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Prepublished online as a Blood First Edition Paper on December 27, 2002; DOI 10.1182/blood-2002-05-1448.
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
From the Department of Pathology and Molecular
Medicine, the Department of Medicine, and the Department of
Anaesthesia, McMaster University, and the Hamilton Regional Laboratory
Medicine Program, Hamilton, ON; and the Department of Health Policy,
Management and Evaluation, University of Toronto, and Program in
eHealth Innovation, University Health Network, Toronto, ON,
Canada.
Heparin-induced thrombocytopenia (HIT) is a transient
antibody-mediated hypercoagulability state strongly associated with lower-limb deep-vein thrombosis (DVT). Whether HIT is additionally associated with upper-limb DVT Heparin-induced thrombocytopenia (HIT) is an acute,
transient prothrombotic disorder caused by heparin-dependent,
platelet-activating antibodies.1-3 HIT can be regarded as
a hypercoagulability state, based upon the greatly elevated levels of
thrombin-antithrombin complexes4,5 (a marker of in vivo
thrombin generation) observed in patients with HIT, as well as the
strong association between HIT and venous and arterial
thrombosis.1-3 Indeed, the most common thrombotic
manifestation of HIT is lower-extremity deep-vein thrombosis (DVT).2,3,6,7 However, previous studies have not examined whether HIT is also associated with upper-extremity DVT. This is an
important question, because it is known that upper-extremity DVT can
complicate chronic hypercoagulability states such as antithrombin deficiency and the antiphospholipid antibody syndrome.8-10
Further, upper-extremity DVT also is known to be associated with
central venous catheter (CVC) use.8-10 Since HIT typically
occurs in hospitalized patients receiving heparin who may also have
been treated with a CVC, addressing this question would provide the
opportunity to study the interaction of a systemic hypercoagulability
state (HIT) with a localizing factor (CVC use) in explaining
HIT-associated upper-extremity DVT.
We reviewed 260 consecutive cases of serologically confirmed HIT
diagnosed in one of 4 academic hospitals in Hamilton, ON, Canada, over
an 18-year period ending June 30, 1998. All patients had a positive
platelet 14C-serotonin release assay: 243 patients
had a 50% or greater fall in the platelet count,3 and 17 patients had a smaller fall in the platelet count, accompanied by
thrombotic or other typical sequelae of HIT, for example, skin lesions
at heparin-injection sites.11,12 Of these 260 patients,
145 had a CVC placed during the 2-week period prior to the episode of
HIT. The remaining 115 patients with HIT did not receive a CVC.
Two non-HIT control groups were identified from studies performed in
the same medical community that met all of the following criteria: a
high rate of CVC use; systematic surveillance for lower-limb DVT using
either contrast venography or compression ultrasonography; systematic
platelet count monitoring; and serological investigations for HIT
antibodies (using the platelet 14C-serotonin release
assay) in patients with clinically suspected HIT. Control group 1 consisted of patients without HIT identified in a study of
postoperative antithrombotic heparin prophylaxis following major
orthopedic surgery (hip arthroplasty), as described.2 Control group 2 consisted of patients without HIT identified in a
study13 of intensive-care unit patients in whom systematic screening for DVT (twice-weekly compression ultrasonography) was performed. Imaging investigations for upper-extremity DVT were performed in HIT patients and controls only if signs or symptoms of
upper-extremity venous thrombosis were present.
All DVTs in HIT patients and in non-HIT controls were confirmed using
either contrast venography or compression ultrasonography. We included
all lower-extremity DVTs involving popliteal or more proximal veins and
all upper-extremity DVTs involving at least one of the brachial,
axillary, subclavian, or internal jugular veins. The reason for
including only proximal lower-limb DVTs was because only control group
1 had undergone screening with contrast venography, thus permitting
routine identification of calf DVT only in this group. Additionally,
HIT has been shown to be strongly associated with proximal lower-limb
DVT, but not with DVT that involves only the calf
veins.2
For the patients with HIT, we considered that a DVT was associated with
their episode of HIT if it occurred 5 or more days after starting
heparin and was associated with a platelet count fall that was linked
serologically to HIT antibodies.2 We further recorded whether the DVTs involved the right or left extremities, as
well as the timing of insertion and removal of the CVC in relation to
the episode of upper-limb DVT. The test of agreement for right versus
left location of CVC use and location of upper-extremity DVT was
performed using the kappa statistic. Comparisons between groups were
made using Table 1 shows that patients with HIT
were significantly more likely to develop either upper-extremity DVT or
proximal lower-extremity DVT compared with either control group of
patients without HIT. Whereas 14 of 260 (5.4%) patients with HIT
developed upper-extremity DVT, this complication was not seen in any of
the 637 postoperative orthopedic surgery patients
(P < .0001) and in only 3 (1.1%) of the 261 intensive-care unit patients (P = .0066). Whereas 42.3% of HIT patients developed proximal lower-limb DVT, only 4.1% of postoperative orthopedic surgery patients and 9.6% of intensive-care unit patients developed proximal lower-limb DVT
(P < .0001 for both comparisons).
