Heparin-Induced Thrombocytopenia

Transcription

N
O
R
T
H
A
M
E
R
I
C
A
N
T
H
R
O
M
Online Newsletter
Heparin-Induced
Thrombocytopenia
Jeanine Walenga, PhD,
from Loyola University
Medical Center in
Chicago, IL, gives us a
comprehensive overview
of Heparin-Induced
Thrombocytopenia
(HIT).
Pages 1-4
B
O
S
I
S
F
O
R
U
M
www.NATFonline.org/eThrombosis September 2007
HIT Case Presentation
Lina Matta, PharmD,
provides a HIT Case
presentation with Quiz
questions.
Pages 5
Future Leaders Journal
Review—Thrombosis
Page 6
Heparin-Induced
Thrombocytopenia
Jeanine M. Walenga, PhD
Cardiovascular Institute, Stritch School of Medicine
Loyola University Chicago
Maywood, Illinois 60148 USA
Heparin-induced thrombocytopenia (HIT) is
an important adverse effect of heparin. HIT is
reported to occur in 1% of medical, 3% of
surgical, and 5% of cardiac surgery or
orthopedic surgery patients, and has also been
diagnosed in other patient populations (1-8).
Progression to overt thrombosis leading to
amputation or death is the most serious
complication occurring in approximately onethird of patients with HIT (9). Thrombosis can
occur anywhere throughout the venous and
arterial circulation. Spontaneous bleeding and
petechiae have been reported only rarely.
Patient Advocacy
NATF Patient
Advocate Kelly Clark
shares her experience
with DVT and PE.
Pages 9-10
other reasons for thrombocytopenia (10-13).
HIT occurs from exposure to unfractionated
heparin (UFH) at prophylactic or treatment
doses or from exogenous sources (e.g.,
catheter flush) (1-9). Low molecular weight
heparin (LMWH) also causes HIT but at a 3fold lower frequency than UFH (14).
HIT is reported to occur in 1% of medical, 3%
of surgical, and 5% of cardiac surgery or
orthopedic surgery patients, and has also
been diagnosed in other patient populations.
Early diagnosis and treatment are important
to improve clinical outcomes. Diagnosis of
HIT is based on a comprehensive HIT
patients
can
present
without
interpretation of clinical and laboratory thrombocytopenia, i.e., the platelet count does
information.
not fall to <100 x 109/L. An abrupt fall in
platelet count in the absence of other
Clinical Presentation
etiologies, and unexplained thrombosis, are
In patients being treated or having been also characteristics of HIT. Symptoms
recently treated with heparin, HIT should be typically appear 4-14 days after exposure to
suspected on the basis of a 30% decrease in UFH, or 8-14 days after exposure to LMWH
platelet count from baseline in the absence of (15). Patients who received heparin within the
www.NATFonline.org/ethrombosis September 2007
Public Policy
Pending legislation that
would make November
DVT Awareness month
in Massachusetts.
Is your state aware?
Page 10
Thrombosis Summit
2007 - Boston, MA
Join us for our
inaugural Thrombosis
Summit, to be held
Saturday, September
29, in Boston, MA.
Page 12
prior 100 days can have an immediate, rapidonset HIT when restarting UFH or LMWH. A
delayed-onset HIT has also been observed
with symptoms appearing several days after
discontinuation of UFH (16).
The post-cardiac surgery patient presents the
greatest challenge due to the typical 40%
platelet count decrease that follows surgery.
Two platelet recovery patterns have been
observed in the cardiac surgery patient with
HIT: a typical post-surgery platelet count
recovery with an abrupt decrease on day 7,
and a slower than typical platelet count
recovery becoming significantly lower than
expected on post-surgery day 3 (17-18).
Careful monitoring for thrombocytopenia and
thrombosis are the primary means for
recognition of HIT. For the first 14 days of
treatment, platelet counts should be
performed every 2 days in patients treated
with LMWH, daily if treated with UFH, and
daily if the patient’s risk of developing HIT is
high. For medical and obstetric patients
treated with LMWH exclusively and no prior
exposure to UFH, it is not necessary to
monitor the platelet count (19,20).
HIT patients experience a spectrum of
thrombotic events including venous and
arterial thrombosis, vascular graft occlusion,
intracardiac
thrombosis,
pulmonary
embolism,
cerebrovascular
accident,
cavernous sinus thrombosis, mesenteric
infarct, renal artery thrombosis, etc.
1
N
O
R
T
H
A
M
E
R
I
C
A
N
T
H
R
O
M
B
Patients with co-morbidities, such as sepsis,
inflammation,
pre-existing
vascular
pathologies, are at higher risk of poorer
clinical outcomes (12). Platelet count nadir,
renal impairment, and surgery are associated
with more severe thrombotic complications
(21). All clinical settings, including the
emergency department, need to be aware of a
patient’s prior UFH/LMWH exposure and
history of HIT.
affinity. Generally, the SRA is more sensitive
than the PAAs. However, HIT patients can
respond positive in the PAA but negative in
the SRA and vice versa (44,45,47). False
negatives occur in both the SRA and the PAAs
but false positives are rare. Due to the
limitations of sensitivity and specificity, these
laboratory tests can confirm a diagnosis of
HIT, but negative results do not exclude a
diagnosis of HIT.
Pathologic Mechanism
The current ELISAs detect IgG, IgA, and IgM
HIT antibodies but only to the PF4/heparin
complex. HIT antibodies targeting IL-8,
NAP-2 or other heparin-binding proteins
cannot be detected. New ELISAs that only
detect IgG-PF4/heparin antibodies have
recently
become
available.
Antibody
generation is far more common than the
development of clinical HIT (46-50). The
clinical relevance of HIT antibody titres
without clinical symptoms is unclear.
Measurable antibody without strong clinical
indication should not be considered HIT.
Thus, the ELISA should not be used as a
screening test since this will over-estimate the
incidence of HIT. A positive ELISA should be
confirmed with a platelet function test for HIT
since the functional tests are more specific
than the ELISAs. On the other hand, since
ELISAs can also fail to diagnose HIT a
negative result should only rule out HIT if the
clinical probabilities are very weak (51).
HIT is an immune response in which
antibodies are mainly targeted to the complex
of heparin and platelet factor 4 (PF4) (22,23).
Antibodies to heparin binding proteins other
than PF4, such as NAP-2 and IL-8, have also
been identified in patients with HIT (24,25).
Heparin binding exposes cryptic regions
within the protein molecule creating
neoepitopes that elicit the formation of HIT
antibodies
(26,27).
Anti-PF4/heparin
antibodies are heterogeneous in affinity and
specificity (28,29). Immunoglobulin G (IgG)
antibodies are the predominant antibody
found in symptomatic HIT patients (30,31).
However, IgA and IgM have also been
identified in patients with symptomatic HIT
(32).
Immune complexes of PF4-heparin and HIT
antibodies that are IgG bind to platelets via
FcIIa receptors, (33) inducing platelet
activation, aggregation, and generation of
highly procoagulant platelet microparticles
(34,35). In addition, HIT antibodies provoke
leukocyte and endothelial cell activation
which
produces
hypercoagulable
and
inflammatory states through tissue factor,
cytokine, and cellular adhesion molecule up
regulation (36-42). This combined cellular
activation leads to a burst of thrombin
generation. The inter-relationships of platelets,
leukocytes,
endothelium,
and
the
inflammatory state determine the clinical
expression of HIT (43).
Laboratory Diagnosis
Two types of laboratory assays for HIT are
available: platelet function tests and ELISA
tests. Each test provides unique and
complementary information (44-47). It is
useful to perform a combination of tests and
to repeat testing over a period of several days
as the HIT antibody titre changes (48).
Platelet function tests include the serotonin
release assay (SRA) and platelet aggregation
assays (PAAs). The PAAs use platelet rich
plasma and detect IgG, IgM, and IgA HIT
antibodies. The SRA, which uses washed
platelets, only detects HIT IgGs with high
2
O
S
I
S
F
O
R
U
M
exposure of patient to lepirudin, physician’s
experience with the drug, and drug
availability (55-57). LMWH can cross-react
with
most
HIT
antibodies
and
is
contraindicated for use in patients with HIT
(10-13,19,20).
Clinical trials have shown the direct thrombin
inhibitors (DTIs) argatroban (58,59) and
