
2
3
4
5
6
7
8
9
Postoperative Day
Warkentin et al. N Engl J Med 1995;332:1330-5
10
11
12
13
14
Day of Postoperative Platelet Count Nadir
60
55%
Orthopedic surgery data
50
Percent
40
Potentially abnormal
on/after day 5
30
32%
20
13%
10
0
1
2
3
<1%
0%
0%
4
5
6
Day of Platelet Count
Postoperative
Nadir (Surgery
Day
= Day 0)
Greinacher & Warkentin. In Marder et al., eds. Hemostasis & Thrombosis. Basic Principles & Clinical Practice, 6th edn. Philadelphia, LW&W 2013.
Day of Postoperative Platelet Count Nadir
60
Comparison:
orthopedic vs cardiac
50
Percent
40
Potentially abnormal
on/after day 5
30
20
10
0
1
2
3
4
5
Day of Platelet Count Nadir (Surgery = Day 0)
6
Greinacher & Warkentin. In Marder et al., eds. Hemostasis & Thrombosis. Basic Principles & Clinical Practice, 6th edn. Philadelphia, LW&W 2013.
Interpreting Platelet Counts
400
81 F
300
Platelet count fall on
day 5 of heparin
(first day of heparin
= day 0)
Colon resection
200
IS THIS HIT?
Day 3
100
nadir
Heparin s.c.
5000 U bid
0
0
2
4
6
8
10
Days after surgery
12
14
16
18
Timing of HIT
All had previous
heparin exposure
within last 100 days
Timing of Typical-Onset HIT
Number of Patients
Rapid
onset
Exposure to
Previous Heparin
Definite
Possible
80
Unlikely
60
Typical onset
40
20
0
1 2 3 4 5 6 7 8 9 10111213
Days after Heparin Exposure
Warkentin & Kelton. N Engl J Med 2001;344:1286-1292
HIT Antibodies are Transient
Frequency of Repeat
Positive Test for HIT-Abs
1.0
Enzyme-immunoassay
0.8
0.6
0.4
Serotonin release assay
P=0.0073
0.2
0
0
25
50
75
100
Days to Negative Assay Result
Warkentin & Kelton. N Engl J Med 2001
125
Platelet Count (x 109/L)
Typical onset
of HIT
Rapid onset
of HIT
Platelet count fall began
Abrupt fall in platelet count from
on day 6 of heparin treatment 179 to 49 x 109/L with
repeat use of heparin (day 30)
250
200
Platelet count nadir
on day 11 (60 x 109/L)
150
100
UFH
50
0
5,000 U bid sc
5,000 U bolus
+ i.v. infusion
-2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38
Days after Starting Heparin
Warkentin & Kelton. N Engl J Med 2001;344:1286
Timing of Onset of HIT
Typical
Rapid
Antibodies newly formed
Antibodies already present
Timing day 5 to 10
irrespective of history
of previous heparin
Timing immediate (<24 h)
Recent heparin
(past 100 days) crucial
What is the explanation for this speedy (5d)
“primary” immunization?
PF4
platelets
B-cell
polyanions
bacteria
granulocyte
One antibody specificity recognizes a large
HIT
isofabacteria
misdirected
hostimmune
defense
variety
= innate humoral
defense
heparin
PF4
B-cell
activated
platelet
anti-PF4/polyanion IgG
granulocyte
HIT
Why do Platelets Fall After Stopping UFH?
Percent Serotonin Release
100
400
81 F
300
Colon resection
200
90
80
70
60
50
40
30
20
typical cut-off
10
0
0
0.1 UFH
0.3 UFH
Heparin (U/mL)
100 UFH
IF THIS IS HIT,
why are platelets
falling off heparin?
100
Heparin s.c.
