What is Heparin?

Heparin was first discovered from the liver and got its name. It is a mucopolysaccharide sulfate composed of glucosamine, L-iduronic glycoside, N-acetylglucosamine, and D-glucuronic acid. The average molecular weight is 15KD, which is strongly acidic. It is also found in lungs, blood vessel walls, intestinal mucosa and other tissues, and is a natural anticoagulant substance in animals. Naturally found in mast cells, it is now mainly extracted from bovine lung or porcine small intestine mucosa. As an anticoagulant, it is a polymer composed of two kinds of polysaccharides alternately connected, and has anticoagulant effect in vivo and in vitro. It is mainly used clinically for thromboembolic diseases, myocardial infarction, cardiovascular surgery, cardiac catheterization, extracorporeal circulation, and hemodialysis. With the development of pharmacology and clinical medicine, the application of heparin has been expanding.

Drug Name: heparin
Foreign name: Heparin

Main indications: Thromboembolic disease, myocardial infarction, cardiovascular surgery
Main medication contraindications: Those who are allergic to heparin and have slow blood clotting
Dosage form: injection

Heparin compounds

Heparin Basic Information

Chinese name: Heparin

Chinese alias: heparin sodium; heparin

English name: Heparin

English alias: thrombophob; HED heparin; clarin; liquaemin; Enoxaparine; Hepathrom; Lipoepin; Panheparin; Hepsal

CAS number: 9005-49-6

Molecular formula: C ₂₆ H ₄₂ N ₂ O ₃₇ S ₅

Structural formula:

Molecular weight: 1134.93000

Exact mass: 1134.01000

PSA: 652.39000

Physical and chemical properties of heparin

Appearance and properties: white or off-white crystalline powder

Density: 2.18 g / cm ³

Boiling point: 644.9ºC at 760mmHg

Flash point: 343.8ºC

Refractive index: 1.711

Stability: Hygroscopic, sodium salt that can be stored at room temperature for at least 12 months.

Storage conditions: Store in a cool, dry, sealed and protected from light. Keep away from fire. Protect containers / cylinders from physical damage.

Heparin Safety Information

Customs code: 3001901000

WGK Germany: 2

Safety instructions: S24 / 25

RTECS number: MI0850000 ^[1]

Heparin production method

Method 1: Enzymolysis-Resin method to obtain 100kg of fresh intestinal mucosa (5% -7% total solids), add 200ml (0.2%) of phenol, if the temperature is low, do not add. Add 0.5-1kg (0.5% -1%) of minced pancreas under stirring, adjust the pH to 8.5-9 with 300-400g / L (30% -40%) NaOH solution, warm to 40-45 ° C, and keep 2- 3h. pH8, add 5kg of coarse common salt (5%) to raise the temperature to about 90 , adjust the pH to about 6.5 with 6mol / L HCl, stop stirring, hold for 20min, and filter with a cloth bag to obtain the enzymatic filtrate. Intestinal mucosa [pancreatic plasma, NaOH] [pH8.5-9, 40-45 ° C, holding 2-3h] intestinal mucosal fluid [NaCl, 6mol / L HCl] [pH8; 90 ° C, pH6.5] filtrate adsorption Wash, elute, take the above filtrate and cool it to below 50 , adjust pH7 with 6mol / L NaOH, add 5kg D-254 strong basic anion exchange resin, stir for about 5h, complete the exchange, discard the liquid, rinse the resin with water Clear, wash with 2mol / L NaCl of the same volume as the resin, stir for 15min, discard the washing solution, and wash twice with 1.2mol / L NaCl twice the resin volume. Elute with 5mol / L NaCl about half the resin volume for 1 h, collect the eluate, then elute twice with 3mol / L NaCl about 1/3 of the resin volume, and combine the eluates. The filtrate [D-254 resin, NaOH] [pH7, 5h] Adsorption [NaCl] [2mol / L 1.2mol / L, 5mol / L, 3mol / L] The eluent precipitates, dehydrates, and will be washed. The deliquored solution was filtered with filter paper, and filtered once. The clarified filtrate was added with 0.9% 95% ethanol treated with activated carbon by volume, and precipitated in the cold place for 8-12h. Discard the siphon supernatant, add distilled water to the precipitate at a rate of 100kg mucosa and 300ml, add 4 times the amount of 95% ethanol, and leave it in the cold for 6h. Collect the precipitate, dehydrate it with anhydrous ethanol once, and dehydrate it twice with acetone. Place in a P2O5 desiccator under vacuum to obtain crude heparin sodium. Eluent Precipitate [anhydrous ethanol; acetone] [P2O5] Crude sodium heparin is decolorized, precipitated, and dried. A 20 g / L (2%) sodium chloride solution is used to prepare 100 g / L (10%) sodium heparin. The solution was oxidatively decolorized with 40g / L (4%) potassium permanganate solution, and 0.65mol potassium permanganate was estimated to be added per 100 million units. First adjust the medicinal solution to pH 8, preheat 80 ° C, add potassium permanganate under stirring, keep it for 2.5h, use talc as a filter aid, filter, and collect the filtrate. The filtrate was adjusted to pH 6.4, and 0.9% 95% ethanol was placed on the cold-treated precipitate for more than 6 hours. The precipitate was collected and dissolved in a 10 g / L (1%) sodium chloride solution, and the amount was 60% based on the crude quality of heparin sodium. -70%, formulate a 50 g / L (5%) sodium heparin solution, and then place it in a cold place with 4 times the amount of 95% ethanol for more than 6 hours, collect the precipitate, dehydrate with anhydrous ethanol and acetone, and wash once with ether. Place it in a P2O5 dryer to get the heparin sodium product. The intestinal mucosa was converted into total solids of 7%, the yield was 20000U / kg, and the highest potency was 141.6U / mg. Crude sodium heparin [20g / L NaCl] sodium heparin solution [KMnO4] [pH8, 80 ° C, 2.5h] filtrate [pH6.4, 6h] precipitate [anhydrous ethanol; acetone; ether] sodium heparin product Preparation of injection: Take the finished product of sodium heparin and dissolve it in a certain amount of water for injection, seal, and sterilize it. Heparin sodium boutique [water for injection] injection

