eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders

Heparin-Induced Thrombocytopenia

Author: Sancar Eke, MD, Renal Fellow, Henry Ford Hospital
Coauthor(s): Sarah K May, MD, Consulting Staff, Department of Hematology-Oncology, Caritas Carney Hospital, Commonwealth Hematology-Oncology PC
Contributor Information and Disclosures

Updated: Jun 16, 2009

Introduction

Background

Heparin has been in clinical use for over 50 years for numerous clinical situations from thromboprophylaxis to treatment of thromboembolic disease and for dialysis. Approximately 12 million individuals, or one third of hospitalized patients, have some heparin exposure yearly.  However, heparin can lead to serious side effects. A well-known adverse effect of heparin exposure is thrombocytopenia.

There are 2 types of heparin-induced thrombocytopenia (HIT). Type 1 heparin-induced thrombocytopenia (HIT) presents within the first 2 days after exposure to heparin, and the thrombocyte count normalizes with continued heparin therapy. It is well known that type 1 heparin-induced thrombocytopenia (HIT) is a nonimmune disorder, and it occurs with the direct effect of heparin on platelet activation.1
 
Type 2 heparin-induced thrombocytopenia (HIT) is an immune-mediated disorder which typically occurs 4-10 days after exposure to heparin, and it is the serious type with its life- and limb-threatening prothrombotic complications.1 In general medical practice, heparin-induced thrombocytopenia (HIT) refers to type 2 heparin-induced thrombocytopenia.
 
Heparin-induced thrombocytopenia (HIT) is an important and life-threatening complication of heparin therapy. Heparin-induced thrombocytopenia (HIT) must be suspected when a patient has a fall in thrombocyte count while receiving heparin—particularly if the fall is over 50% of the baseline count, even if the platelet count nadir remains >150 x 109/L—by skin lesions at heparin injection sites, or by systemic reactions.2

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center, Circulatory Problems Center, and Lung and Airway Center. Also, see eMedicine's patient education articles Deep Vein Thrombosis (Blood Clot in the Leg, DVT) and Pulmonary Embolism.

Pathophysiology

Heparin-induced thrombocytopenia (HIT) is a severe complication of heparin therapy caused by antibodies to complexes between heparin and platelet factor 4 (PF4).3 These antibodies are present in nearly all patients with the clinical diagnosis of heparin-induced thrombocytopenia (HIT). However, the antibodies are also present in many patients who have been exposed to heparin but who do not have clinical manifestations of heparin-induced thrombocytopenia (HIT). Plasma from more than 90% of patients with HIT contains anti–PF4-heparin antibodies.3

Immune complexes of heparin-induced thrombocytopenia (HIT) antibodies and PF4/heparin bind to the surface of platelets and induce their activation by cross-linking FcIIA receptors and bind to the surface of the endothelium, inducing procoagulant activity.4,5,6 Platelets activated with heparin-induced thrombocytopenia (HIT) immunoglobulin G (IgG) increase their release and surface expression of PF4. Thus, a positive feedback loop is created as further release of PF4 with platelet activation occurs.7

Unfractionated heparin and tetrameric PF4 have been demonstrated form ultralarge (>670 kDa) complexes (ULCs) with an optimal ratio of PF4 to heparin of approximately 1:1.8 These ULCs were stable and visible by electron microscopy. Far fewer ULCs were formed when small-intermediate molecular weight heparins were used, and none were formed with the pentasaccharide fondaparinux sodium. The capacity of PF4 to form ULCs composed of multiple PF4 tetramers arrayed in a lattice with several molecules of UFH is believed to play a fundamental role in autoantibody formation, antibody-dependent platelet activation, and the propensity for thrombosis in patients with heparin-induced thrombocytopenia (HIT).8

Frequency

United States

Studies in the literature quote frequencies of heparin-induced thrombocytopenia (HIT) as high as 1-5%.9,10,11 Many studies that reported heparin-induced thrombocytopenia (HIT) frequencies to be as high as 5% were performed in postorthopedic surgery patients who received unfractionated heparin (UFH) thromboprophylaxis for 10-14 days.12

