Runny nose

Treatment of hemorrhagic vasculitis in children. Modern aspects of anticoagulant therapy in the acute period of ischemic stroke Risk of hemorrhagic complications during heparin therapy

Complications of antithrombotic therapy for acute coronary syndrome.

Honored Doctor of the Russian Federation, anesthesiologist-resuscitator of the ICU State Budgetary Healthcare Institution "Bryansk Regional Cardiological Dispensary"

The basis of treatment for ACS (acute coronary syndrome) without ST segment elevation is active antithrombotic therapy, which consists of the use of antiplatelet agents aspirin and clopidogrel in combination with an anticoagulant - heparin (unfractionated or low molecular weight) or a synthetic factor Xa inhibitor (fondaparinux). The most important component of antithrombotic therapy in the treatment of ST-segment elevation ACS is thrombolytic therapy. Complications of antithrombotic therapy will be presented next.

The main complications of thrombolysis:

1. Bleeding(including the most severe - intracranial) - develop as a result of inhibition of blood coagulation processes and lysis of blood clots. The incidence of serious bleeding is no more than 3%. The risk of stroke during systemic thrombolysis is 0.5-1.5% of cases; stroke usually develops on the first day after thrombolysis. The patient's age over 65 years, body weight less than 70 kg, a history of arterial hypertension, as well as the use of tPA (tissue plasminogen activator) as a thrombolytic can be considered as risk factors for hemorrhagic stroke. Undoubtedly, an important issue in the prevention of hemorrhagic complications is the adequate implementation of concomitant anticoagulant and antiplatelet therapy. This is especially true for the prescription of heparin, since a prolongation of the aPTT (activated partial thromboplastin time) of more than 90 s correlates with an increased risk of cerebral hemorrhages. To stop minor bleeding (from the puncture site, from the mouth, nose), pressing the bleeding area is sufficient.
For more significant bleeding (gastrointestinal, intracranial), an intravenous infusion of aminocaproic acid is necessary - 100 ml of a 5% solution is administered over 30 minutes and then 1 g/hour until the bleeding stops, or tranexamic acid 1-1.5 g 3-4 once a day intravenously, in addition, transfusion of fresh frozen plasma is effective. It should be remembered that when using antifibrinolytic drugs, the risk of coronary artery reocclusion and reinfarction increases, so they should be used only for life-threatening bleeding.

2. Arrhythmias, occurring after restoration of coronary circulation (reperfusion) are “potentially benign” and do not require intensive care.
This applies to a slow nodal or ventricular rhythm (with a heart rate less than 120 per minute and stable hemodynamics); supraventricular and ventricular extrasystole (including allorhythmic); atrioventricular block I and II (Mobitz type I) degree.
Emergency treatment is required: - ventricular fibrillation (defibrillation and a set of standard resuscitation measures are required); - bidirectional fusiform ventricular tachycardia of the “pirouette” type (defibrillation, intravenous bolus administration of magnesium sulfate are indicated); - other types of ventricular tachycardia (use lidocaine administration or perform cardioversion); - persistent supraventricular tachycardia (stopped by intravenous jet administration of verapamil or novocainamide); - atrioventricular block II (Mobitz type II) and III degree, sinoatrial block (atropine is injected intravenously in a dose of up to 2.5 mg, if necessary, emergency cardiac pacing is performed).

3. Allergic reactions.
The incidence of anaphylactic shock when using tPA is less than 0.1%. Rash, itching, periorbital edema occur in 4.4% of cases, severe reactions (Quincke's edema, anaphylactic shock) - in 1.7% of cases. If an anaphylactoid reaction is suspected, the streptokinase infusion should be immediately stopped and a bolus of 150 mg prednisolone administered intravenously. In case of severe hemodynamic depression and the appearance of signs of anaphylactic shock, 0.5 - 1 ml of a 1% solution of adrenaline is administered intravenously, continuing the administration of steroid hormones intravenously. For fever, aspirin or paracetamol is prescribed.

4. Recurrence of pain after thrombolysis is relieved by intravenous fractional administration of narcotic analgesics. With an increase in ischemic changes on the ECG, intravenous drip administration of nitroglycerin is indicated, or if the infusion has already been established, an increase in the rate of its administration.

5. For arterial hypotension in most cases, it is sufficient to temporarily stop the thrombolytic infusion and elevate the patient's legs; if necessary, the blood pressure level is adjusted by administering fluids, vasopressors (dopamine or norepinephrine intravenously drip until systolic blood pressure stabilizes at 90-100 mm Hg).

Thrombolytic drugs are not used for ACS without ST segment elevations on the ECG. Data from large studies and meta-analyses did not reveal the benefits of thrombolysis in patients with unstable angina and non-Q wave MI; on the contrary, the administration of thrombolytic drugs was associated with an increased risk of death and myocardial infarction.

Complications of heparin therapy:

bleeding, including hemorrhagic stroke, especially in the elderly (from 0.5 to 2.8%); hemorrhages at injection sites; thrombocytopenia; allergic reactions; osteoporosis (rare, only with long-term use).

If complications develop, it is necessary to administer a heparin antidote - protamine sulfate, which neutralizes the anti-IIa activity of unfractionated heparin at a dose of 1 mg of the drug per 100 units of heparin. At the same time, discontinuation of heparin and use of protamine sulfate increase the risk of thrombosis. The development of complications when using heparin is largely associated with the characteristics of its pharmacokinetics. Heparin is eliminated from the body in two phases: a rapid elimination phase, as a result of the drug binding to membrane receptors of blood cells, endothelium and macrophages, and a slow elimination phase, mainly through the kidneys. The unpredictability of receptor uptake activity, and therefore the binding of heparin to proteins and the rate of its depolymerization, determines the second “side of the coin” - the impossibility of predicting therapeutic (antithrombotic) and side (hemorrhagic) effects. Therefore, if it is not possible to control the aPTT, it is impossible to talk about the required dose of the drug, and therefore about the usefulness and safety of heparin therapy. Even if the aPTT is determined, the dose of heparin can only be controlled with intravenous administration, since with subcutaneous administration there is too much variability in the bioavailability of the drug.