CVC use was a crucial factor in explaining an increased risk of
upper-limb DVT, which occurred in 14 of 145 (9.7%, 95% CI, 5.4-15.7)
patients with both HIT and CVC use, compared with none of the 115 (0%,
95% CI, 0.0-3.2) HIT patients without a CVC
(P = .000 35). In contrast, use of a CVC did not confer
an increased risk of lower-extremity proximal DVT in either the HIT or
the control populations without HIT. Among all HIT and control patients who had CVC use, the frequency of upper-extremity DVT was significantly higher in the patients with HIT: 14 of 145 (9.7%) compared with 3 of
484 (0.6%, 95% CI, 0.1-1.8); odds ratio, 17.1 (4.9-60.5; P < .0001).
Table 2 shows the influence of the side
of placement of the CVC (right versus left upper-extremity placement)
in determining the location of the upper-extremity DVT. All 14 upper-extremity DVTs occurred at the CVC site (right, 12; left, 2;
kappa = 1.0; P = .011). In 7 patients, the DVT became
clinically evident when the CVC was still indwelling. For the remaining
7 patients, the DVT became clinically evident a median of 4 days
(range, 2-10 days) following removal of the CVC, indicating that the
localizing prothrombotic effect of the intravascular catheter persists
for a time, most likely by residual injury to the upper-extremity vessel resulting from the recent placement of the CVC. This represents another way that CVC use can influence clinical outcome in HIT besides
its known role as a potential source for heparin
exposure.11
Although we used a retrospective case-control study design, we believe our study was unlikely to have suffered from ascertainment bias, for example, because physicians may have been more likely to diagnose upper-extremity DVT in a patient with acute HIT. In our patients, all upper-limb imaging studies were performed because of signs or symptoms of upper-limb DVT, and none were obtained because of routine screening of upper-limb vessels for DVT in asymptomatic patients with HIT. Further, our control patients were identified from 2 prospective clinical studies in which all patients underwent daily clinical assessment for thrombosis. In conclusion, our study shows that HIT is strongly associated
with both upper-extremity and lower-extremity DVT (Table 1), consistent with the view of HIT as a hypercoagulability
state.4,5 However, our study also has identified a strong
additional factor, namely the localizing influence of a CVC, in
determining the occurrence of upper-extremity DVT among patients with
HIT, and particularly in determining the site of the upper-limb DVT.
Indeed, in all 14 patients with HIT-associated upper-extremity DVT, the
DVT occurred in the same limb in which the CVC had been placed. These
data indicate that while HIT confers a systemic prothrombotic
risk
Submitted May 16, 2002; accepted December 5, 2002.
Prepublished online as Blood First Edition Paper, December 27, 2002; DOI 10.1182/blood-2002- 05-1448.
Supported by the Heart and Stroke Foundation of Ontario (grant no. T-4502) and by the Canadian Insitutes of Health Research (grant no. MOP-49571).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Theodore E. Warkentin, Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences, Hamilton General Site, 237 Barton Street East, Hamilton, ON L8L 2X2 Canada; e-mail: twarken{at}mcmaster.ca.
1. Chong BH, Pitney WR, Castaldi PA. Heparin-induced thrombocytopenia: association of thrombotic complications with heparin-dependent IgG antibody that induces thromboxane synthesis in platelet aggregation. Lancet. 1982;2:1246-1249[Medline] [Order article via Infotrieve].
2.
Warkentin TE, Levine MN, Hirsh J, et al.
Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin.
N Engl J Med.
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Warkentin TE, Kelton JG.
Temporal aspects of heparin-induced thrombocytopenia.
N Engl J Med.
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Warkentin TE, Elavathil LJ, Hayward CPM, Johnston MA, Russett JI, Kelton JG.
The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia.
Ann Intern Med.
1997;127:804-812
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Greinacher A, Eichler P, Lubenow N, Kwasny H, Luz M.
Heparin-induced thrombocytopenia with thromboembolic complications: meta-analysis of 2 prospective trials to assess the value of parenteral treatment with lepirudin and its therapeutic aPTT range.
