Heparin induced thrombocytopenia (HIT) is a specific complication of heparin treatment, in which the level of platelets in the blood decreases, the probability of paradoxical thrombosis sharply increases. There are HIT types 1 and 2, the greatest danger of thrombosis is type 2 of the disease. Clinical manifestations include arterial and venous thrombosis, skin lesions (purpura, hemorrhages, necrosis), systemic reactions. The diagnosis is made on the basis of anamnestic data, registered thrombocytopenia in a blood test and special laboratory tests. Treatment consists in the immediate withdrawal of heparin and its replacement with another anticoagulant.
D69.5 Secondary thrombocytopenia
Heparin induced thrombocytopenia was first described in 1957 by vascular surgeons Roger Wiseman and Richard Tobin. Type 1 occurs in 20-30% of patients receiving heparin. Type 2 develops somewhat less frequently – in 1-5% of patients. Women suffer 2 times more often than men. The risk of HIT is 3 times higher when using heparin obtained from bovine lungs than from pig intestines. In medical practice, the term heparin induced thrombocytopenia refers to type 2, since it is associated with thrombosis.
Type 1 HIT is based on direct activation of platelets by the heparin molecule through specific receptors (P2Y12 and IIb/IIIa), leading to aggregation of blood plates and subsequent thrombocytopenia. The cause of type 2 is the production of antibodies to the heparin complex and 4-platelet factor (a factor secreted by activated platelet granules). The probability of pathology is directly proportional to the molecular weight of the drug.
This condition develops more often against the background of the use of unfractionated heparin (5%) than low-molecular weight (1%). Risk factors for heparin induced thrombocytopenia include diseases or pathological conditions requiring treatment with anticoagulants – congenital and hereditary thrombophilia, upcoming surgical interventions (especially cardiological and orthopedic), the creation of an arterio-venous fistula for hemodialysis.
The mechanism of occurrence of type I HIT is quite simple – nonimmune activation and aggregation of platelets occurs without the risk of thrombosis. The pathogenetic mechanism of type II HIT has a more complex nature. The key pathogenetic link is the production of antibodies (class G immunoglobulins) to the heparin/platelet factor 4 (TF4) complex.
As a result of the interaction of heparin-dependent antibodies and the TF4 complex, immune complexes are formed that are adsorbed on the membrane of blood plates. Antibody fragments bind to avidic receptors of blood plates, which leads to their degradation, the release of vasoactive (serotonin, adenosine diphosphate, histamine) and procoagulant chemical agents.
Immune complexes also settle on the walls of blood vessels, bind to endothelial glycocalyx heparan sulfate, cause activation of macrophages that damage endothelial cells. As a result, tissue thromboplastin is expressed, which, in turn, increases the synthesis of thrombin (the main component of the blood coagulation system).
There are 2 types of heparin induced thrombocytopenia:
- Type 1 (non-immune, early). It is characterized by moderate thrombocytopenia (a decrease of 10-30% from the baseline level), which occurs almost immediately after the use of heparin (day 1-3) and resolves quickly after discontinuation of the drug or spontaneously.
- Type 2 (immune, late). It is an immuno-mediated reaction. The platelet level drops by 50% or more after 3-10 days from the start of heparin therapy. Thrombocytopenia can persist for a long time even after the drug is discontinued. The risk of thrombosis, including fatal ones, is very high.
With type I HIT, there are no symptoms. In type II, clinical manifestations occur 3-10 days after administration of the drug, however, in some cases, signs may be detected in the first 24 hours. This can happen if the patient received heparin within the previous 100 days (due to the circulation of antiheparin antibodies in the blood).
Clinical symptoms are directly determined by the localization of thrombosis. Venous thrombosis is most common, especially in the deep veins of the lower extremities. Thrombotic lesions are manifested by gradually increasing aching or dull pain, which increases with walking and palpation, swelling of the extremities, a change in the color of the skin (to purplish-cyanotic).
For arterial thrombosis, sharp and severe pain is typical (in the arm – with brachial artery thrombosis, in the abdomen – with occlusion of the mesenteric artery, in the chest – with coronary artery thrombosis), paleness of the skin, etc. Sometimes there are acute systemic reactions in the form of fever, increased blood pressure, palpitations and respiratory movements. Rarely there are skin lesions – hemorrhages, purpura, skin necrosis, more often localized in the abdominal skin.
Type 2 of heparin induced thrombocytopenia is characterized by a fairly high prevalence of serious complications. The probability of thrombosis correlates with the level of platelets and is 30-50% in moderate and up to 90% in severe thrombocytopenia. Approximately 20-30% of all thrombosis are fatal. The main causes of death are myocardial infarction, ischemic stroke, pulmonary embolism.