5000 U bid
0
0
2
4
6
8
10
Days after surgery
12
14
16
18
Delayed‐Onset HIT
Delayed‐onset HIT:
Definition
1
to fall,
platelet count begins
or 2
continues to fall, despite stopping all heparin
1
Warkentin & Kelton. Ann Intern Med 2001; 135: 502
2 Warkentin. Hematol/Oncol Clin N Am 2010; 24: 755.
HIT‐Ab (OD)
3
Immunizing heparin exposure
2
1
0
0
2
4
6
8
10
12
14
16
Macrovascular to Microvascular Thrombosis
Postoperative
thrombocytopenia,
day 1‐4 (hemo‐
dilution, platelet
consumption)
200
Consumptive coagulopathy
intensifies during 2nd week
INR , PTT  , fibrinogen
Progressive platelet activation
and PF4 release (vicious cycle)
Protein C pathway activation

300
100
UFH (intra‐ or peri‐op)
± UFH or LMWH prophylaxis
(“delayed‐onset HIT” if off heparin)
0
0
2
4
Warkentin. Hematol/Oncol Clin N Am 2010; 24: 755‐75.
6
8
10
12
14
16
Delayed-Onset HIT
180,000
160,000
Platelet Count (per mm3)
Left-lower limb proximal DVT
and pulmonary embolism
Heparin 5,000 U (preoperative)
once by subcutaneous injection
Gastric bypass
surgery
700
600
Progressive
stroke
140,000
500
Plasma
fibrinogen
levels
120,000
100,000
400
300
80,000
200
40,000
Platelet
counts
20,000
Platelet transfusion
pre-inferior vena cava
filter insertion
133 mg/dL
100
7,000/mm3
0
0
5
10
15
20
25
Days after Starting Heparin
Warkentin & Bernstein. N Engl J Med 2003: 348: 1067-9.
0
30
35
40
Plasma Fibrinogen (mg/dL)
Hemodilution
Heparin
Rechallenge
(Previous HIT)
Heparin Rechallenge
• N=20 patients with previous HIT
– 0/3 medical pts formed Abs (despite full course of hep!)
– 11/17 (65%) surgical pts formed anti‐PF4/H Abs
• 8/11 (73%) anti‐PF4/H Ab+ pts became +SRA
– high SRA+ frequency (? memory for plt‐activating Abs)
–1/8 pts  recurrent HIT (despite no postop heparin!) HOW IS THIS POSSIBLE?
• Thus, reasonable to consider heparin re‐exposure, especially for cardiac or vascular surgery (caveat: delayed‐onset HIT remains possible)
Warkentin & Sheppard. Blood 2014. [Epub ahead of print]
Two Episodes of HIT
Platelet count (x10-9/L)
A
250
225
200
175
150
125
100
75
50
25
0
Cardiac surgery (heparin) exposure
1st Episode of HIT (1998)
Onset
of HIT,
day 7
DVT and PE
Nadir = 26 (day 10)
Danaparoid, therapeutic-dose with transition to warfarin therapy
0
7
14
21
28
35
42
49
56
63
56
71 86
63 76
Platelet count (x10-9/L)
B
250
225
200
175
150
125
100
75
50
25
0
Cardiac surgery (heparin re-exposure)
2nd Episode of HIT (2009)
Onset
IV IgG
of HIT,
day 7
DVT by US
IV IgG
Nadir = 20 (day 10)
Fondaparinux
(2.5 mg/day)
0
7
Fondaparinux, therapeutic-dose (7.5 mg per day)
14
21
28
35
Days after surgery
42
49
SRA+ on Day 6, Delayed-onset HIT Abs, No Fx X-Reactivity
2nd Episode of HIT
3.0
Day 6 SRA
seroconversion
80
2.5
2.0
60
Day 6 EIA-IgG
seroconversion
1.5
40
1.0
Day 7 EIA-IgM
seroconversion
0
20
OD cutoff <0.45
0
0
5
EIA-IgG
10
15
20
Days after surgery
EIA-IgA
25
EIA-IgM
0.5
D
Serotonin release, percent
100
EIA-IgG, EIA-IgA, EIA-IgM (OD units)
Serotonin release, percent
C
2nd Episode of HIT
(day 10)
100
80
60
40
20
0
0
30
0
100 0 0.4 1.2
0.3
0.1 0.8 100
UFH (IU/mL) Fonda (μg/mL)
neat 1/8 1/16 1/32 1/64 1/128
Patient
number
Previous HIT Episode
G
A
Weeks to
rechallenge
M
3
132
8
180
*
15
422
20
20
10
37
* *
Antibody OD: 0.45 - 0.99
G
A
47
1.00 – 1.99
M
*
515
16
11
Heparin Rechallenge
*
≥2.00
Wanaka et al. J Thromb Haemost 2010
Typical‐onset HIT
Rapid‐onset HIT
Delayed‐onset HIT
Persisting HIT
Spontaneous HIT
UFH (70,000 IU)
160
PERSISTING HIT, i.e.,
Platelet count (x10‐9/L)
140
Duration of HIT >30 days
120
100
100
Onset of HIT, d6
80
60
Platelet count nadir = 13 d11
40
20
0
Cardiac surgery
Enoxaparin
Fondaparinux
Rivaroxaban
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 36 44 79 88112126
Kopolovic & Warkentin. CMAJ 2014 in press.