In addition, it should be noted that bleeding caused by the administration of heparin is associated not only with the effect of the drug on the blood coagulation system, but also on platelets. Thrombocytopenia is a fairly common complication of heparin administration. The drug should be immediately discontinued if the patient detects red blood cells in the urine, petechial rashes on the skin, unusual bleeding of the gums, nasal, intestinal or other bleeding, as well as if the number of platelets in the hemogram drops by half compared to the initial value. After 5-7 days from the start of heparin therapy, the activity of aminotransferases (especially alanine) sharply increases in a number of patients, which is most often mistakenly interpreted as a sign of current hepatitis. Use of heparin for more than 10-15 days increases the risk of possible development of osteoporosis. Low molecular weight heparin derivatives cause thrombocytopenia much less frequently. Longer inhibition of thrombin activity and higher, compared with heparin, bioavailability of these anticoagulants allow them to be prescribed in low doses and it is easier to control the therapeutic effect.

Combination of clopidogrel with aspirin, complications.

Based on the data from the CURE study, the combination of clopidogrel with aspirin is recommended for all patients with ACS without ST segment elevation on the ECG, both in the case of CBA (coronary balloon angioplasty) and without planned intervention on the coronary arteries. The dose of aspirin when combined with clopidogrel should not exceed 100 mg/day. The recommended duration of clopidogrel administration in patients who have undergone ACS is up to 9 months if the drug is well tolerated and there is no risk of bleeding. In the case of coronary artery bypass surgery, clopidogrel is discontinued 5–7 days before surgery.

Combination therapy was associated with an increase in the number of serious bleeding complications: 3.7% versus 2.7%, p = 0.001, but there was no statistical difference in life-threatening bleeding (2.2% versus 1.8%). A relationship was noted between the increase in the number of bleedings and the dose of aspirin when combined with clopidogrel. The risk of bleeding was almost 2 times higher when taking aspirin >200 mg/day than when taking<100 мг/сут.

Platelet receptor IIb/IIIa inhibitors, complications.

Platelet receptor IIb/IIIa inhibitors are essentially universal antiplatelet drugs that block the final stage of platelet aggregation, namely the interaction between activated receptors and adhesive proteins (fibrinogen, von Willebrand factor, fibronectin).

The most common complications with the use of platelet receptor IIb/IIIa inhibitors are bleeding and thrombocytopenia. Thrombocytopenia is rare, and stopping the infusion of IIb/IIIa receptor inhibitors usually results in normalization of platelet counts. Less commonly, platelet transfusions may be required when using absiximab. There are reports of a reduced risk of complications when low molecular weight heparins are used in combination with platelet receptor IIb/IIIa inhibitors instead of unfractionated heparins.

Literature

2. Kirichenko angina. Study guide. Moscow, 1998.

3. Kryzhanovsky and treatment of myocardial infarction. Kyiv: Phoenix, 2 pages.

4. Acute coronary syndrome without persistent ST segment elevation on the ECG. Recommendations of the working group of the European Society of Cardiology (ESC). Supplement to the journal "Cardiology", 2001, No. 4. -28s.

5. Federal guidance for doctors on the use of medicines (formulary system) Issue III. - M.: "ECHO", 20 p.

6. Yavelov of acute coronary syndrome without ST segment elevation. Heart: a magazine for medical practitioners. 2002, vol. 1, no. 6, pp. 269-274.

7. Yavelov aspects of thrombolytic therapy for acute myocardial infarction. Pharmateka. 2003; No.6: 14-24

Anesthesiologist-resuscitator, ICU

Chief Physician Honored Doctor of the Russian Federation

Heparin is used to prevent and treat venous thrombosis and pulmonary embolism. It is also used in the treatment of unstable angina and myocardial infarction, to prevent acute reocclusion after angioplasty or stenting, to prevent thrombosis during vascular surgery, and in high doses for hemodialysis or extracorporeal circulation. In patients with DIC, heparin can be used to reduce the activation of hemostasis.

Heparin is used for anticoagulant therapy during pregnancy. In this situation, it is the anticoagulant of choice, since warfarin is contraindicated during pregnancy due to its teratogenic effect. Heparin does not cross the placenta and does not cause any anticoagulant effect in the fetus. However, it may increase the risk of bleeding during labor, so its administration is stopped shortly before the onset of labor or planned surgical delivery.

To prevent thromboembolic complications, heparin is used subcutaneously at a dose of 5000 units. every 8-12 hours; in patients at higher risk, an 8-hour dosing regimen is more appropriate. For the treatment of venous thromboembolism, heparin is used according to the following regimen (level of evidence – I): 5000 units IV bolus followed by IV infusion of 1680 units/hour. For unstable angina or acute myocardial infarction without thrombolytic therapy, heparin is administered 5000 units. IV bolus and then 32,000 units. within 24 hours by infusion (level of evidence – I). If thrombolytic therapy is performed during myocardial infarction, then heparin is administered 5000 units. IV bolus and then 24,000 units. within 24 hours by infusion (level of evidence – I).

Complications of heparin therapy

The main complications of heparin therapy are presented in Table 3.2.

Table 3.2. Complications of heparin therapy

Heparin-associated bleeding. On average, they develop in 5% of patients receiving therapeutic doses of heparin. The development of bleeding depends more on the total daily dose, rather than on the method of administration of heparin. The risk of hemorrhage increases with the simultaneous administration of antiplatelet drugs, thrombolytics and other drugs that potentiate the anticoagulant effect of heparin. The risk of hemorrhagic complications increases with renal failure, peptic ulcer, open wound surface (after surgery), advanced age or concomitant hemostatic defect.

Heparin - induced osteoporosis. A decrease in bone density is observed in 30% of patients receiving heparin for 1 month or more. Heparin leads to osteoporosis by decreasing osteogenesis and increasing bone resorption. Heparin-induced osteoporosis takes a long time to resolve (possibly because heparin binds to bone tissue).

Heparin-induced thrombocytopenia (HIT). Develops during heparin therapy in 1-5% of patients. Type I HIT is caused by the direct proaggregation effect of heparin. It is characterized by moderate thrombocytopenia (platelet count > 100 thousand/μl) and does not require specific therapy.

Type II HIT develops 4-14 days after the start of heparin administration and has an immune pathogenesis - the development of autoantibodies against the complex of platelet factor 4 and heparin. Antibodies activate platelets, the complement system, cause damage to endothelial cells with exposure to tissue factor and collagen, thereby promoting the development of thrombosis. Thrombocytopenia in this case is significant (often< 100 тыс/мкл). Необходима немедленная отмена гепарина и продолжение антикоагулянтной терапии рекомбинантным гирудином, данапароидом или фондапарином.

