Heparin-induced thrombocytopenia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Priyamvada Singh, M.B.B.S. [2] Shyam Patel [3]

The association between heparin and thrombosis with thrombocytopenia was noted in the 1950s. In the 1970s, it was noted that heparin exposure resulted in development of antibodies. In 2000, argatroban became available on the market for treatment of HIT. As of 2012, the American College of Chest Physicians (ACCP) updated their guidelines for management of HIT.

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 I and type 2. Type II HIT is the main adverse effect of heparin use.

Heparin-induced thrombocytopenia is diagnosed when the platelet count falls by > 50% typically after 5-10 days of heparin therapy. Heparin exposure triggers the release of PF4 from endothelial surfaces. Complexes of heparin and PF4 serve as neoepitopes, or new antigens, and can induce production of antibodies, since this large complex serves as an unfamiliar antigen to the body. Binding of IgG from the large complexes into the Fc gamma RII receptors triggers activation of the target cells containing the receptors and eventual release of platelet microparticles. This results in production of thrombin, which is highly thrombogenic and contributes to clot formation. Ultimately, this leads to thrombotic complications in the venous and arterial systems.

Heparin-induced thrombocytopenia is caused by a variety of factors. It is typically caused by unfractionated heparin (moreso than low-molecular weight heparin). Females are more likely to develop HIT. Patients undergoing cardiac surgery are more likely to develop HIT.

Heparin-induced thrombocytopenia is diagnosed when the platelet count falls by > 50% typically after 5-10 days of heparin therapy. It should be differentiated by other causes of thrombocytopenia like hemolytic uremic syndrome, thrombotic thrombocytopenia, disseminated intravascular coagulation, post-transfusion purpura, and systemic lupus erythematosis.

Worldwide, the prevalence of HIT (in persons exposed to heparin) ranges from a low of 200 per 100,000 persons to a high of 5,000 per 100,000 persons. In pediatric populations, the prevalence of HIT (in persons exposed to heparin) ranges from a low of 1,500 per 100,000 persons to a high of 3,700 per 100,000 persons with an average prevalence of 2,600 per 100,000 persons. In neonatal populations, the prevalence of HIT (in persons exposed to heparin) is as low as 330 per 100,000 persons. HIT is more prevalent in the African American race than the Caucasian race and occurs more commonly in females compared to males.

Increased risk for heparin-induced thrombocytopenia depends on type of heparin (unfractionated heparin more than low molecular weight heparin), duration of therapy, females, and type of patients (commoner in surgical patients that require large amount of heparin), and other factors. Protective risk factors include use of low molecular weight heparin, low PF4 antibody titers, and others.

There are no screening methods for HIT. A diagnostic workup includes assessment of the anti-PF4 IgG optical density. However, this is not a screening tool for HIT.

The natural history of HIT evolves over a period of a few weeks and terminates within 1 year. The development of antibodies to heparin-PF4 is the initial event, the disappearance of these antibodies is the final event. The complications of HIT include thrombotic events and hemorrhagic events. Thrombotic events are more common. The most severe complication of HIT is disseminated intravascular coagulation The prognosis of HIT depends on the presence and severity of thrombosis. If a patient experiences a high degree of thrombotic manifestations, the mortality can be quite high.

The history of HIT always involves exposure to heparin. Typical features of a patient’s history depend on the type and location of thrombosis and whether the platelet count is sufficiently low to result in bleeding. Venous and arterial thromboses can result in variable symptoms. Symptoms of deep vein thrombosis include leg pain, swelling, and/or erythema. Symptoms of pulmonary embolism include dyspnea, pleuritic chest, and/or hypotension. Symptoms of arterial occlusion of a limb include limb pain and necrosis. Bleeding can occur spontaneously when the platelet count reaches very low levels, such as less than 10000 per microliter, though this is rare in HIT.

The physical exam for HIT focuses on the skin, pulmonary, and musculoskeletal exam. These are the common areas of thrombotic manifestations. Bleeding can also occur in these organs. A complete physical exam can help with evaluation of thrombosis or bleeding in other organs.

A variety of laboratory tests can be used to aid in the diagnosis of HIT. A complete blood count is always necessary and will show low platelet count. A high value of the PF4 IgG optical density can suggest HIT. Confirmatory testing is done with the serotonin release assay (SRA), heparin-induced platelet aggregation (HIPA) assay, or other functional assay. These confirmatory tests have high specificity.

