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31–38.
160. Wormald JR , Lane TR , Herbert PE , et al. Total preservation of
patency and valve function a er percutaneous pharmacomechanical thrombolysis using the Trellis-8 system for an acute, extensive deep vein thrombosis , An R Coll Surg Engl. 2012 . 94 ( 2 ):
e103–e105.
161. Comerota AJ , Gale SS. Techniques of contemporary ileofemoral and infrainguinal venous thrombectomy, J Vasc Surg. 2006 .
43 ( 1 ): 185–191.
162. Meissner MH , Gloviczki P , Comerota AJ , et al. Early thrombus
removal strategies for acute venous thrombosis: Clinical practice
guidelines of the Society for Vascular Surgery and the American
Venous Forum, J Vasc Surg. 2012 . 55 ( 5 ): 1449–1462.
163. Decousus H , Leizorovicz A , Parent F, et al. A clinical trial of
vena cava lters in the prevention of pulmonary embolism in
patients with proximal deep-vein thrombosis, N Engl J Med. 1998 .
338 ( 7 ): 409–415.
164. Mismetti P , Rivron-Guillot K , uenet S , et al. A prospective
long-term study of 220 patients with a retrievable vena cava lter
for secondary prevention of venous thromboembolism, Chest.
2007 . 131 ( 1 ): 223–229 .
165. Young T , Tang H , Aukes J , etal. Vena caval lters for the prevention of pulmonary embolism , Cochrane Database Syst Rev. 2007 .
4 : CD0006212 .
166. Tschoe M , Kim HS , Brotman DJ , etal. Retrievable vena cava lters:Aclinical review , J Hosp Med. 2009 . 4 ( 7 ): 441–448 .
167. Strei M B . Ve n a c a v a lters:Acomprehensive review, Blood. 2000 .
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CONVENTIONAL TREATMENT OF DEEP VENOUS THROMBOSIS • 331
41.
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DIAGNOSIS AND MANAGEMENT OF
HEPARININDUCED THROMBOCYTOPENIA
eodore E . Warkentin
INTRODUCTION
e Vein Book would be incomplete without a discussion of
heparin-induced thrombocytopenia (HIT) for three reasons. First, deep venous thrombosis (DVT) is almost always
initially treated with heparin, thus creating the potential
for this immune-mediated adverse drug reaction. Second,
venous thrombosis itself is the most common complication
of HIT.
with warfarin can precipitate severe venous limb ischemia
(phlegmasia cerulea dolens), with potential for limb loss
(venous limb gangrene).
HIT can be de ned as any clinical event (or events) best
explained by platelet-activating anti-platelet factor 4 (PF4)/
heparin antibodies (“HIT antibodies”) in a patient who is
receiving, or who has recently received, heparin.
patients, this includes a large platelet count fall that usually
exceeds 50%.
stems from its strong association with thrombosis.
e key event in HIT pathogenesis is formation of
platelet-activating antibodies of immunoglobulin G (IgG)
class that recognize a “self” protein, PF4, bound to heparin. Multimolecular complexes of PF4, heparin, and IgG
form on platelet surfaces, leading to platelet activation (via
platelet Fc IgG receptors) and formation of procoagulant
platelet-derived microparticles, thereby stimulating hypercoagulability (increased thrombin generation). Heparin
molecules bind to PF4 in relation to their chain length,
perhaps explaining why unfractionated heparin (UFH)
is more likely to cause HIT than low molecular weight
heparin (LMWH) or fondaparinux.
1,2
ird, the treatment of HIT-associated DVT
DEFINITIONOFHIT
1
In most
1–3
e clinical importance of HIT primarily
P A T H O G E N E S I S
3,4
Once triggered, the
prothrombotic risk of HIT persists (or even worsens) for
several days, despite stopping heparin.
1,5
CLINICAL PRESENTATION
T H E “ 4 T ’ S ”
rombocytopenia is common in heparin-treated patients,
yet only a minority have HIT. Aclinical scoring system, the
“4 T’s,” helps predict which patients have HIT, based on
assessment of: T hrombocytopenia, T iming, T hrombosis,
and the absence of o T her explanation(s) (see Table41.1).
