Heparin-induced thrombocytopenia (HIT) is the development of
thrombocytopenia
Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients an ...
(a low
platelet
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
count), due to the administration of various forms of
heparin
Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Since heparins depend on the activity of antithrombin, they are considered anticoagulants. Specifically it is also used in the treatm ...
, an
anticoagulant
Anticoagulants, commonly known as blood thinners, are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where the ...
. HIT predisposes to
thrombosis
Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thro ...
(the abnormal formation of blood clots inside a
blood vessel
The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away ...
) because platelets release microparticles that activate
thrombin
Thrombin (, ''fibrinogenase'', ''thrombase'', ''thrombofort'', ''topical'', ''thrombin-C'', ''tropostasin'', ''activated blood-coagulation factor II'', ''blood-coagulation factor IIa'', ''factor IIa'', ''E thrombin'', ''beta-thrombin'', ''gamma- ...
, thereby leading to thrombosis. When thrombosis is identified the condition is called heparin-induced thrombocytopenia and thrombosis (HITT). HIT is caused by the formation of abnormal
antibodies
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
that activate platelets. If someone receiving heparin develops new or worsening thrombosis, or if the platelet count falls, HIT can be confirmed with specific
blood test
A blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a hypodermic needle, or via fingerprick. Multiple tests for specific blood components, such as a glucose test or a cholester ...
s.
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
Danaparoid sodium (Orgaran) is an anticoagulant with an antithrombotic action due to inhibition of thrombin generation (TGI) by two mechanisms: indirect inactivation of Factor Xa via AT and direct inhibition of thrombin activation of Factor IX (an ...
,
fondaparinux
Fondaparinux (trade name Arixtra) is an anticoagulant medication chemically related to low molecular weight heparins. It is marketed by GlaxoSmithKline. A generic version developed by Alchemia is marketed within the US by Dr. Reddy's Laboratories.
...
,
argatroban
Argatroban is an anticoagulant that is a small molecule direct thrombin inhibitor. In 2000, argatroban was licensed by the Food and Drug Administration (FDA) for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocyto ...
, and
bivalirudin
Bivalirudin (Bivalitroban), sold under the brand names Angiomax and Angiox and manufactured by The Medicines Company, is a direct thrombin inhibitor (DTI).
Chemically, it is a synthetic congener of the naturally occurring drug hirudin, found in ...
.
While heparin was discovered 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
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
, and a "low molecular weight" form that is generally given subcutaneously. Commonly used low molecular weight heparins are
enoxaparin
Enoxaparin sodium, sold under the brand name Lovenox among others, is an anticoagulant medication (blood thinner). It is used to treat and prevent deep vein thrombosis (DVT) and pulmonary embolism (PE) including during pregnancy and following c ...
,
dalteparin
Dalteparin is a low molecular weight heparin. It is marketed as Fragmin. Like other low molecular weight heparins, dalteparin is used for prophylaxis or treatment of deep vein thrombosis and pulmonary embolism to reduce the risk of a stroke or ...
,
nadroparin
Nadroparin (trade names Fraxiparin '', Fraxodi, among others) is an anticoagulant belonging to a class of drugs called low molecular weight heparins (LMWHs). Nadroparin was developed by Sanofi-Synthélabo.
Nadroparin is used in general and orthope ...
and
tinzaparin
Tinzaparin is an antithrombotic drug in the heparin group. It is a low molecular weight heparin (LMWH) marketed as Innohep worldwide. It has been approved by the U.S. Food and Drug Administration (FDA) for once daily treatment and prophylaxis of ...
.
In HIT, the platelet count in the blood falls below the normal range, a condition called
thrombocytopenia
Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients an ...
. 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.