Method two: salting-resin extraction, take fresh pig intestinal mucosa and put it into the reaction pot, add sodium chloride at 30g / L (3%), adjust the pH to 9 with NaOH, gradually increase the temperature to 50-55 , keep it warm for 2h, and continue to increase the temperature Hold at 95 for 10min, cool below 50 , filter with 30 mesh double gauze, and collect the filtrate. Pig intestinal mucosa [NaCl; NaOH] [pH9; 50-55 ] Filtrate adsorption, washing, elution, precipitation Take the filtrate cooled below 50 , add 714-type (strongly alkaline) Cl-type resin (new resin dosage) (2%), stirred for 8h and then left overnight. The next day, the upper layer was removed by siphoning, the resin was collected, rinsed with water until the washing solution was clear, and dried by filtration. Stir with 2 times the amount of 1.4mol / L sodium chloride for 2h, then filter dry; then stir with 1 times the amount of 1.4mol / L sodium chloride. 2h, filter dry; continue to use 2 times the amount of resin 3mol / L sodium chloride and stir to elute for 8h, filter dry; then use 1 times the amount of 3mol / L sodium chloride to stir and elute for 2h, filter dry, combine the filtrate, add An equal amount of 95% ethanol was precipitated, and the supernatant was removed by siphoning, and the precipitate was collected. The acetone was dehydrated and dried to obtain a crude product. Filtrate [714 type resin] Adsorbed matter [NaCl] [1.4mol / L, 3mol / L] Eluent [95% ethanol, acetone] The crude product is dissolved, decolorized, precipitated, and the dried crude product is dissolved 15 times 10 g / In L (1%) sodium chloride solution, add 6mol / L hydrochloric acid to adjust the pH to about 1.5, filter to clear, then adjust the pH11 with 5mol / L sodium hydroxide, and add hydrogen peroxide (concentration: 30%) at 3%. Store at 25 ° C. Start to continuously adjust the pH to 11, and then add hydrogen peroxide at 1% on the second day, adjust the pH11, and continue to stand for a total of 48h. Filter, adjust pH 6.5 with 6mol / L hydrochloric acid, add equal amount of 95% ethanol to precipitate. overnight. The supernatant was removed by siphoning the next day, and the precipitate was washed and dehydrated with acetone and dried to obtain the heparin sodium product. The total yield is 20000U / kg intestinal mucosa (calculated based on the solid amount of intestinal mucosa of 5% -7%). Crude [1% NaCl, 6mol / L HCL] [pH1.5] filtrate [NaOH, H2O2] [pH11, 25 , 48h] filtrate [6mol / L HCl, 95% ethanol] [pH6.5, 24h ] Precipitate [acetone] Heparin sodium boutique

Method three: CTAB * extraction method (* hexadecyltrimethylamine bromide is a long-chain quaternary ammonium salt) is used to extract and complex the porcine intestinal mucosa fluid (V): Na2SO4 (m): aluminum sulfate (m): CTAB (V) = 1: 0.15: 0.04: 0.001. Take the fresh pig small intestine mucosa and put it into the reaction tank, add sodium sulfate while stirring, dissolve, adjust the pH 11-11.5 with alkaline solution, raise the temperature to 50 ° C, stir for 2 hours, add aluminum sulfate, and after dissolving, adjust pH 7 with sodium hydroxide. 5-8, warm to 95 ° C, hold for 10min, and filter while hot. When the filtrate is cooled below 60 ° C, slowly add CTAB and diatomaceous earth, stir and adsorb for 1h, leave it overnight, and wash the filter cake with 40 ° C hot distilled water It is colorless and dried to obtain complex. Pig intestinal mucosa fluid [Na2SO4, lye, Al2 (SO4) 3] [pH11-11.5, 50 , 2h; pH7.5-8, 95 , 10min] Extract [CTAB, diatomaceous earth] [60 Below , 1h] filter cake [distilled water] complex dissociation, precipitation Take the complex and dissolve it in an appropriate amount of sodium chloride solution, adjust the pH to 4 with glacial acetic acid, raise the temperature to 60 ° C, keep it for 30 minutes, and filter it still .