A chest X-ray is not a standard diagnostic workup test done for HIT, but it is useful for patients who develop thrombotic complications involving the chest. Chest X-ray can show Hamptom’s hump, Westermark’s sign, or Fleischner’s sign.

CT scan is not part of the standard diagnostic workup for HIT, but it can be very useful if there is concern about bleeding or thrombosis from HIT in certain anatomical areas. For example, CT of the head can reveal intracranial bleeding or thrombosis. As another example, CT of the abdomen or pelvis can reveal intraabdominal bleeding or retroperitoneal hemorrhage.

There is no specific role for MRI in diagnosis of HIT. However, MRI can be useful to help delineate a bleeding or thrombotic complication of HIT in a specific anatomical area, similar to the role of a CT scan. MRI offers better anatomical detail and is thus more sensitive that CT scan. However, the test is more expensive, so one must weigh the cost-benefit ratio. MRI is particularly useful for suspected dural venous sinus thrombosis.

There are no other relevant imaging findings that are specific to HIT.

There are no other diagnostic studies for HIT.

Treatment of HIT involves prompt withdrawal of heparin or heparinoid and replacement with a suitable alternative anticoagulant. Lepirudin, fondaparinux, bivalirudin, argatroban, danaparoid or other direct thrombin inhibitors are used to treat the thrombotic state. Out of these lepirudin and argatroban are available for use in USA. Clinical practice guidelines are available from the American College of Chest Physicians to direct treatment.^[1]

Primary prevention for HIT focuses on avoidance of heparin or heparin products. If there is no exposure to heparin, HIT cannot develop. For patients who much receive heparin, the use of low molecular weight heparin is preferred over unfractionated heparin with regards to prevention of HIT.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shyam Patel [2]

The association between heparin and thrombosis with thrombocytopenia was noted in the 1950s. In the 1970s, it was noted that heparin exposure resulted in development of antibodies. In 2000, argatroban became available on the market for treatment of HIT. As of 2012, the American College of Chest Physicians (ACCP) updated their guidelines for management of HIT.

• In 1958, Rodger Weissman and Richard Tobin of Hitchcock Memorial Hospital and Dartmouth Medical School describes the phenomenon of HIT.^{[1] [2]} They noted an alarming increase in the incidence of peripheral arterial embolism after systemic heparin therapy.^[1] They reported 10 cases of embolism and thrombotic complications after heparin. ^[1] Emboli were noted in the femoral, popliteal, and cerebral circulation. This seminal study paved the way for future investigations into the pathophysiology of HIT.

• In 1973, Curry and colleagues noted that heparin exposure could lead to development of antibodies.^[3] It was suggested that antibody formation was the pathophysiologic basis for HIT. The term “immune” thrombocytopenia was used to describe this phenomenon.^[3]

• In 1977, a study by Rhodes and colleagues from Duke University Medical Center described 8 cases of thrombotic and hemorrhagic complications after heparin exposure.^[4] These patients were found to have myocardial infarction, pulmonary embolism, and aorto-iliac occlusion.^[4] The mean hospital stay was noted to be 54 days, suggesting the severity of the disease at the time. This study proposed discontinuation of heparin as the management strategy, as platelet inhibition did not seem to help.^[4]

• In 2000, argatroban was approved by the Food and Drug Administration (FDA) for treatment of HIT. It still remains one of the treatments of choice today.

• In 2012, the American College of Chest Physicians (ACCP) developed the 9th edition of guidelines for management of HIT.

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]

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 I and type 2. Type II HIT is the main adverse effect of heparin use.

