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430 Anticoagulation Therapy
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TABLE 18-8: Post-HIT Probability Assessment Tool Proposed by
Chong
Score and Probability: >7 = definite; 5–6 = probable; 3–4 = possible; and <3 = unlikely.
a
b
(100 units/mL), which characterizes the heparin antibody (suppresses the antibody reaction).
8
Indicator
Onset:
1 point—onset of thrombocytopenia is <4 days or >14 days
3 points—onset of thrombocytopenia
a
(or a substantial decrease in platelet by >50% between
4–14 days after exposure)
2 points—other causes of thrombocytopenia excluded
2 points—thrombocytopenia resolves after stopping agent
1 point—thrombocytopenia recurs on heparin reexposure
1 point—thrombosis associated with thrombocytopenia
Laboratory tests:
•
Immunoassay positive (2 points)
Functional assay: two-point system positive
•
Functional assay: non-two-point system
•
b
(3 points)
b
(3 points)
Thrombocytopenia defined as platelet count <150 K/mm3 or drop >50%.
In the two-point system, there is the addition of a control using a high heparin concentration
TABLE 18-9: HIT Evaluation in the Setting of Cardiopulmonary
Bypass (CPB) Surgery
Variable
Platelet count time course:
• 2 points if initial platelet count drop and full recovery >5 days with a notable subsequent
drop in the next few days
• 1 point if initial platelet count drop and small recovery in ~2 days followed by a
subsequent decline over the next few days
Note: Platelet count drops are very common post-cardiopulmonary bypass and why scoring is
based on some recovery prior to a secondary drop.
Time from CPB to assessment day: 2 points if ≥5 days
CPB duration: 1 point if ≥118 minutes
Classification:
≥ 2 = High probability of HIT
< 2 = Low probability of HIT
CPB: cardiopulmonary bypass, HIT: heparin-induced thrombocytopenia
9
HEPARIN-INDUCED THROMBOCYTOPENIA 431
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• Assessment tools (e.g., 4Ts) can assist in
determining the risk for HIT and potential
diagnosis to determine the management strategy.
However, after adoption into clinical practice,
neither tool has been prospectively validated to
improve the treatment outcomes of patients who
may or may not have HIT.
Laboratory Considerations in Evaluation of HIT
See Tables 18-10 and 18-11.
TABLE 18-10: Assays for Potential Presence of HIT
• Platelet activation or functional assays detect platelet activation when the patient’s serum is
incubated with normal platelets and heparin.
•
Antigen or immunoassays detect presence of antiplatelet factor 4/heparin antibodies;
these antibodies may or may not be pathogenic.
Combination of a positive antigen assay OD >1 and pre-test intermediate probability score
•
to high provides the similar accuracy as a SRA assay.
In the presence of a OD of 0.4–1 and a low-to-moderate pre-test probability, can consider
•
a SRA assay to confirm the diagnosis.
•
For patients receiving heparin agents, routine use of HIT antibody screens in the absence
of thrombocytopenia, thrombosis, heparin-induced skin lesions, or other signs of HIT
should be generally avoided. Over-testing can lead to excessive costs and exposure to
more costly anticoagulants as well as bleeding risks because false positives are common
with immunoassays.
Assay Approach Assay Examples
Platelet activation: lack standardized controls
Washed platelet assays
Flow cytometry Annexin V-binding assay
PF-4 immunoassays
Lateral flow immunoassay
Serotonin release assay (SRA)
Platelet aggregation test (PAT)
Heparin-induced platelet activation (HIPA)
ATP release using lumiaggregometry
Platelet microparticle assay using flow cytometry
Serotonin release using flow cytometry
Enzyme-linked immunosorbent assay (ELISA)
Rapid assays (particle gel immunoassay (PaGIA)
Particle immuno-filtration assay (PIFA)
Chemiluminescent immunoassay
Latex immunoassay
5
ATP: adenosine triphosphate, OD: optical density
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TABLE 18-11: Differences Between Common Assays Used to
Detect HIT
Considerations Serotonin Release
Measures Radiolabeled serotonin
Advantages High sensitivity (99%);
Disadvantages Lack of standardization,
Comment Consideration for long-
4,10,11
Assay
release for aggregated
platelets in presence of
low-dose heparin.
high specificity (95%)
donor platelet
sensitivity dependent,
requires special
equipment. Expensive;
radio isotopes involved.
term decisions where
re-exposure to heparin
anticipated and clinical
diagnosis unclear.
