Heparin-induced thrombocytopenia

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Overview

Heparin-induced thrombocytopenia (HIT) with or without thrombosis (HITT) is thrombocytopenia (low platelet counts) due to the administration of heparin. While it is mainly associated with unfractionated heparin (UFH), it can also occur with exposure to low-molecular weight heparin (LMWH), but at significantly lower rates. Despite the low platelet count, it is a thrombotic disorder, with very high rates of thrombosis, in the arteries with or without venous complications. Of note, the rate of DVT (Deep Vein Thrombosis) is roughly 4 times that of arterial thrombosis, and while thrombocytopenia is the most common "event" in HIT, DVT is in fact the most common complication.

HIT typically develops 4-14 days after the administration of heparin. Heparin (UFH) is used in cardiovascular surgery, as prevention or treatment for deep-vein thrombosis and pulmonary embolism and in various other clinical scenarios. LMWH is increasingly used in outpatient prophylaxis regimes.

There are two forms of HIT. Type II HIT is the main adverse effect of heparin use.

Type I

Patients have a transient decrease in platelet count without any further symptoms. This recovers even if heparin is continued to be administered. Platelet counts rarely fall below 100,000. It occurs in 10-20% of all patients on heparin. It is not due to an immune reaction and antibodies are not found upon investigation.

Type II

This form is due to an autoimmune reaction with antibodies formed against platelet factor 4 (PF4), neutrophil-activating peptide 2 (NAP-2) and interleukin 8 (IL8) which form complexes with heparin. The most common being to the heparin-PF4 complex. It appears that heparin binding to platelet factor 4 causes a conformational change in the protein, rendering it antigenic. The antibodies found are most commonly of the IgG class with or without IgM and IgA class antibodies. IgM and IgA are rarely found without IgG antibodies. Type II HIT develops in about 3% of all patients on UFH and in 0.1% of patients on LMWH, and causes thrombosis in 30% to 40% of these patients. The other patients are able to compensate for the activation of hemostasis that leads to thrombosis. Clot formation is mainly arterial and rich in platelets ("white clot syndrome"), in contrast with fibrin-rich clots (which are red due to trapped red blood cells). Most thrombotic events are in the lower limbs, skin lesions and necrosis may also occur at the site of the heparin infusion

The most important enzyme in type II HIT is thrombin, the generation of which is increased following platelet activation. Platelet activation follows the binding of heparin to PF4 and the cross linking of receptors on the platelet surface.

Genetic risk factors for thrombosis such as factor V Leiden, prothrombin gene mutation, methylenetetrahydrofolate reductase (MTHFR) polymorphism and platelet-receptor polymorphisms do not increase the risk of developing HIT associated thrombosis.

Risk for HIT is higher in women than in men, and HIT occurs more commonly in surgical than in non-surgical settings.^[1]

Diagnosis

The most specific tests are: the serotonin release assay (SRA), the heparin induce platelet aggregation (HIPA) assays and the solid-phase immunoassay (SPI). The sensitivity of these tests is 94% at best. The gold standard is the SRA where antibodies from the patient’s serum result in release of radiolabeled serotonin attached to platelets from a normal patient. The HIPA looks for platelet aggregation that is present with heparin, platelets and patient serum but does not occur in the absence of heparin. It has a >90% specificity but is limited by low sensitivity. The SPI is an enzyme-linked immunosorbent assay (ELISA) that tests for the presence or absence of heparin-PF4 complexes. Because it does not determine whether the antibodies are functionally significant, it is best used in conjunction with one of the two prior tests. ^{[1] [1] [1] [1]}

Treatment

Treatment is by prompt withdrawal of heparin and replacement with a suitable alternative anticoagulant. To block the thrombotic state, lepirudin, fondaparinux, bivalirudin, argatroban, danaparoid or other direct thrombin inhibitors are used. Low molecular weight heparin is contraindicated in HIT.

According to systematic review, patients treated with lepirudin for heparin-induced thrombocytopenia showed a relative risk reduction of clinical outcome (death, amputation, etc.) to be 0.52 and 0.42 when compared to patient controls. In addition, patients treated with argatroban for HIT showed a relative risk reduction of the above clinical outcomes to be 0.20 and 0.18. ^[1]

Pharmacotherapy

Acute Pharmacotherapies

• Check platelet counts twice weekly while on heparin. Withdrawal heparin immediately of HIT is suspected. Platelet transfusion worsens thrombosis, and warfarin therapy is should be avoided for 3-5 days after heparin cessation and/or until thrombocytopenia resolves (>100,000).
• Use of heparinoids and direct thrombin inhibitors is the safest and most effective therapeutic approach to HIT for both those who need ongoing anticoagulation and for thrombosis prevention. Hirudin or Leprudin are direct thrombin inhibitors that have been shown to be effective. Danaproid (Orgaran) is a heaparinoid composed of 85% heparan sulphate, 10% dermatan sulphate and 5% chondroitin sulphate that has approximately 10% cross reactivity with heparin. It has been shown to reduce mortality from thrombotic complications to 5% from 28%. Other agents that have been used include aspirin (ASA), acrid (viper venom), prostaglandin’s and GpIIb/IIIa have not been had reproducible efficacy or have not been used in enough patients to warrant routine use.
• The in vitro cross reactivity of LMWH with heparin dependant antibodies is approximately 60-100%. Nonetheless, a theoretical argument for the use of LMWH in therapy for HIT has been made. The theory is that the LMWH overall interaction of heparin with PF4 will diminish. Though there are reports of LMWH being effective in controlling HIT in the presence of cross-reacting antibodies, the consensus is not to administer LMWH unless the absence of cross reactivity has been determined.