Complications of pathology are also ischemic gangrene of the lower extremities (20%) and massive bleeding (22%), most often intracranial, retroperitoneal. A rare but characteristic adverse consequence is hemorrhagic necrosis of the adrenal glands (sometimes bilateral), leading to acute adrenal insufficiency and collapse.
The profile of the specialist supervising the patient with this disease is determined by the underlying pathology for which heparin treatment was performed. There is a special HIT probability scale (4Ts), which evaluates 4 criteria: the level of platelets, the time of occurrence of clinical and laboratory symptoms, the presence of thrombosis and other causes of thrombocytopenia.
According to the number of points scored, the risk of having a disease is calculated. The same scale will allow you to reliably differentiate type 1 from type 2 even before receiving the results of laboratory tests. To confirm the diagnosis, an additional examination is prescribed, including:
- Blood test. In the general blood test – thrombocytopenia, there are no other changes. In the coagulogram, deviations in the direction of hypercoagulation are possible.
- Instrumental research. To confirm thrombosis, electrocardiography, ultrasound examination of the vessels of the upper and lower extremities, CT of the brain are performed. Sometimes they resort to selective angiography with the introduction of a contrast agent.
- Analysis for autoantibodies to G / TF4. Antibodies to the complex of platelet factor 4 and heparin are determined by the method of enzyme immunoassay. The main disadvantage of the test is a high percentage of false positive results, but a negative reaction allows you to reliably exclude pathology.
- Serotonin Release Test (SRT). Recognized as the “gold standard” of HIT diagnostics. The method is based on the detection of antiheparin antibodies using serotonin labeled with a radioactive isotope. Due to the need to use special equipment and reagents, which are not available in all laboratories, it is almost not used in standard practice.
- Platelet Aggregation Test (PAT). The most popular method, due to the rapid receipt of results, technical simplicity and high sensitivity of the analysis. The degree of aggregation of donor platelets in the patient’s serum with the addition of heparin is evaluated.
Differential diagnosis is performed with thrombocytopenia of other origin (immune thrombocytopenia, thrombotic thrombocytopenic purpura, disseminated intravascular coagulation syndrome). The condition also needs to be distinguished from other diseases accompanied by thrombosis (antiphospholipid syndrome, congenital thrombophilia).
For the treatment of type 1 pathology, it is enough to cancel heparin so that the platelet concentration returns to normal. In some cases, thrombocytopenia resolves spontaneously without any intervention. Type II treatment is necessarily carried out in a hospital (in case of a serious condition of the patient – in the intensive care unit), consists of the following stages:
- Immediate discontinuation of the drug. It is necessary to exclude the ingestion of heparin in any form into the patient’s body. At the same time, it should be borne in mind that many catheters for the pulmonary artery, filters in extracorporeal hemofiltration and blood circulation devices are coated with heparin, and the central venous systems are washed with heparin dissolved in saline.
- Replacement of anticoagulant. Since the immune complexes that cause thrombosis, despite the cancellation of the drug, continue to circulate in the blood for a long time, it is necessary to prescribe an alternative anticoagulant. The drugs of choice for treatment are direct thrombin inhibitors (bivalirudin, dabigatran) and blood clotting factor X inhibitors (fondaparinux sodium, rivaroxaban).
- Vitamin K antagonists. If the patient requires prolonged anticoagulant therapy (for example, in the presence of prosthetic valves), after normalization of the level of blood plates, factor X and thrombin inhibitors are replaced with warfarin, starting with minimal doses. At the same time, regular strict monitoring of the INR indicator in the coagulogram is carried out.
- Fighting complications. In case of thrombosis, their treatment is performed according to the standard scheme without the use of heparin (antiplatelet agents, thrombolysis, percutaneous coronary intervention, etc.).
- Platelet infusion. Even despite deep thrombocytopenia, platelet transfusion is performed in very rare cases, for example, with the development of massive bleeding.
Prognosis and prevention
The first type of HIT is characterized by a favorable prognosis. The second type of HIT is characterized by high mortality rates (10-15%), primarily from thromboembolic complications (myocardial infarction, ONMC, PE). In isolated cases, patients die from massive bleeding and vascular collapse due to acute insufficiency of the adrenal cortex.
Primary prevention of this condition is reduced to regular monitoring of the concentration of platelets in the blood of a patient receiving heparin. If a patient has already been diagnosed with heparin induced thrombocytopenia in the anamnesis, it is recommended to prescribe another “non-heparin” anticoagulant for the treatment and prevention of thromboembolic conditions.
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