PF4 Immunoassays Platelet Aggregation
Heparin-dependent
antibodies. Can
either be polyclonal
or monoclonal (IgG
only) depending on
manufacturer.
Presence of PF4
antibodies.
Fast turnaround; low
false-negative rate.
Sensitive and specific;
rapid turnaround time.
Low specificity; high
(~25%) false-positive
rate.
No controls and
limited experience with
outcomes.
ELISA: Commonly used;
one product (GTI ELISA)
has conformation step.
Impact of this step
clinically unclear.
Assay
Platelet activation
Easy to perform
>90% specificity
Very low sensitivity
(40%) leading to
high false-negative
rates. Requires
aggregometer. Other
causes of platelet
activation can
influence test.
Not routinely
recommended given
availability of SRA and
ELISA.
ELISA: enzyme-linked immunosorbent assay, PF4: platelet factor 4, SRA: serotonin release assay
Note:
•
With the exception of the SRA, all the other assays have a lower positive predictive value.
Available immunoassays may be polyspecific or IgG-specific with differences in optical density
•
thresholds. Because pathogenic HIT antibodies are IgG, a monoclonal IgG specific test should
be more specific for HIT, but false positives remain a concern.
• Many clinicians get very confused with HIT
testing concepts. In addition to assessing
pre-test probability, when ordering laboratory
assessments, remember the basic concepts.
Platelet factor 4 (PF4) antibody enzyme-linked
immunosorbent assay (ELISA) assays are often
useful as an initial screen and, in general, a
negative value helps rule out a diagnosis of HIT.
The serotonin release assay (SRA) has a high
HEPARIN-INDUCED THROMBOCYTOPENIA 433
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positive predictive value and may be helpful in
the diagnosis of HIT in situations where it is
otherwise unclear (lower pre-test probability with
an indeterminate PF4 antibody, etc.).
PRINCIPLES OF PHARMACOTHERAPY
MANAGEMENT
Initial Management of Suspected HIT
See Table 18-12 and Figure 18-1.
TABLE 18-12: Initial Management of Suspected HIT
Intervention Comment
Remove all exposure
to heparin-related
agents where possible
Reverse concurrent
warfarin therapy
Initiate alternative
anticoagulant
Platelet transfusions Prophylactic transfusions of platelets in the absence of bleeding
ACCP: American College of Chest Physicians, HIT: heparin-induced thrombocytopenia, LMWH:
low molecular weight heparin, VKA: vitamin K antagonist
Avoid heparin or LMWH; consider all heparin-related sources
including flushes, coated lines, dialysis rinses; LMWH should be
avoided (ACCP grade 1C).
Vitamin K should be considered to reverse the effects of a VKA in
acute HIT (ACCP grade 2C).
Stopping heparin agent alone does not stop the progression of HIT
and may increase risk for thrombosis from loss of anticoagulant effects;
an alternative non-heparin agent needs to be started (ACCP grade
1C) (see Tables 18-13 through 18-17 for agent options). If significant
bleeding concerns are present and alternative anticoagulant therapy
poses a notable risk, consider frequent assessment for thrombosis
(i.e., duplex ultrasonography with compression) and initiate alternative
therapy as soon as possible.
should be avoided. Platelet transfusions should be given only if
bleeding or during a procedure with high risk of bleeding (ACCP
grade 2C).
5,6,12
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Suspected HIT; Evaluate probability of HIT
High probability of HIT
(4T ≥ 6)
Discontinue any heparin or LMWH
Further testing may
not be necessary. Proceed
with treatment using an
alternative anticoagulant (DTI).
Strongly positive PF4 test
AND High probability of HIT
HIT probability high enough
to warrant continued
alternative management. If
there is strong desire to avoid
alternative anticoagulation, a
SRA test can be considered
HIT unlikely, appropriate traditional
*A 4T score of 3 has been considered as a cutoff for low probability of HIT in some settings, and there is no need to initiate a
DTI. A PF4 test can be considered if the result alters management.
Definitions of “positivity” quantifications vary.
** SRA assay may be considered if the patient is anticipated to require procedures preferring the use of heparin
(i.e., cardiopulmonary bypass).
***If the risk of major bleeding exceeds the risk of thrombosis, surveillance for thomboembolism should be considered and the
DTI started when feasible.
Probability of positive SRA high if 4T score high probability and OD >1.4.
Probability of negative SRA high if 4T score low probability and OD < 0.4.