Days after cardiac surgery
UFH (70,000 IU)
Serotonin‐release (percent)
160
Platelet count (x10‐9/L)
140
120
100
Results of SRA
(d8 serum)
100
80
60
40
20
Results of SRA
(d11 serum)
serum
dilution
neat
1/4
1/8
1/16
1/32
1/64
1/128
1/256
Negative for
fondaparinux
cross‐reactivity
0
Onset of HIT, d6
d8
0 0.1 0.3 100 0 0.1 0.4 0.8 1.2 10 100
UFH (IU/mL)
Fondaparinux (μg/mL)
0 0.1 0.3 100
UFH (IU/mL)
d11
d14
d18
sample day
Percent release (1/4 serum dilution)
80
serum
dilution
1/4
1/16
1/64
1/256
93
76
92
81
92
62
89
53
d44
Percent release (neat)
release with (mean 0.1, 0.3) U/mL UFH
release with 0 U/mL UFH
95
10
d88
Percent release (neat)
94
3
60
Platelet count nadir = 13 d11
40
20
0
Cardiac surgery
Enoxaparin
Fondaparinux
Per cent release at 0 U/ml UFH
(“buffer control”) inversely
proportional to platelet counts
Rivaroxaban
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 36 44 79 88112126
Kopolovic & Warkentin. CMAJ 2014 in press.
Days after cardiac surgery
Spontaneous HIT
(or Autoimmune HIT)
DEFINITION
disorder mimicking HIT both clinically and serologically except for no proximate heparin
Warkentin et al. Am J Med Med 2008; 121: 632.
Pruthi et al. J Thromb Haemost 2009; 7: 499.
Jay & Warkentin. J Thromb Haemost 2008; 6: 1598.
Warkentin et al. Blood 2014; in press.
Spontaneous HIT Syndrome
250
Platelet Count (x10-9/L)
200
62-y.o. male admitted for acute thrombotic stroke
Platelet count = 65 x 109/L
No recent hospitalizations, no previous heparin
150
Platelet transfusions
1U 1U
1U
2U
100
50
% Serotonin Release
Serotonin-release assay and enzyme-immunoassays (3 assays):
POSITIVE on day 0 and day 14
100
80
60
40
0
Platelet count nadir, 27 x 109/L
0
ASA 325 mg daily x 5
Mechanical thrombectomy
Intra-arterial t-PA (15 mg)
UFH 1000 IU
Complicated by multiple rethromboses
requiring multiple thrombectomies
0
1
2
3
4
5
6
7
Fondaparinux
7.5 mg SC
daily x 3
8
9
0
0.1
0.3
100
Heparin (U/mL)
Warfarin
Argatroban IV
target 2-times
baseline APTT
10 11 12 13 14 15 16
Days after Admission for Stroke
Warkentin et al. Blood 2014; in press.
typical cut-off
20
Treatment of HIT
Six HIT Treatment Principles
• 2 Do’s
Stop Heparin (LMWH, flushes,…)
Danaparoid (not in U.S.)