A study by Smythe and colleagues estimated the frequency of heparin-induced thrombocytopenia (HIT) to be 0.76% of patients receiving therapeutic-doses of UFH and <0.1% of patients receiving antithrombotic prophylaxis with UFH, with an overall risk of heparin-induced thrombocytopenia (HIT) of about 0.2% among all heparin-exposed patients.13 In the same study, 49% of all new heparin-induced thrombocytopenia (HIT) cases were in surgery patients for coronary artery bypass and/or valve replacement.13

Mortality/Morbidity

Immune heparin-induced thrombocytopenia (HIT) is a severe prothrombotic condition, with affected individuals having a 20-50% risk of developing new thromboembolic events.14 The mortality rate is approximately 20%, and an additional approximate 10% of patients require amputations or suffer other major morbidity.15,16,17

Thrombosis associated with heparin-induced thrombocytopenia (HIT) can involve the arterial system, the venous system, or both. Thrombotic complications may include cerebrovascular accidents (CVAs), myocardial infarction (MI), limb ischemia, deep venous thrombosis (DVT), and, rarely, ischemia of other organs. The thrombotic complications are fatal in about 29% of patients, and an additional 21% have to undergo limb amputations.18

A consecutive study with 108 hospitalized patients diagnosed with heparin-induced thrombocytopenia (HIT) showed that thrombotic complications occurred in about 29%, and early, severe falls in platelet counts in elderly patients receiving heparin appear to be associated with the development of thrombotic complications.16

Race

A study by Lewis et al reported that white patients had significantly less risk than nonwhite patients for the thrombotic events, irrespective of the heparin-induced thrombocytopenia (HIT)presentation.19 This study showed that nonwhites are approximately 2-3 times more likely than whites to progress to a heparin-induced thrombocytopenia – associated thrombotic outcome, particularly with regard to new thromboses.19

Sex

Men have significantly less risk than women patients for the thrombotic composite in heparin-induced thrombocytopenia (HIT) patients with thrombosis. Women diagnosed with heparin-induced thrombocytopenia (HIT) and thrombosis are 1.7 times more likely than men to have a new heparin-induced thrombocytopenia-associated thrombotic event.19

The increased frequency of heparin-induced thrombocytopenia (HIT) in females was found most strikingly in patients treated with UFH, among whom females were significantly more likely than males to develop heparin-induced thrombocytopenia (HIT). There was no relationship between sex and the risk for heparin-induced thrombocytopenia (HIT) among patients treated with low molecular weight heparin (LMWH).20 LMWH in prevention of heparin-induced thrombocytopenia (HIT) may have the greatest absolute benefit in females undergoing surgical thromboprophylaxis.20

Age

A study with a total of 408 patients diagnosed with heparin-induced thrombocytopenia (HIT) indicated that 66% of those patients were older than age 60 years.21

Clinical

History

There are 3 characteristic features of heparin-induced thrombocytopenia (HIT) that can distinguish it from other causes of thrombocytopenia: (1) the timing of the onset of thrombocytopenia, a platelet count decrease that begins between days 5 and 14 of beginning heparin treatment; (2) the severity of the thrombocytopenia (usually mild to moderate), with platelet counts only rarely less than 15 x 109/L; and (3) large-vessel venous or arterial thrombosis in association with thrombocytopenia.22

Physicians should think of the possibility of heparin-induced thrombocytopenia (HIT) if venous thromboembolism (VTE) develops during or soon after UFH use; if thrombocytopenia is present, alternative anticoagulation should be used until heparin-induced thrombocytopenia (HIT) is excluded.23 Delayed-onset heparin-induced thrombocytopenia (HIT) develops several days after heparin cessation. In patients with previous heparin exposure, heparin-induced thrombocytopenia (HIT) may have a rapid onset (within hours of reexposure)

Clinical features of heparin-induced thrombocytopenia (HIT) that help distinguish it from other forms of thrombocytopenia include the timing of onset (usually 5-14 d after beginning an immunizing exposure to heparin), the severity of the thrombocytopenia (usually mild to moderate), and the presence of thrombosis or other sequelae.
 