lepirudin (60,61) to be safe and effective for
reducing the thrombosis and associated
morbidity / mortality in patients with HIT.
Argatroban is approved for the prophylaxis
and treatment of HIT thrombosis, as well as
for
anticoagulation
of
HIT
patients
undergoing
interventional
cardiology
procedures. Lepirudin is approved for the
treatment of HIT thrombosis. Both argatroban
and lepirudin can be monitored with the
aPTT. A third DTI, bivalirudin, is under
development.
The
pharmacokinetics
and
pharmacodynamics of the DTIs differ
(11,55,56). Lepirudin is cleared through the
kidneys, whereas argatroban is cleared
through the liver. Lepirudin has a longer halflife than argatroban. Antibodies to lepirudin
can develop in 50% of patients which, upon
re-exposure to lepirudin, can result in severe
anaphylactic reactions with fatal outcomes
(62). All DTIs affect clot-based laboratory
assays (e.g., PT/INR, aPTT, factor assays)
(63,64). Argatroban has a more pronounced
The current laboratory tests for HIT do not effect on the PT/INR than lepirudin (64,65).
have sufficient sensitivity and specificity to be
used as the sole tool to diagnosis HIT. Any Danaparoid is a non-heparin anticoagulant
laboratory test for HIT should only be that has been used to successfully treat HIT
performed when there is a strong clinical patients since the 1980’s (66). Studies have
suspicion of HIT. Initial therapeutic decisions shown danaparoid to have a similar efficacy
should not be dependent upon a positive as lepirudin but with a better safety profile
laboratory test, but should be based upon with regard to bleeding, accumulation with
clinical findings (i.e., thrombocytopenia and/ renal failure, and immunization (67). It has a
or new thromboembolic events). Clinical sustained effect, can be used either
judgement with appropriate use and intravenously or subcutaneously, and does not
knowledgeable
interpretation
of
the require routine monitoring. Although crosslaboratory test results are important for the reactivity of danaparoid with HIT antibodies
diagnosis of HIT.
is uncommon, treatment regimens should
include platelet count monitoring (47).
Patient Management
UFH and LMWH should be stopped when the
diagnosis of HIT is suspected (10-13,19,20). It
is not sufficient to merely remove the heparin
(52). Due to the strong hypercoagulable state
and high risk of thrombosis associated with
HIT, it is recommended that all HIT patients
be treated with a non-heparin anticoagulant
that does not cross-react with HIT antibodies
such as argatroban, lepirudin, or danaparoid
(10-13,19,20,53,54). Certain factors need to be
considered when making a clinical treatment
decision including patient renal and liver
function, patient risk of bleeding, prior
Fondaparinux is a heparin-derived, factor Xa
inhibitor that is approved for prophylaxis of
post-orthopedic surgery venous thrombosis as
well as for treatment of deep venous
thrombosis and pulmonary embolism. It does
not bind PF4 or cross-react with pre-formed
HIT antibodies (68,69). Several documented
case studies suggest that fondaparinux may
provide adequate anticoagulation in HIT
patients; however, no studies have been
performed to date and it is not approved for
this clinical indication.
For special populations of patients with HIT
N
O
R
T
H
A
M
E
R
requiring anticoagulation, such as pregnant,
pediatric, and hemodialysis, specific drug and
dose issues need to be considered. HIT
patients requiring cardiac surgery are best
anticoagulated with UFH but only if they are
HIT antibody negative at time of surgery. For
patients wit HIT antibody titre, although
lepirudin and bivalirudin have been used
dosing and monitoring regimens for cardiac
surgery are not optimized. Danaparoid is
contraindicated for use in cardiac surgery.
I
11.
12.
13.
14.
For long-term anticoagulation of patients with
HIT thrombosis vitamin K antagonists can be
used. It is important that treatment only be
initiated after rise of platelet counts to >100 x
109/L or to pre-HIT values to avoid warfarininduced limb gangrene/skin necrosis (70).
Starting doses need to be low (5 mg warfarin,
6 mg phenprocoumon) and given with
overlapping administration of argatroban,
lepirudin, or danaparoid for at least 5 days
(19,20).
15.
16.
17.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Walls JT, Curtis JJ, Silver D, Boley TM, Schmaltz RA,
Nawarawong W. Heparin-induced thrombocytopenia
in open heart surgical patients: sequelae of late
recognition. Ann Thorac Surg. 1992;53:787-91.
Arepally
G,
Cines
DB.
Heparin-induced
thrombocytopenia and thrombosis. Clin Rev Allergy
Immunol. 1998;16:237-47.
Kadidal VV, Mayo DJ, Horne MK. Heparin-induced
thrombocytopenia (HIT) due to heparin flushes: a
report of three cases. J Intern Med. 1999;246:325-9.
Warkentin TE, Sheppard JA, Horsewood P, Simpson
PJ, Moore JC, Kelton JG. Impact of the patient
population on the risk for heparin-induced
thrombocytopenia. Blood. 2000;96:1703-8.
Liu JC, Lewis BE, Steen LH, Grassman ED, Bakhos M,
Blakeman B, et al. Patency of coronary artery bypass
grafts
in
patients
with
heparin-induced
thrombocytopenia. Am J Cardiol. 2002;89:979-81.
Girolami B, Prandoni P, Stefani PM, Tanduo C,
Sabbion P, Eichler P, et al. The incidence of HIT in
hospitalized
medical
patients
treated
with
subcutaneous unfractionated heparin: a prospective
cohort study. Blood. 2003;101:2955-9.
Verma AK, Levine M, Shalansky SJ, Carter CJ, Kelton
JG. Frequency of heparin-induced thrombocytopenia
in
critical
care
patients.
Pharmacotherapy.
2003;23:745-53.
Mehta R, Golichowski A. Treatment of heparin
induced thrombocytopenia and thrombosis during
the first trimester of pregnancy. J Thromb Haemost.
2004;2:1665-6.
Warkentin TE, Kelton JG. A 14-year study of heparininduced
thrombocytopenia.
Am
J
Med
1996;101:502-507.
Walenga JM, Frenkel EP, Bick RL. HIT, paradoxical
thromboembolism, and other adverse effects of
heparin-type therapy. In: Bick RL (ed): Hematology/
Oncology Clinics of North America. Thrombosis and
Thrombophilia:
Diagnosis
and
Management.
Saunders, Philadelphia, PA, 2003;17(1):259-282.
18.
19.
20.
21.
22.
23.
24.
25.
26.
C
A
N
T
H
R
O
M
B
Walenga JM. Heparin-induced thrombocytopenia and
treatment with thrombin inhibitors. Jpn J Thromb
Hemost 2005;16(6):623-640.
Alving BM. How I treat heparin-induced
thrombocytopenia and thrombosis. Blood 2003;101
(1):31-37.
Gruel Y, Pouplard C, Nguyen P, Borg JY, Derlon A,
Juhan-Vague I, Regnault V, Samama M, the French
Heparin-Induced Thrombocytopenia Study Group.
Biological and clinical features of low-molecularweight heparin-induced thrombocytopenia. Br J
Haematol 2003;121(5):786-792.
Gruel Y, Pouplard C, Nguyen P, Borg JY, Derlon A,
Juhan-Vague I, et al. Biological and clinical features of
low-molecular-weight
heparin-induced
thrombocytopenia. Br J Haematol. 2003;121:786-92.
Lubenow N, Kempf R, Eichner A, Eichler P, Carlsson
LE,
Greinacher
A.
Heparin-induced
thrombocytopenia:
temporal
pattern
of
thrombocytopenia in relation to initial use or
reexposure to heparin. Chest. 2002;122:37-42.
Rice L, Attisha WK, Drexler A, Francis JL. Delayedonset heparin-induced thrombocytopenia. Ann Intern
Med. 2002;136:210-5.
Gerdisch M, Wallis DE, Birger-Botkin S, Prechel MM,
Jeske WP, Jacobs K, Castellanos Y, Messmore HL,
Bakhos M, Walenga JM. Pre-operative platelet count
as baseline is not predictive of HIT following cardiac
surgery. Blood 2002;100(11):688a.
Pouplard C, May MA, Regina S, Marchand M,
Fusciardi J, Gruel Y. Changes in platelet count after
cardiac surgery can effectively predict the
development of pathogenic heparin-dependent
antibodies. Br J Haematol 2005;128:837-841.
Warkentin TE, Greinacher A. Heparin-induced
thrombocytopenia: recognition, treatment, and
prevention: the Seventh ACCP Conference on
Antithrombotic and Thrombolytic Therapy. Chest.
2004;126:311S-37S.
International Consensus Statement Committee.
Prevention
and
treatment
of
venous
thromboembolism. International consensus statement.
(Guidelines according to scientific evidence.) Int
Angiol 2006;25:101-161.
Greinacher A, Farner B, Kroll H, Kohlmann T,
Warkentin TE, Eichler P. Clinical features of heparininduced thrombocytopenia including risk factors for
thrombosis. Thromb Haemost 2005;94:132-135.