Low molecular weight heparins

The presence of clinical problems with heparin therapy (unpredictable absorption and bioavailability during subcutaneous administration, complications) led to the development and introduction into practice of low molecular weight heparins (LMWH). Low molecular weight heparins are produced by chemical or enzymatic processing of heparin to reduce the size of the polysaccharide chains, resulting in substances with low molecular weight (on average approximately 4000–5000 kDa) (Table 3.3).

Table 3.3. LMWH group drugs

Like unfractionated heparin (UFH), the anticoagulant effect of LMWHs occurs through their interaction with antithrombin III. In the presence of LMWH, antithrombin III inactivates factor Xa, like unfractionated heparin, but is less able to inactivate thrombin due to the shorter length of the polysaccharide. A comparison of the important clinical properties of heparin and LMWH is shown in Table 3.4.

Table 3.4. Comparative characteristics of LMWH and UFH

	NFG	NMG
Molecular weight	15-20 thousand kDa	Average 5000 kDa
Bioavailability	30%	100%
Half life	1-2 hours	3-5 hours
Elimination from the body	Cellular saturation	Mainly kidneys
Dose-dependent clearance	+	-
Ability to bind to endothelial cells	+	-
The antithrombotic effect is due to	Mainly antithrombin activity	30% anti-Xa activity, 70% via ITP release
APTT prolongation	expressed	minimum
Rebound thromboses	causes	don't call
Autoimmune thrombocytopenia	+	not significant
The need for laboratory control	+	-
Transplacental transition	+	-
Increased permeability of the vascular wall	+	-
Complications of use: hemorrhages, alopecia, osteoporosis	+	-

LMWHs can be used intravenously, but are usually administered subcutaneously due to their almost complete absorption and the apparent convenience of this route of administration. In addition, unlike heparin, LMWHs bind much less to plasma proteins and blood cells. Consequently, their plasma concentrations and effects are more predictable. LMWH also has a longer half-life than unfractionated heparin. Based on this, it is possible to administer LMWH subcutaneously once or twice a day. LMWHs are excreted primarily through the kidneys, so in patients with impaired renal function, monitoring the level of anti-Xa activity and dose adjustment are necessary. Obese patients also present certain difficulties in selecting the required dose.

The use of LMWH is increasing, covering more and more areas where UFH was previously traditionally used. Many clinical studies have been conducted on the use of LMWH for the prevention and treatment of thromboembolic complications. Dosage regimens for LMWH drugs approved for use in Russia are presented in Table 3.5.

General surgery - moderate risk of venous thromboembolism (VTE)
Dalteparin (Fragmin)	2500 units subcutaneously 1-2 hours before surgery and once a day after surgery
Enoxyparine (Clexane)	20 mg subcutaneously 1-2 hours before surgery and 1 time per day after surgery
Nadroparin (Fraxiparin)
General surgery - high risk of VTE
Dalteparin (Fragmin)	5000 units subcutaneously 8-12 hours before surgery and 1 time per day after surgery
Enoxyparine (Clexane)	40 mg subcutaneously 1-2 hours before surgery and 1 time per day after surgery
Nadroparin (Fraxiparin)	2850 units subcutaneously 2-4 hours before surgery and 1 time per day after surgery
Traumatology and orthopedics
Dalteparin (Fragmin)	5000 units subcutaneously 8-12 hours before surgery, 12-24 hours after surgery and then 1 time per day
Enoxyparine (Clexane)	40 mg subcutaneously 10-12 hours before surgery and 1 time per day after surgery
Nadroparin (Fraxiparin)	54 units/kg subcutaneously 12 hours before surgery and 1 time per day after surgery

The pharmacokinetic properties of LMWH drugs allow them to be administered subcutaneously for the treatment of acute venous thrombosis and pulmonary embolism; the effectiveness and safety of this method of administration have been clinically established (level of evidence – I):

Enoxaparin – 1 mg\kg (100 units\kg) after 12 hours subcutaneously;

Nadroparin –90 units/kg after 12 hours subcutaneously;

Dalteparin – 100 units/kg every 12 hours subcutaneously.

Similar doses are used in the treatment of acute coronary syndromes; Clinical studies have shown a higher effectiveness of LMWH compared to UFH in patients with unstable angina and acute myocardial infarction.

The main complication of LMWH use is bleeding. Major bleeding occurs at approximately the same rate as with UFH treatment in similar patient groups. Heparin-induced thrombocytopenia is much less common with LMWH (approximately 10%-15%) than with heparin; however, due to cross-reactivity to antibodies, LMWH are not optimal for long-term anticoagulant therapy in patients treated with heparin. -induced thrombocytopenia. Osteoporosis with the use of LMWH is observed much less frequently than with the use of UFH, but there is not yet enough clinical data on this.

References

1. Anand S.S., Brimble S., Ginsberg J.S. Management of iliofemoral thrombosis in a pregnant patient with heparin resistance. Arch Intern Med 1997; 157:815-816.

2. Becker R.G., Corrao J.M., Bovill E.G. et al. Intravenous nitroglycerin-induced heparin resistance: a qualitative antithrombin III abnormality. Am Heart J 1990; 119:1254–1261.

3. Bhandari M., Hirsh J., Weitz J. et al. The effects of standard and low molecular weight heparin on hone nodule formation in vitro. Thromb Haemost 1998; 80:413-417.

4. Bjornsson T.O., Wolfram B.S., Kitchell B.B. Heparin kinetics determined by three assay methods. Clin Pharmacol Ther 1982; 31:104-113.

5. Blajchman M.A., Young E., Ofosu F.A. Effects of unfractionated heparin, dermatan sulfate and low molecular weight heparin on vessel wall permeability in rabbits. Ann NY Acad Sci 1989; 556:245-254.

6. Clowes A.W., Karnovsky M.J. Suppression by heparin of smooth muscle cell proliferation in injured arteries. Nature 1977; 265:625-626.

7. Cruickshank M.K., Levine M.N., Hirsh J. et al. A standard heparin nomogram for the management of heparin therapy. Arch Intern Med 1991; 51:333-337.

8. Dahlman T., Lindvall N., Helgren M. Osteopenia in pregnancy during long-term heparin treatment: a radiological study post-partum. Br J Obstet Gynaecol 1990; 97:221-228.