1,2
Evaluation of this scoring system suggests that HIT antibodies are unlikely (<5%) when a low score (≤3) is obtained,
6
but likely (50–80%) with a high score (≥6).
An intermediate score (4 or 5)usually indicates a clinical pro le compatible with HIT but also with another plausible explanation,
such as sepsis.
Most patients with HIT have moderate thrombocy-
topenia, with platelet count nadirs usually between 20 to
9
150× 10
develop a platelet count fall to less than 20 × 10
/L (median nadir, 60× 10 9 /L); only 5 to 10%
9
1,2
/L.
At least 90% of patients evince a 50% or greater platelet
count fall; especially in postoperative patients (who usually exhibit thrombocytosis a er postoperative day 5), even
a large platelet count decline may not necessarily cause the
9
platelet count to fall below 150× 10
/L. 3
Typically, the platelet count begins to fall 5 to 10days
a er starting heparin, although a more rapid platelet
count fall can occur if HIT antibodies are already present
7
because of a recent exposure to heparin.
is link between
“rapid-onset HIT” and recent heparin use is explained by the
unusual transience of HIT antibodies, which become undetectable a median of 50 to 80days (depending on the assay
7
performed) a er an episode of HIT.
Indeed, the transience
of HIT antibodies, together with the inability to regenerate
HIT antibodies before day 5 following reexposure, provides
332
Table41.1 CLINICAL SCORING SYSTEM FOR HIT:THE “4T’S”
https://t.me/med1917
POINTS 0, 1, OR 2 FOR EACH OF 4 CATEGORIES:MAXIMUM POSSIBLE SCORE=8
2 1 0
rombocytopenia >50% platelet fall to nadir >20 30–50% platelet fall (or >50%
Timing* of onset of platelet
fall (or other sequelae of
HIT)
rombosis or other sequelae proven new thrombosis; skin
O er cause(s) of platelet fall none evident Possible de nite
Pretest probability score:6–8= HIGH; 4–5=INTERMEDIATE; 0–3=LOW
*First day of immunizing heparin exposure consideredday0.
Reprinted, with modi cations, from Reference 6 with permission.
days 5–10; or <day 1 with recent
heparin (past 30days)
necrosis; or anaphylactoid
reaction a er IV UFH bolus
fall resulting from surgical
hemodilution); or nadir 10–19
>day 10 or timing unclear; or
<day 1 with recent heparin
(past31–100days)
progressive or recurrent
thrombosis; erythematous
skin lesions; suspected
thrombosis (not proven)
<30% platelet fall; or nadir <10
<day 4 (no recent heparin)
None
a rationale for using intraoperative heparin anticoagulation
during cardiac or vascular surgery in a patient with previous HIT, provided that platelet-activating antibodies are no
7,8
longer detectable.
Rarely, HIT begins several days a er heparin already has
been stopped (“delayed-onset HIT”); this syndrome is asso-
9
ciated with strong positive tests for HIT antibodies.
Sera
from these patients activate platelets in vitro without the
need to add heparin.
rombosis is the most important complication of
1–5
HIT and occurs in most patients.
Both venous and arte-
rial thrombi can occur (see Table41.2). e odds ratio for
2,10
thrombosis ranges from 20 to 40.
Table41.2 THROMBOSIS AND OTHER SEQUELAEOFHIT
VENOUS THROMBOSIS ARTERIAL THROMBOSIS MISCELLANEOUS
DVT (50%):new, progressive,
recurrent; lower limb (o en
bilateral); upper limb (at site of
venous catheter); phlegmasia
cerulea dolens
Coumarin-induced venous limb
gangrene (5–10% of DVT treated
with coumarin)
PE (25%):with or without
right-sided cardiac intra-atrial or
intraventricular thrombi
Cerebral (dural) sinus thrombosis (rare)
Splanchnic vein thrombosis:adrenal
hemorrhagic infarction*
(rare):bilateral (acute or chronic
adrenal insu ciency) or unilateral;
mesenteric or portal vein
thrombosis
*secondary to adrenal vein thrombosis
Estimated frequencies of the various complications of HIT are given in parentheses. Rare indicates an estimated frequency <3% of HIT patients.