Amiral J, Bridey F, Dreyfus M, et al. PF4 complexed to
heparin is the target for antibodies generated in
heparin-induced
thrombocytopenia.
Thromb
Haemost 1992;68:95-96.
Greinacher A, Potzsch B, Amiral J, Dummel V, Eichner
A,
Mueller-Eckhardt
C.
Heparin-associated
thrombocytopenia: isolation of the antibody and
characterization of a multimolecular PF4-heparin
complex as the major antigen. Thromb Haemost.
1994;71:247-51.
Amiral J, Marfaing-Koka A, Wolf M, et al. Presence of
auto-antibodies to interleukin-8 or neutrophilactivating peptide-2 in patients with heparinassociated-thrombocytopenia. Blood 1996;88:410-416.
Regnault V, de Maistre E, Gruel Y, Nguyen P, Tardy B,
Lecompte T. Platelet activation induced by human
antibodies to interleukin-8. Blood 2003;101:1419-1421.
Newman PM, Chong BH. Heparin-induced
thrombocytopenia: new evidence for the dynamic
binding of purified anti-PF4-heparin antibodies to
platelets and the resultant platelet activation. Blood.
2000;96:182-7.
O
S
27.
Suh JS, Aster RH, Visentin GP. Antibodies from
patients with heparin-induced thrombocytopenia
recognize different epitopes on heparin:platelet factor
4. Blood 1998;91:916-922.
Amiral J, Pouplard C, Vissac AM, et al. Affinity
purification of heparin-dependent antibodies to
platelet factor 4 developed in HIT: biological
characteristics and effects on platelet activation. Br J
Haematol 2000;109(2):336-341.
Ahmad S, Walenga JM, Jeske WP, Cella G, Fareed J.
Functional heterogeneity of antiheparin-platelet factor
4 antibodies: implications in the pathogenesis of the
HIT syndrome. Clin Appl Thromb Hemost 1999;5
(Suppl 1):S32-S37.
Ahmad S, Untch B, Haas S, Hoppensteadt DA,
Messmore HL, Walenga JM, Fareed J. Differential
prevalence of anti-heparin-PF4 immunoglobulin
subtypes in patients treated with clivarin and heparin:
implications in the HIT pathogenesis. Mol Cell
Biochem 2004;258:163-170.
Walenga JM, Prechel MM, Jeske WP, Bakhos M.
Unfractionated heparin compared with low molecular
weight heparin as related to heparin-induced
thrombocytopenia. Curr Opin Pulmon Med
2005;11:385-391.
Amiral J, Wolf M, Fischer A, Boyer-Neumann C,
Vissac A, Meyer D. Pathogenicity of IgA and/or IgM
antibodies to heparin-PF4 complexes in patients with
heparin-induced thrombocytopenia. Br J Haematol.
1996;92:954-9.
Kelton JG, Sheridan D, Santos A, Smith J, Steeves K,
Smith C, et al. Heparin-induced thrombocytopenia:
laboratory studies. Blood. 1988;72:925-30.
Kelton JG. The pathophysiology of heparin-induced
thrombocytopenia. Chest 2005;127(2):9S-20S.
Warkentin TE, Hayward CP, Boshkov LK, Santos AV,
Sheppard JA, Bode AP, et al. Sera from patients with
HIT generate platelet-derived microparticles with
procoagulant activity: an explanation for the
thrombotic
complications
of
HIT.
Blood.
1994;84:3691-9.
Walenga JM, Jeske WP, Prechel MM, Bakhos M.
Newer insights on the mechanism of heparin-induced
thrombocytopenia. Semin Thromb Hemost. 2004;30
Suppl 1:57-67.
Visentin GP, Ford SE, Scott JP, Aster RH. Antibodies
from
patients
with
heparin-induced
thrombocytopenia/thrombosis are specific for platelet
factor 4 complexed with heparin or bound to
endothelial cells. J Clin Invest. 1994;93:81-8.
Walenga JM, Michal K, Hoppensteadt D, , Wood JJ,
Bick RL, Robinson JA. Vascular damage correlates
between heparin-induced thrombocytopenia and the
antiphospholipid syndrome. Clin Appl Thromb
Hemost 1999;(Suppl 1):S76-S84.
Fareed J, Walenga JM, Hoppensteadt DA, Jeske WP,
Lietz H, Ahmad S, et al. Selectins in the HIT
syndrome: pathophysiologic role and therapeutic
modulation. Semin Thromb Hemost. 1999;25 Suppl
1:37-42.
Herbert JM, Savi P, Jeske WP, Walenga JM. Effect of
SR121566A, a potent GPIIb/IIIa antagonist, on the
HIT serum/heparin-induced platelet mediated
activation of human endothelial cells. Thromb
Haemost 1998;80:326-331.
Blank M, Shoenfeld Y, Tavor S, Praprotnik S, Boffa
MC, Weksler B, et al. Anti-platelet factor 4/heparin
antibodies from patients with heparin-induced
thrombocytopenia provoke direct activation of
microvascular endothelial cells. Int Immunol.
2002;14:121-9.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
I
S
F
O
R
U
M
3
N
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
4
O
R
T
H
A
M
E
R
Pouplard C, Iochmann S, Renard B, Herault O,
Colombat P, Amiral J, et al. Induction of monocyte
tissue factor expression by antibodies to heparinplatelet factor 4 complexes developed in heparininduced thrombocytopenia. Blood. 2001;97:3300-2.
Walenga JM, Jeske WP, Messmore HL. Mechanisms of
venous and arterial thrombosis in heparin-induced
thrombocytopenia. J Thromb Thrombol 2000;10:S13S20.
Walenga JM, Jeske WP, Fasanella AR, Wood JJ, Bakhos
M. Laboratory tests for the diagnosis of heparininduced thrombocytopenia. Semin Thromb Hemost.
1999;25 Suppl 1:43-9.
Walenga JM, Jeske WP, Fasanella AR, Wood JJ, Ahmad
S, Bakhos M. Laboratory diagnosis of heparininduced thrombocytopenia. Clin Appl Thromb
Hemost. 1999;5 Suppl 1:S21-7.
Pouplard C, Amiral J, Borg JY, Laporte-Simitsidis S,
Delahousse B, Gruel Y. Decision analysis for use of
platelet aggregation test, serotonin release assay, and
heparin-platelet factor 4 ELISA for the diagnosis of
HIT. Am J Clin Pathol. 1999;111:700-6.
Elalamy I, Lecrubier C, Horellou MH, Conard J,
Samama MM. Heparin-induced thrombocytopenia:
laboratory diagnosis and management. Ann Med.
2000;32 Suppl 1:60-7.
Walenga JM, Jeske WP, Wood JJ, Ahmad S, Lewis BE,
Bakhos M. Laboratory tests for heparin-induced
thrombocytopenia: a multicenter study. Semin
Hematol 1999;36(1)(Suppl 1):22-28.
Pouplard C, May MA, Iochmann S, Amiral J, Vissac
AM, Marchand M, Gruel Y. Antibodies to platelet
factor 4-heprin after cardiopulmonary bypass in
patients anticoagulated with unfractionated heparin
or a low molecular weight heparin: clinical
implications for HIT. Circulation 1999;99:2530-2536.
Lindhoff-Last E, Nakov R, Misselwitz F, Breddin HK,
Bauersachs R. Incidence and clinical relevance of
heparin-induced antibodies in patients with deep
vein thrombosis treated with unfractionated or lowmolecular-weight
heparin.
Br
J
Haematol
2002;118:1137-1142.
Fohlen-Walter A, De Maistre E, Mulot A, MarchandArvier M, Lecompte T. Does negative heparin-platelet
factor 4 enzyme-linked immunosorbent assay
effectively
exclude
heparin-induced
thrombocytopenia? J Thromb Haemost. 2003;1:1844-5.
Wallis DE, Workman DL, Lewis BE, Steen L, Pifarré R,
Moran JF. Failure of early heparin cessation as
treatment for heparin-induced thrombocytopenia. Am
J Med. 1999;106:629-35.
Walenga JM, Koza MJ, Lewis BE, Pifarré R. Relative
heparin-induced thrombocytopenic potential of low
molecular weight heparins and new antithrombotic
agents. Clin Appl Thromb Hemost. 1996:S21-7.
Jeske WP, Jay AM, Haas S, Walenga JM. HIT potential
of GAG and non-GAG based antithrombotic agents.
Clin Appl Thromb Hemost 1999;5(Suppl 1):S56-S62.
Messmore H, Jeske W, Wehrmacher W, Walenga J.
Benefit-risk assessment of treatments for heparininduced thrombocytopenia. Drug Saf. 2003;26:625-41.
Jeske WP, Walenga JM. Antithrombotic drugs for the
treatment of heparin-induced thrombocytopenia.
Curr Opin Investig Drugs 2002;3(8):1171-1180.
Hirsh J, Heddle N, Kelton JG. Treatment of heparininduced thrombocytopenia: a critical review. Arch
Intern Med. 2004;164:361-9.
Lewis BE, Wallis DE, Berkowitz SD, Matthai WH,
Fareed J, Walenga JM, Kelton JG, for the ARG-911
Study Investigators. Argatroban anticoagulant
therapy
in
patients
with
heparin-induced
I
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
C
A
N
T
H
R
O
M
B
thrombocytopenia. Circulation 2001;103:1838-1843.
Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG;
for the Argatroban-915 Investigators. Argatroban
anticoagulation in patients with heparin-induced
thrombocytopenia. Arch Intern Med 2003;163:1849-56.
Greinacher A, Völpel H, Janssens U, et al.
Recombinant hirudin (lepirudin) provides safe and
effective anticoagulation in patients with heparininduced thrombocytopenia: a prospective study.
Circulation 1999;99: 73-80.
Greinacher A, Janssens U, Berg G, et al. Lepirudin
(recombinant hirudin) for parenteral anticoagulation
in patients with heparin-induced thrombocytopenia.
Circulation 1999;100: 587-593.
Greinacher A, Lubenow N, Eichler P. Anaphylactic
and anaphylactoid reactions associated with lepirudin