9. de Swart C.A.M., Nijmeyer B., Roelofs J.M.M. el al. Kinetics of intravenously administered heparin in normal humans. Blood 1982; 60:1251–1258.

10. Doyle D. J., Turpie A. G. C., Hirsh J. el al. Adjusted subcutaneous heparin or continuous intravenous heparin in patients with acute deep venous thrombosis: a randomized trial. Ann Intern Med 1987; 107:441-445.

11. Edson J.R., Krivit W., White J.G. Kaolin partial thromboplastin time: high levels of procoagulants producing short clotting times or masking deficiencies of other procoagulants or low concentrations of anticoagulants. J Lab Clin Med 1967; 70:463-470.

12. Eika C. Inhibition of thrombin-induced aggregation of human platelets in heparin. Scand J Hematol 1971; 8:216-222.

13. Fisher A.R., Bailey C.R., Shannon C.N. et al. Heparin resistance after aprotinin. Lancet 1992; 340:1230-1231.

14. Francis C.W., Berkowitz S.D. Antithrombotic and thrombolytic agents. In: Kitchens C.S., ed. Consultative Hemostasis and Thrombosis. W.B.: Saunders Company; 2004. 375-393.

15. Ginsberg J.S. Thromboembolism and pregnancy. Thromb Haemost 1999; 82:620-625.

16. Gould M.K., Dembitzer A.D., Sanders G.D. et al. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A cost-effectiveness analysis. Ann Intern Med 1999; 130:789-700.

17. Hirsh J., Salzman E.W., Murder V.J. Treatment of venous thromboembolism. In: Colman B.W., Hirsh J., Murder V.J. et al. (eds.). Hemostasis and thrombosis: basic principles and clinical practice. Philadelphia, PA: Lippincott; 1994. 1346-1366.

18. Hirsh J., Warkentin T.E., Shaughnessy S.G. et al. Heparin and low-molecular-weight heparin. Mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 2001;119(suppl):64-94.

19. Hull R.D., Raskob G.E., Hirsh J. el al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med 1986; 315:1109–1114.

20. Hull R.D., Raskob G.E., Rosenbloom D. et al. Heparin for five days as compared with ten days in the initial treatment of proximal venous thrombosis. N Engl J Med 1990; 322:1260–1264.

21. Kaplan K.L., Francis C.W. Heparin-induced thrombocytopenia. Blood Rev 1999; 13:1-7.

22. Kelton J.G., Hirsh J. Bleeding associated with antithrombotic therapy. Semin Hematol 1980; 17:259-291.

23. Koopman M.M.W., Prandoni P., Piovella F. et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med 1996; 334:682-687.

24. Lane D.A. Heparin binding and neutralizing protein. In: Lane D. A., Lindahl U. (eds.). Heparin, chemical and biological properties, clinical applications. London, UK: Edward Arnold; 1989. 363-374.

25. Levine M.N., Hirsh J., Cent M. et al. A randomized trial comparing activated thromboplastin time with heparin assay in patients with acute venous thromboembolism requiring large daily doses of heparin. Arch Intern Med 1994; 154:49-56.

26. Levine M., Gent M., Hirsh J. et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996; 334:677-681.

27. Levine S.P., Sorenson R.R., Harris M.A. et al. The effect of platelet factor 4 on assays of plasma heparin. Br J Hematol 1984; 57:585-596.

28. Lijnen H.R., Hoylaerts M., Collen D. Heparin binding properties of human histidine-rich glycoprotein: mechanism and role in the neutralization of heparin in plasma. J Biol Chem 1983; 258:3803–3808.

29. Lindahl U., Backstrom G., Hook M. et al. Structure of the antithrombin-binding site of heparin. Proc Natl Acad Sci USA 1979; 76:3198–3202.

30. Marci C.D., Prager D. A review of the clinical indications for the plasma heparin assay. Am J Clin Pathol 1993; 99:546-550.

31. McLean J. The thromboplastic action of cephalin. Am J Physiol 1916; 41:250-257.

32. Olson J.D., Arkin C.A., Brandt J.T. et al. College of American Pathologists Conference XXXI on Laboratory Monitoring of Anticoagulant Therapy: laboratory monitoring of unfractionated heparin therapy. Arch Pathol Lab Med 1998; 122:782-798.

33. Olsson P., Lagergren H., Ek S. The elimination from plasma of intravenous heparin: an experimental study on dogs and humans. Acta Med Scand 1963; 173:619-630.

34. Pini M., Pattacini C., Quintavalla R. et al. Subcutaneous vs intravenous heparin in the treatment of deep venous thrombosis: a randomized clinical trial. Thromb Haemost 1990; 64:222-226.

35. Prandoni P., Lensing A.W., Buller H.R. et al. Comparison of subcutaneous low molecular weight heparin with intravenous standard heparin in proximal deep vein thrombosis. Lancet 1992; 339:441-445.

36. Raschke R.A., Reilly B.M., Guidry J.R. et al. The weight-based heparin dosing nomogram compared with a "standard care" nomogram. A randomized controlled trial. Ann Intern Med 1993; 119:874-881.

37. Rosenberg R.D., Bauer K.A. The heparin-antithrombin system: a natural anticoagulant mechanism. In: Column R.W., Hirsh J., Marder V.J. et al. (eds.). Hemostasis and thrombosis: basic principles and clinical practice. Philadelphia: J. B. Lippincott; 1994. 837-860.

38. Shaughnessy S.G., Young E., Deschamps P. el al. The effects of low molecular weight and standard heparin on calcium loss from the fetal rat calvaria. Blood 1995; 86:1368–1373.

39. Visentin G.P., Ford S.E., Scott J.P. et al. Antibodies from patients with heparin-induced thrombocytopenia/ thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells. J Clin Invest 1994; 93:81-88.

40. Warkentin T.E. Heparin-Induced Thrombocytopenia. In: Kitchens C.S., ed. Consultative Hemostasis and Thrombosis. W.B.: Saunders Company; 2004. 355-372.

41. Weitz J.I. Low-molecular-weight heparins. N Engl J Med 1997; 337:688-689.

42. Whitfield L.H., Lele A.S., Levy G. Effect of pregnancy on the relationship between concentration and anticoagulant action of heparin. Clin Pharmacol Ther 1983; 34:23-28.