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2000;96:846-851 6. Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med. 1996;101:502-507[CrossRef][Medline] [Order article via Infotrieve]. 7. Nand S, Wong W, Yuen B, Yetter A, Schmulbach E, Gross Fisher S. Heparin-induced thrombocytopenia with thrombosis: incidence, analysis of risk factors, and clinical outcomes in 108 consecutive patients treated at a single institution. Am J Hematol. 1997;56:12-16[CrossRef][Medline] [Order article via Infotrieve]. 8. Elliott G. Upper-extremity deep vein thrombosis. Lancet. 1997;349:1188-1189[CrossRef][Medline] [Order article via Infotrieve]. 9. Hingorani A, Ascher E, Yorkovich RPA, et al. Upper extremity deep venous thrombosis: an underrecognized manifestation of a hypercoagulable state. Ann Vasc Surg. 2000;14:421-426[CrossRef][Medline] [Order article via Infotrieve]. 10. Leebeek FWG, Stadhouders NAM, van Stein D, Gómez-García EB, Kappers-Klunne MC. Hypercoagulability states in upper-extremity deep venous thrombosis. Am J Hematol. 2001;67:15-19[CrossRef][Medline] [Order article via Infotrieve]. 11. Warkentin TE. Clinical picture of heparin-induced thrombocytopenia. In: Warkentin TE,Greinacher A, eds. Heparin-induced Thrombocytopenia. 2nd ed. New York, New York: Marcel Dekker, Inc; 2001:43-86. 12. Warkentin TE. Heparin-induced skin lesions. Br J Haematol. 1996;92:494-497[Medline] [Order article via Infotrieve]. 13. Cook D, Crowther M, Meade M, et al. Deep venous thrombosis in medical-surgical ICU patients: prevalence, incidence and risk factors [abstract]. Crit Care. In press.
© 2003 by The American Society of Hematology.
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  J. G. Kelton and T. E. Warkentin Heparin-induced thrombocytopenia: a historical perspective Blood, October 1, 2008; 112(7): 2607 - 2616. [Full Text] [PDF]
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I. Apostolidou, M. F. Sweeney, E. Missov, L. D. Joyce, R. John, and R. C. Prielipp Acute Left Atrial Thrombus After Recombinant Factor VIIa Administration During Left Ventricular Assist Device Implantation in a Patient with Heparin-Induced Thrombocytopenia Anesth. Analg., February 1, 2008; 106(2): 404 - 408. [Abstract] [Full Text] [PDF]
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J. H. Levy, K. A. Tanaka, and M. J. Hursting Reducing Thrombotic Complications in the Perioperative Setting: An Update on Heparin-Induced Thrombocytopenia Anesth. Analg., September 1, 2007; 105(3): 570 - 582. [Abstract] [Full Text] [PDF]
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 T. E. Warkentin and M. A. Crowther When is HIT Really HIT? Ann. Thorac. Surg., January 1, 2007; 83(1): 21 - 23. [Full Text] [PDF]
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 I.-K. Jang and M. J. Hursting When Heparins Promote Thrombosis: Review of Heparin-Induced Thrombocytopenia Circulation, May 24, 2005; 111(20): 2671 - 2683. [Full Text] [PDF]
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T. E. Warkentin New Approaches to the Diagnosis of Heparin-Induced Thrombocytopenia Chest, February 1, 2005; 127(2_suppl): 35S - 45S. [Abstract] [Full Text] [PDF]
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 A. T. Gurbuz, W. G. Elliott, and A. A. Zia Heparin-induced thrombocytopenia in the cardiovascular patient: diagnostic and treatment guidelines Eur. J. Cardiothorac. Surg., January 1, 2005; 27(1): 138 - 149. [Abstract] [Full Text] [PDF]
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T. E. Warkentin and A. Greinacher Heparin-Induced Thrombocytopenia: Recognition, Treatment, and Prevention: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest, September 1, 2004; 126(3_suppl): 311S - 337S. [Abstract] [Full Text] [PDF]
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 L. Risch and A. R. Huber Improving the Definition of Heparin-Induced Thrombocytopenia Arch Intern Med, August 9, 2004; 164(15): 1699 - 1699. [Full Text] [PDF]
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 D. B. Cines, J. B. Bussel, R. B. McMillan, and J. L. Zehnder Congenital and Acquired Thrombocytopenia Hematology, January 1, 2004; 2004(1): 390 - 406. [Abstract] [Full Text] [PDF]
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T. E. Warkentin, W. C. Aird, and J. H. Rand Platelet-Endothelial Interactions: Sepsis, HIT, and Antiphospholipid Syndrome Hematology, January 1, 2003; 2003(1): 497 - 519. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
either with or without central venous
catheter (CVC) use
2 Fisher exact test (2-sided). The odds ratio
was calculated using the Mantel-Haenszel statistic.