Heparin use

This product is the raw material of the anticoagulant heparin ^[1] .

Heparin drug description

Heparin classification

Circulatory Drugs> Antithrombotic Drugs> Anticoagulants

Heparin dosage form

Injection: 2ml (100U), 2ml (500U), 2ml (1000U), 2ml (5000U), 2ml (12500U) each.

Pharmacological effects of heparin

The ratio of low molecular weight heparin activity / anticoagulant activity is 1.5 to 4.0, while ordinary heparin is 1, which maintains the antithrombotic effect of heparin and reduces the risk of bleeding. It has the advantages of long half-life and high bioavailability. It is widely used in the prevention and treatment of thromboembolic diseases. Its effectiveness and safety are better than ordinary heparin. The dose-response relationship is clear. The fixed dose can be adjusted without laboratory monitoring. Easy to apply. Some experiments have proved that Hiru-log peptide from hirudin is safer than heparin. Low-molecular-weight heparin can reduce the immune activity of rat kidney transplantation. Methods: Allogeneic recipients were subcutaneously injected with low molecular weight heparin 2mg / (kg · d), 5 days a week for 24 weeks. Results: After low-molecular-weight heparin treatment, transplanted kidney mononuclear phagocytes reduced the infiltration of T cells and reduced the expression of major histocompatibility antigen M HC-. The experimental results show that low-molecular-weight heparin can reduce the immune activity of the transplanted kidney in mice and reduce the chronic rejection of the transplanted kidney.

1. Anticoagulation:

heparin

(1) Enhance the affinity of antithrombin 3 and thrombin, and accelerate the inactivation of thrombin;

(2) Inhibit the adhesion and aggregation of platelets;

(3) Enhance the activity of protein c, stimulate the release of anticoagulant substances and fibrinolytic substances from vascular endothelial cells.

2. Inhibit platelets, increase the permeability of blood vessel walls, and regulate angiogenesis.

3. It has the function of regulating blood lipids.

4. It can act on multiple links of the complement system to inhibit the system from excessive activation. Related to this, heparin also has anti-inflammatory and anti-allergic effects.

Heparin pharmacokinetics

Heparin is not absorbed orally, and is well absorbed subcutaneously, intramuscularly, or intravenously. After absorption, it is distributed in blood cells and plasma, and part of it can diffuse into extravascular tissue spaces. After intravenous injection, it can be highly combined with plasma low-density lipoprotein to form a complex, and can also be combined with globulin and fibrinogen. It can be taken up by the monocyte-phagocytic system into the liver for metabolism, and heparinase acts through the liver. Decomposed into urinary heparin. The half-life of heparin after intravenous injection was 1 to 6 hours, with an average of 1.5 hours. And there is a correlation with the dosage; intravenous injection of 100U / kg, 200U / kg or 400U / kg according to body weight has half-life of 56, 96, 152 minutes. People with chronic liver and renal insufficiency and obesity will have delayed metabolism and excretion of heparin, and may have accumulation in the body. Due to its large molecule, heparin cannot pass through the pleura and peritoneum, nor through the placenta. Plasma heparin concentrations are not affected by dialysis. Heparin onset time is related to the mode of administration. Direct intravenous injection can immediately exert the maximum anticoagulant effect, and the effect gradually decreases in the future. The coagulation time returns to normal after 3 to 4 hours. An intravenous drip given a load can immediately exert anticoagulant effects, otherwise the onset time depends on the drip rate. Subcutaneous injection generally takes effect within 20 to 60 minutes, and there are individual differences. The metabolite of heparin is generally uroheparin, which is excreted by the kidney, and 50% of it can be excreted in its original form after a large amount of intravenous injection ^[2] .