In one study, 12 patients were described who experienced thrombocytopenia or symptoms of thrombosis an average of 9 days after all heparin was withdrawn.24 This phenomenon was referred as delayed-onset heparin-induced thrombocytopenia. Delayed-onset heparin-induced thrombocytopenia (HIT) should be considered when a patient presents with thrombosis and unexplained thrombocytopenia up to 3 weeks after the end of heparin therapy.24

Physical

Heparin-induced thrombocytopenia (HIT) may present with unusual characteristic sequelae, including warfarin-associated venous limb gangrene, bilateral adrenal hemorrhagic infarction, heparin-induced skin lesions, or acute systemic reactions following an intravenous heparin bolus. In contrast to other drug-induced immune thrombocytopenia syndromes, in general, heparin-induced thrombocytopenia (HIT) is not associated with bleeding.22

In addition to the occurrence of thrombocytopenia within the appropriate time frame, a diagnosis of heparin-induced thrombocytopenia (HIT) is suggested by the presence of skin lesions at heparin injection sites and acute systemic reactions including chills, fever, dyspnea, chest pain; flushing may be observed following intravenous heparin administration.25 Patients with heparin-induced thrombocytopenia (HIT) can also present with DVT, which can progress to limb loss if the use of coumarin leads to severe protein C depletion (coumarin-induced venous limb gangrene).26

Causes

Heparin-induced thrombocytopenia (HIT) is caused by antibody formation to heparin-PF4 complexes. A study showed that heparin-induced thrombocytopenia (HIT) is more frequently encountered with UFH compared with LMWH.15 Case studies have also demonstrated the probability of developing heparin-induced thrombocytopenia (HIT) with minimal heparin exposure via intravascular flushes to maintain the patency of indwelling arterial or venous catheters.27,28,29,30,31
 
Fondaparinux is a new anticoagulant that catalyzes the inhibition of factor Xa (but not thrombin) by antithrombin, and this results in the inhibition of thrombin generation. A study suggested that fondaparinux may be associated with formation of anti–PF4/heparin antibodies but, in contrast to LMWH, it is unlikely to cause heparin-induced thrombocytopenia (HIT) because of the poor reactivity of antibodies against PF4/fondaparinux.32

More on Heparin-Induced Thrombocytopenia

Overview: Heparin-Induced Thrombocytopenia
Differential Diagnoses & Workup: Heparin-Induced Thrombocytopenia
Treatment & Medication: Heparin-Induced Thrombocytopenia
Follow-up: Heparin-Induced Thrombocytopenia
Multimedia: Heparin-Induced Thrombocytopenia
References
Further Reading
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References

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Further Reading

Related eMedicine Topics

Clinical Trials
 National Guideline Clearinghouse

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Keywords

heparin, heparin-induced thrombocytopenia, HIT, platelets, thrombosis, thrombocytopenia, heparin-induced thrombocytopenia-thrombosis, blood, coagulation, intravascular, platelets, Fc-receptor IIa

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Contributor Information and Disclosures

Author

Sancar Eke, MD, Renal Fellow, Henry Ford Hospital
Sancar Eke, MD is a member of the following medical societies: American College of Physicians and Massachusetts Medical Society
Disclosure: Nothing to disclose.

Coauthor(s)

Sarah K May, MD, Consulting Staff, Department of Hematology-Oncology, Caritas Carney Hospital, Commonwealth Hematology-Oncology PC
Disclosure: Nothing to disclose.

Medical Editor

Paul Schick, MD, Emeritus Professor, Department of Internal Medicine, Thomas Jefferson University Medical College; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital, Wynnewood, PA
Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Hematology, International Society on Thrombosis and Haemostasis, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

 
 
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