43. Young E., Prins M.H., Levine M.N. et al. Heparin binding to plasma proteins, an important mechanism for heparin resistance. Thromb Haemost 1992; 67:639-643.

44. Young E., Wells P., Holloway S. et al. Ex-vivo and in-vitroevidence that low molecular weight heparins exhibit less binding to plasma proteins than unfractionated heparin. Thromb Haemost 1994; 71:300-304.

Hemorrhagic syndrome caused by heparin

Heparin, if used incorrectly and insufficiently controlled, can cause both hemorrhagic and thrombotic complications.

Bleeding caused by heparin can be divided into local, occurring at the sites of drug administration, and generalized, associated with its effect on the entire hemostatic system.

Local hemorrhages are formed only with subcutaneous or intramuscular administration of the drug, and with intravenous administration they do not form (except in cases of through puncture of a vein).

With intramuscular injections of the drug, the resulting hemorrhages due to greater blood supply (vascularization) of the tissue are much larger (although less noticeable) than with subcutaneous administration.

Absorption of heparin from muscle occurs 2 times faster than from subcutaneous tissue, but when a hematoma forms in the injection area, it slows down sharply. It is very difficult to dose the drug and create controlled hypocoagulation when administered intramuscularly.

Subcutaneous administration of heparin is quite common in the treatment of thrombosis, as well as in the treatment of disseminated intravascular coagulation syndromes.

There is individual intolerance to heparin: subcutaneous administration of the drug is accompanied by acute pain, the development of hemorrhages and even necrosis of the skin over them.

The generalized hemorrhagic effect of heparin is caused either by its overdose or by unrecognized background disorders of hemostasis, in which heparin administration is contraindicated.

Heparin dosage in units per kilogram of body weight is purely indicative, suitable only for calculating the initial test dose.

In some cases, it is useful to additionally introduce blood products containing antithrombin III into the body (for example, frozen plasma), or remove acute phase proteins and paraproteins from the patient’s blood (plasmapheresis). These effects restore the sensitivity of the hemostatic system to heparin, and it is no longer possible to increase the dose of the drug.

With long-term intravenous administration of heparin, it is easier to control its hypocoagulant effect. With good monitoring, this method of administration gives the least number of hemorrhagic complications. Intravenous administration of heparin every 4 hours is much less effective and more dangerous, when large changes in hemocoagulation occur - from almost complete blood incoagulation to hypercoagulation (the half-life of heparin from the circulation is 70-100 minutes, and by the end of the 3-4th hour it almost none in the blood). Hemorrhagic and thrombotic complications with such intermittent administration occur 7 times more often than with long-term administration. To mitigate these differences, combined methods of drug administration (subcutaneous and intravenous) are used.

The adequacy of monitoring the effect of heparin by global (whole blood clotting time, thromboelastography, activated partial thromboplastin time, autocoagulation test) and partial methods is critical.

Clinic

Hemorrhagic syndrome during treatment with heparin occurs much less frequently and is, as a rule, much milder than when treated with indirect anticoagulants. This is explained by the fact that heparin does not disrupt the synthesis of coagulation factors, but only blocks their activated forms, has a short-term effect and is quickly removed from the bloodstream.

This drug poses a serious danger in patients with existing, although perhaps undetected, bleeding or with other processes (vascular, destructive) that are easily complicated by bleeding. For example, it can provoke heavy bleeding in peptic ulcers, erosive gastritis, acute erosions and ulcers.

Quite often, the use of heparin provokes pulmonary hemorrhages in patients with bronchiectasis, in case of stagnation in the pulmonary circulation, bleeding from the veins of the esophagus with cirrhosis of the liver, and cerebral hemorrhages in patients with hypertension.

Extensive and multiple hemorrhages are observed mainly with a very significant overdose of heparin or with a secondary decrease in the patient’s number of platelets in the blood (some patients develop so-called heparin thrombocytopenia).

Treatment

Reducing the dose of heparin or stopping it quickly normalizes hemostasis; Additionally, you can administer a small dose of protamine sulfate, a drug that inhibits heparin. For every 100 units of heparin administered over the last 4 hours, 0.5–1 mg of protamine sulfate in a 1% solution is administered intravenously. If the effect is insufficient, then an additional 0.25 mg of the drug is administered. An overdose of protamine sulfate should be avoided, since when administered in excess, it itself causes hypocoagulation, which doctors often mistakenly interpret as heparin.

This text is an introductory fragment. From the book General and Clinical Immunology by N.V. Anokhin

From the book Anesthesiology and Resuscitation author Marina Aleksandrovna Kolesnikova

From the book Hospital Pediatrics: Lecture Notes by N.V. Pavlova

From the book Urology by O. V. Osipova

From the book Faculty Therapy author Yu. V. Kuznetsova

From the book Blood Diseases by M. V. Drozdov

From the book Homeopathy. Part II. Practical recommendations for choosing medications by Gerhard Köller

From the book The Complete Guide to Nursing author Elena Yurievna Khramova

From the book Encyclopedia of Clinical Obstetrics author Marina Gennadievna Drangoy

From the book Children's Heart author Tamara Vladimirovna Pariyskaya

From the book Rosehip, hawthorn, viburnum in cleansing and restoring the body author Alla Valerianovna Nesterova

From the book Complete Medical Diagnostics Guide by P. Vyatkin

From the book Official and Traditional Medicine. The most detailed encyclopedia author Genrikh Nikolaevich Uzhegov

From the book Homeopathic Handbook author Sergei Alexandrovich Nikitin

From the book Men's Health. Continuation of a full life by Boris Gurevich

From the book Modern Home Medical Directory. Prevention, treatment, emergency care author Victor Borisovich Zaitsev

Heparin, if used incorrectly and insufficiently controlled, can cause both hemorrhagic and thrombotic complications.

Bleeding caused by heparin can be divided into local, occurring at the sites of drug administration, and generalized, associated with its effect on the entire hemostatic system.

Local hemorrhages are formed only with subcutaneous or intramuscular administration of the drug, and with intravenous administration they do not form (except in cases of through puncture of a vein).

Subcutaneous administration of heparin is quite common in the treatment of thrombosis, as well as in the treatment of disseminated intravascular coagulation syndromes.

There is individual intolerance to heparin: subcutaneous administration of the drug is accompanied by acute pain, the development of hemorrhages and even necrosis of the skin over them.