Heparin adverse reactions

The main adverse reaction of heparin is easy to cause spontaneous bleeding, which is manifested by various mucosal hemorrhage, joint cavity hemorrhage and wound bleeding, etc., and heparin-induced thrombocytopenia is a drug-induced thrombocytopenia, which is under treatment of heparin A serious complication. There are two main types of thrombocytopenia caused by drugs:

(1) Bone marrow is caused by inhibition of drug toxicity;

(2) The drug is caused by the destruction of platelets through the immune mechanism. Among the latter, heparin, quinine, quinidine, gold salts and sulfa drugs are more common. The clinical symptoms are extremely inconsistent. The platelet count is reduced to (1.0 80) × 10 9 / L. The mild ones are asymptomatic. In severe cases, intracranial hemorrhage or heparin may cause immune damage to endothelial cells. It may be combined with life-threatening pulmonary embolism and arterial thrombosis lethal. The diagnosis relies mainly on:

(1) Thrombocytopenia during medication;

(2) Elimination of thrombocytopenia after discontinuation. Severe patients can detect drug-dependent platelet antibodies in the serum, but the sensitivity is not high and often false negative. The key to treatment is to immediately stop the relevant drugs, and in severe cases, platelet, hormone, glycerin or plasma exchange can be used. Heparin should not be used for hemolytic uremic syndrome. Hemolytic uremic syndrome (HUS) is one of the common causes of acute renal failure in children. HUS90% of childhood typical diarrhea is caused by hemorrhagic E. coli O157: H7. At present, it is believed that the central part of the pathogenesis of HUS is endotoxin-induced damage to endothelial cells, followed by activation of the coagulation system, release of inflammatory mediators, and endothelin-nitrogen oxide axis disorders. Various organs of the body are affected to varying degrees, mainly the kidneys, followed by the brain. Treatment emphasizes supportive therapy and early dialysis. The treatment of typical HUS does not promote the use of heparin, antibiotics and hormones. Atypical HUS can be used for plasma exchange, which has a certain effect.

Countermeasures: For mild overdose, the drug can be discontinued; for severe overdose, in addition to drug withdrawal, heparin-specific antidote-protamine

Occasional allergic reactions. Long-term application can cause hair loss, osteoporosis and spontaneous fractures ^[2] .

Heparin indication

1. Amniotic fluid embolism, stillbirth syndrome, abnormal transfusion reaction, fulminant purpura, sepsis, heat stroke and metastatic cancer; but it is not effective for DIC caused by snake bite.

2. As an anticoagulant in vitro (such as blood transfusion, extracorporeal circulation, hemodialysis, peritoneal dialysis, and in vitro experiments on blood samples).

3. It has been reported that heparin can promote the release of lipoprotein lipase (clearance factor) from tissues, which in turn catalyzes the hydrolysis of triacylglycerols to clear blood lipids; it can also enhance the inhibitory effect of antithrombin III on angiotensin, so Can inhibit the acute attack of hereditary angioedema ^[2] .

Heparin contraindications

1. Uncontrolled active bleeding.

2. Patients with bleeding disorders and coagulation disorders (including hemophilia, thrombocytopenic or vascular purpura).

3. Trauma or bleeding after surgery.

4. Threatened abortion.

5. Subacute infective endocarditis.

6. Stomach and duodenal ulcers.

7. Severe liver and kidney dysfunction.

8. Jaundice.

9. Severe hypertension.

10. Active tuberculosis.

11. Visceral tumors ^[2] .

Heparin considerations

1. (1) have a history of allergic diseases and asthma; (2) procedures that are prone to bleeding such as oral surgery; (3) those who have taken enough anticoagulants orally; (4) those who have excessive menstrual flow; (5) Pregnant and postpartum women (due to the fact that heparin increases the risk of maternal bleeding in the last 3 months of pregnancy or postpartum).

2. The effects of drugs on the elderly: Elderly people over 60 years old (especially elderly women) are more sensitive to heparin and are prone to bleeding during medication, so the dosage should be reduced and follow-up should be strengthened.

3. The effect of the drug on the test value or diagnosis: (1) Heparin can prolong the prothrombin time of prothrombin, increase the retention time of the sodium sulfobromophthalide (BSP) test and cause a false positive reaction, leading to an increase in T3 and T4 concentrations, thereby Inhibits the release of pituitary thyroid-stimulating hormone; (2) When the amount of heparin reaches 15,000 20,000U, the serum cholesterol concentration decreases.

4. The whole blood coagulation time (test tube method) should be measured before treatment, and the primary time and time of thrombin should be measured in the one-stage method; the whole blood coagulation time (test tube method), hematocrit, stool occult blood test, urine occult blood test should be measured during treatment. And platelet count.

5. Clinically, heparin dosage was adjusted according to partial thromboplastin time (APTT). The coagulation time needs to be kept 2 to 3 times before treatment, APTT is 1.5 to 2.5 times before treatment, heparin dosage and dosing interval can be adjusted at any time; on the first day of treatment, the above observations should be observed before each medication, and thereafter It is measured several times a day, and once a day when the maintenance amount is used. For the elderly, hypertension and patients with liver and kidney dysfunction, because it is sensitive to heparin response, more attention should be paid to monitoring.

6. When long-term anticoagulation treatment is required, heparin can be used with oral anticoagulation with coumarins. Heparin should be stopped after 36 to 48 hours, and then anticoagulation should be maintained with oral anticoagulants alone.