(Reprinted, with modi cations from Reference2)
Aortic or iliofemoral thrombosis resulting in
acute limb ischemia or infarction (5–10%) or
spinal cord infarction (rare)
Acute thrombotic stroke (3–5%)
Myocardial infarction (3–5%)
Cardiac intraventricular or intra-atrial
thrombosis, in situ or via embolization of
DVT (rare)
rombosis involving miscellaneous arteries
(rare):upper limb, renal, mesenteric, spinal,
and others
Embolization of thrombus from heart or
proximal aorta can also contribute to
microvascular ischemic syndromes
Venous thrombosis is the most common complication of
HIT, usually manifesting as unilateral or bilateral lower
limb DVT.
with HIT, with half of these (i.e., 25% overall) developing
symptomatic pulmonary embolism. In one study, upper
limb DVT occurred in 10% of HIT patients with use of a
central venous catheter (CVC); compared with controls,
both HIT and CVC use were strongly associated with
upper limb DVT, illustrating that a localizing risk factor
(vessel injury from the CVC) interacts with systemic hypercoagulability (HIT), thereby in uencing the type and location of thrombosis.
VENOUS THROMBOSIS ANDHIT
1,2
Indeed, DVT occurs in about 50% of patients
11
Heparin-induced skin lesions at injection
sites (10–20%):erythematous plaques, skin
necrosis
Coumarin-induced skin necrosis involving
“central” sites (breast, abdomen, thigh, calf,
etc.; rare)
Acute anaphylactoid reactions post IV heparin
bolus (25% of sensitized patients receiving
IV bolus or SC LMWH injection):
I n ammatory:fever, chills, ushing
Cardiorespiratory:tachycardia, hypertension,
dyspnea, cardiopulmonary arrest (rare)
Gastrointestinal:nausea, vomiting, diarrhea
Neurological:transient global amnesia,
pounding headache
Overt DIC (10–20%)
DIAGNOSIS AND MANAGEMENT OF HIT • 333
PHLEGMASIA CERULEA DOLENS
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AND VENOUS LIMB GANGRENE
LIMB ISCHEMIA AND
THROMBOCYTOPENIA
Venous limb ischemia (phlegmasia cerulea dolens, venous
limb gangrene) can result if coumarins such as warfarin are used to treat DVT associated with HIT (see
2,12–15
Figure41.1).
is results from disturbed procoagulantanticoagulant balance: HIT creates hypercoagulability
(increased thrombin generation), and coumarin impairs
synthesis of the vitamin K–dependent natural anticoagulant, protein C. A supratherapeutic international normalized ratio (INR), usually >3.5, is characteristic of venous
limb ischemia, and represents a surrogate marker for
severe protein C depletion (re ecting parallel reduction in
factor VII). Rarely, overt (decompensated) disseminated
intravascular coagulation (DIC) can explain microvascular
thrombosis and limb ischemia in the absence of coumarin
2
(see Figure 44.1).
Venous gangrene is a more common
explanation for limb loss in HIT than the white clot syndrome (discussed subsequently).
ARTERIAL THROMBOSIS
Occlusion of large or medium-sized arteries by platelet- and
leukocyte-rich “white clots” is the classic explanation for
2
limb ischemia in HIT (see Figure41.1).
e distal aorta
and iliofemoral arteries are most frequently involved, leading
to acute limb ischemia with absent pulses. e thrombi can
form either in situ or as a result of embolization from a more
proximal location, including the le ventricle or proximal
aorta. Other arterial events that are relatively common in
HIT include thrombotic stroke and myocardial infarction.
Table 41.3 lists several diagnostic considerations when a
patient presents with the combination of thrombocytope-
16
nia and an ischemic limb.
Absence of pedal pulses suggests
occlusion of large arteries by thromboemboli. Palpable (or
Doppler-identi able) pulses, especially in the setting of
DVT, suggests venous limb ischemia, due to coumarin or
At least 5% of patients with HIT develop limb necrosis
17
requiring amputation.
Sometimes, limb loss is iatrogenic
(warfarin-related) and thus potentially preventable (see
later). Timely thrombectomy can salvage limbs in some
circumstances (see later).