Fondaparinux (off-label)
Give alternative anticoagulant
Lepirudin (discontinued)
• 2 Don’ts
Argatroban (APPROVED)
Bivalirudin (off-label)
No warfarin (vit K if warfarin given)
No prophylactic platelet transfusions
• 2 Diagnostics
Test for HIT antibodies
Ultrasound for lower‐limb DVT
Adapted from Warkentin TE. Circulation. 2004; Warkentin et al. Chest 2008
AT3-Dependent Anti-FXa Inhibitors vs DTIs
Anti-FXa Inhibitors
DTIs*
(Danaparoid, Fondaparinux) (Argatroban, Lepirudin)
Non-HIT indications
Numerous
Not established
Long (fonda ~17h)
Short (<1h)
Prophylactic/therapeutic
Therapeutic only
Direct (anti-FXa levels)
Indirect (PTT)
No effect
No effect
↑INR (esp. arg)
? Inhibit APC gen’n
No (covalent AT3-Xa)
Yes (non-covalent)
Reversibility
√
√
√
√
√
√
√
Platelet activation
√ Inhibits (danap only)
Half-life
Dosing
Monitoring
Effect on INR
Protein C pathway
Drug clearance
Renal
Inhibit clot-bound IIa
No
Approved for HIT
Cost
√ Yes (danaparoid)
√ Low (fondaparinux)
Adapted from: Warkentin TE. Hematology Am Soc Hematol Educ Program 2011
No effect
Hepatic
√ Yes
√ Yes
High
*Desirudin & bivalirudin
are potential options
HIT‐Ab (OD)
3
Immunizing heparin exposure
2
1
0
0
2
4
6
8
10
12
14
16
Macrovascular to Microvascular Thrombosis
Postoperative
thrombocytopenia,
day 1‐4 (hemo‐
dilution, platelet
consumption)
200
Consumptive coagulopathy
intensifies during 2nd week
INR , PTT  , fibrinogen
Progressive platelet activation
and PF4 release (vicious cycle)
Protein C pathway activation

300
100
UFH (intra‐ or peri‐op)
± UFH or LMWH prophylaxis
(“delayed‐onset HIT” if off heparin)
0
0
2
4
Warkentin. Hematol/Oncol Clin N Am 2010; 24: 755‐75.
6
8
10
12
14
16
Platelet count
(x109/L)
PTT Confounding Argatroban for HIT
100
80
60
40
20
0
Progressive ischemic limb necrosis necessitating amputations
APTT (sec)
80
APTT
target
range
60
40
Pre-argatroban ↑PTT
APTT
normal
range
Argatroban
(µg/kg/min)
20
0
Argatroban
0.50
0.25
0
14
Warkentin. Hematol/Oncol Clin N Am
2010; 24: 755-75.
15
16
17
Days after immunizing intraoperative heparin exposure
18
HIT‐Associated DIC and “PTT Confounding” of Direct Thrombin Inhibitor (DTI) Therapy of HIT
Simple Rule:
If “baseline” (pre‐
treatment) PTT is ↑, PTT‐based nomogram is unlikely to be successful (“PTT confounding”)
PTT Confounding of DTI Therapy
Platelet Count (x109 L-1)
400
PTT INR
133 4.0
81F
Warfarin
Bilateral
DVT
Admission to ICU
Profound hypotension
(adrenal crisis)
Hip fracture
300
Surgery
100 3.0
Neurologic injury
Onset of HIT
200
67
2.0
33
1.0
0
0
166
126
100
PTT = 35 s
(ULN)
80
50
18 = Platelet count nadir
0
UFH 5000 U Dalteparin 2500 U once sc,
then 5000 sc OD
bid sc
Arg dosing, mcg/kg/min
1.0
1.7
0.1
−4
−2
0
Linkins & Warkentin. 2011;37:653.
2
4
6
8
10
12
14
16
18
20
22
24
Days after Starting Immunizing Heparin
26
2.0
1.0
0
Warkentin:
“[For] those patients with severe HIT who evince concomitant DIC, their hypercoagulability state can be ‘untreatable’ with the approved DTIs, at least when employing standard PTT monitoring regimens.”
Warkentin TE. Exp Opin Drug Safety, 2014 Jan; 13: 25-43.