[
The most common symptom of HIT is enlargement or extension of a previously diagnosed blood clot, or the development of a new blood clot elsewhere in the body. This may take the form of clots either in ]arteries
An artery (plural arteries) () is a blood vessel in humans and most animals that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated blood; the two exceptions are the pu ...
or vein
Veins are blood vessels in humans and most other animals that carry blood towards the heart. Most veins carry deoxygenated blood from the tissues back to the heart; exceptions are the pulmonary and umbilical veins, both of which carry oxygenated b ...
s, causing arterial or venous thrombosis, respectively. Examples of arterial thrombosis are stroke
A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...
, myocardial infarction
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...
("heart attack"), and acute leg ischemia. Venous thrombosis may occur in the leg or arm in the form of deep vein thrombosis
Deep vein thrombosis (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and enla ...
(DVT) and in the lung
The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of t ...
in the form of a pulmonary embolism
Pulmonary embolism (PE) is a blockage of an pulmonary artery, artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream (embolism). Symptoms of a PE may include dyspnea, shortness of breath, chest pain p ...
(PE); the latter usually originates in the leg, but migrates to the lung.
In those receiving heparin through an intravenous infusion, a complex of symptoms ("systemic reaction") may occur when the infusion is started. These include fever
Fever, also referred to as pyrexia, is defined as having a body temperature, temperature above the human body temperature, normal range due to an increase in the body's temperature Human body temperature#Fever, set point. There is not a single ...
, chills, high blood pressure
Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...
, a fast heart rate, shortness of breath
Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing disc ...
, and chest pain
Chest pain is pain or discomfort in the chest, typically the front of the chest. It may be described as sharp, dull, pressure, heaviness or squeezing. Associated symptoms may include pain in the shoulder, arm, upper abdomen, or jaw, along with n ...
. This happens in about a quarter of people with HIT. Others may develop a skin rash consisting of red spots.[
]
Mechanism
The administration of heparin can cause the development of HIT antibodies, suggesting heparin may act as a hapten
In immunology, haptens are small molecules that elicit an immune response only when attached to a large carrier such as a protein; the carrier may be one that also does not elicit an immune response by itself (in general, only large molecules, i ...
, thus may be targeted by the immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
. In HIT, the immune system forms antibodies against heparin when it is bound to a protein called platelet factor 4
Platelet factor 4 (PF4) is a small cytokine belonging to the CXC chemokine family that is also known as chemokine (C-X-C motif) ligand 4 (CXCL4) . This chemokine is released from alpha-granules of activated platelets during platelet aggregation, ...
(PF4). These antibodies are usually of the IgG
Immunoglobulin G (Ig G) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG ...
class and their development usually takes about 5 days. However, those who have been exposed to heparin in the last few months may still have circulating IgG, as IgG-type antibodies generally continue to be produced even when their precipitant has been removed. This is similar to immunity
Immunity may refer to:
Medicine
* Immunity (medical), resistance of an organism to infection or disease
* ''Immunity'' (journal), a scientific journal published by Cell Press
Biology
* Immune system
Engineering
* Radiofrequence immunity desc ...
against certain microorganisms, with the difference that the HIT antibody does not persist more than three months.[ HIT antibodies have been found in individuals with ]thrombocytopenia
Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients an ...
and thrombosis
Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thro ...
who had no prior exposure to heparin, but the majority are found in people who are receiving heparin.
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.[ In addition, the ]reticuloendothelial system
In anatomy the term "reticuloendothelial system" (abbreviated RES), often associated nowadays with the mononuclear phagocyte system (MPS), was originally launched by the beginning of the 20th century to denote a system of specialised cells that eff ...
(mostly the spleen) removes the antibody-coated platelets, further contributing to the thrombocytopenia.
Formation of PF4-heparin antibodies is common in people receiving heparin, but only a proportion of these develop thrombocytopenia or thrombosis.[ This has been referred to as an "iceberg phenomenon".][
]
Diagnosis
HIT may be suspected if blood tests show a falling platelet count in someone receiving heparin, even if the heparin has already been discontinued. Professional guidelines recommend that people receiving heparin have a complete blood count
A complete blood count (CBC), also known as a full blood count (FBC), is a set of medical laboratory tests that provide cytometry, information about the cells in a person's blood. The CBC indicates the counts of white blood cells, red blood cell ...