HIT: heparin-induced thrombocytopenia, DTI: direct thrombin inhibitor, LMWH: low molecular
ELISA: enzyme-linked immunosorbent assay, OD: optical density, PF4: platelet factor 4, SRA: serotonin release assay
Weakly positive or
indeterminate PF4 test
(OD <1) AND High
probability 4T score for HIT
Consider functional platelet assay (Serotonin
Release Assay) if the result will change the
management approach, or continue alternative
anticoagulation if warranted.**
Negative Serotonin Release
Assay
therapy can be reconsidered
using “4Ts” risk score
High or intermediate
probability of HIT
(4T = 4–5)
Discontinue any heparin or LMWH, initiate
an alternative anticoagulant e.g., direct
thrombin inhibitor (DTI) therapy***
Consider HIT ELISA assay
Strongly positive (OD > 1),
weakly positive or
indeterminate PF4 test
AND Intermediate
probability of HIT
Positive Serotonin Release
Assay
HIT probable, continue
alternative anticoagulation
Negative PF4 test
AND High probability
Consider alternative
diagnosis; HIT
indeterminate. Assess
risk and benefit of using
a DTI or fondaparinux.
Can repeat the PF4 assay
in a few days
Consider a SRA if the
result will alter
management
Low probability of HIT
(4T ≤ 3)*
Heparin, LMWH, or fondaparinux
may be continued, or therapy may
be withheld at clinicians’ discretion.
Consider alternative diagnosis.
Watch and repeat HIT evaluation
if other causes not apparent.
Monitor for thrombosis
of HIT
restarting heparin/LMWH or
Another option is to continue
Monitor platelet count and
weight heparin,
Negative PF4 test
AND Intermediate
probability of HIT
Consider alternative
diagnosis; can consider
consider fondaparinux.
DTI/Fondaparinux and
repeat the PF4 assay.
signs of thrombosis
FIGURE 18-1. Flow Diagram
Diagram describes a generalized approach to decisions incorporating the use of the 4T
scoring system, functional and immunoassays, and anticoagulation therapy decisions
when HIT is suspected.
General treatment of HIT depends on the phase (Tables 18-2, 18-6, and
18-12). In general, an initial non-heparin anticoagulant should be initiated
(not warfarin alone); once the platelet count is recovering, other longer term
agents such as warfarin can be started. In the trials assessing argatroban and
lepirudin, the majority of patients were transitioned to warfarin. Transitioning
to warfarin is described in Table 18-19. Despite limited published experiences, fondaparinux is another option commonly used—even with initial
management of HIT (Table 18-18).
Treatment of HIT
See Tables 18-13 through 18-18.
HEPARIN-INDUCED THROMBOCYTOPENIA 435
Argatroban (2C)
Bivalirudin (2C)
Danaparoid (2C)
Fondaparinux
Warfarin (Grade
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(continued)
Comments
b
4,5,12-14
Assay (usual target
range)
a
Half-life
Elimination
Chemistry Route of
prolongs INR. Alternative assay options: dTT or ECA.
Alternative assay options: dTT or ECA.
Not marketed in U.S. (approved for HIT in EU, Canada); no effect
on INR; IV, or sub-Q.
(0.5–0.8 units/mL)
Peak effect post-sub-Q
injection at 4–5 hr
25 min aPTT: 1.5–2.5 x baseline Not approved for HIT (except during PCI) but commonly used.
Hepato-biliary 40–50 min aPTT: 1.5–3 × baseline FDA-approved for HIT prophylaxis or treatment, including PCI;
DTI: L-arginine
Enzymatic
derivative
DTI: 20-aa
(80%); renal
(20%)
Renal; other 25 hr Anti-Xa activity level
hirudin analogue
Mixture of
GAGs with
predominant
anti-Xa activity
case reports of HIT from fondaparinux have been reported.
Renal; other 17 hr NA Not approved for HIT; use has become more common; however,
Sulfated penta-
saccharide with
HIT without alternative anticoagulant agent in place or early
Hepatic 35–45 hr INR 2–3 Potential for microvascular thrombosis when given during acute
anti-Xa activity
Inhibits hepatic
production
occurrence of INR values over the target range (see Table 18-19
for more details).
of vitamin K
dependent
clotting factors
demonstrated; place in therapy unclear.
14–17 hr ECA Case reports only; effect on PF4 or PF4/heparin antibody not
Renal (80%); gut
esterases and
non-CYP liver
metabolism
inhibitor
Agent (ACCP
grade)
TABLE 18-13: Agents Used in the Management of HIT
(Grade 2C)
2C)
Dabigatran Direct thrombin
436 Anticoagulation Therapy
Half-life determined in normal subjects and may be longer in many patients with HIT.
Baseline is the patient’s baseline aPTT off heparin or the laboratory mean if the patient’s baseline value is notably elevated.
aa: amino acid, anti-Xa: anti-factor Xa activity, aPTT: activated partial thromboplastin time, DTI: direct thrombin inhibitor, dTT: dilute thrombin time, ECA: ecarin chromogenic
assay, EU: European Union, FDA: U.S. Food and Drug Administration, hr: hour, INR: international normalized ratio, IV: intravenous, min: minutes, NA: not applicable, PCI:
percutaneous coronary intervention, PF4: platelet factor 4, sub-Q: subcutaneous, x: times, Xa: factor Xa
Lepirudin has been removed from the international market and is no longer available.
In the setting of acute PE, the combination of thrombolysis with a DTI has been reported in a case report.
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Case reports only; effect on PF4 or PF4/heparin antibody not
Case reports only; effect on PF4 or PF4/heparin antibody not
Comments
demonstrated; place in therapy unclear.
demonstrated; place in therapy unclear.
15
b
Assay (usual target
a
Half-life
assay adjusted for
range)
5–9 hr Chromogenic anti-Xa
hepatic
Elimination
Chemistry Route of
Rivaroxaban Xa inhibitor Renal (66%);
Agent (ACCP
grade)
TABLE 18-13: (Continued)
assay adjusted for
rivaroxaban
apixaban
9–14 hr Chromogenic anti-Xa
hepatic
Apixaban Xa inhibitor Renal (25%);
8–10 hr NA No case reports yet; place in therapy unclear.
hepatic
Edoxaban Xa inhibitor Renal (50%);
a
b
Note:
HEPARIN-INDUCED THROMBOCYTOPENIA 437
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TABLE 18-14: Argatroban in HIT
Evidence supporting
argatroban
Dosing Initiate at 2 mcg/kg/min IV with titrations (max 10 mcg/kg/min) to
Monitoring Typically aPTT 2–6 hr after each titration. Note: In patients at lower
Common adverse
events
aPTT: activated partial thromboplastin time, HIT: heparin-induced thrombocytopenia, HITT:
heparin-induced thrombocytopenia-related thrombosis syndrome, hr: hours, IV: intravenous, sec:
seconds, x: times
Note: For more detailed information, see Chapter 5.
In two multicenter, nonrandomized, historical-controlled trials, patients
with HIT or HITT treated with argatroban had significantly decreased
composite all-cause death, all-cause amputation, or new thrombosis
and new thrombosis and death caused by thrombosis compared to
historical controls. Patients treated with argatroban also had more
rapid rises in platelet count.
target an aPTT of 1.5 to 3 x the baseline aPTT (max 100 sec) (see
Chapter 5).
Note: The mean dose used in the clinical trials was lower at 1.5-1.6
mcg/kg/min. Notably lower doses are common depending on the
patient’s presentation. See Chapter 5.
doses (e.g., rate <1 mcg/kg/min), elimination may be slower and
steady-state may not be achieved within 6 hr.
Diarrhea, pain, rash, unspecified hemorrhage, purpura,
thrombophlebitis
TABLE 18-15: Bivalirudin in HIT
Evidence supporting
bivalirudin
Several case series in over 800 patients with HIT initially treated
with bivalirudin have demonstrated similar rates of new thrombosis,
mortality, death related to thrombosis, major bleeding, and a
decreased rate of HIT-related amputation as argatroban. The largest
study to date included 461 patients with suspected, confirmed, or
previous history of HIT.
Clinical trials have been conducted on the use of bivalirudin in patients
with HIT concerns undergoing cardiac bypass graft surgery.
16,17
5,18-20
Dosing Initiate at 0.15–0.20 mg/kg/hr IV and titrate to target aPTT of 1.5–2.5
Monitoring aPTT 2–6 hr after each titration.
Common adverse
events
aPTT: activated partial thromboplastin time, CrCl: creatinine clearance, hr: hours, HIT: heparininduced thrombocytopenia, IV: intravenous, min: minute, RRT: renal replacement therapy, x: times
Note: For more detailed information, see Chapter 5.
x the baseline aPTT. Patients with renal dysfunction require dose
reductions. Based on case studies, suggested initial doses are:
Clearance creatinine (CrCl 30–60 mL/min): 0.08–0.1 mg/kg/hr
CrCl <30 mL/min or receiving RRT: 0.03–0.05 mg/kg/hr
For more dosing insights, see Chapter 5 on Direct Thrombin Inhibitors.