in patients with heparin-induced thrombocytopenia.
Circulation. 2003;108:2062-5.
Walenga JM, Fasanella AR, Iqbal O, Hoppensteadt
DA, Ahmad S, Wallis DE, Bakhos M. Coagulation
laboratory testing in patients treated with argatroban.
Semin Thromb Hemost 1999;25(Suppl 1): 61-66.
Walenga JM, Drenth AF, Mayuga M, Hoppensteadt
DA, Prechel MM, Harder S, Watanabe H, Osakabe M,
Breddin HK. Transition from argatroban to oral
anticoagulation
with
phenprocoumon
or
acenocoumarol: effect on coagulation factor testing.
Clin Appl Thromb Hemost 2007, in press.
Harder S, Graff J, Kilikhardt U, von Hentig N,
Walenga JM, Watanabe H, Osakabe M, Breddin HK.
Transition from argatroban to oral anticoagulation
with phenprocoumon or acenocoumarol: effects on
PT, aPTT, and ecarin clotting time. Thromb Haemost
2004;91:1137-45.
Magnani
HN,
Gallus
A.
Heparin-induced
thrombocytopenia (HIT): a report of 1,478 clinical
outcomes of patients treated with danaparoid
(Orgaran) from 1982 to mid-2004. Thromb Haemost
2006;95:967-81.
Chong BH, Gallus AS, Cade JF, Magnani H,
Manoharan A, Oldmeadow M, et al. Prospective
randomised open-label comparison of danaparoid
with dextran 70 in the treatment of HIT with
thrombosis: a clinical outcome study. Thromb
Haemost. 2001;86:1170-5.
Walenga JM, Jeske WP, Bara L, Samama MM, Fareed J.
State-of-the-art
article.
Biochemical
and
pharmacologic rationale for the development of a
heparin pentasaccharide. Thromb Res 1997;86(1):1-36.
Ahmad S, Jeske WP, Walenga JM, Hoppensteadt DA,
Wood JJ, Herbert JM, Messmore HL, Fareed J.
Synthetic pentasaccharides do not cause platelet
activation by antiheparin-platelet factor 4 antibodies.
Clin Appl Thromb Hemost 1999;5(4):259-266.
Warkentin TE, Elavathil LJ, Hayward CP, Johnston
MA, Russett JI, Kelton JG. The pathogenesis of venous
limb gangrene associated with HIT. Ann Intern Med.
1997;127:804-12.
Please address all questions to:
North American Thrombosis Forum
1620 Tremont Street, Suite 3022
Roxbury Crossing, MA 02120
Email inquiries can be sent to
info@NATFonline.org. Please list
“HIT Question” in the subject heading.
O
S
I
S
F
O
R
U
M
Join WikiDoc.org – Online
Medical Community
Healthcare is enriched when medical
knowledge flows freely.
WikiDoc, www.wikidoc.org, is an
international organization whose
mission is to expand free access to
accurate, timely and unbiased
medical information and to provide
resources for both patients and
healthcare providers alike. WikiDoc
is building the largest online
collection of medical information
available on one website.
Accessible to both health care
professionals and patients, the
information resides on a "Wiki" and
can be co-created and co-edited by all
members of the international medical
community. The “news” in
medicine is reported with a current
emphasis on cardiovascular
medicine.
Join a Wiki community in the area of
cardiology, pulmonary embolism,
deep venous thrombosis, stroke, or
peripheral artery disease.
Co-creation, care, and community:
www.wikidoc.org
N
O
R
T
H
A
M
E
R
Heparin-Induced
Thrombocytopenia:
Case Presentation
Lina Matta, PharmD, BCPS Clinical Pharmacy Practice Manager Brigham and Women’s Hospital
Boston, Massachusetts 02115 USA
DS is a 63-year-old male admitted with chest
pain radiating to both arms and accompanied
by nausea and weakness.
Upon presentation to the ED his EKG
demonstrates ST-elevations in the inferior
leads with first degree AV block. Cardiac
Catheterization shows occlusion in the
proximal LAD artery (100%). A DES was
placed to establish TIMI 3 flow. Medications
given intra-procedure included heparin and
eptifibatide continuous infusion. ECHO
reported inferior, apical, and septal akinesis
and EF 25%.
Past medical history is significant for CAD s/
p three ACS events and s/p CABG in 2002,
CHF, chronic renal insufficiency (Cr 1.8-2.1),
hypertension, gout, GERD, and AF.
Medications on admission:
Aldactone 50 mg po Daily
Atorvastatin 40mg po Daily
Metoprolol XL 50 mg Daily
Aspirin 81 mg po Daily
Clopidorgrel 75 mg po Daily
Colchicine 0.6 mg po Every Other Day
Warfarin 3 mg po Daily
Admission Labs:
Na 135
WBC 7.40
K 4.8 HgB 11.0
Cl 103
HCT 32.6
CO2 22
PLT: 228 BUN 51
Cr 2.3
Glu 182
ALT 84
AST 388
CKMB 258
TnI 223
I
C
A
N
T
H
R
M
B
O
S
I
S
F
O
R
U
M
Hospital Course:
Cl 110
HCT 31.6
CKMB < assay
CO2 28
PLT 110 TnI 1.2
BUN 34
Days 1-3
PTT 1.5 x Control
Following catheterization, patient is admitted Cr 2.1
INR 1.8
to the CCU with cardiogenic shock and Glu 110
worsening respiratory status. He is intubated
and an intra-aortic balloon pump (IABP) is
placed to maintain adequate perfusion.
During the CCU admission, the patient Lina Matta, PharmD, BCPS
becomes increasingly anuric with worsening
renal function. The renal team is consulted 1. What are the first steps that should be
and continuous veno-venous hemofiltration taken in this patient’s medication regimen?
Answer: Stop heparin and warfarin. Make
(CVVH) is started.
sure no heparin flushes are being
VS: Temp 101 degrees; BP 80-100/50-80; HR 80 administered.
2. What are the criteria that the patient
bpm,
demonstrates for HIT?
Rhythm: NSR
Answer: Thrombocytopenia (drop by > 50%),
use of heparin for > 4 days, positive ELISA
Medications on Day 3:
Heparin 750 Units/hour, clopidogrel 75 mg po test.
daily, aspirin 325 mg daily, captopril 12.5 mg 3. What are some of the weaknesses of the
three times daily, esomperazole 20mg daily, ELISA test?
fentanyl 80 mcg/hour, midazolam 2 mg/hour, Answer (directly from Dr. Walenga’s article):
dobutamine 3 mcg/kg/min, atorvastatin “The clinical relevance of HIT antibody titres
80mg daily, Senna 2 tablets twice daily, is unclear. Measurable antibody without
potassium chloride IV SCALE, magnesium strong clinical indication should not be
chloride IV SCALE, insulin continuous considered HIT.”
4. What anticoagulants would you consider
infusion per ICU protocol.
for this patient?
Answer: Argatroban may be preferred since it
Laboratory Values on Day 3
is not cleared via the kidneys.
Na 139
WBC 8.50
ALT 84
Warfarin may be started following overlap
K 4.9 HgB 10.0
AST 112
with argatroban for at least 5 days AND once
Cl 106
HCT 31.6
CKMB 7.1
platelet function has returned to baseline
CO2 26
PLT 180 TnI 27
values.
BUN 36
PTT 1.5 x Control
5. What is the therapeutic marker of
Cr 1.8
INR 1.4
argartoban therapy?
Glu 105
Answer: PTT. The INR is often “falsely”
elevated.
Days 4-6:
Patient’s cardiac and renal function improving
and IABP and CVVH are stopped. Patient has
been transferred out of the CCU and to the
Step-Down Unit for continued medical
management.
His
EKG
demonstrates
resolution of ST-elevations and atrial
fibrillation. Of note, platelet count on Day 6
was noted to be 110. An ELISA PF4 test Baroletti SA, Goldhaber SZ. Heparin-induced
returns POS on Day 6.
thrombocytopenia. Circulation 2006;114:e355-e356.
Patient Education—
VS: Temp 98 degrees; BP 120-140/70-90; HR 90
beats per minute
Rhythm: atrial fibrillation, again
Medications on Day 6:
Heparin 900 Units/hour, clopidogrel 75 mg po
daily, aspirin 325 mg daily, captopril 12.5 mg
three times daily, esomperazole 20mg daily,
amiodarone 400mg po three times daily,
atorvastatin 80mg daily, potassium chloride IV
SCALE, magnesium chloride IV SCALE,
warfarin 3 mg po daily
Temp 98°; BP 75-110/40-70 mmHg; RR 16-22
Laboratory Values on Day 6
breaths/minute; HR 60 beats per minute JVP
Na 142
WBC 8.00 ALT 50
12; Crackles at the base of his lungs
K 5.1 HgB 10.0
AST 95
O
The journal Circulation has a section dedicated
to patient education entitled, “Patient Pages.”
All Patient Page articles are available online
and are free to the public.
The Cardiology Patient Page article, “HeparinInduced Thrombocytopenia,” by Steven
Baroletti, PharmD and Samuel Z. Goldhaber,
MD, provides an excellent overview of HIT
geared to the patient population.
To read this article in its entirety, please visit:
http://circ.ahajournals.org/cgi/content/full/
114/8/e355
5
N
O
R
T
H
A
M
E
R
I
C
A
N
T
H
R
O
M
B
O
S
I
S
F
O
R
U
M
The PREPIC trial (a centralized RCT with two-by-two factorial design,
on 400 patients with the mean age of 73 years, assessing the efficacy of
IVCF as an adjunct to UFH or LMWH for PE prevention in patients
with proximal DVT) was the only study included. Four types of filters