(which includes a platelet count) on a regular basis while receiving heparin
Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Since heparins depend on the activity of antithrombin, they are considered anticoagulants. Specifically it is also used in the treatm ...
.
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.[ A score of 0–8 points is generated; if the score is 0–3, HIT is unlikely. A score of 4–5 indicates intermediate probability, while a score of 6–8 makes it highly likely. Those with a high score may need to be treated with an alternative drug, while more sensitive and specific tests for HIT are performed, while those with a low score can safely continue receiving heparin, as the likelihood that they have HIT is extremely low.] 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.
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
The enzyme-linked immunosorbent assay (ELISA) (, ) is a commonly used analytical biochemistry assay, first described by Eva Engvall and Peter Perlmann in 1971. The assay uses a solid-phase type of enzyme immunoassay (EIA) to detect the presence ...
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
Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
, 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.[
If someone has been diagnosed with HIT, some recommend routine ]Doppler sonography
Doppler ultrasonography is medical ultrasonography that employs the Doppler effect to perform imaging of the movement of tissues and body fluids (usually blood), and their relative velocity to the probe. By calculating the frequency shift of ...
of the leg veins to identify deep vein thromboses, as this is very common in HIT.[
]
Treatment
Given the fact that HIT predisposes strongly to new episodes of thrombosis, simply discontinuing the heparin administration is insufficient. Generally, an alternative anticoagulant is needed to suppress the thrombotic tendency while the generation of antibodies stops and the platelet count recovers. To make matters more complicated, the other most commonly used anticoagulant, warfarin
Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent strok ...
, should not be used in HIT until the platelet count is at least 150 x 109/L because a very high risk of warfarin necrosis
Warfarin-induced skin necrosis is a condition in which skin and subcutaneous tissue necrosis (tissue death) occurs due to acquired protein C deficiency following treatment with anti-vitamin K anticoagulants (4-hydroxycoumarins, such as warfarin). ...
exists in people with HIT who have low platelet counts. Warfarin necrosis is the development of skin gangrene in those receiving warfarin or a similar vitamin K inhibitor. If the patient was receiving warfarin at the time when HIT is diagnosed, the activity of warfarin is reversed with vitamin K
Vitamin K refers to structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-synthesis modification of certain proteins that are required for blood coagulation ...
.[ Transfusing platelets is discouraged, as a theoretical risk indicates that this may worsen the risk of thrombosis; the platelet count is rarely low enough to be the principal cause of significant hemorrhage.][
Various nonheparin agents are used as alternatives to heparin therapy to provide anticoagulation in those with strongly suspected or proven HIT: ]danaparoid
Danaparoid sodium (Orgaran) is an anticoagulant with an antithrombotic action due to inhibition of thrombin generation (TGI) by two mechanisms: indirect inactivation of Factor Xa via AT and direct inhibition of thrombin activation of Factor IX (an ...
, fondaparinux
Fondaparinux (trade name Arixtra) is an anticoagulant medication chemically related to low molecular weight heparins. It is marketed by GlaxoSmithKline. A generic version developed by Alchemia is marketed within the US by Dr. Reddy's Laboratories.
...
, bivalirudin
Bivalirudin (Bivalitroban), sold under the brand names Angiomax and Angiox and manufactured by The Medicines Company, is a direct thrombin inhibitor (DTI).
Chemically, it is a synthetic congener of the naturally occurring drug hirudin, found in ...
, and argatroban
Argatroban is an anticoagulant that is a small molecule direct thrombin inhibitor. In 2000, argatroban was licensed by the Food and Drug Administration (FDA) for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocyto ...