7. Heparin is not effective when taken orally. Intravenous injection, intravenous drip and deep subcutaneous injection can be used. Intramuscular injection is generally not recommended because it can cause hematoma at the injection site. Subcutaneous injection should penetrate deep into the fatty layer (such as ridges and abdominal adipose tissue). The site needs to be constantly changed. Do not move the needle during injection. The injection site should not be rubbed, but requires local compression.

8. Intramuscular injection of other drugs should be avoided during administration.

9. Heparin is rapidly metabolized, a slight overdose can be discontinued; severe overdose of protamine is used for slow intravenous injection to neutralize, usually 1mg protamine can neutralize 100U heparin; if heparin has been injected for more than 30min, protamine Dosage should be halved.

10. Heparin can interfere with the determination of prothrombin time, so the test must be repeated 4 hours after using heparin.

11. If AT- in plasma is reduced, heparin is less effective, and plasma or AT- needs to be transfused.

12. In clinical practice, small doses of heparin are usually used to prevent thrombosis, while large doses are used to treat thrombosis.

13. The following drugs are contraindicated with heparin: amikacin sulfate, cefotaxime, cefoperand, cefoperazone, ceftiofen sodium, gentamicin sulfate, kanatoxin, tobramycin, lactobionic acid Erythromycin, vancomycin, polymyxin B, doxorubicin, daunorubicin, hydrocortisone sodium succinate, narcotic analgesics, chlorpromazine, promethazine, etc.

14. People who are allergic to heparin reactions should be more vigilant. People with allergic qualities, especially those who are allergic to pork, beef or other animal proteins, may be given 6 to 8 mg of heparin as the test amount. If there is no special reaction after 0.5 h, Give the full amount.

15. Heparin is different from thrombolytic drugs (such as urokinase, etc.) and has no lytic effect on the formed thrombus.

16. Heparin is prone to cause intraorbital and intracranial hemorrhage. It should not be used as a preventive medicine during ophthalmology and neurological surgery and patients with bleeding disorders.

17. Spontaneous bleeding tendency is the main danger of heparin overdose. Early overdose manifestations include bleeding from the mucous membranes and wounds, bleeding gums when brushing teeth, skin bruising or purpura, and nosebleeds. Excessive menstrual flow, etc .; signs of internal bleeding when severe, manifested as abdominal pain, bloating, back pain, paralytic intestinal obstruction, hemoptysis, vomiting blood, hematuria, bloody stool, and persistent headache.

18. For intravenous administration, it is best to pump it with a micro-infusion pump, pump it at 100U / kg, and measure APTT at any time to adjust the dosage ^[2] .

Dosage of heparin

1. (1) Deep subcutaneous injection: General dosage: 5000 10000U for the first time, then 8000 10000U every 8 hours or 15000 20,000U every 12 hours, the total amount is about 30,000 40,000U per day. It is also used as follows: 5000 ~ 10000U for the first administration and injection every 8 ~ 12 hours thereafter. The daily total is about 12500 ~ 40,0000U. If the daily total is controlled at 12,500U, APTT is generally not required to be measured, and APTT is required to monitor when the amount is large. Prevention of thrombosis in high-risk patients (mostly to prevent deep venous thrombosis after abdominal surgery): 5000 U was administered 2 hours before surgery, and 5000 U was administered every 8 to 12 hours thereafter for a total of 7 days. (2) Intravenous injection: 5000 ~ 10000U each time, once every 4 ~ 6 hours, or 100U / kg every 4 hours according to body weight, diluted with sodium chloride injection. (3) Intravenous infusion: 20,000 to 40,000U are administered daily, and 1 000ml sodium chloride injection is added for continuous infusion, but 5000U should be injected intravenously as the first dose before infusion.

2. Children: (1) Intravenous injection: 50U / kg for the first time according to body weight, 50 100U every 4 hours thereafter. (2) Intravenous infusion: 50U / kg is administered for the first time according to body weight, and then 20,000U / m is administered daily for body surface area. Slowly infusion is added to sodium chloride injection ^[2] .

Heparin drug interactions

1. Metimazole (Tababazole), propylthiouracil, etc. have a synergistic effect with heparin.

2. The combination of heparin and coumarin and its derivatives can cause severe deficiency of factor and cause bleeding.

3. Heparin combined with aspirin and non-steroidal anti-inflammatory analgesics (including mefenamic acid, salicylic acid, etc.) can inhibit platelet function and induce gastrointestinal ulcer bleeding.

4. Heparin combined with dipyridamole and dextran can inhibit platelet function.

5. The combination of heparin and adrenocortical hormone, adrenocorticotropic hormone, etc., can easily induce gastrointestinal ulcer bleeding.

6. Other drugs such as itanilide, tissue plasminogen activator (t-PA), urokinase, streptokinase and heparin may increase the risk of bleeding.

