Treatment and Prevention of Heparin-Induced Thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)

doi:10.1378/chest.08-0677

Chest

Volume 133, Issue 6, Supplement, June 2008, Pages 340S-380S

https://doi.org/10.1378/chest.08-0677 Get rights and content

This chapter about the recognition, treatment, and prevention of heparin-induced thrombocytopenia (HIT) is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patient values may lead to different choices. Among the key recommendations in this chapter are the following: For patients receiving heparin in whom the clinician considers the risk of HIT to be > 1.0%, we recommend platelet count monitoring over no platelet count monitoring (Grade 1C). For patients who are receiving heparin or have received heparin within the previous 2 weeks, we recommend investigating for a diagnosis of HIT if the platelet count falls by ≥ 50%, and/or a thrombotic event occurs, between days 5 and 14 (inclusive) following initiation of heparin, even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia has occurred (Grade 1C). For patients with strongly suspected (or confirmed) HIT, whether or not complicated by thrombosis, we recommend use of an alternative, nonheparin anticoagulant (danaparoid [Grade 1B], lepirudin [Grade 1C], argatroban [Grade 1C], fondaparinux [Grade 2C], or bivalirudin [Grade 2C]) over the further use of unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) therapy or initiation/continuation of vitamin K antagonists (VKAs) [Grade 1B]. The guidelines include specific recommendations for nonheparin anticoagulant dosing that differ from the package inserts. For patients with strongly suspected or confirmed HIT, we recommend against the use of vitamin K antagonist (VKA) [coumarin] therapy until after the platelet count has substantially recovered (usually, to at least 150 x 10⁹/L) over starting VKA therapy at a lower platelet count (Grade 1B); that VKA therapy be started only with low maintenance doses (maximum, 5 mg of warfarin or 6 mg of phenprocoumon) over higher initial doses (Grade 1B); and that the nonheparin anticoagulant (eg, lepirudin, argatroban, danaparoid) be continued until the platelet count has reached a stable plateau, the international normalized ratio (INR) has reached the intended target range, and after a minimum overlap of at least 5 days between nonheparin anticoagulation and VKA therapy rather than a shorter overlap (Grade 1B). For patients receiving VKAs at the time of diagnosis of HIT, we recommend use of vitamin K (10 mg po or 5 to 10 mg IV) [Grade 1C].

Section snippets

SUMMARY OF RECOMMENDATIONS

1.0 Recognition of HIT

Management of Direct Thrombin Inhibitor-VKA Overlap

2.2.1. For patients with strongly suspected or confirmed HIT, we recommend against the use of VKA (coumarin) therapy until after the platelet count has substantially recovered (ie, usually to at least 150 x 10⁹/L) over starting VKA therapy at a lower platelet count (Grade 1B) ; that VKA therapy be started only with low, maintenance doses (maximum, 5 mg of warfarin or 6 mg of phenprocoumon) rather than with higher initial doses (Grade 1B) ; and that the nonheparin anticoagulant (eg, lepirudin,

LMWH for HIT

2.3.1. For patients with strongly suspected HIT, whether or not complicated by thrombosis, we recommend against use of LMWH (Grade 1B).

Prophylactic Platelet Transfusions for HIT

2.4.1. For patients with strongly suspected or confirmed HIT who do not have active bleeding, we suggest that prophylactic platelet transfusions should not be given (Grade 2C).

3.0 Special Patient Populations

Patients With Previous HIT Undergoing Cardiac or Vascular Surgery

3.1.1. For patients with a history of HIT who are HIT antibody negative and require cardiac surgery, we recommend the use of UFH over a nonheparin anticoagulant (Grade 1B). 3.1.2. For patients with a history of HIT who are antibody positive by platelet factor 4 (PF4)-dependent enzyme immunoassay (EIA) but antibody negative by washed platelet activation assay, we recommend the use of UFH over a nonheparin anticoagulant (Grade 2C).

Remark: Preoperative and postoperative anticoagulation, if

Patients With Acute or Subacute HIT Undergoing Cardiac Surgery

3.2.1. For patients with acute HIT (thrombocytopenic, HIT antibody positive) who require cardiac surgery, we recommend one of the following alternative anticoagulant approaches (in descending order of preference): delaying surgery (if possible) until HIT has resolved and antibodies are negative (then see Recommendation 3.1.1.) or weakly positive (then see Recommendation 3.1.2.) [Grade 1B] ; using bivalirudin for intraoperative anticoagulation during cardiopulmonary bypass (if techniques of

Percutaneous Coronary Interventions

3.3.1. For patients with strongly suspected (or confirmed) acute HIT who require cardiac catheterization or percutaneous coronary intervention (PCI), we recommend a nonheparin anticoagulant (bivalirudin [Grade 1B] , argatroban [Grade 1C] , lepirudin [Grade 1C] , or danaparoid [Grade 1C]) over UFH or LMWH (Grade 1B).