Bleeding, injection site reaction, headache, anxiety, insomnia, pelvic or
back pain
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TABLE 18-16: Danaparoid in HIT*
Chemistry Danaparoid is a mixture of depolymerized glycosaminoglycans:
Pharmacology Indirect inhibition through antithrombin on factor Xa; anti-factor Xa:
Cross-reactivity with
heparin antibodies
Observations in HIT
management
*Currently not available in the United States.
ACT: activated clotting time, aPTT: activated partial thromboplastin time, HIT: heparin-induced
thrombocytopenia, INR: international normalized ratio, LMWH: low molecular weight heparin
heparan sulfate (84%), dermatan sulfate (12%), and chondroitin sulfate
(4%); a lower degree of sulfation and charge density compared to
LMWH limits its binding to plasma proteins and platelets.
anti-factor Ila ratio >22:1; no effect unless at high doses on the aPTT,
INR, or ACT.
10% cross reactivity but not of any noted clinical significance in HIT.
In an assessment of 62 patients treated with danaparoid and
transitioned to warfarin, compared to ancrod plus warfarin or warfarin
alone; a new thrombosis, death or limb amputations and bleeding
rates were significantly lower with danaparoid.
In a retrospective analysis of 1,478 cases of HIT receiving danaparoid,
a survival rate of 84% with new thrombosis during treatment of 9.7%
and 16.4% having an inadequate treatment response (new/extended
thrombosis, platelet count reduction, or unplanned amputation during
treatment); major bleeding occurred in 8.1%.
Similar efficacy (80%) to lepirudin if at therapeutic doses with a lower
bleeding rate (2.5% vs. 10.4%) in one analysis.
21
HEPARIN-INDUCED THROMBOCYTOPENIA 439
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TABLE 18-17: Danaparoid Dosing and Monitoring
Indication Danaparoid Dose Anti-Factor Xa
Acute HIT management Bolus:
VTE prophylaxis (history
of HIT)
VTE treatment 2,250 units IV bolus followed by 400 units/hr
Intermittent hemodialysis
(for preventing
thrombosis of the circuit)
Continuous renal
replacement therapy
Cardiac catheterization ≤75 kg: 2,250 units IV preprocedure
PCI/balloon pump Cardiac cath-preprocedure then 150–200
Cardiopulmonary bypass 125 units/kg IV bolus
< 60 kg: 1,500 units
60–75 kg: 2,250 units
>75–90 kg: 3,000 units
>90 kg: 3,750 units
Accelerated post bolus initial infusion:
400 units/hr × 4 hr then 300 units/hr × 4 hr
then 200 units/hr (subsequently adjusted
by anti-factor Xa activity levels calibrated to
danaproid of 0.5 to 0.8 units/L)
Maintenance infusion:
•
Normal renal function: 200 units/hr
• Renal dysfunction (Scr >220 micromils/L
or 2.5 mg/dL): 150 units/hr
750 units sub-Q q 8–12 hr
× 4 hr then 150–200 units/hr
Option: 1,500–2,250 units sub-Q q 12 hr
3,750 IV prior to first two dialysis sessions,
3,000 units for third dialysis, then reduce to
2,250 units
2,250 units IV bolus followed by 400 units/hr
× 4 hr then 300 units/hr × 4 hr, then 150–400
units/hr
75–90 kg: 3,000 units
>90 kg: 3,750 units
units/hr for 1–2 days
Post-PCI until balloon pump removed
Post-thoracotomy
Prime circuit: 3 units/mL, 7 units/kg/hr IV
infusion after bypass initiated, and stopping
45 min prior to going off circuit
3-5
Targets
0.5–0.8 units/mL
0.5–0.8 units/mL
Predialysis:
<0.3 units/mL
During dialysis:
0.5–0.8 units/mL
During
hemodialysis:
0.5–0.8 units/mL
Embolectomy/vascular
surgery
Cardiac cath: cardiac catheterization, HIT: heparin-induced thrombocytopenia, hr: hour, IV:
intravenous, PCI: percutaneous coronary intervention, sub-Q: subcutaneous, VTE: venous
thromboembolism, x: times
2,250 units IV preoperatively, 750 units in
250 mL 0.9% saline up to 50 mL uses as
intraoperative flushes
Postoperative:
Low risk: 750 units sub-Q q 8 hr
High risk:150–200 units/hr starting 6 hr or
more after procedure
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