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.^[1] 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.^[1] The time course for thrombocytopenia is usually 5-14 days after heparin exposure.^[2]

• Type I HIT occurs in 10-20% of all patients on heparin. In this form patients characteristically have a transient decrease in platelet count (rarely <100,000 per microliter) without any further symptoms.
• thrombocytopenia recovers even if heparin is continued to be administered. It is not due to an immune reaction, and antibodies are not found upon investigation.
• It is due to heparin-induced platelet clumping; it is innocuous.^[3]

• Type II HIT is more classic form of HIT. It is due to an autoimmune reaction with antibodies formed against the heparin-platelet factor 4 (PF4) complex. Antibodies can also develop against neutrophil-activating peptide 2 (NAP-2) and interleukin 8 (IL-8) which form complexes with heparin.
• Heparin binding to PF4 causes a conformational change in the protein, rendering it antigenic. Antibodies bind to these complexes, activate the surrounding platelets and generate thrombin. Type II HIT develops in about 3% of all patients on unfractionated heparin (UFH) and in 0.1% of patients on low-molecular weight heparin (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 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 (i.e. rigors, fever, hypertension, tachycardia) and cardiopulmonary collapse. Single or trivial doses of heparin, such as catheter flushes, can cause type II HIT.
• The onset of thrombocytopenia is independent of the type of heparin, dose and route of administration, and antibodies can persist for 4-6 weeks but disappear after 3 months. The presence of HIT antibodies, even at higher titer, does not predict an increase in complications. An increase in the titers of the antibodies do, however, result in an increase in the in-vitro activation of the coagulation system.
• The ELISA test, though not ideal, is the best predictive diagnostic test of type II HIT. It has been suggested that type II HIT only occurs with high antibody titers and after persistent exposure to heparin; also it suggests that antigens different from the heparin-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.^[4]

• 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.^[5]

• This is characterized by a sudden development of thrombocytopenia within 24 hours in the setting of pre-formed antibodies to heparin-PF4.^[1] The presence of pre-formed circulating antibodies is due to exposure to heparin within the past 30 days.

• 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.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Priyamvada Singh, M.B.B.S. [2] Shyam Patel [3]

Heparin-induced thrombocytopenia is diagnosed when the platelet count falls by > 50% typically after 5-10 days of heparin therapy. Heparin exposure triggers the release of PF4 from endothelial surfaces. Complexes of heparin and PF4 serve as neoepitopes, or new antigens, and can induce production of antibodies, since this large complex serves as an unfamiliar antigen to the body. Binding of IgG from the large complexes into the Fc gamma RII receptors triggers activation of the target cells containing the receptors and eventual release of platelet microparticles. This results in production of thrombin, which is highly thrombogenic and contributes to clot formation. Ultimately, this leads to thrombotic complications in the venous and arterial systems.

An understanding of the pathophysiology of HIT requires an understanding of normal physiology.

Normal physiology:

• Under normal circumstances, platelet factor 4 (PF4) is synthesized by platelet precursors called megakaryocytes.^[1] It is stored in the alpha granules of platelets. It is a positively charged protein that functions to antagonize the effects of heparin-like proteins like heparin sulfate and chondroitin sulfate on the cell surface.^[2] PF4 is located intracellularly, but upon platelet activation, PF4 is released. Since is it a positively charged protein, it binds to negatively charged glycosaminoglycans, such as heparan sulfate.
• Under normal circumstances, antithrombin is then displaced from heparan sulfate, resulting in the normal desired coagulation.^[1] PF4 thus contributes to the release of antithrombin from the cell surface, promoting clotting (platelet plugging).
• Under normal circumstances, there are no endogenous antibodies to PF4.
• Under normal circumstances, exogenous heparin administration results in activation of antithrombin III, which in turn inhibits factors II, IX, X, XI, XII, and XIII. The allows for adequate anticoagulation for patients.

Pathophysiology:

• This begins with heparin exposure, which can trigger the release of PF4 from endothelial surfaces. Heparin can then form ultra-large multimolecular complexes with PF4 via electrostatic forces.^[3] The epitopes of PF4 that are known to bind to heparin include proline-37 and proline-34.^[4][5]
• These complexes of heparin and PF4 serve as neoepitopes, or new antigens, and can induce production of antibodies, since this large complex serves as an unfamiliar antigen to the body.^[2] IgG antibodies are typically produced to the multimolecular complexes.^[3][6]
• Immune complexes eventually form within a few days of exposure to heparin. The immune complexes consist of heparin, PF4 and IgG.^[2] The crystallized fragment domain, or (Fc) domain of IgG can bind to Fc receptors, such as FC gamma RII, on the surface of a variety of immune cells, including platelets, neutrophils, and monocytes.
• Binding of IgG from the large complexes into the Fc gamma RII receptors triggers activation of the target cells containing the receptors and eventual release of platelet microparticles. This results in production of thrombin, which is highly thrombogenic and contributes to clot formation.^[2] It also leads to production of platelet-fibrin thrombi.^[4][7]
• Widespread systemic thrombosis can lead to significant morbidity and mortality.

