Heparin-induced thrombocytopenia classification

Heparin-induced thrombocytopenia
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2], Aric C. Hall, M.D., [3] Shyam Patel [4]

Overview

Heparin-induced thrombocytopenia is diagnosed when the platelet count falls by > 50% typically after 5-10 days of heparin therapy. There are two forms of HIT. Type II HIT is the main adverse effect of heparin use.

Classification

A diagnosis of HIT requires the presence of heparin exposure and the subsequent development of antibodies to heparin-PF4 complex. It is typically accompanied by thrombocytopenia (platelet count < 150,000 per microliter). Thrombosis is a common complication but is not required for a diagnosis of HIT. In 10-15% of patients, a decrease in platelet count does not occur. In some cases, the platelet count can decrease by 30-50% and the nadir remains above 150,000 per microliter. The time course for thrombocytopenia is usually 5-14 days after heparin exposure.

Type I

• In this form patients characteristically have a transient decrease in platelet count (rarely <100,000) without any further symptoms.
• This thrombocytopenia recovers even if heparin is continued to be administered.
• 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.
• HIT-1 is due to heparin-induced platelet clumping; it is innocuous.

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 form is to the heparin-PF4 complex.
• Heparin binding to platelet factor 4 causes a conformational change in the protein, rendering it antigenic.
• Antibodies bind to these complexes, activate the surrounding platelets and generate thrombin.
• The antibodies found are most commonly are 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
• Most thrombotic events are in the lower limbs, skin lesions and necrosis may also occur at the site of the heparin infusion.
• Rapid-onset HIT can result in life-threatening acute systemic reactions (eg rigors, fever, hypertension, tachycardia) and cardiopulmonary collapse.
• Single or trivial doses of heparin, such as catheter flushes, can cause HIT.
• In HIT2 the onset of thrombocytopenia is independent of the type of heparin, dose and route of administration.
• HIT antibodies can persist for 4-6 weeks but disappear after 3 months.
• The presence of HIT antibodies, even at higher titer, doesn't predict an increase in complications.
• An increase in the titers of the antibodies do, however, give an increase in the in-vitro activaton of the coagulation system.
• The ELISA test, though not ideal, is the best predictive diagnostic test of HIT2. It has been suggested that HIT2 only occurs with high antibody titers and after persistent exposure to heparin; also it suggests that antigens different from the H-PF4 complex can be involved. There may be a HIT antibody active in a non-heparin dependent manner. Data exists suggesting that there are "superactive" HIT antibodies capable of activating platelets without heparin.

Isolated HIT

Isolated HIT refers to the presence of HIT but absence of thrombosis. Diagnostic criteria are thrombocytopenia after heparin exposure and presence of antibodies to the heparin-PF4 complex, without evidence of clot formation.

Rapid-Onset HIT

This is characterized by a sudden development of thrombocytopenia within 24 hours in the setting of pre-formed antibodies to heparin-PF4. The presence of pre-formed circulating antibodies is due to exposure to heparin within the past 30 days.

Delayed-Onset HIT

This is characterized by development of thrombocytopenia after 3 weeks from heparin cessation. This is in contrast with rapid-onset HIT in which the thrombocytopenia occurs abruptly.