Young T, Aukes J, Hughes R, Tang H. Vena caval filters for the prevention
were used in this trial but no clear data is available about subgroup
of pulmonary embolism. Cochrane Database of Systematic Reviews 2007,
analysis based on filter type. In summary, at an eight year follow-up,
Issue 3. Art. No.: CD006212. DOI: 10.1002/14651858.CD006212.pub2.
IVCF reduced the total number of symptomatic PE events (hazard
ratio 0.37, 95% CI 0.17 to 0.79 in favor of a filter) whilst increasing the
To view the full Abstract, please visit: www.NATFonline.org/ethrombosis
rate of documented recurrent DVT events (hazard ratio 1.52, 95% CI
1.02 to 2.27). No significant difference was observed at any time point
Reviewed by Shadi Kalantarian, MD
in overall symptomatic venous thromboembolic events, all-cause
mortality, or occurrence of post-thrombotic syndrome. It is important
The possibility of preventing PE by placing a barrier in the migration to recognize that this study examined the potential extension of IVCF
path of the clot was first introduced by Trousseau in the 19th century. to anticoagulation candidates, not its more common current
Femoral vein ligation and IVC ligation were early surgical indications for patients with contraindications to or failure of
interventions that were based on this hypothesis. However, major anticoagulant therapy.
concerns about the considerable reduction in venous return, and the
risk of embolization through the well developed collaterals, led to Due to the lack of robust well designed studies, this systematic review,
efforts for introduction and gradual improvement of Inferior Vena similar to the previous review by Girard et al., failed to find
Cava Filters (IVCFs) for patients with DVT.
generalizable conclusions about the outcomes or indications of IVC
filter placement. The current generalizability of PREPIC is limited by
Since the1950s, IVCFs have been increasingly used for prevention of its lack of statistical power to assess for differences in symptomatic PE
pulmonary embolism. However, the growth rate of pertinent rates at the earlier (2-year) time point, the unavailability of validated
evidence has not been commensurate with the growing use of such measures of post-thrombotic syndrome at the time the study was
devices. The seventh ACCP guidelines on antithrombotic and conducted, and interval improvements in anticoagulant therapy which
thrombolytic therapy recommend IVCFs for patients suffering from a have since occurred. Anticoagulation remains the cornerstone of
proximal DVT “with a contraindication for, or a complication of treatment of VTE and should be initiated and maintained as indicated
anticoagulation treatment, as well as in those with recurrent by the guidelines as soon as there is no contraindication for it.
thromboembolism despite adequate anticoagulation”.
Retrievable filters are theoretically superior to permanent filters but
they need to be meticulously examined.
This systematic review performed by Young et al. aimed at assessing
the effectiveness of vena caval filters for prevention of PE. Mortality, This systematic review emphasizes the enormous knowledge gap for
fatal PE, filter related complications, recurrent DVT, and post- indications and outcomes of IVC filter placement, highlighting
thrombotic syndrome were the secondary outcomes.
priorities for further research.
Vena Caval Filters for the Prevention of
Pulmonary Embolism
Peripheral Vascular Diseases Group Specialized Register, MEDLINE, References:
CENTRAL, and EMBASE were searched for RCTs and CCTs
examining efficacy of filters for PE prevention.
1.
Young T, Aukes J, Hughes R, Tang H. Vena caval filters for the prevention
Of the originally evaluated eleven papers, only one RCT was found,
with a 2-year primary report and an updated 8-year follow up 2.
report. Eight studies were excluded because of poor methodological
quality, and one was a cost-effectiveness analysis.
6
of pulmonary embolism. Cochrane Database of Systematic Reviews 2007,
Issue 3. Art. No.: CD006212. DOI: 10.1002/14651858.CD006212.pub2.
Hann CL, Streiff MB. The role of vena caval filters in the management of
venous thromboembolism. Blood Rev. 2005;19(4):179-202.
N
3.
4.
5.
O
R
T
H
A
M
E
R
I
C
A
N
Büller HR, Agnelli G, Hull RD, Hyers TM, Prins MH, Raskob GE.
Antithrombotic therapy for venous thromboembolic disease: the Seventh
ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest.
2004;126(3 Suppl):401S-428S.
The PREPIC Study Group. Eight-year follow-up of patients with
permanent vena cava filters in the prevention of pulmonary embolism: the
PREPIC (Pre´vention du Risque d’Embolie Pulmonaire par Interruption
Cave) randomized study. Circulation. 2005;112:416–422.
Decousus H, Leizorovicz A, Parent F, Page Y, Tardy B, Girard P. et al. A
clinical trial of vena caval filters in the prevention of pulmonary embolism
in patients with proximal deep-vein thrombosis. Prévention du Risque
d'Embolie Pulmonaire par Interruption Cave Study Group. N Engl J Med.
1998 12;338(7):409-15.
Girard P, Stern JB, Parent F. Medical literature and vena cava filters: so far
so weak. Chest. 2002 Sep;122(3):963-7.
T
H
R
O
M
B
O
S
I
S
F
O
R
U
M
VTE prophylaxis or those who were eligible based on enrollment
criteria for randomized clinical trials demonstrating a benefit from
pharmacological prophylaxis, less than two-thirds actually received
prophylaxis. Although rarely used in other countries, intermittent
pneumatic compression was the most common form of prophylaxis
among patients enrolled in the United States. While low-molecular
weight heparins were most frequently used in other countries,
subcutaneous unfractionated heparin was the most common
pharmacological modality in the United States.
Although the study was not a randomized controlled trial, the large
IMPROVE registry analysis provides an important “real-world” view
of VTE prophylaxis patterns among acutely ill medical patients in the
United States and abroad. Similar to other recent studies, IMPROVE
6.
highlights critical deficiencies in the implementation of VTE
prophylaxis according to established guidelines among the vulnerable
About Shadi Kalantarian, MD: Shadi Kalantarian is student of medicine patient population of hospitalized medical patients.
and a research fellow at Modarres Cardiovascular Research Center, Shaheed
Beheshti University of Medical Sciences. Her research subjects of interest are The IMPROVE registry should be viewed as an important call-toatherosclerosis, thromboembolic disease, and arrhythmology. Currently she is action for clinicians and investigators to seek new ways of improving
heading a systematic review on surgical AF ablation with the Cochrane implementation of evidence-based guidelines for VTE prophylaxis
among acutely ill hospitalized medical patients.
Collaboration.
VTE Prophylaxis in Acutely Ill
Hospitalized Medical Patients:
IMPROVE Findings
Tapson VF, Decousus H, Pini M, Chong BH, Froehlich JB, Monreal M,
Spyropoulos AC, Merli GJ, Zotz RB, Bergmann JF, Pavanello R, Turpie AG,
Nakamura M, Piovella F, Kakkar AK, Spencer FA, Fitzgerald G, Anderson
FA; for the IMPROVE Investigators. Venous thromboembolism prophylaxis
in acutely ill hospitalized medical patients: Findings from the International
Medical Prevention Registry on Venous Thromboembolism. CHEST 2007 Jun
15; [Epub ahead of print].
Reviewed by Gregory Piazza, MD
How well do clinicians follow evidence-based guidelines for the
venous thromboembolism (VTE) prophylaxis of acutely ill hospitalized
medical patients? This analysis from the International Medical
Prevention Registry on Venous Thromboembolism (IMPROVE)
evaluated VTE prophylaxis patterns among 15,156 hospitalized
medical patients from 52 medical centers and 12 countries. In the
United States and other participating countries, 52% and 43% of
hospitalized medical patients, respectively, should have received VTE
prophylaxis according to the American College of Chest Physicians
(ACCP) guidelines. Of these patients who met the ACCP criteria for
About Gregory Piazza, MD: Dr. Piazza completed medical Internship and
Residency at the Beth Israel Deaconess Medical Center in Boston,
Massachusetts. He also served as a Chief Medical Resident at the Beth Israel
Deaconess Medical Center. Dr. Piazza is currently a third year clinical fellow
in the Cardiovascular Division at the Beth Israel Deaconess Medical Center.
His Clinical research is undertaken simultaneously at the Venous
Thromboembolism Research Group, where he is focusing on characteristics of
hospitalized medical patients with DVT and complications of anticoagulation
management.
Use of Preventive Measures for Air
Travel-related VTE in Professionals Who
Attend Medical Conferences
Kuipers S, Cannegieter SC, Middeldorp S, Rosendaal FR, Buller HR. Use of
preventive measures for air travel-related venous thrombosis in professionals
who attend medical conferences. J Thromb Haemost 2006;4:2373-2376.
Reviewed by Chiara Piovella, MD
In this observational study, the authors report a recent survey
comparing travel-related thrombosis prophylaxis methods in attendees
of three international conferences held last August in Sydney (the XXth
ISTH Congress, the 15th ISDB Congress, and the 13th Cochrane
7
N
O
R
T
H
A
M
E
R
I
C
A
N
T
Colloquium). The analysis revealed that ISTH delegates used
prophylactic measures more often than others, and that medical
doctors used LMWH prophylaxis more often than other ISTH
delegates.
The most common risk factors were found to be estrogen use, varicose
veins, thrombophilia and history of VTE. 49% of the individuals with
prior VTE used anticoagulation pharmacoprophylaxis (33% LMWH
and 16% warfarin) compared to 23% of the individuals without risk
factors. Anticoagulation prophylaxis was also used by 40% of attendees
with thrombophilia. In contrast, only 5% of hormonal therapy users
and 15% of those with varicose veins used anticoagulant prophylaxis.
Moreover, only 36% of passengers with varicose veins used elastic
stockings.
H
R
O
M
B
O
S
I
S
F
O
R
U
M
appropriate prophylaxis when assessing the data year-by-year from
2002 through 2005. Among Internal Medicine and Subspecialty
Medicine physicians, cardiologists had the highest rate of appropriate
VTE prophylaxis. Ironically, hematologists and oncologists had one of
the lowest rates of prophylaxis.
In a separate survey of inpatients in Canada, the situation may be even
bleaker. Of 4,124 Canadian medical admissions, only 16% received
appropriate prophylaxis (2).
Evidence-based medicine justifies VTE prophylaxis. There is an 8-fold
greater death rate from autopsy proven PE among unprophylaxed
surgical patients (3). And three major pharmacological prophylaxis
trials in hospitalized medical patients—MEDENOX (4), PREVENT (5),
and ARTEMIS (6)—showed that VTE prophylaxis can cut the rate of
In general, travelers with risk factors used anticoagulation and VTE in half. Meta-analyses confirm these findings (7, 8). Furthermore,
graduated compression stockings significantly more often than those asymptomatic proximal DVT at 3 weeks after hospitalization is
without risk (22 % vs 4% and 36% vs 13%, respectively). In contrast, the associated with a marked increase in death rates at 90 days (9).
use of aspirin was not significantly different between the groups (27%
vs. 19%), suggesting either that these passengers were already on VTE is much easier and less expensive to prevent than to diagnose or
aspirin for another reason or alternatively that passengers with and treat (10). And by preventing inpatient VTE, the rate of communitywithout risk factors may have considered aspirin relatively harmless acquired outpatient VTE will decrease because most outpatient VTE
can be traced back to a hospitalization or surgical procedure within the
and potentially beneficial.
prior 90 days (11).
In conclusion, the study shows that preventive measures (medical and
non-medical) for air travel-related thrombosis are widely used. A lack References
of consensus is apparent from the wide variation in
thromboprophylaxis use by nationality and professional background.
1.
Amin A, Stemkowski S, Lin J, et al. Thromboprophylaxis rates in US
Prospective studies with anticoagulants, especially in predefined highmedical centers: success or failure? J Thromb Haemostas 2007; 5:
risk groups (thrombophilia, obesity, prior thrombosis, or hormonal
1610-1616.
therapy) are therefore recommended. Guidelines for passengers based 2. Kahn SR, Panju A, Geerts W, et al. Multicenter evaluation of the use of
on risk assessment approved by expert consensus are necessary. In the
venous thromboembolism prophylaxis in acutely ill medical patients in
meantime, passengers with risk factors should be advised on the
Canada. Thrombosis Research 2007; 119: 145-155.
potential risk of long-haul flights and available prophylactic measures. 3. International Multicentre Trial: Prevention of fatal postoperative
pulmonary embolism by low doses of heparin. Lancet 1975 July 12;45-51.
Samama MM, Cohen AT, Darmon JY, et al: A comparison of enoxaparin
with placebo for the prevention of venous thromboembolism in acutely ill
medical patients. Prophylaxis in Medical Patients with Enoxaparin Study
Group. N Engl J Med 1999;341:793-800.
Leizorovicz A, Cohen AT, Turpie AG, et al: Randomized, placebocontrolled trial of dalteparin for the prevention of venous
thromboembolism in acutely ill medical patients. Circulation 2004;
110:874-879.
6.
Cohen AT, Davidson BL, Gallus AS, et al: Efficacy and safety of
fondaparinux for the prevention of venous thromboembolism in older
acute medical patients: randomised placebo controlled trial. BMJ 2006;
Amin A, Stemkowski S, Lin J, et al. Thromboprophylaxis rates in US medical
332:325-329.
centers: success or failure? J Thromb Haemostas 2007; 5: 1610-1616.
7.
Dentali F, Douketis JD, Gianni M, Lim W, Crowther MA. Meta-analysis:
Anticoagulant
prophylaxis
to
prevent
symptomatic
venous
thromboembolism in hospitalized medical patients. Annals of Internal
Medicine. 2007; 146: 278-288.
Reviewed by Kim M. Hickman, BS; Samuel Z. Goldhaber, MD
8.
Wein L, Wein S, Haas SJ, Shaw J, Krum H. Pharmacological venous
thromboembolism prophylaxis in hospitalized medical patients a metaAmin and colleagues (1) studied 200,000 high-risk hospitalized medical
analysis of randomized controlled trials. Arch Intern Med. 2007; 167:
patients and showed that U.S. hospitals have failing grades for
1476-1486.
thromboprophylaxis against pulmonary embolism (PE) and deep vein
9.
Vaitkus PT, Leizorovicz A, Cohen AT, Turpie AG, Olsson CG, Goldhaber
thrombosis (DVT). The absolute rate of prophylaxis was low. And
SZ.
Mortality rates and risk factors for asymptomatic deep vein
among those prophylaxed, the pharmacologic regimens were often
thrombosis in medical patients. Thromb Haemost. 2005; 93: 76-79.
inadequate with respect to proper drug, dose, and duration.
10. Goldhaber SZ, Turpie AG. Prevention of venous thromboembolism among
hospitalized medical patients. Circulation. 2005; 111: e1-3.
The overall VTE thromboprophylaxis rate should have been 100% but
11. Spencer FA, Lessard D, Emery C, Reed G, Goldberg RJ. Venous
was only 62%, of whom only half received appropriate prophylaxis.
thromboembolism in the outpatient setting. Arch Intern Med. 2007; 167:
The least frequently prophylaxed patients had cancer, severe lung
1471-1475.
About Chiara Piovella, MD: Dr Piovella completed her medical Internship, 4.
Residency, and Fellowship in Internal Medicine at the I.R.C.C.S Policlinico
San Matteo in Pavia, Italy. She worked as a fellow in the Thromboembolic
Disease Unit of Policlinico San Matteo in Pavia. Her major research effort this
past year has been related to heparin-induced thrombocytopenia. Dr. Piovella 5.
is currently a Venous Thromboembolism Research Group Fellow.
Thromboprophylaxis Rates In US
Medical Centers: Success or Failure?
disease, or acute spinal cord injury (without undergoing surgery).
Fortunately, there was a slight trend toward increasing use of
8
N
O
R
T
H
A
M
E
R
I
C
A
N
T
H
R
O
M
B
O
S
I
S
F
O
R
U
M
Kelly was diagnosed with a pulmonary embolism in early 2007. It has now become
her passion to raise public awareness, educate patients and health care providers,
and improve thrombosis medical standards.— This is her story.
Kelly Clark is a 40-year-old professional and mother of
two young children, who resides in Aliso Viejo,
California. In early 2007, Kelly was diagnosed with a
pulmonary embolism following arthroscopic knee
surgery.
Thrombosis awareness, education, and