Heparin poisoning

Heparin (heparin) is a mucopolysaccharide sulfate with a relative molecular weight of 6000 to 20,000. Low-molecular-weight heparin is made by de-aggregating standard heparin through physical separation, chemical lysis, and synthesis. It is mainly used for the prevention and treatment of thrombosis and embolism, and for the treatment of disseminated intravascular coagulation (DIC) for various reasons, as well as other anticoagulation in vivo and in vitro, such as myocardial infarction and pulmonary, brain, peripheral vascular embolism, extracorporeal circulation, etc.

Heparin is not absorbed orally. After intravenous injection, the effect is rapid and the duration is short. The plasma half-life is 1.5 to 2.5 hours, and the effect disappears in 3 to 4 hours. When the liver and kidney function of the patient is poor, the retention time in the body is prolonged. Heparin has a strong anticoagulant effect in vivo and in vitro. It mainly blocks the activation of coagulation factors a, Xa, a, and a, blocks the formation of thrombin by prothrombin, and blocks platelet aggregation to achieve anticoagulant effects.

Low molecular weight heparin has a relative molecular weight of 3000 to 7000. It can inhibit coagulation factor a, a, a, Xa under the mediation of heparin cofactor and antithrombin III. It has strong affinity with antithrombin III. Endothelial cells mediate the effects, promote the release of tissue plasminogen activators and prostacyclin-like substances, and enhance fibrinolytic activity. Overdose can easily lead to bleeding.

Clinical manifestation

If the application dose is too large, spontaneous bleeding can occur, such as bleeding on the skin, mouth and nasal mucosa, joints, and internal organs. A large amount of bleeding can lead to shock, and even bleeding of important organs such as the brain, spinal cord, and adrenal glands. Those who are allergic to heparin may develop acute rhinitis, severe asthma, urticaria, conjunctivitis, angioedema, fever, etc., with occasional anaphylactic shock. In addition, some patients may still have vasospasm reactions, which are manifested as pain, ischemia, or bruising in the affected limb; or paresthesia in the extremities; systemic vasospasm, epidermal congestion, headache, and shortness of breath. Osteoporosis and spontaneous fractures may occur when treated for more than 4 months. Occasionally hair loss, local intramuscular pain, fat atrophy, and skin necrosis. A few patients may have arrhythmias. Very few patients develop heparin-based antiplatelet antibodies after heparin is used, which can cause severe platelet deficiency and bleeding.

Laboratory inspection

1. Thrombocytopenia.

2. Prolonged coagulation time, up to 20 ~ 30min.

3. Prothrombin time prolonged, reaching more than 2 times normal.

4. Hyperkalemia.

diagnosis

The main points of diagnosis of heparin poisoning are:

1. Medical history: A clear history of heparin application.

2. With clinical manifestations of heparin poisoning.

3. Laboratory inspection confirmed.

treatment

The main points of treatment for heparin poisoning are:

1. Stop medication immediately after symptoms of poisoning.

2. If there is obvious bleeding tendency, protamine should be added to physiological saline intravenously. The dosage can be given in the ratio of 1: 1 according to the last heparin dosage, that is, 1 mg of protamine is used for 1 mg of heparin. The injection time should be more than 10min to avoid hypotension. Transfusion of fresh blood or coagulation factors if necessary. Allergic patients use antihistamines or adrenocortical hormones. Active rescue should occur when anaphylactic shock occurs. Visceral bleeding should be treated accordingly, such as gastrointestinal bleeding, Yunnan Baiyao can be taken orally ^[3] .

Heparin expert review

Heparin is a sodium glucosamine sulfate extracted from the intestinal mucosa of pigs. It is a mucopolysaccharide and exerts anticoagulant effects by activating antithrombin III (AT-). It has effects on all three stages of the coagulation process. It has anticoagulant effect in vivo and in vitro, which can prolong coagulation time, prothrombin time and thrombin time. It is not absorbed orally, it is well absorbed subcutaneously and intramuscularly, and the anticoagulant effect is better after intravenous injection ^[2] .

Clinical application of heparin

1. Heparin is the drug of choice that needs to achieve rapid anticoagulation. It can be used for surgical prevention of thrombosis and anticoagulation therapy for pregnant women. For patients with acute myocardial infarction, heparin can be used to prevent venous thromboembolism in patients and prevent large Arterial embolism occurred in patients with anterior wall transmural myocardial infarction.

2. Another important clinical application of heparin is to maintain the extracorporeal circulation of the blood during cardiac, surgical and renal dialysis.

3. For the treatment of disseminated intravascular coagulation (DIC) caused by various reasons, but also for the treatment of glomerulonephritis, nephrotic syndrome, rheumatoid arthritis, etc.