The generalized hemorrhagic effect of heparin is caused either by its overdose or by unrecognized background disorders of hemostasis, in which heparin administration is contraindicated.

Heparin dosage in units per kilogram of body weight is purely indicative, suitable only for calculating the initial test dose.

an additional 0.25 mg of the drug is administered. An overdose of protamine sulfate should be avoided, since when administered in excess, it itself causes hypocoagulation, which doctors often mistakenly interpret as heparin.

Treatment of hemorrhagic vasculitis in children is a complex therapeutic problem. Treatment should be comprehensive, active, early, in compliance with the general principles of therapy for this disease.
The basic principles include: bed rest, hypoallergenic diet, antibacterial therapy (as indicated), anticoagulant therapy, suppression of immune complex inflammation, infusion therapy, disaggregant therapy, enterosorption, “alternative” therapy.

Bed rest(strict) is prescribed for the entire period of hemorrhagic syndrome. A week after the last rash, bed rest becomes less strict (usually it lasts 3-4 weeks). If motor activity is impaired, there may be repeated rashes - “orthostatic purpura”.

Diet therapy for hemorrhagic vasculitis should be hypoallergenic. Excluded: fried and extracted foods, chocolate, citrus fruits, muffins, coffee, strawberries, chips, eggs, apples, cocoa, canned foods, products containing dyes, flavors, and products that cause allergies in the patient.

It is undesirable to consume products that enhance peristalsis. Fermented milk products and drinking plenty of fluids (decoctions of black currants, rose hips, vegetable juices) are indicated.

At renal form Diet No. 7 is prescribed, which is aimed at reducing swelling and... This is a predominantly plant-based diet with the exception of meat and table salt. If there is no swelling, the amount of fluid is not limited. In case of edema, the volume of fluid administered depends on the amount of urine excreted over the previous day.

Products containing oxalic acid, essential and extractive substances are excluded. After achieving remission, salt can be added to the diet. After 2 weeks from the start of remission, 0.5 g of salt per day is allowed, after 1.5-2 weeks from the start of remission - 3-4 g of salt per day. After 1 month from the start of remission, boiled meat is included in the diet, after 3 months, meat broth.

At abdominal form, if pain is present, diet No. 1a is prescribed. It is aimed at sparing the gastrointestinal tract (mechanical, chemical, thermal). Products that irritate the mucous membrane of the gastrointestinal tract and stimulate gastric secretion are excluded: raw fruits and vegetables, meat broths, bread, refractory fats, seasonings, spicy foods, dry foods, baked goods. Food should be pureed, boiled in water or steam. Cold and hot dishes are also excluded.

In the absence of abdominal pain, the patient is transferred to diet No. 1. Food is given boiled, but not pureed. You can give crackers. Fruits and vegetables, spicy and fatty foods are still excluded. When remission is achieved, the patient is transferred to a hypoallergenic diet (for a year).

Etiotropic therapy consists of eliminating the allergen, fighting infection, and sanitizing existing foci of infection.
It has been proven that viral and bacterial infections occupy a leading place among the factors preceding the development of hemorrhagic vasculitis. Often, treatment of concomitant infectious manifestations affects the positive outcome of the disease. As a result, treatment of chronic diseases of the nasopharynx, treatment of helminthiasis, herpes infection, intestinal dysbiosis, viral hepatitis, etc. is carried out.

Since in childhood the leading place is occupied by the pathology of the respiratory system, we have to resort to.
Antibacterial therapy is also prescribed for the development of nephritis, persistent wave-like course of the disease, and the presence of chronic foci of infection.

Preference is given to penicillin antibiotics (penicillin, ampicillin, ampiox), macrolides (clarithromycin, azithromycin, roxithromycin), cephalosporins.
In the presence of helminthic infestation, deworming is carried out. Deworming is also indicated for persistent recurrence of skin syndrome.

Pathogenetic therapy

Taking into account the pathogenesis of the disease, therapy is carried out in the following areas:

Blockade of the formation of immune complexes (glucocorticoids, cytostatics);
Removal of immune complexes (infusion therapy, plasmapheresis);
Correction of hemostasis (antiplatelet agents, anticoagulants, fibrinolysis activators);
Suppression of immune complex inflammation (non-steroidal anti-inflammatory drugs, glucocorticoids, cytostatics).

Treatment of hemorrhagic vasculitis should be individualized, depending on the clinical manifestations of the disease. But the use of antiplatelet agents or anticoagulants is mandatory.

Anticoagulant therapy

Anticoagulant therapy is indicated for moderate to severe hemorrhagic vasculitis. For mild cases, antiplatelet agents can be used as monotherapy. But still, in most cases it is necessary to resort to heparin therapy. Heparin therapy is the basic method of treating hemorrhagic vasculitis. To carry it out, sodium heparin or low molecular weight heparins are used.

The anticoagulant activity of sodium heparin is associated with the effect on (activated by antithrombin III), activation of the 1st complement component, effect on thrombin and activation of prothrombin Xa.

Heparin has anticoagulant, antiallergic, anti-inflammatory, lipolytic, fibrinolytic effects.

Heparin therapy is effective if certain rules are followed:

It is necessary to choose the correct dose of the drug.
— for a simple form, heparin is prescribed at a dose of 100-150 IU/kg per day;
— with a mixed form — 200-400 IU/kg per day;
— for nephritis — 200-250 IU/kg/day;
— for the abdominal form, up to 500 IU/kg/day.
With the correct dose, the blood clotting time should increase by 2 times from the initial level. In the absence of clinical or laboratory effect, the dose of heparin is increased by 50-100 units/kg/day. You should also be aware that the lack of effect from high doses of heparin may be due to a deficiency of antithrombin III or a high content of acute phase proteins of inflammation. The duration of heparin use can range from 7 days to 2-3 months. The duration depends on the form and severity of the disease. For a moderate form, usually 25-30 days, for a severe form, 45-60 days, for nephritis - 2-3 months;
Ensure uniform action of heparin throughout the day.
This can be achieved by continuous intravenous administration of the drug, which is practically difficult to do. Also, intravenous administration of heparin every 4 hours does not lead to the desired hypocoagulation, since after 2.5-3 hours the effect of heparin is not recorded. Preference is given to subcutaneous administration of sodium heparin every 6 hours into the anterior abdominal wall in equal doses. This administration of the drug creates a depot and a more uniform and prolonged hypocoagulative effect (due to the peculiarities of the blood supply to this area);
Conduct laboratory monitoring of the hypocoagulant effect of heparin
It is necessary to check blood clotting before the next administration of heparin. If hypocoagulation is insufficient, the dose of the drug is increased. If the blood clotting time increases by more than 2 times from the initial level, the dose of heparin is reduced. A mistake is considered to be reducing the frequency of administration (number of injections). It is necessary to first reduce the single dose of the drug, and then the frequency of administration ;
If necessary, additionally administer antithrombin III.
For heparin to act, its plasma cofactor antithrombin III (the main thrombin inhibitor) is required. AT III is the main potential of the anticoagulant system and if it is depleted, heparin therapy is not effective.
The main source of AT III is fresh frozen plasma. In addition to AT III, there are other antithrombotic components in the plasma (plasminogen, fibronectin, protein C, physiological antiplatelet agents), which normalize the coagulation process and antiprotease activity of the plasma.
Fresh frozen plasma is administered 10-15 ml/kg per day in one or two doses. Along with it, heparin is administered: 500 units of heparin per 50 ml of plasma. A contraindication for plasma administration is capillary toxic Schönlein–Henoch nephritis. When AT III is administered, the effect of heparin increases, which must be taken into account for further calculation of heparin.
Plasma administration for hemorrhagic vasculitis is currently being reconsidered. This is due to the fact that plasma also contains other protein substances, which are a source of antigenic stimulation and can aggravate the immunopathological process. Of course, it is better to administer ready-made AT III drugs, such as Cybernine, Antithrombin III human. But these drugs are not yet approved for use in children.

Heparin administration is discontinued 7 days after the last rash appears. First, the dose of the drug is reduced by 100 units/kg/day every 2-3 days, and then the frequency of administration. The criteria for heparin withdrawal are an increase in blood clotting by 2.5-3 times or the presence of hemorrhages at the injection sites.

For anticoagulant therapy, both unfractionated heparin and fractionated (fine, low molecular weight) heparin can be used.

In recent years, finely divided heparins (Fraxiparin, Fragmin, Clivarin, Clexane, Fluxum, Calciparin) have begun to be used more often.
The administration of these drugs is less traumatic (administered 1-2 times a day). Thus, fraxiparin is administered once a day subcutaneously into the anterior abdominal wall at a dose of 150-200 IU/kg (course of treatment is 5-7 days).

Low molecular weight heparins have a more pronounced antithrombotic effect and less pronounced anticoagulant activity compared to heparin. They have a rapid and long-lasting antithrombotic effect due to inhibition of factor Xa (4 times more pronounced than heparin). They also inhibit the formation of thrombin, which provides their anticoagulant effect.

In addition, finely divided heparins are characterized by:

rare frequency of bleeding;
higher bioavailability when administered subcutaneously;
less need for blood clotting control (as they have little effect on blood clotting).

Hormone therapy

The main goal of hormonal therapy is to stop the immune process.

Glucocorticoids are indicated for:

the presence of two or more syndromes;
wave-like course of skin rashes;
widespread skin rashes with a pronounced thrombohemorrhagic component and necrosis;
significant exudative component of the rash;
abdominal syndrome (severe);
nephritis with nephrotic syndrome or macrohematuria.

Glucocorticoids have pronounced anti-inflammatory and immunosuppressive effects. When using glucocorticoids, the circulation of immune complexes is significantly reduced and the increased level of proteases is normalized.

With early administration of glucocorticoids, the clinical symptoms of the disease are quickly relieved, the duration of therapy is reduced, and further kidney damage is prevented.
Prednisolone is prescribed at a dose of 0.5-1.0 mg/kg per day for 3-4 weeks.
With the development of nephritis, the dose of prednisolone is increased to 2 mg/kg per day for 1-2 months, then the dose is reduced by 2.5 mg once every 5-7 days until complete withdrawal.

However, one should remember the hypercoagulable effect of glucocorticoids, which inhibit the fibrinolysis system and activate the coagulation system and platelets. Therefore, they are recommended to be used in conjunction with antiplatelet agents and anticoagulants. Also, when using prednisolone, potassium supplements should be prescribed.

In severe cases of the disease, pulse therapy is used. During pulse therapy, 1000 mg of methylprednisolone (250 mg in a bottle) diluted in 200 ml of saline is simultaneously administered at a rate of 60 drops per minute. For nephrotic syndrome, pulse therapy is carried out 3 days in a row, or every other day. If necessary, it can be repeated once a month, up to 10-12 times. The use of pulse therapy has fewer side effects and gives a better effect than oral glucocorticoids in regular dosages.

Plasmaphoresis

Plasmaphoresis is used for treatment-refractory forms of hemorrhagic vasculitis. The therapeutic effect of plasmaphoresis is the elimination of immune complexes, breakdown products, inflammatory mediators, and platelet aggregation factors. As a result, cellular immunity is unblocked and the properties of the blood are restored.

Indications for plasmaphoresis:

High content of immune complexes;
Severe abdominal syndrome;
Nephritis with nephrotic syndrome;
Acute renal failure.

The course of treatment is 3-8 sessions. Initially, 3 sessions are carried out daily, then once every 3 days.
Plasmaphoresis helps improve microcirculation, increase the activity of immune cells, and increase sensitivity to drugs. However, you should know that plasmaphoresis removes only large circulating complexes from the blood.
The best effect of plasmaphoresis is observed when it is carried out in the first 3 weeks of the disease.

Disaggregant therapy

Disaggregant therapy improves microcirculation by blocking platelet aggregation. It is indicated for all forms of the disease.
The following drugs are used for disaggregant therapy:

Dipyridamole (chimes) - 3-8 mg/kg per day in 4 divided doses;
Pentoxifylline (trental) - 5-10 mg/kg per day in 3 doses;
Ticlopidine (ipatone) - 10-15 mg/kg/day 3 times a day

In severe cases of the disease, two drugs with different mechanisms of action are used. You can prescribe chimes with trental or with indomethacin, which also has a disaggregation effect.

Disaggregants should be used long-term:

For mild cases - 2-3 months;
For moderate severity – 4-6 months;
In case of severe recurrent course and nephritis, up to 12 months;
In case of chronic course - in courses for 3-6 months.