prevention have now become her passion. We are pleased
to welcome Kelly as a NATF Patient Advocate.
I returned to work just a few short days after
undergoing arthroscopic knee surgery from a
tilted kneecap. Within two weeks, I started
experiencing severe pain in my knee and calf.
The swelling was increasing, and it felt hot to
the touch. In fact, there was so much swelling
that you could not see the natural crease
behind my knee. I just assumed it was part of
the healing process after knee surgery, since I
had never heard of deep vein thrombosis
(DVT) before.
When I returned to my
orthopedics’ office for my 2-week follow-up
appointment, I explained my symptoms; the
swelling of my knee, excruciating pain, and
inability to sleep because of that pain. None
At work 6 days later, I had just returned to my
desk after chatting with a co-worker over
coffee, when I suddenly lost consciousness.
When I came to, I experienced a shortness of
breath that felt like I was suffocating. I was
freezing cold, but sweating. Fortunately, I am
a member of our company’s medical response
It is estimated that over 200,000
new cases of VTE occur annually. Of team and CPR/First Aid certified, so I knew
immediately that something was wrong. I
these, 30% die within 30 days, onecalled out to a co-worker who was also on the
fifth suffer sudden death due to PE,
response team, and asked for help. She
brought the oxygen to me, while other
and about 30% develop recurrent
members of the medical response team
VTE within 10 years.
arrived. Even with the oxygen I was unable to
(Heit JA. Semin Thromb Hemost 2002;28:3-13)
breathe. I then asked her to call 911. After just
a matter of minutes, the paramedics arrived to
find me having difficulty breathing, my skin
thought I was just trying to get more pain
was colorless, and my lips had turned blue.
medication, which offended me. I remember
They immediately rushed me into the
getting into my car after that appointment and
ambulance and transported me to the hospital.
calling my father crying, powerless to
While in route, I went into full cardiac arrest
understand why I was in so much pain, and
and they began CPR.
unable to believe there was nothing anyone
could do to relieve it.
of the pain medication I had been given
provided any relief. My doctor instructed me
to go home, elevate my knee, and continue to
ice it. I got the distinct impression that he
9
N
O
R
T
H
A
M
E
R
The Emergency Room doctor was able to
revive me upon arrival at the hospital. My
parents arrived shortly thereafter. Later that
morning I seized, and went into another
cardiac arrest. With CPR, they were able to
revive me once again. The medical team
ordered a CT scan and found a massive
pulmonary embolus (large blood clot in the
lungs) and several smaller blood clots. At this
point, the Attending Physician went to my
parent’s and told them I would not survive.
He suggested that my family members and
friends be called to come and say their
goodbyes. My sister flew in from Memphis,
Tennessee, and my brother drove down from
Santa Barbara. Family friends also arrived. I
am a single mother of two young children,
who were taken out of school and brought to
the hospital immediately so they could say
goodbye to their mommy. Everyone has said
to me "I can't believe what you went through,"
but to me, I can't believe what my family must
have endured that day. My parents, having to
witness their daughter laying unconscious
with tubes down her throat, were forced to
make terrifying life or death decisions about
my treatment. The doctor informed them that
there was a drug called tPA (tissue
plasminogen
activator),
which
could
potentially dissolve the clot—at a cost. The
risk of hemorrhage was severe. At that point
no one thought there was much of a choice—I
was going to die either way. My parents
allowed the doctor to administer the tPA and
also implant a permanent Vena Cava Filter to
help prevent future clots from going into my
lungs. Remarkably, several hours later, I
began to show signs of improvement.
I spent the next 7 days in the Intensive Care
Unit before I was able to go home. It took
another 2 months before I was able to return
to work. In order to prevent future blood
clots, I will be on warfarin (blood thinning
medication) for the rest of my life. Because of
this, I have had to come to terms with the fact
that my whole lifestyle will have to change. I
will no longer be able to have children, and
there are many physical activities I can no
longer participate in. In spite of this, I am so
grateful to be alive! I am grateful for the quick
thinking of those paramedics, and my ER
doctor.
Recovery has been slow. It seemed to take a
long time for my lungs to return to normal.
Simple things, like walking to and from the
mailbox, made me completely out of breath. I
continued to experience chest pressure for
months. I also had damage to my vocal
chords from being intubated, which today has
almost healed.
I
C
A
N
T
H
R
O
M
B
8 months later, I still have a DVT in my left
leg. I also have a few veins that have no blood
flow due to the clots. I suffer from pain and
swelling as a result of the DVT. Some days the
pain forces a slight limp when I walk. Though
I find some relief in the morning, as the day
goes by the pain, discoloration, and swelling
increases. I have become accustom to wearing
open-toed shoes because of the unpredictable
swelling. I have also, on occasion, caught
myself dragging my foot because my leg feels
so heavy. Over the past 8 months, I have been
to so many different doctors and each one tells
me something different. An Interventional
Radiologist at UCLA said he couldn’t remove
the clots because they are “too old”. I even
had another doctor tell me that DVT is not
painful.
Looking back, I can’t help but think that if the
symptoms of DVT had been in my discharge
papers from my knee surgery, I would have
gone to the emergency room on my own and
not had to rely on my doctor for the diagnosis.
The only symptoms mentioned in my
discharge papers were the symptoms of
possible infection at the incision area—yet,
now I know that knee and hip surgery are risk
factors for DVT. Maybe at my doctor’s office
when they originally scheduled the surgery, I
could have been given a pamphlet on DVT to
educate me on the risks and symptoms—
another missed opportunity at prevention.
Today, I truly believe that a simple pamphlet
listing the warning signs and symptoms of
DVT could save the lives of so many people.
Not just patients having surgery, but patients
who are hospitalized, woman on birth control
or hormone replacement therapy, or just
released from giving child birth, and other
individuals who might be at risk. DVT and
pulmonary embolism (PE) are like a ticking
time bomb. Had I known the warning signs—
had my doctor thought to order an ultrasound
of my legs—my children and family would
never have had to hold my hand and say
goodbye to me.
• Cancer
• Prior DVT or PE
• Hypercoagulability (genetic
predisposition for blood clots)
• Surgery
• Advanced age (>70 years of age)
• Obesity (BMI >29)
• Bed rest, or prolonged immobility
• Oral contraceptives or hormone
replacement therapy
O
S
I
S
F
O
R
U
M
Pending Legislation
in Massachusetts—
Thrombosis
Awareness Month
The following is a draft of the Commonwealth of
Massachusetts Resolution (pending) to name
November 2007, “Thrombosis Awareness Month,”
sponsored by Massachusetts State Representative
Angelo J. Puppolo, Jr.
WHEREAS, more than 900,000 people in the
United States are estimated to develop venous
thromboembolism or clots in the veins every
year. Of these, about 380,000 people develop
deep vein thrombosis which occurs in the
inner veins of the leg; and
WHEREAS, Pulmonary embolism a serious
and often fatal complication of deep vein
thrombosis, affects about 530,000 people in the
United States each annually; and
WHEREAS, almost 300,000 people die each
year in the U.S. due to blood clots in the veins
and this number is greater than the number of
people who die each year of AIDS, breast
cancer, or automobile accidents; and
WHEREAS, hereditary thrombophilia, an
inherited predisposition to blood clots affects
approximately 1 in 20 people in the United
States; and