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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]

Heparin-induced thrombocytopenia is caused by a variety of factors. It is typically caused by unfractionated heparin (moreso than low-molecular weight heparin). Females are more likely to develop HIT. Patients undergoing cardiac surgery are more likely to develop HIT.

• HIT is always caused by exogenous heparin or heparinoid exposure.
• Duration of heparin treatment: long duration, up to 2 weeks is associated with the greatest risk.^[1]
• The type of heparin involved: unfractionated heparin (UFH) puts patients at greater risk of HIT than low molecular weight heparin LMWH.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Priyamvada Singh, M.B.B.S. [2] Shyam Patel [3]

Heparin-induced thrombocytopenia is diagnosed when the platelet count falls by > 50% typically after 5-10 days of heparin therapy. It should be differentiated by other causes of thrombocytopenia like hemolytic uremic syndrome, thrombotic thrombocytopenia, disseminated intravascular coagulation, post-transfusion purpura, and systemic lupus erythematosis.

HIT must be differentiated from other diseases that present with thrombocytopenia. Please scroll down to view the table.

Table legend: HIT, heparin-induced thrombocytopenia; DIC, disseminated intravascular coagulation; HUS, hemolytic-uremic syndrome; ITP, immune thrombocytopenia purpura; PTP, post-transfusion purpura; SLE, systemic lupus erythematosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Priyamvada Singh, M.B.B.S. [2] Shyam Patel [3]

Worldwide, the prevalence of HIT (in persons exposed to heparin) ranges from a low of 200 per 100,000 persons to a high of 5,000 per 100,000 persons. In pediatric populations, the prevalence of HIT (in persons exposed to heparin) ranges from a low of 1,500 per 100,000 persons to a high of 3,700 per 100,000 persons with an average prevalence of 2,600 per 100,000 persons. In neonatal populations, the prevalence of HIT (in persons exposed to heparin) is as low as 330 per 100,000 persons. HIT is more prevalent in the African American race than the Caucasian race and occurs more commonly in females compared to males.

• Worldwide, the prevalence of HIT (in persons exposed to heparin) ranges from a low of 200 per 100,000 persons to a high of 5,000 per 100,000 persons.^[1][2]
• In pediatric populations, the prevalence of HIT (in persons exposed to heparin) ranges from a low of 1,500 per 100,000 persons to a high of 3,700 per 100,000 persons with an average prevalence of 2,600 per 100,000 persons.^[2] The prevalence is 1-3% in children exposed to unfractionated heparin and undergoing cardiac surgery.^[3]
• In neonatal populations, the prevalence of HIT (in persons exposed to heparin) is as low as 330 per 100,000 persons.^[2]

• The case fatality rate of HIT is 20-30% for patients who develop thrombosis.^[4]
• For patients who have HIT but do not develop thrombosis, the case fatality rate is unknown but is lower than 20-30%.^[4]

• The adult population is more prone to development of HIT than the pediatric population. Please see the Prevalence section above for the prevalence of HIT in pediatric and neonatal populations.

• Females are more commonly affected with HIT than males. The female to male ratio is approximately 2.4 to 1.^[5] This is thought to be related to higher predilection for autoimmune tendencies in females compared to males.

• HIT is more prevalent in the African American race than the Caucasian race.^[5]

HIT has a major impact on society in developed countries. Development of HIT can lead to high morbidity and mortality in hospitals and can increase health care costs. For example, the development of thrombotic complications can lead to the need for prolonged anticoagulation and monitoring, which places a burden on the healthcare system.

There is minimal data on HIT in developing countries. There is no variation in prevalence of HIT in developing countries.

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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]

Increased risk for heparin-induced thrombocytopenia depends on type of heparin (unfractionated heparin more than low molecular weight heparin), duration of therapy, females, and type of patients (commoner in surgical patients that require large amount of heparin), and other factors. Protective risk factors include use of low molecular weight heparin, low PF4 antibody titers, and others.