Heparin exists naturally in mammalian mast cells and neutrophils. In the past decades, heparin raw materials used in European and American countries were mainly extracted from bovine lung, bovine intestine or porcine small intestine mucosa. However, due to the spread of "mad cow disease" in recent years, and studies have shown that bovine-derived heparin is twice as likely to cause side effects such as thrombocytopenia as pig-derived heparin, many countries are more inclined to use pig-derived heparin.
Standard heparin: The first heparin used in clinical practice is called standard heparin, unfractionated heparin or unfractionated heparin. It is mainly used clinically for anticoagulation and antithrombotic therapy, and it can treat diffuse intravascular coagulation and Thrombosis, and anticoagulant treatment in hemodialysis, extracorporeal circulation, catheterization, microvascular surgery and other operations. At the same time, clinical applications and studies have shown that standard heparin also has a variety of other biological activities and clinical uses, including anti-inflammatory, anti-allergic, hypolipidemic, anti-atherosclerosis, anti-medium membrane smooth muscle cell (SMC) proliferation, anti-virus, Anti-cancer effects.
Low molecular weight heparin: In order to reduce the side effects of heparin which are prone to bleeding, thrombocytopenia, and osteoporosis, low molecular weight heparin was first developed in Europe in the late 1980s. A large number of clinical studies have confirmed that low-molecular-weight heparin has the advantages of strong antithrombotic effect and small side effects. .
Because heparin realizes the unique mechanism of anticoagulant and antithrombotic effect by interfering with several links in the coagulation process, its clinical application value is still under continuous research and development. With the continuous increase of research and development, heparin will continue to develop new indications, which will also become an important development space for heparin products in the future.

Heparin is widely used clinically to prevent and treat thromboembolic diseases, early treatment of diffuse intravascular coagulation, and anticoagulation in vitro. Clinical application and research show that in addition to its anticoagulant effect, heparin also has a variety of biological activities and clinical uses. This is briefly described below.

Angina pectoris

Combined with aspirin for unstable angina pectoris To observe the risk of myocardial infarction (MI) and death in patients with unstable angina pectoris treated with aspirin plus heparin and aspirin alone, patients were randomly divided into aspirin plus heparin group and aspirin alone group . Studies have reported the incidence of myocardial infarction and death. In patients with unstable angina pectoris who received aspirin plus heparin compared with aspirin alone, the total relative risk (RR) of MI or death during randomized treatment was 0.67 [95% confidence limit (CI), 0.44 to 1.02] . Comparing aspirin plus heparin to patients receiving aspirin alone, the total RR for the secondary endpoint was: repeated ischemic pain 0.68 (95% CI, 0.40 to 1.17), MI or death 0.82 2 to 12 weeks after random treatment (95% CI, 0.56 to 1.20); recanalization of the vessel 1.03 (95% CI, 0.74 to 1.43); major bleeding 1.99 (95% CI, 0.52 to 7.65). None of the test results found significant statistical heterogeneity. Conclusion: Patients with unstable angina pectoris have a 33% lower risk of MI or death than those who receive aspirin plus heparin. There is sufficient evidence that most patients with unstable angina pectoris should receive both aspirin and heparin.

Crystal epithelial cells

Inhibition of lens epithelial cell proliferation or capsular opacification is the primary complication of extracapsular cataract extraction. Heparin can inhibit the proliferation or migration of lens epithelial cells. The proliferation, migration, and fibrosis of lens epithelial cells play an important role in the occurrence of posterior capsule opacification. At present, the prevention of opacity of the posterior capsule mainly involves the complete removal of lens epithelial cells and cortex during surgery, and implantation of lenticular or kyphotic posterior chamber intraocular lenses. Its treatment mainly depends on laser posterior capsulotomy. Studies have found that the migration of crystal epithelial cells by Dispase (a neutral protease), edetic acid (EDTA), heparin, and the antimetabolites 5-fluorouracil, daunorubicin, colchicine, and mitomycin, and ( Or) Proliferation is inhibited. The proliferation or inhibitory effect of various cytokines on lens epithelial cells is also remarkable.

Dural sinus thrombosis

In recent years, foreign countries have made some progress in the treatment of dural sinus thrombosis with heparin and tissue plasminogen activator (tPA). Tissue plasminogen activator (tPA) is safer than urokinase, and combined with small molecule heparin is more effective than heparin alone.

Ulcerative colitis

There have been many studies on immune abnormalities, infections and oxygen free radical damage in the pathogenesis of ulcerative colitis (UC). In addition, studies have found that in patients with ulcerative colitis, WF, anticardiolipin antibodies, prothrombin fragments 1 + 2, thrombin antithrombin complex, D-dimer, tissue factor pathway inhibitors, platelets Prethrombotic status indicators such as protein are significantly different from healthy controls, and reports of successful treatment of refractory UC with heparin suggest that microthrombosis may be one of the important pathogenesis of UC.