Activators of fibrinolysis.

In hemorrhagic vasculitis, depression of fibrinolysis has been identified, therefore there are indications for the administration of fibrinolysis activators. Non-enzyme activators are prescribed - nicotinic acid and xanthinol nicotinate. They are vasoactive substances and promote the release of vascular plasminogen activators into the bloodstream. But it should be remembered that their effect is short-term (no more than 20 minutes after intravenous administration). They are prescribed at a dose of 3-5 mg/kg/day, taking into account individual sensitivity. For the same purpose, you can use nikoshpan - 0.1 g 2 times a day.

Infusion therapy

Infusion therapy for hemorrhagic vasculitis is used to improve peripheral microcirculation.

Indications for infusion therapy are:

Severe hemorrhagic rashes;
Hypercoagulation;
Abdominal syndrome;
Severe thrombocytosis;
Hematocrit above 40%.

For infusion therapy, low molecular weight plasma replacement solutions are used at a dose of 20 ml/kg/day. They improve the rheological properties of blood, prevent aggregation of red blood cells and platelets, and absorb and remove toxins from the body.

For the abdominal form, a glucose-novocaine mixture is used (glucose 5% and novocaine 0.25% in a 3:1 ratio). The dose of the mixture is 10 ml/kg of body weight, but not more than 100 ml. In addition to the analgesic effect, novocaine improves peripheral blood circulation and blocks the action of cholinesterase, which is increased in hemorrhagic vasculitis.

Antispasmodics

Antispasmodics are prescribed for the abdominal form. Use noshpa 2% -2 ml, aminophylline 5 mg per kg per day in 200 ml saline. solution.

Antihistamines

The prescription of antihistamines is pathogenetically justified during the initial manifestations of hemorrhagic vasculitis, when there is a release of histamine and other similar substances. Tavegil, suprastin, terfenadine, cetirizine, etc. are used. In the first days of the disease, their parenteral use is possible. The course of using antihistamines is no more than 7 days.
But there is another point of view - that the use of antihistamines, as well as vascular strengthening agents, is not justified, since they aggravate hemocoagulation changes.

Enterosorption

Enterosorbents are used when food agents are the provoking factor of the disease. They bind toxins and active substances in the intestines, which prevents them from entering the bloodstream. The duration of therapy with enterosorbents in acute cases is from 2 to 4 weeks. With an undulating course, up to 1-3 months. Used: carbolene, enterosgel, smecta, litovit, enterodes, nutriclinz, polyphepan. Drugs in this group should be used with caution in the abdominal form, as increased bleeding or increased pain is possible.

Alternative therapy

This therapy is used for undulating or recurrent skin rashes. This includes the use of anti-inflammatory therapy, cytostatics, and membrane stabilizers.

Anti-inflammatory drugs are used for:

Persistent, wave-like course of hemorrhagic purpura;
With high leukocytosis, a significant increase in NER;
With hyperfibrinogenemia, increased seromucoids;
For articular form, when glucocorticoids are not prescribed;
When there are contraindications to the use of glucocorticoids.

The drugs used are: ibuprofen (15-20 mg/kg per day), diclofenac sodium (1-2 mg/kg per day), indomethacin (3-4 mg/kg), etc.
The action of these drugs is associated with limiting the development of various phases of inflammation. They also have a disaggregating effect, which has a beneficial effect on treatment. They are used with caution in case of kidney disease, due to the possibility of increased hematuria. Duration of treatment is from 4 to 8 weeks.

4-aminoquinoline derivatives

These drugs are prescribed when the activity of severe forms of the disease subsides while prednisolone is discontinued or its dose is reduced. The following drugs are used: Plaquenil, Delagil. They have anti-inflammatory, immunosuppressive, antiplatelet effects.
Plaquenil is prescribed at a dose of 4-6 mg/kg once at night, for a course of 4-12 months. It is used for nephrotic and mixed forms of nephritis, for gross hematuria while reducing the dose of prednisolone. The use of Plaquinil for nephritis in most cases allows one to achieve remission.

It should be noted that the effect of the use of 4-aminoquinoline derivatives develops after 6-12 weeks from the start of therapy. Be sure to monitor a general blood test (leukopenia is possible) and undergo an examination by an ophthalmologist (there may be pigment deposition on the cornea, decreased vision).

Cytostatics

Cytostatics should be used with caution, as they suppress the bone marrow, immunity and cause various complications.

Indications for their use are:

Rapidly progressing course of nephritis;
Ineffectiveness of glucocorticoids;
Contraindications to treatment with glucocorticoids;
Relapse of nephritis with gross hematuria;
Severe skin syndrome with areas of skin necrosis.

In children they use: cyclophosphamide (2-3 mg/kg/day) and azathioprine (2 mg/kg). The course of treatment is at least 6 months. Treatment is carried out under the control of a general blood test. In case of leukopenia, cytostatics are discontinued.

Membrane stabilizers

Membrane stabilizers are natural catalysts for the synthesis of urokinase, as a result of which the inflammatory process is reduced.

Indications for their use:

Severe skin rashes;
Wave-like course of skin rashes;
Presence of jade.

Therapy with these drugs reduces the permeability of the vascular wall, has an immunomodulatory effect, improves trophic processes, and enhances the effect of anti-inflammatory drugs.

Use: Essentiale Forte - 2 mg/kg/day, retinol - 1.5-2 mg/kg, lipostabil, dimephosphone - 50-75 mg/kg. The course of treatment is at least 1 month. Treatment is carried out in repeated courses.

Immunomodulators.

Immunomodulators are used for undulating skin purpura and capillary toxic nephritis.
The following are used: dibazole (1-2 mg/kg in 2 doses for 4-5 weeks), levamisole (2 mg/kg per day for 3 days with breaks between courses of 5 days), immunal (10-20 drops 3 times a day). day for 8 weeks), tonsilgon (15 drops 3 times a day for 6 weeks). Antioxidants are also used for immunomodulation purposes.

In conclusion, I would like to note that the main principle of drug therapy for hemorrhagic vasculitis is to reduce the amount of medications to the required minimum and quickly discontinue the drug if an allergic reaction occurs to it.

Mikhail Lyubko

Literature: Modern approaches to the treatment of Henoch-Schönlein purpura and its prospects. O.S. Tretyakov. Simferopol.