3.3.2. For patients with previous HIT (who are antibody negative) who require cardiac catheterization or PCI, we suggest use of a nonheparin anticoagulant (see Recommendation 3.3.1.)

Platelet Count Monitoring for HIT

HIT occurs most commonly in certain patient populations, such as postoperative patients who receive standard, unfractionated heparin (UFH) for ≥ 1 week (for review, see Lee and Warkentin⁶). One definition classifies an adverse reaction as “common” if its incidence is > 1%.³⁰ In other clinical settings, the estimated risk of HIT can be described as “uncommon” (0.1 to 1%) or “rare” (< 0.1%).³⁰ As described later, there is evidence that initial isolated HIT has a substantial risk of evolving to

TREATMENT OF HIT

HIT is a prothrombotic condition that is associated with increased in vivo thrombin generation (as evidenced by the presence of elevated levels of thrombin-antithrombin complexes¹⁰⁵) and thus can be considered an acquired, hypercoagulability syndrome.¹³ However, unlike other acquired hypercoagulability syndromes (eg, antiphospholipid antibody syndrome, malignancy-associated thrombosis), HIT is transient, with recovery of platelet counts to normal levels within days or weeks, and disappearance

Patients With Previous HIT Undergoing Cardiac or Vascular Surgery

In general, one is reluctant to expose a patient with a history of known (or strongly suspected) drug hypersensitivity to the drug in question. However, there are several reasons why HIT is an important exception to this general rule. First, among patients with typical-onset HIT, there is no trend to earlier onset of HIT in those patients with a history of previous heparin exposure.³¹ Second, among patients with rapid-onset HIT preexisting HIT antibodies can be detected in patient blood

UFH vs LMWH

A metaanalysis⁴⁰ of five studies (two RCTs) of postoperative thromboprophylaxis (post-orthopedic, n = 4; post-cardiac, n = 1) that examined the frequency of serologically confirmed HIT found a marked reduction in the risk of HIT with LMWH compared with UFH (common OR = 0.10 [95% CI, 0.03-0.33]; p < 0.001). A more recent metaanalysis⁴¹ confirmed the lower risk of HIT with LMWH in postsurgical thromboprophylaxis (OR = 0.072 [95% CI, 0.02-0.23]; p < 0.0001). Further evidence supporting a lower

CONLICT OF INTEREST DISCLOSURES

Dr. Warkentin discloses that he has received grant monies from the Heart & Stroke Foundation of Ontario, as well as industry-related sources of Organon and GlaxoSmithKline. Dr. Warkentin also received consultant fees from Organon, GlaxoSmithKline, and GTI, Inc, and has served on the speakers bureaus of Organon, GlaxoSmithKline, Sanofi-Aventis.

Professor Greinacher discloses that he has received grant monies from projects funded by Graduiertenkolleg, BMBF, Krupp-Kolleg, and EFRE, and has been

REFERENCES (284)

AP Hong et al.
Central venous catheters and upper-extremity deep-vein thrombosis complicating immune heparin-induced thrombocytopenia
Blood
(2003)
B Girolami et al.
The incidence of heparin-induced thrombocytopenia in hospitalized medical patients treated with subcutaneous unfractionated heparin: a prospective cohort study
Blood
(2003)
TE Warkentin
Management of heparin-induced thrombocytopenia: a critical comparison of lepirudin and argatroban
Thromb Res
(2003)
TE Warkentin et al.
A 14-year study of heparin-induced thrombocytopenia
Am J Med
(1996)
DE Wallis et al.
Failure of early heparin cessation as treatment for heparin-induced thrombocytopenia
Am J Med
(1999)
A Greinacher et al.
Replacement of unfractionated heparin by low-molecular-weight heparin for postorthopedic surgery antithrombotic prophylaxis lowers the overall risk of symptomatic thrombosis because of a lower frequency of heparin-induced thrombocytopenia [letter]
Blood
(2005)
TE Warkentin et al.
Impact of the patient population on the risk for heparin-induced thrombocytopenia
Blood
(2000)
TE Warkentin et al.
Laboratory testing for the antibodies that cause heparin-induced thrombocytopenia: how much class do we need?
J Lab Clin Med
(2005)
TE Warkentin et al.
Testing for heparin-induced thrombocytopenia antibodies
Transfus Med Rev
(2006)
GK Lo et al.
Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings
J Thromb Haemost
(2006)

ZQ Li et al.