Acute cerebral infarction

In order to observe the clinical efficacy of low molecular heparin in the treatment of acute cerebral infarction and its effect on hemodynamic parameters, 30 patients with acute cerebral infarction were treated with low molecular heparin (LMWH) (observation group), and patients with acute cerebral infarction were treated conventionally. Thirty patients were used as the control group (control of blood pressure, application of calcium antagonists, removal of free radicals, application of brain metabolism activators, etc.). Results: The total effective rate in the observation group was 90%, which was significantly higher than 63.3% in the control group (P <0.05). Before and after treatment, the neurological deficit score was significantly lower in the observation group than in the control group (P <0.05). After treatment, the blood viscosity, plasma specific viscosity, reduction specific viscosity, erythrocyte sedimentation rate, and erythrocyte sedimentation equation K values of the observation group were significantly lower than those before treatment (P <0.01). Conclusion: Low-molecular-weight heparin is safe and reliable in the clinical application of patients with acute cerebral infarction, and has strong anticoagulant, antithrombotic and blood viscosity reducing effects.

Severe burn

Severe burns are complicated by multiple organ dysfunctions throughout the body, with a high mortality rate. Scars and contractures often remain after wound healing, with varying degrees of deformity or dysfunction. There have been many clinical and animal experimental studies on the use of aminodextran (GAG) in the treatment of burns, and its anticoagulant, anti-infection, and vascular regeneration mechanisms have been initially revealed. These mechanisms are conducive to tissue repair and re-epithelialization. GAG includes heparin, dermatan sulfate, keratin sulfate, chondroitin sulfate 4, 6 and hyaluronic acid. Heparin contains a large number of sulfate groups and is the most acidic GAG. It is mainly given by parenteral route, topical application and inhalation. Medicine is also made into gel pills for oral administration, or combined with synthetic skin, or as raw materials for synthetic skin. Heparin treatment of burns can relieve pain, anticoagulation, inhibit inflammatory response, promote blood vessel regeneration, restore local blood supply, and can affect collagen synthesis and degradation. After the wound is healed, the skin is smooth and scars and scar contractures are reduced. Heparin can also protect the intestinal barrier function and reduce the occurrence of bacterial translocation; protect lung tissue and improve lung function; protect and improve kidney function; improve body immunity and prevent infection. Local application of heparin is an effective method for treating burns.

other

In the application of heparin in tumors: the anti-cancer mechanisms of heparin include enhancing immune system function, anti-proliferation, and inhibiting metastasis of tumor cells. Heparin can be used in combination with steroids to treat tumors. It can also be used in the treatment of radiation syndromes and tumor complications. The effects of heparin on the inflammatory process: the relationship between heparin and mast cells, and heparin's inhibition of leukocyte adhesion to vascular endothelium and subsequent migration to tissues have shown that heparin has an effect on the mechanism of inflammation.

Heparin test

APTT

APTT remains one of the options for monitoring UFH. It is very simple, fast and cheap project. However, it is difficult to standardize. The APTT test requires that all proteins in the entire coagulation waterfall are intact, so that heparin levels can be accurately measured. Patients with lupus anticoagulant or antiphospholipid syndrome usually have elevated APTT and they must be monitored using a heparin test. In addition to factors with different levels of coagulation factors, reagents and instruments can affect their sensitivity to heparin, leading to a final difference of up to four times between results in the laboratory. The International Society for Thrombosis and Hemostasis and the Standardization Committee (ISTH SSC) attempted to establish a standard method, similar to the ISI used in the PT experiment, to establish a correction factor for the APTT trial. However, due to the diversity of phospholipids, activators and instruments, this work has only achieved a little progress. ISTH recommends that each APTT detection system should use the recommended method to calibrate the anti-Xa activity of heparin and obtain the corresponding APTT monitoring range.

Protamine sulfate neutralization test

The test is based on the principle of UFH, a highly negatively charged molecule, protamine sulfate, a positively charged protein, and neutralization. Protamine sulfate with different concentrations was added to the plasma, and then thrombin was added to measure the clotting time. Returning thrombin coagulation time to normal protamine sulfate concentration is considered to be the concentration of heparin, and this process is only used for UFH.

Detection of anti-Xa activity

The principle of the chromogenic substrate method to detect the anti-Xa activity of heparin is the same: heparin in the sample forms a complex with AT, which inhibits the excessive addition of factor Xa. The measurement of the remaining factor Xa activity is performed by its interaction with specific substrates to release pNA. This response is inversely proportional to heparin concentration. The only difference is the reaction incubation time, the buffer used for dilution, the substrate, and whether or not external AT is added. Dextran sulfate in the buffer can reduce the effects of PF4.

One-step detection

One-step measurement of heparin makes testing simpler and reduces time. This method does not add exogenous AT.

Detection is based on the principle of competition suppression. Xa was added to the plasma to mix with the substrate, and immediately there were 2 reactions at the same time: the substrate was hydrolyzed by Xa and Xa was inhibited by the heparin-AT complex. Once the reaction reaches equilibrium, the pNA released from the substrate is inversely proportional to the heparin concentration in the plasma to be measured. In this test, no exogenous AT was added and it was completely dependent on the amount of AT in the patient's plasma. This represents the patient's true heparin functional response. Patients with AT levels between 35% and 130% will not be affected by heparin concentrations.