Avoiding Treatment Failure Due to PTT Confounding
Anti-Xa u/mL ( )
1.0
0.8
therapeutic
range
0.6
0.4
0.2
Platelet count x 109/L ( )
400
DIC
PTT
27→ 42
Fbgn
2.8 → 1.0
PSO4
neg- >4+
300
heart
surgery
Danaparoid held
1. Low platelets
2. Procedure
200
Plt = 17 (falling)
Ischemic feet
100
Warfarin given
0
Danaparoid sodium…adjusted by anti-Xa levels
0
5
Warkentin
Hematol/Oncol Clin N Am 2010
10
15
20
25
30
Days after starting heparin
35
Fondaparinux for HIT
Studies with >5 Patients and +EIA
N (% with
New
HIT-thrombosis) Thrombosis
Major
Bleeding
Kuo & Kovacs 2005
N=5 (100%)
0/5 (0%)
0/5 (0%)
Lobo et al. 2007
N=7 (86%)
0/7 (0%)
0/7 (0%)
Grouzi et al. 2009
N=24 (58%)
0/24 (0%)
0/24 (0%)
Goldfarb & Blostein 2011* N=8 (75%)
0/8 (0%)
0/8 (0%)
Warkentin et al. 2011** N=16 (56%)
0/16 (0%)
1/16 (6%)
Pooled data
N=60 (67%)
0/60 (0%)
1/60 (1.7%)
* All 8 patients had positive SRA or strong positive EIA (>2.00 OD units)
** All 16 patients had positive SRA (mean EIA = 2.53 OD units)
Warkentin. Hematol/Oncol Clin N Am 2010; 24: 755-75; plus Warkentin et al. & Goldfarb & Blostein. J Thromb Haemost 2011 (Dec)
Prevention of HIT
Meta-Analysis of UFH vs LMWH
Study
Risk of HIT: Odds Ratio (95% CI)
Leyvraz 1991 **
Warkentin 1995 *
Ganzer 1999 *
* Enoxaparin
** Dalteparin
Pouplard 1999 **
Mahlfeld 2002 *
Common odds ratio = 0.10
(95% CI, 0.03-0.30)
Total (95% CI)
0.001
0.01
0.1
Favors LMWH
1
10
100
Favors UFH
Warkentin. Blood 2005;106:2600 [Commentary on Martel et al. Blood 2005:106:2710].
1000
Preventing HIT in the ICU with LMWH
(Dalteparin)
PROTECT Trial: main findings
(“as-treated”a analysis)
Outcome
Dalteparin
(N = 1827)
UFH
(N = 1832)
Proximal DVT
94 (5.1%)
108 (5.9%)
PE (any)b
22 (1.2%)
42 (2.3%)
0.48 (0.27, 0.84)
0.01
Death (in-hosp.)
396 (21.7%)
446 (24.3%)
0.90 (0.78, 1.04)
0.15
Bleeding (major)
100 (5.5%)
105 (5.7%)
0.98 (0.73, 1.31)
0.88
5 (0.3%)
12 (0.7%)
0.47 (0.16, 1.37)
0.17
HIT
Hazard ratio
(95% CI)
0.91 (0.68, 1.23) 0.54
HIT (per-protocolc) 3/1566 (0.2%) 12/1561 (0.8%) 0.27 (0.08, 0.98)
a
b
c
P
0.046
Excludes patients where consent withdrawn, incorrectly randomized, or study drug not given.
Includes all PE’s classified as: “definite”, “probable” or “possible”
Excludes patients with VTE on study entry; includes patients who received study drug ≥2 d;
and who had ≥ technically-adequate noninvasive imaging for DVT
Warkentin TE. Crit Care Clin 2011 Oct; 27 (4): 805-823, summarizes N Engl J Med 2011; 364: 1305-1314.
Heparin Use and HIT Post-Cardiac Surgery
1996 1997 1998 1999 2000 2001 2002 2003
May’96-Jun’97
UFH
6/157
(3.8%)
Apr’98-Dec’99
3/104
(2.9%)
Jan’00 ---------- Dec’03
2/176
(1.1%)
11/437
(2.5%)
8/1703
8/1874
(0.5%)
(0.4%)
0/171
(0.0%)
LMWH
1/201
(0.5%)
7/1502
(0.5%)
80% reduction
95% CI
2.19, 17.34
p<0.0001
Objectives
Learning Objectives‐‐ Review:
THEME #1 Characteristic timing features of HIT
THEME #2 Strong reactivity at buffer control
THEME #3 Treatment of HIT: Indirect Xa inhibitors vs DTIs

Heparin-Induced Thrombocytopenia (HIT)

Transcription

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