Defining a second epitope for heparin-induced thrombocytopenia/thrombosis antibodies using KKO, a murine HIT-like monoclonal antibody

Blood

(2002)

JS Suh et al.

Antibodies from patients with heparin-induced thrombocytopenia/thrombosis recognize different epitopes on heparin: platelet factor 4

Blood

(1998)

N Lubenow et al.

Heparin-induced thrombocytopenia: temporal pattern of thrombocytopenia in relation to initial use or reexposure to heparin

Chest

(2002)

S Ahmad et al.

Differential effects of clivarin and heparin in patients undergoing hip and knee surgery for the generation of anti-heparin-platelet factor 4 antibodies

Thromb Res

(2002)

JL Francis et al.

Comparison of bovine and porcine heparin in heparin antibody formation after cardiac surgery

Ann Thorac Surg

(2003)

P Prandoni et al.

The incidence of heparin-induced thrombocytopenia in medical patients treated with low-molecular-weight heparin: a prospective cohort study

Blood

(2005)

TE Warkentin et al.

Inside blood commentary

Blood

(2005)

N Martel et al.

Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis

Blood

(2005)

TE Warkentin et al.

Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia

Blood

(2006)

J Lepercq et al.

Venous thromboembolism during pregnancy: a retrospective study of enoxaparin safety in 624 pregnancies

Br J Obstet Gynaecol

(2001)

IA Greer et al.

Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism

Blood

(2005)

MB Fausett et al.

Heparin-induced thrombocytopenia is rare in pregnancy

Am J Obstet Gynecol

(2001)

D Popov et al.

Pseudopulmonary embolism: acute respiratory distress in the syndrome of heparin-induced thrombocytopenia

Am J Kidney Dis

(1997)

D Green et al.

Thrombocytopenia in a prospective, randomized, double-blind trial of bovine and porcine heparin

Am J Med Sci

(1984)

PJ Powers et al.

Studies on the frequency of heparin-associated thrombocytopenia

Thromb Res

(1984)

BM Alving et al.

In vitro studies of heparin-induced thrombocytopenia

Thromb Res

(1977)

TE Warkentin et al.

No significant improvement in diagnostic specificity of an anti-PF4/polyanion immunoassay with use of high heparin confirmatory procedure

J Thromb Haemost

(2006)

TE Warkentin et al.

Anti-platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin

Blood

(2005)

C Pouplard et al.

Development of antibodies specific to polyanion-modified platelet factor 4 during treatment with fondaparinux

J Thromb Haemost

(2005)

A Greinacher et al.

Heparin-induced thrombocytopenia: a prospective study on the incidence, platelet-activating capacity and clinical significance of anti-PF4/heparin antibodies of the IgG, IgM, and IgA classes

J Thromb Haemost

(2007)

RL Levine et al.

Heparin-induced thrombocytopenia in the emergency department

Ann Emerg Med

(2004)

MA Smythe et al.

Delayed-onset heparin-induced thrombocytopenia

Ann Emerg Med

(2005)

MM Prechel et al.

Activation of platelets by heparin-induced thrombocytopenia antibodies in the serotonin release assay is not dependent on the presence of heparin

J Thromb Haemost

(2005)

SZ Goldhaber et al.

Prevention of venous thrombosis after coronary artery bypass surgery (a randomized trial comparing two mechanical prophylaxis strategies)

Am J Cardiol

(1995)

TE Warkentin et al.

Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin

N Engl J Med

(1995)

TE Warkentin et al.

An improved definition of immune heparin-induced thrombocytopenia in postoperative orthopedic patients

Arch Intern Med

(2003)

DH Lee et al.

Frequency of heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia. 4th ed

(2007)

TE Warkentin et al.

Clinical picture of heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia. 4th ed

(2007)

S Nand et al.

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

(1998)

TE Warkentin et al.

Heparin-induced thrombocytopenia: towards consensus

Thromb Haemost

(1998)

TE Warkentin

Heparin-induced thrombocytopenia: pathogenesis and management

Br J Haematol

(2003)

TE Warkentin

Platelet count monitoring and laboratory testing for heparin-induced thrombocytopenia

Arch Pathol Lab Med

(2002)

A Greinacher et al.

Heparin-induced thrombocytopenia [in German]

Dtsch Ártz

(2003)

A Greinacher et al.

Clinical features of heparin-induced thrombocytopenia including risk factors for thrombosis: a retrospective analysis of 408 patients

Thromb Haemost

(2005)

C Pouplard et al.

Antibodies to platelet factor 4-heparin after cardiopulmonary bypass in patients anticoagulated with unfractionated heparin or a low-molecular-weight heparin: clinical implications for heparin-induced thrombocytopenia

Circulation

(1999)

TE Warkentin

Heparin-induced skin lesions

Br J Haematol

(1996)

TE Warkentin et al.

Laboratory diagnosis of immune heparin-induced thrombocytopenia

Curr Hematol Rep

(2003)

D Juhl et al.

Incidence and clinical significance of anti-PF4/heparin antibodies of the IgG, IgM, and IgA class in 755 consecutive patient samples referred for diagnostic testing for heparin-induced thrombocytopenia

Eur J Haematol

(2006)

J Amiral et al.

Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia [letter]

Thromb Haemost

(1992)

J Amiral et al.

Affinity purification of heparin-dependent antibodies to platelet factor 4 developed in heparin-induced thrombocytopenia: biological characteristics and effects on platelet activation

Br J Haematol

(2000)

Cited by (745)

D-type peptides based fluorescent probes for “turn on” sensing of heparin
2024, Bioorganic Chemistry
Developing “turn on” fluorescent probes was desirable for the detection of the effective anticoagulant agent heparin in clinical applications. Through combining the aggregation induced emission (AIE) fluorogen tetraphenylethene (TPE) and heparin specific binding peptide AG73, the promising “turn on” fluorescent probe TPE-1 has been developed. Nevertheless, although TPE-1 could achieve the sensitive and selective detection of heparin, the low proteolytic stability and undesirable poor solubility may limit its widespread applications. In this study, seven TPE-1 derived fluorescent probes were rationally designed, efficiently synthesized and evaluated. The stability and water solubility were systematically estimated. Especially, to achieve real-time monitoring of proteolytic stability, the novel Abz/Dnp-based “turn on” probes that employ the internally quenched fluorescent (IQF) mechanism were designed and synthesized. Moreover, the detection ability of synthetic fluorescent probes for heparin were systematically evaluated. Importantly, the performance of d-type peptide fluorescent probe XH-6 indicated that d-type amino acid substitutions could significantly improve the proteolytic stability without compromising its ability of heparin sensing, and attaching solubilizing tag 2-(2-aminoethoxy) ethoxy) acid (AEEA) could greatly enhance the solubility. Collectively, this study not only established practical strategies to improve both the water solubility and proteolytic stability of “turn on” fluorescent probes for heparin sensing, but also provided valuable references for the subsequent development of enzymatic hydrolysis-resistant d-type peptides based fluorescent probes.
Perfusion standards and guidelines
2022, Cardiopulmonary Bypass: Advances in Extracorporeal Life Support
One of the most important elements of cardiovascular perfusion is the design and safe conduct of extracorporeal support. The turn of the 21st century in medicine was accompanied by the development of evidence-based medicine (EBM)—defined as “the conscientious and judicious use of current best evidence in conjunction with clinical expertise and patient values to guide health care decisions.” EBM includes the acquisition of knowledge in currently available published research, diffusion and dissemination of thought leaders, and end-user adoption into local clinical practice. While EBM has existed in healthcare for nearly 30 years, its emergence in perfusion has been slow to develop. This chapter will review the historic and ongoing strategies to provide both clinical practice and professional standards and guidelines to field of perfusion.
A case of tongue cancer complicated by heparin-induced thrombocytopenia during perioperative management
2021, Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology
In patients with vascular diseases, heparinization is necessary for surgery. Here, we report the case of a 77-year-old man who presented with heparin-induced thrombocytopenia (HIT) during the postoperative management of tongue cancer. The patient was already on warfarin owing to arteriosclerosis obliterans, and was perioperatively administered heparin by a cardiologist. The prothrombin time-international normalized ratio (PT-INR) was stabilized, and heparin administration was terminated on postoperative day 23. However, on postoperative day 41, the PT-INR was prolonged; warfarin was discontinued, and heparin was re-administered. On day 6 after heparin re-administration (postoperative day 47), the patient developed sudden fever. Contrast-enhanced computed tomography (CT) imaging was performed to evaluate the fever and showed a thrombus at the L5 level of the inferior vena cava. Blood examination showed a platelet count of 108,000 /μL; however, the next day, the count was 87,000 /μL. On day 10 after heparin re-administration (postoperative day 51), contrast-enhanced CT imaging showed an increase in thrombus formation. Therefore, inferior vena cava filter insertion surgery was performed on day 13 of heparin re-administration (postoperative day 54). The patient was diagnosed with HIT because of thrombocytopenia and increased thrombin after the re-administration of heparin, which was discontinued on postoperative day 64; argatroban (an anti-thrombin drug) was administered for HIT treatment. The patient was discharged with an indwelling inferior vena cava filter and intestinal fistula.
Effect of bivalirudin on coagulation in neonatal (cord) and adult human blood in vitro
2024, Paediatric Anaesthesia
D-Type Peptides Based Fluorescent Probes for “Turn On” Sensing of Heparin
2024, SSRN
Diagnosis and management of heparin-induced thrombocytopenia: Third edition
2024, British Journal of Haematology