• Duration of heparin treatment: A long duration of heparin expsosure, such as 2 weeks, is associated with the greatest risk.^[1]
• Type of heparin: Unfractionated heparin (UFH) has a greater risk than low molecular weight heparin (LMWH. Bovine heparin carries a higher risk for HIT than porcine heparin.^[2]
• Type of patient: Surgical patients are at higher risk than medical; cardiac surgical patients have the highest risk of all.^[3] This is though to be related to differences in basal level of circulating platelet factor 4 (PF4) and platelet activation in these various populations. The incidence of HIT in cardiac surgery or orthopedic surgery patients is 1-5%.^[4]
• Sex: Females have a higher risk than males. The odds ratio (OR) is 2.4:1.^[3] This is thought to be related to higher predilection for autoimmune tendencies in females compared to males.
• Race: African Americans are more prone to HIT than Caucasians.^[3]
• PF4 optical density (OD): The degree of elevation of the OD valve of the PF4 IgG is directly correlated with the risk for HIT. For patients with a Pf4 IgG OD of < 0.4, the risk of HIT is typically < 5%. No follow up testing is required. For patients with a PF4 IgG OD of > 1.0, the risk of HIT is signicantly higher (3.4-6-fold increase risk of thrombosis), requiring follow up testing with a functional assay such as the 14C-serotonin release assay or the heparin-induced platelet aggregation assay.^[2]
• Genetic polymorphisms: Polymorphisms in the crystallized fragment (Fc) gamma receptor have been suggested to play in role in the risk for HIT. It is presumed that high affinity receptors result in stronger IgG binding to platelet membranes, allowing for the release of procoagulants.
• There is no increase in risk of HIT with genetic risk factors for thrombosis such as factor V Leiden, prothrombin gene mutation, methylenetetrahydrofolate reductase (MTHFR) polymorphism and platelet-receptor polymorphisms.

• Type of heparin: Use of low molecular weight heparin such as enoxaparin carries a lower risk for HIT. Porcine heparin carries a lower risk for HIT compared to bovine heparin.^[2]
• Type of patient: Pediatric or obstetric patients have a lower risk for HIT than medical or surgical patients. Obstetrics patients have a 0.1-1% risk of developing HIT, as compared to 1-5% risk in surgical patients.^[4]
• PF4 optical density: A low PF4 IgG OD of less than 0.4 suggests a very low risk for HIT.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Shyam Patel [2]

There are no established screening methods for HIT.

There are no screening methods for HIT. A diagnostic workup includes assessment of the anti-PF4 IgG optical density. However, this is not a screening tool for HIT.

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Editor(s)-in-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Priyamvada Singh, M.D. [2] Nazia Fuad M.D.

Aplastic anaemia has a mixed clinical course. Untreated aplastic anemia leads to rapid death, typically within six months. Complications following development of aplastic anemia are infections, bleeding and paroxysmal nocturnal hemoglobinuria. Graft-versus-host disease and graft failure are the possible complications following bone marrow transplant in these patients. Mild cases resolve on their own requiring little or no treatment. Well-matched bone marrow transplants from siblings have been successful in young individuals with a long-term survival rate of 80%-90%.

• Aplastic anaemia has a mixed clinical course. ^[1]
• Some patients develop mild symptoms that require little or no therapy.
• Others develop life-threatening pancytopenia presenting with a medical emergency.
• Untreated aplastic anemia leads to rapid death, typically within six months.

Aplastic anemia patients can develop following complications:^[2]

• Infections
• Bleeding
• paroxysmal nocturnal hemoglobinuria (PNH, anemia with thrombopenia and/or thrombosis)
• Graft-versus-host disease
• Graft failure.
• Myelodysplastic syndrome

• Correct and prompt diagnosis with early therapy improves the 5 year survival rate.^[3]
• Occasionally, milder cases of the disease resolve on their own.
• Relapses of previously controlled disease are, much more common.
• Well-matched bone marrow transplants from siblings have been successful in young, otherwise healthy people, with a long-term survival rate of 80%-90%.
• Most successful BMT recipients eventually reach a point where they consider themselves cured for all practical purposes, although they need to be compliant with follow-up care permanently.
• Older people (who are generally too frail to undergo bone marrow transplants) and people who are unable to find a good bone marrow match have five year survival rate of up to 75%.