WHEREAS, positive life style choices and/ or
treatment during high-risk situations could
prevent blood clots in a significant number of
these individuals; now
RESOLVED, That the Massachusetts General
Court in Recognition of the importance of the
ongoing fight against Deep Vein Thrombosis,
Hereby recognizes November 2007 as
Thrombosis
awareness
month
in
Massachusetts; and be it further
RESOLVED, That a copy of these resolutions
be forwarded by the Clerk of the House of
Representatives to the Thrombosis Association
THROMBOSIS AWARENESS MONTH
In the State of Massachusetts
Is Your State Aware?
To learn more about public policy and patient
advocacy, please visit:
www.NATFonline.org/policy_advocacy.html
(NEJM 2005;352:969-977)
10
N
O
R
T
H
A
M
E
R
Under the Auspices of International
Union of Angiology (IUA), International
Academy of Clinical and Applied
Thrombosis (ICATH), Working Group
on LMWH Generics of the SSC on
Anticoagulation of the ISTH , North
American Thrombosis Forum (NATF)
and South Asian Society of
Atherosclerosis and Thrombosis
(SASAT)
The North American Thrombosis Forum is
proud to endorse the “International Summit
on Antithrombotic Drugs,” to be held Friday,
October 12, in New Delhi, India.
This international summit is organized to
recognize the timely issues related to the
evolution of guidelines for the objective and
ethical development of generic antithrombotic
drugs with particular reference to Low
Molecular Weight Heparins (LMWHs).
Current guidelines for the generic conversion
of branded antithrombotic drugs, in particular
heparins, are inadequate at this time.
Moreover, in the case of LMWHs these
guidelines are invalid. Very little has been
done by various organizations to address
these issues. This has led to the development
I
C
A
N
T
H
R
O
M
B
and
introduction
of
several
generic
antithrombotic drugs globally, some of which
were withdrawn after the initial approval, to
avoid patient care adverse-related issues. The
IUA, SASAT and ICATH have addressed these
issues periodically. More recently, the EMEA
and other peer groups have also addressed
concerns related to the current status of this
problem. This summit is organized to brief
the distinguished panel on the problems and
issues, generate scientific input for objective
guidelines
for
the
development
of
antithrombotic drugs, in particular the
LMWHs. The deliberations of these meetings
will be published as a white paper in
International Angiology and JCATH. The
listed experts are being contacted for their
participation in this meeting. Those experts
who are unable to attend this meeting will
provide their input to the respective chairs via
e-mail or phone conferences, which will be
incorporated in the final document.
O
S
I
S
F
O
R
U
M
admitted
for
medical,
surgical
and
interventional indications. These drugs play a
valuable role in the treatment of various
disorders such as myocardial infarction,
thrombotic
stroke
and
venous
thromboembolism. The mechanisms by which
these drugs produce their effects are complex
and not completely understood at this time.
Most of the effects produced by these drugs
are indirect and may involve the modulation
of plasmatic, vascular and target organ
specific effects. Moreover, some of these drugs
produce the release and generation of certain
endogenous antithrombotic mediators.
The recent development of generic versions of
antithrombotic drugs warrants discussion on
this topic.
The International Summit on
Antithrombotic Drugs provides for expert
opinion and discussion, and will provide a
platform for the development of specific
guidelines for the requirements in approving
generic versions of the branded products.
This Summit is organized to discuss important
The Need
issues and to generate a white paper for
Thrombosis
represents
a
complex publication in SASAT, IUA and ICATH
pathophysiological
syndrome
with sponsored publications. Other public forums
multifactorial
etiologies.
Anticoagulants, such as the NATF will also be used for
antiplatelet and thrombolytic drugs have been disseminating the information generated
used for the treatment of various thrombotic during the Summit.
www.SASAT.org
disorders and for prophylaxis in patients
11
N
O
R
T
H
A
M
E
R
I
C
A
N
T
H
R
O
M
B
O
S
I
S
F
O
R
U
M
This 1-day symposium emphasizing Clinical Science and professional education is intended to provide a concise,
state-of-the-art overview of prophylaxis measures and critical developments in the diagnosis, treatment, and
prevention of thrombotic disorders. Focused sessions in 5 key areas include 1) translational research, 2) clinical research, 3)
prevention and education, 4) public policy, and 5) advocacy (featuring special guest lecturers Melanie Bloom, Ajay Kakkar, MD,
Sanjay Kaul, MD, MPH, and Susan B. Shurin, MD).
This program is intended for physicians, nurses, physician assistants, pharmacists, hospitalists, and hospital administrators interested
in thrombosis prevention and treatment.
Tuition:
Location:
Directors:
Offered by:
There is no cost to attend this program. Pre-registration is required.
The program will be held at the historic Fairmont Copley Plaza Hotel, at 138 St. James Avenue, in Boston, Massachusetts.
Samuel Z. Goldhaber, MD, Jawed Fareed, PhD, and Arthur A. Sasahara, MD
North American Thrombosis Forum (NATF), Brigham and Women's Hospital, Department of Medicine, and Harvard
Medical School, Department of Continuing Education
For more information, or to register, please visit: http://www.natfonline.org/thrombosis_summit2007.html
Our Mission
The North American Thrombosis Forum (NATF) is a nonprofit organization that focuses on unmet needs and issues related to thrombosis and
cardiovascular diseases such as deep vein thrombosis, pulmonary embolism, myocardial infarction, peripheral arterial occlusive disease, and
stroke. The five areas of major focus are: 1) basic translational research, 2) clinical research, especially diagnosis and therapy, 3) prevention and
education, 4) public policy, and 5) advocacy. NATF's legacy will be to improve patient care, outcomes, and public health by supporting
thrombosis-related programs, such as novel research projects, innovative educational programs, public policy initiatives, regulatory issues and
advocacy, and to broaden training opportunities for physicians, scientists, and other health professionals.
How You Can Help
As a Fledgling Organization, we rely upon your participation, energy, spirit of volunteering, and philanthropy that characterize the culture of
North America. With your support, NATF sponsors several multidisciplinary thrombosis education programs annually: 1) "Proactive
Prophyalxis," a multidisciplinary symposium geared to healthcare professionals, patients, and caregivers, and 2) the NATF "Thrombosis
Summit," an annual event focused to meet all five NATF mission points. NATF also strives to promote the educational events of our partner
thrombosis organizations. Support of NATF educational programs ensures that we can continue to offer a comprehensive web-based network
for both healthcare professional and patient education resources. For more information, please visit our website: www.NATFonline.org
Board of Directors Samuel Z. Goldhaber, MD — President, Founding Director Jawed Fareed, PhD — Founding Director Arthur A. Sasahara, MD — Founding Director
John Fanikos, RPh, MBA — Treasurer, Director
Staff and Volunteers
Kim D. Mahoney — Executive Director, Secretary
Kelly Clark — Patient Advocate
Scientific Advisory Board
Geno Merli, MD — Chair
Jeanine M. Walenga, PhD — Vice Chair
Stephen Fredd, MD
Carlos Jerjes-Sanchez Diaz, MD
Kenneth V. Leeper, MD
Gundu Rao, PhD
Jeffrey I. Weitz, MD
Ann K. Wittkowsky, PharmD, CACP, FASHP, FCCP
North American Thrombosis Forum
1620 Tremont Street, Suite 3022; Roxbury Crossing, Massachusetts 02120 - USA
Phone (617) 525-8326 • Fax (617) 738-7652 • Email info@NATFonline.org • URL www.NATFonline.org
12

Heparin-Induced Thrombocytopenia

Transcription

Similar documents

- Bob the Builder

love... - Devonshire Mall

Matthew`s game - Parkfield Primary School

Volume 12 Version F

Using the Hauppauge WinTV DVB-T Electronic

Hits of the Sixties 2

Electchester Housing Companies - AFL

Rebelmix One Sheet v20080317

Platelet count by village

Pop Duos 2