View all citing articles on Scopus

: Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

View full text

Chest

SupplementAntithrombotic and Thrombolytic Therapy, 8th ED: ACCP GuidelinesTreatment and Prevention of Heparin-Induced Thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)

Section snippets

SUMMARY OF RECOMMENDATIONS

Management of Direct Thrombin Inhibitor-VKA Overlap

LMWH for HIT

Prophylactic Platelet Transfusions for HIT

Patients With Previous HIT Undergoing Cardiac or Vascular Surgery

Patients With Acute or Subacute HIT Undergoing Cardiac Surgery

Percutaneous Coronary Interventions

Platelet Count Monitoring for HIT

TREATMENT OF HIT

Patients With Previous HIT Undergoing Cardiac or Vascular Surgery

UFH vs LMWH

CONLICT OF INTEREST DISCLOSURES

Blood

Blood

Thromb Res

Am J Med

Am J Med

Blood

Blood

J Lab Clin Med

Transfus Med Rev

J Thromb Haemost

Blood

Blood

Chest

Thromb Res

Ann Thorac Surg

Blood

Blood

Blood

Blood

Br J Obstet Gynaecol

Blood

Am J Obstet Gynecol

Am J Kidney Dis

Am J Med Sci

Thromb Res

Thromb Res

J Thromb Haemost

Blood

J Thromb Haemost

J Thromb Haemost

Ann Emerg Med

Ann Emerg Med

J Thromb Haemost

Am J Cardiol

Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin

N Engl J Med

An improved definition of immune heparin-induced thrombocytopenia in postoperative orthopedic patients

Arch Intern Med

Frequency of heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia. 4th ed

Clinical picture of heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia. 4th ed

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

Heparin-induced thrombocytopenia: towards consensus

Thromb Haemost

Heparin-induced thrombocytopenia: pathogenesis and management

Br J Haematol

Platelet count monitoring and laboratory testing for heparin-induced thrombocytopenia

Arch Pathol Lab Med

Heparin-induced thrombocytopenia [in German]

Dtsch Ártz

Clinical features of heparin-induced thrombocytopenia including risk factors for thrombosis: a retrospective analysis of 408 patients

Thromb Haemost

Antibodies to platelet factor 4-heparin after cardiopulmonary bypass in patients anticoagulated with unfractionated heparin or a low-molecular-weight heparin: clinical implications for heparin-induced thrombocytopenia

Circulation

Heparin-induced skin lesions

Br J Haematol

Laboratory diagnosis of immune heparin-induced thrombocytopenia

Curr Hematol Rep

Incidence and clinical significance of anti-PF4/heparin antibodies of the IgG, IgM, and IgA class in 755 consecutive patient samples referred for diagnostic testing for heparin-induced thrombocytopenia

Eur J Haematol

Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia [letter]

Thromb Haemost

Affinity purification of heparin-dependent antibodies to platelet factor 4 developed in heparin-induced thrombocytopenia: biological characteristics and effects on platelet activation

Supplement
Antithrombotic and Thrombolytic Therapy, 8th ED: ACCP Guidelines
Treatment and Prevention of Heparin-Induced Thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)