Patients Undergoing Surgery or PCI

Patients with HIT should be treated with Bivalirudin, a direct thrombin inhibitor to support these procedures.

Secondary Prevention

Patients with HIT should be treated with Bivalirudin, a direct thrombin inhibitor to support future procedures.

Reference

External links

• Cleveland clinic page on HIT
• HIT page

Additional Reading

• Kumar, Vinay, Abul Abbas, and Nelson Fausto. Robbins and Cotran Pathologic Basis of Disease, 7th ed. (2005). ISBN 0-7216-0187-1

v • d • e WikiDoc Research Resources for Heparin-induced thrombocytopenia (Click show to right to view)
Articles on Heparin-induced thrombocytopenia	Most recent articles on Heparin-induced thrombocytopenia • Most cited articles on Heparin-induced thrombocytopenia • Review articles on Heparin-induced thrombocytopenia • Articles on Heparin-induced thrombocytopenia in N Eng J Med, Lancet, BMJ
Media (Slides, Video, Images, MP3) on Heparin-induced thrombocytopenia	Powerpoint slides on Heparin-induced thrombocytopenia • Images of Heparin-induced thrombocytopenia • Photos of Heparin-induced thrombocytopenia • Podcasts & MP3s on Heparin-induced thrombocytopenia • Videos on Heparin-induced thrombocytopenia
Evidence Based Medicine Regarding Heparin-induced thrombocytopenia	Cochrane Collaboration on Heparin-induced thrombocytopenia • Bandolier on Heparin-induced thrombocytopenia • TRIP on Heparin-induced thrombocytopenia
Cost Effectiveness of Heparin-induced thrombocytopenia	Cost Effectiveness of Heparin-induced thrombocytopenia
Clinical Trials Involving Heparin-induced thrombocytopenia	Ongoing Trials on Heparin-induced thrombocytopenia at Clinical Trials.gov • Trial results on Heparin-induced thrombocytopenia • Clinical Trials on Heparin-induced thrombocytopenia at Google
Guidelines / Policies / Government Resources (FDA/CDC) Regarding Heparin-induced thrombocytopenia	US National Guidelines Clearinghouse on Heparin-induced thrombocytopenia • NICE Guidance on Heparin-induced thrombocytopenia • NHS PRODIGY Guidance • FDA on Heparin-induced thrombocytopenia • CDC on Heparin-induced thrombocytopenia
Textbook Information on Heparin-induced thrombocytopenia	Books and Textbook Information on Heparin-induced thrombocytopenia
Pharmacology Resources on Heparin-induced thrombocytopenia	Dosing of Heparin-induced thrombocytopenia • Drug interactions with Heparin-induced thrombocytopenia • Side effects of Heparin-induced thrombocytopenia • Allergic reactions to Heparin-induced thrombocytopenia • Overdose information on Heparin-induced thrombocytopenia • Carcinogenicity information on Heparin-induced thrombocytopenia • Heparin-induced thrombocytopenia in pregnancy • Pharmacokinetics of Heparin-induced thrombocytopenia •
Genetics, Pharmacogenomics, and Proteinomics of Heparin-induced thrombocytopenia	Genetics of Heparin-induced thrombocytopenia • Pharmacogenomics of Heparin-induced thrombocytopenia • Proteomics of Heparin-induced thrombocytopenia
Newstories on Heparin-induced thrombocytopenia	Heparin-induced thrombocytopenia in the news • Be alerted to news on Heparin-induced thrombocytopenia • News trends on Heparin-induced thrombocytopenia
Commentary on Heparin-induced thrombocytopenia	Blogs on Heparin-induced thrombocytopenia
Patient Resources on Heparin-induced thrombocytopenia	Patient resources on Heparin-induced thrombocytopenia • Discussion groups on Heparin-induced thrombocytopenia • Patient Handouts on Heparin-induced thrombocytopenia • Directions to Hospitals Treating Heparin-induced thrombocytopenia • Risk calculators and risk factors for Heparin-induced thrombocytopenia
Healthcare Provider Resources on Heparin-induced thrombocytopenia	Symptoms of Heparin-induced thrombocytopenia • Causes & Risk Factors for Heparin-induced thrombocytopenia • Diagnostic studies for Heparin-induced thrombocytopenia • Treatment of Heparin-induced thrombocytopenia
Continuing Medical Education (CME) Programs on Heparin-induced thrombocytopenia	CME Programs on Heparin-induced thrombocytopenia
International Resources on Heparin-induced thrombocytopenia	Heparin-induced thrombocytopenia en Espanol • Heparin-induced thrombocytopenia en Francais
Business Resources on Heparin-induced thrombocytopenia	Heparin-induced thrombocytopenia in the Marketplace • Patents on Heparin-induced thrombocytopenia
Informatics Resources on Heparin-induced thrombocytopenia	List of terms related to Heparin-induced thrombocytopenia

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Acknowledgement and Attribution Regarding Sources of Content

Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .