Heparin-induced thrombocytopenia (HIT) is the development of thrombocytopenia (a low platelet count), due to the administration of various forms of heparin, an anticoagulant. HIT predisposes to thrombosis (the abnormal formation of blood clots inside a blood vessel). When thrombosis is identified the condition is called heparin-induced thrombocytopenia and thrombosis (HITT). HIT is caused by the formation of abnormal antibodies that activate platelets, which release microparticles that activate thrombin, leading to thrombosis. If someone receiving heparin develops new or worsening thrombosis, or if the platelet count falls, HIT can be confirmed with specific blood tests.
The treatment of HIT requires stopping heparin treatment, and both protection from thrombosis and choice of an agent that will not reduce the platelet count any further. Several alternatives are available for this purpose; mainly used are danaparoid, fondaparinux, argatroban, and bivalirudin.
While purified heparin was first used in humans in the 1930s, HIT was not reported until the 1960s.
Signs and symptoms
Heparin may be used for both prevention and the treatment of thrombosis. It exists in two main forms: an "unfractionated" form that can be injected under the skin (subcutaneously) or through an intravenous infusion, and a "low molecular weight" form that is generally given subcutaneously. Commonly used low molecular weight heparins are enoxaparin, dalteparin, nadroparin and tinzaparin.
In HIT, the platelet count in the blood falls below the normal range, a condition called thrombocytopenia. However, it is generally not low enough to lead to an increased risk of bleeding. Most people with HIT, therefore, do not experience any symptoms. Typically, the platelet count falls 5–14 days after heparin is first given; if someone has received heparin in the previous three months, the fall in platelet count may occur sooner, sometimes within a day.
In those receiving heparin through an intravenous infusion, a complex of symptoms ("systemic reaction") may occur when the infusion is started. These include fever, chills, high blood pressure, a fast heart rate, shortness of breath, and chest pain. This happens in about a quarter of people with HIT. Others may develop a skin rash consisting of red spots.
The IgG antibodies form a complex with heparin and PF4 in the bloodstream. The tail of the antibody then binds to the FcγIIa receptor, a protein on the surface of the platelet. This results in platelet activation and the formation of platelet microparticles, which initiate the formation of blood clots; the platelet count falls as a result, leading to thrombocytopenia.
However, not all people with a falling platelet count while receiving heparin turn out to have HIT. The timing, severity of the thrombocytopenia, the occurrence of new thrombosis, and the presence of alternative explanations, all determine the likelihood that HIT is present. A commonly used score to predict the likelihood of HIT is the "4 Ts" score introduced in 2003. In an analysis of the reliability of the 4T score, a low score had a negative predictive value of 0.998, while an intermediate score had a positive predictive value of 0.14 and a high score a positive predictive value of 0.64; intermediate and high scores, therefore, warrant further investigation.
{| class="wikitable"
! Element
! The 4T score for heparin-induced thrombocytopenia
|-
! Thrombocytopenia
| align="left" | 2 points if the fall in platelet count is >50% of the previous value, AND the lowest count (nadir) is 20–100 billion/liter<BR/>1 point if the fall is 30–50% or the nadir is 10–19 billion/liter<BR/>No points if the fall is less than 30% or the nadir is <10 billion/liter.
|-
! Timing
| align="left" | 2 points if the fall is between days 5–10 after commencement of treatment<BR/>1 point if the fall is after day 10. If someone has been exposed to heparin within the last 30 days and then has a drop in platelet count within a day of reexposure, 2 points are given. If the previous exposure was 30–100 days ago, 1 point<BR/>If the fall is early but there has been no previous heparin exposure, no points.
|-
! Thrombosis
| align="left" | 2 points in new proven thrombosis, skin necrosis (see below), or systemic reaction<BR/>1 point if progressive or recurrent thrombosis, silent thrombosis or red skin lesions<BR/>No points if there are no symptoms.
|-
! Alternative cause possible
| align="left" | 2 points if no other cause<BR/>1 point if there is a possible alternative cause<BR/>No points if there is a definite alternative cause.
|}
The first screening test in someone suspected of having HIT is aimed at detecting antibodies against heparin-PF4 complexes. This may be with a laboratory test of the enzyme-linked immunosorbent assay type. This ELISA test, however, detects all circulating antibodies that bind heparin-PF4 complexes, and may also falsely identify antibodies that do not cause HIT. Therefore, those with a positive ELISA are tested further with a functional assay. This test uses platelets and serum from the patient; the platelets are washed and mixed with serum and heparin. The sample is then tested for the release of serotonin, a marker of platelet activation. If this serotonin release assay (SRA) shows high serotonin release, the diagnosis of HIT is confirmed. The SRA test is difficult to perform and is usually only done in regional laboratories. Lepirudin production stopped on May 31, 2012.
Epidemiology
Up to 8% of patients receiving heparin are at risk to develop HIT antibodies, but only 1–5% on heparin will progress to develop HIT with thrombocytopenia and subsequently one-third of them may develop arterial or venous thrombosis. The exact number of cases of HIT in the general population is unknown. What is known is that women receiving heparin after a recent surgical procedure, particularly cardiothoracic surgery, have a higher risk, while the risk is very low in women just before and after giving birth. HIT is less common in those receiving low molecular weight heparin compared to unfractionated heparin.
History
While heparin was introduced for clinical use in the late 1930s, new thrombosis in people treated with heparin was not described until 1957, when vascular surgeons reported the association. The fact that this phenomenon occurred together with thrombocytopenia was reported in 1969; prior to this time, platelet counts were not routinely performed.
Initially, various theories existed about the exact cause of the low platelets in HIT. Gradually, evidence accumulated on the exact underlying mechanism.
Treatment was initially limited to aspirin and warfarin, but the 1990s saw the introduction of a number of agents that could provide anticoagulation without a risk of recurrent HIT. It is a rare adverse event (1:1 million to 1:100,000) resulting from COVID-19 vaccines (particularly adenoviral vector vaccines). This is also known as thrombosis with thrombocytopenia syndrome or TTS.