MISCELLANEOUS COMPLICATIONS
Less than 10% of patients who develop HIT during subcutaneous (SC) injections of UFH or LMWH develop necrotiz-
1,2
ing skin lesions at the injection sites.
to be at relatively high risk of developing arterial thrombosis.
ese patients appear
2
HIT can also present as an acute systemic (or anaphy-
1,2,18
lactoid ) reaction .
ese follow intravenous (IV) bolus
injection of heparin to a patient with circulating HIT antibodies. Symptoms and signs, which begin 5 to 30 min post
injection, are listed in Table41.2. Abrupt platelet count
declines accompany these reactions.
Approximately 10 to 20% of patients with HIT show
laboratory evidence of overt (decompensated) DIC,
including elevated INR and/or activated partial thromboplastin time (APTT), reduced brinogen, red cell
ree Ischemic Limb Syndromes in HIT
1
Coumarin-induced
venous limb
gangrene
2
White clot
syndrome
Figure41.1 ree ischemic limb syndromes in HIT. (1)Coumarin-induced venous limb gangrene is characterized by acral (distal extremity) necrosis
in a limb with DVT. e INR is usually >3.5. (2)White clot syndrome is characterized by large artery occlusion by platelet-rich white clots.
(3)Rarely, microvascular thrombosis secondary to DIC can explain acral limb necrosis even in the absence of coumarin therapy; a ected limbs may
or may not have associated DVT. For comparison, the classic form of coumarin-induced skin necrosis is shown, which usually involves nonacral sites,
such as breast, abdomen, orthigh.
Reprinted, with modi cations, from Reference 15, with permission.
DVT
Acral
necrosis
Limb artery
thrombosis
Acral
necrosis
334 • VENOUS THROMBOEMBOLISM
± DVT
Acral
necrosis
Coumarin-induced
skin necrosis
(nonacral necrosis)
3
Microvascular
thrombosis
2°to DIC
(no coumarin)
Table41.3 DIAGNOSTIC CONSIDERATIONS IN APATIENT WITH LIMB ISCHEMIA AND THROMBOCYTOPENIA
https://t.me/med1917
Concurrence of limb ischemia/necrosis and thrombocytopenia suggests one of several hematologic emergencies.
(A) HIT-associated arterial thrombosis. Occlusion of large lower-limb arteries by platelet-rich “white clots” is characteristic of HIT. e
major clue is an otherwise unexplained platelet count fall that begins 5 or more d a er starting heparin. Urgent thromboembolectomy
may be limb-sparing. Sensitive assays for HIT antibodies give strong positive results.
( B) Adenocarcinoma-associated DIC. Severe venous or arterial thrombosis can develop in patients with metastatic adenocarcinoma who have
DIC, especially within hours a er stopping heparin. Aclinical clue is an otherwise unexplained rise in platelet count that occurred during
initial heparin therapy.
(C) Warfarin-induced phlegmasia cerulea dolens/venous limb gangrene. Coumarin anticoagulants (e.g., warfarin) can lead to venous ischemia
(phlegmasia cerulea dolens) or venous limb gangrene in patients with DIC caused by HIT or adenocarcinoma. Limb loss can occur even
though the limb pulses are palpable.
(D) Sepsis-associated macro- or microvascular thrombosis. Acquired natural anticoagulant failure (e.g., antithrombin or protein C depletion)
can complicate DIC associated with sepsis, leading to acral limb ischemia or necrosis.
(E) Septic embolism. Rarely, infective endocarditis or aneurysmal thrombosis leads to the constellation of thrombocytopenia associated with
infection and acute limb ischemia.
(F) Antiphospholipid syndrome. Autoimmune thrombocytopenia and hypercoagulability can interact to produce acute limb ischemia and
thrombocytopenia in a patient with antiphospholipid syndrome.
Reprinted, with modi cations, from Reference 16 with permission.
fragments, or circulating nucleated red cells. 2 ese patients
can develop ischemic limb necrosis in spite of nonhepa-
14,17,19
rin anticoagulant therapy.
Indeed, HIT-associated
DIC—by elevating APTT values—can result in suboptimal therapy by APTT-adjusted therapeutic agents (“APTT
17,19
confounding”).
LABORATORY TESTING FOR HIT
ANTIBODIES
Two types of assays detect HIT antibodies.
1,20
Most widely
used are the commercial enzyme-immunoassays (EIAs)
that test for antibodies reactive against PF4/polyanion
complexes. In contrast, platelet activation assays exploit
this pathologic feature of HIT. As a general rule, the stronger a positive test is, the greater the likelihood the patient
21
hasHIT.
P L A T E L E T A C T I V A T I O N A S S A Y S
e best platelet activation assays utilize “washed” platelets, for example, the platelet serotonin release assay (SRA).
When performed by experienced labs, this assay is sensitive
for clinically important HIT antibodies, with high speci c-
20
ity (usually >95%).
However, washed platelet activation
assays are technically demanding and available in only a few
reference centers.
PF4/POLYANION IMMUNOASSAYS
Solid-phase EIAs detect antibodies that react with PF4
complexed with heparin or other polyanions. IgG-speci c
EIAs have similar high sensitivity as polyspeci c EIAs (that
detect additionally IgA and IgM), but with greater diagnostic speci city (since only IgG antibodies causeHIT).
ICEBERGMODEL
Figure 41.2 shows the interrelationships among di erent
HIT antibody assays, thrombocytopenia (i.e., HIT), and
the subset with HIT-associated thrombosis (HIT-T).
4,20
Five features are illustrated: (1)washed platelet activation
assays (e.g., SRA) and EIAs have similar high sensitivity
for clinical HIT; (2)the SRA has greater diagnostic speci-
c i t y for clinical HIT than the EIAs; (3)the IgG-speci c
EIA has greater diagnostic speci city than the polyspeci c EIA-IgG/A/M; (4)only a subset of heparin-treated
patients who form antibodies develop clinical HIT; and
(5)increased risk of thrombosis is not observed in patients
who develop antibodies in the absence of a signi cant platelet countfall.
HIT-THIT
No increase in
thrombosis rate
compared with
antibody-negative
controls
Figure41.2 Iceberg model of HIT. is model depicts several features
of HIT, including the hierarchy of sensitivity and speci city of three
di erent types of assays:(i)platelet activation assay that utilizes
washed platelets, for example, platelet SRA; (ii) PF4/heparin EIA that
detects IgG class antibodies (EIA-IgG); and (iii) polyspeci c EIA that
detects antibodies of IgG, IgM, and/or IgA class (EIA-IgG/A/M).
Clinical HIT indicates either of the top two levels of the iceberg,
including the subset of patients with HIT complicated by thrombosis
(HIT-T). e frequency of thrombosis among patients who do not
develop thrombocytopenia is similar to that of antibody-negative
controls.
SRA
+
+
+
EIAIgG
EIAIgG/A/M
DIAGNOSIS AND MANAGEMENT OF HIT • 335
T R E A T M E N T
https://t.me/med1917
In the United States, two nonheparin anticoagulants,
lepirudin (see later) and argatroban (see later), are approved
Section Aof Table41.4 lists six general principles of treat-
1,8,17
ment.
If heparin is stopped in a patient with strongly
suspected (or serologically con rmed) HIT, an appropriate nonheparin anticoagulant should be initiated. is is
for treatment of HIT. Fondaparinux, although not speci cally approved for HIT, appears e ective for this disor-
17,23
and is increasingly utilized for this indication (see
der,
below).
because 35 to 50% of patients with serologically con rmed
HIT develop symptomatic thrombosis (including 5%
thrombotic death rate) when heparin is stopped because of
1,5,8
thrombocytopenia alone (“isolated” HIT).
Interestingly,
antibody levels can decrease, and platelet counts can recover,
22
even if heparin is continued in some patients withHIT.
Given the high frequency of DVT, routine duplex ultra-
16,17
sonography is recommended.
Testing for HIT antibod-
ies provides important corroborative (if strongly positive) or
21
contrary (if negative or only weakly positive) information.
Anegative test for HIT antibodies allows for resumption
of heparin.