. Not all agents are available in all countries, and not all are approved for this specific use. For instance, argatroban is only recently licensed in the United Kingdom, and danaparoid is not available in the United States.[ Fondaparinux, a factor Xa inhibitor, is commonly used off label for HIT treatment in the United States.
According to a ]systematic review
A systematic review is a Literature review, scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from publ ...
, people with HIT treated with lepirudin
Lepirudin is an anticoagulant that functions as a direct thrombin inhibitor.
Brand name: Refludan, Generic: Lepirudin rDNA for injection.
Lepirudin is a recombinant hirudin derived from yeast cells. Lepirudin is almost identical to hirudin extr ...
showed a relative risk reduction
In epidemiology, the relative risk reduction (RRR) or efficacy is the relative decrease in the risk
In simple terms, risk is the possibility of something bad happening. Risk involves uncertainty about the effects/implications of an activity with ...
of clinical outcome (death, amputation, etc.) to be 0.52 and 0.42 when compared to patient controls. In addition, people treated with argatroban for HIT showed a relative risk reduction
In epidemiology, the relative risk reduction (RRR) or efficacy is the relative decrease in the risk
In simple terms, risk is the possibility of something bad happening. Risk involves uncertainty about the effects/implications of an activity with ...
of the above clinical outcomes to be 0.20 and 0.18. 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. After vascular surgery, 34% of patients receiving heparin developed HIT antibodies without clinical symptoms. 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
Cardiothoracic surgery is the field of medicine involved in surgical treatment of organs inside the thoracic cavity — generally treatment of conditions of the heart ( heart disease), lungs (lung disease), and other pleural or mediastinal st ...
, have a higher risk, while the risk is very low in women just before and after giving birth. Some studies have shown that HIT is less common in those receiving low molecular weight 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.][ A 1973 report established HIT as a diagnosis, as well as suggesting that its features were the result of an immune process.][
Initially, various theories existed about the exact cause of the low platelets in HIT. Gradually, evidence accumulated on the exact underlying mechanism.][ In 1984–1986, John G. Kelton and colleagues at ]McMaster University Medical School
The Michael G. DeGroote School of Medicine, known as the McMaster University School of Medicine prior to 2004, is the medical school of McMaster University in Hamilton, Ontario, Canada. It is operated by the McMaster Faculty of Health Sciences. ...
developed the laboratory tests that could be used to confirm or exclude heparin-induced thrombocytopenia.[
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.][ Older terminology distinguishes between two forms of heparin-induced thrombocytopenia: type 1 (mild, nonimmune mediated and self-limiting fall in platelet count) and type 2, the form described above. Currently, the term HIT is used without a modifier to describe the immune-mediated severe form.][
In 2021 a condition resembling HIT but without heparin exposure was described to explain unusual ]post-vaccination embolic and thrombotic events
Post-vaccination embolic and thrombotic events, termed vaccine-induced immune thrombotic thrombocytopenia (VITT), vaccine-induced prothrombotic immune thrombocytopenia (VIPIT), thrombosis with thrombocytopenia syndrome (TTS), vaccine-induced imm ...
after the Oxford–AstraZeneca COVID-19 vaccine
The Oxford–AstraZeneca COVID19 vaccine, sold under the brand names Covishield and Vaxzevria among others, is a viral vector vaccine for prevention of COVID-19. Developed in the United Kingdom by Oxford University and British-Swedish comp ...
. It is a rare adverse event (1:1 million to 1:100,000) resulting from COVID-19 vaccine
A COVID19 vaccine is a vaccine intended to provide acquired immunity against severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), the virus that causes coronavirus disease 2019 ( COVID19).
Prior to the COVID19 pandemic, an e ...
s (particularly adenoviral vector vaccines). This is also known as Thrombosis with Thrombocytopenia Syndrome or TTS.
References
External links
{{Diseases of megakaryocytes, us=y
Coagulopathies