Table41.4 TREATMENT PRINCIPLES WHEN HIT IS STRONGLY SUSPECTED OR CONFIRMED
A. General principles
1. Discontinue and avoid all heparin (including LMWH).
2. Give a nonheparin, alternative anticoagulant.
3. Postpone warfarin pending substantial platelet count recovery (give vitamin K if warfarin has already been started).
4. Test for HIT antibodies.
5. Investigate for lower limb DVT.
6. Avoid prophylactic platelet transfusions.
B. Nonheparin anticoagulant options during vascular surgery
CONTRAINDICATIONS:WARFARIN,
PLATELET TRANSFUSIONS, VENA
CAVA FILT E R S
Wa r f a r i n
Warfarin is ine ective in acute HIT and predisposes to
microvascular thrombosis.
more common manifestation of coumarin necrosis in HIT
than is “classic” skin necrosis. In patients with acute HIT,
it is recommended that warfarin be postponed (or avoided
12–15
Venous limb gangrene is a
Lepirudin
Intraoperative bolus*:0.2–0.4 mg/kg IV (immediately before vascular clamping) followed by 0.05–0.10 mg/kg/h** (target APTT, 1.5–2.5×
baseline);
Intraoperative “ ush” solution consisting of 0.1 mg/ml lepirudin (maximum, 250 ml administered during surgery);
Postoperative anticoagulation, ranging from 0.05 mg/kg/h (target APTT 1.5–2.0× baseline APTT) or 15 mg bid SC in patients at relatively
low risk for postoperative reocclusion (e.g., surgery involving aorta, iliac, femoral, or carotid arteries) to 0.10 mg/kg/h (target APTT
1.5–2.5× baseline) for patients at relatively high risk of postoperative reocclusion (e.g., popliteal bypass).**
Argatroban
Intraoperative bolus*:0.1 mg/kg bolus, followed by 0.5 to 2g/kg/min infusion (= 0.03 to 0.12 mg/kg/h) for intraoperative and postoperative
anticoagulation (target APTT 1.5–3.0× baseline APTT).
Danaparoid
Intraoperative bolus*:2,250 anti-Xa U for patient weighing 60–75kg (bolus dose adjusted to 1,500 and 3,000 U for patients weighing <60 and
>75kg, respectively).
Intraoperative “ ush” solution:750 U in 250 ml normal saline (maximum, 250 ml if the intraoperative bolus has been given).
Postoperative anticoagulation, ranging from low (prophylactic dose), i.e., 750 U bid or tid SC or higher (therapeutic dose) usually 200 U/h
(with target anti-Xa levels between 0.5 and 0.8 U/ml)
* Assumes patient has absent or low drug levels at start of surgery (otherwise bolus may not be required).
** In case of renal insu ciency, dosing must be decreased by up to 90%. As anesthesia results in decreased renal perfusion, the dose of lepirudin should be reduced by
approximately 30% (with APTT adjustments) during surgery and in the early postoperative period even in a patient stably anticoagulated prior to surgery. e APTT
should be monitored frequently during and following surgery.
Use of these agents for intraoperative anticoagulation represents “o -label”use.
bid, twice-daily; tid, thrice daily; U,units.
Section Ais modi ed from Reference 29. Section B is modi ed from Reference 28, which also provides additional supporting literature.
336 • VENOUS THROMBOEMBOLISM
completely) pending substantial resolution of thrombo-
https://t.me/med1917
9
cytopenia (preferably, platelet count >150×10
subsequent gradual initiation of warfarin anticoagulation.
/L), with
8
Administration of vitamin K is advised when acute
HIT is diagnosed a er warfarin has already been started:
8,14
besides reducing risk of coumarin necrosis, this reduces risk
of underdosing of lepirudin and argatroban, since warfarin
prolongs the APTT used to monitor these anticoagulants.
Platelet Transfusions
Prophylactic platelet transfusions are not recommended,
as petechiae and other evidence of impaired hemostasis
usually are not seen in HIT; in theory, transfused platelets
might contribute to increased thromboticrisk.
Vena Cava Filters
In my opinion, vena cava lters should be avoided, as their
use in acute HIT o en is complicated by massive lower
limb venous thrombosis. Further, the presence of a lter might tempt physicians to avoid or minimize needed
anticoagulation.
ALTERNATIVE NONHEPARIN
ANTICOAGULANTS
in overdosing and bleeding, and therefore consensus con-
8
ference guidelines
follows: (1) no bolus; (2) initial infusion rate, 0.05 to
recommend much lower dosing, as
0.10 mg/kg/h (assumes normal renal function, otherwise
dosing is much lower
8
); and (3)APTT monitoring at 4-h
intervals until steady state is reached, and a er any dose
adjustment. An important problem arises when there is
baseline APTT prolongation (e.g., severe HIT-associated
DIC, preceding coumarin therapy, hepatic dysfunction,
etc.): in this situation, APTT monitoring is not reliable,
17,19
potentially contributing to adverse outcomes.
Compared with historical controls, lepirudin treatment
of serologically con rmed HIT complicated by thrombosis was associated with reduced thrombotic events, from
approximately 25% to 7% (relative risk reduction [RRR],
17
0.72).
isolatedHIT.
Lepirudin also appeared e ective for treating
8
Lepirudin’s foreign structure can trigger antihirudin
antibodies that sometimes alter its pharmacokinetics, for
example, drug accumulation resulting from impaired renal
excretion of lepirudin-IgG complexes. us, daily APTT
monitoring is required. Fatal anaphylaxis following IV
bolus administration has been reported.
Recently (April 2012), the manufacturer discontinued
lepirudin world-wide, although it may remain available in
some jurisdictions through another manufacturer.
Five alternative nonheparin anticoagulants have a rational
17
basis for use in managing HIT.
ree (lepirudin, argatroban, bivalirudin) are direct thrombin inhibitors (DTIs),
whereas two (danaparoid, fondaparinux) can be classi ed as
indirect (antithrombin [AT]-dependent) inhibitors of activated factor X(Xa).
L E P I R U D I N R E F L U D A N
Lepirudin is a recombinant hirudin that forms irreversible
17
1:1 complexes with thrombin.
(Hirudin is the thrombin
inhibitor produced by the medicinal leech.) is 65-amino
acid polypeptide (6,980 Da) exhibits exceptionally high
a nity for thrombin (Ki=0.0001nmol/L) resulting from
bivalent binding, as it recognizes both the brin(ogen)
binding site and a region near the active (catalytic) site
of thrombin. Its irreversible binding to thrombin could
contribute to its e cacy. e half-life of lepirudin (about
80min) increases greatly in renal insu ciency. As no antidote exists, major dose reduction is required for renally
compromised patients.
Lepirudin is approved by the US Food and Drug
Administration (FDA) for the treatment of HIT complicated by thrombosis. e approved dose (normal kidneys)
is 0.4 mg/kg by IV bolus followed by an initial infusion
rate at 0.15 mg/kg/h, adjusted for target APTT 1.5 to 2.5
times baseline. However, this protocol frequently results
A R G A T R O B A N
Argatroban (Argatroban [US], Novastan [non-US]) is
a synthetic, small-molecule DTI derived from arginine
(527 Da). It reversibly binds to the active site pocket of
thrombin alone and thus is a univalent DTI. e Ki of
argatroban for human thrombin is 40 nmol/L, indicat-
17
ing lower a nity for thrombin than hirudin.
Its half-life
is 40 to 50 min, and it undergoes hepatobiliary excretion.
Argatroban is FDA-approved for the prophylaxis or treatment of thrombosis in patients withHIT.
Argatroban is not immunogenic, and anaphylaxis has
not been reported. e usual dose is 2g/kg/min adjusted
by APTT (usual target, 1.5–3 times baseline APTT), but
lower starting doses are frequently given (0.5–1.2g/kg/
8
e starting dose should be reduced by 75% in a
min).
patient with signi cant liver dysfunction, or in a patient in
the intensive careunit.
Compared with historical controls, argatroban treatment of clinically suspected HIT complicated by thrombosis was associated with reduced thrombotic events,
from approximately 35% to 16% (RRR, 0.55). e lower
RRR compared with lepirudin could re ect the shorter
mean treatment duration of argatroban therapy in its
clinical evaluation compared with lepirudin (7 vs. 14 d,
10
respectively),
or perhaps di erences in its fundamental
mechanism of action (reversible vs. irreversible thrombin
inhibition).
DIAGNOSIS AND MANAGEMENT OF HIT • 337
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