Ask Your Question - Anticoagulation
1. To which classification does Innohep® belong?
Innohep® is an injectable anticoagulant belonging to the following therapeutic groups....
2. Should the air bubble be removed before injection of the prefilled DVT prophylaxis syringes?
It is not necessary to remove the air bubble from the prefilled syringe before the injection as injection of the small air bubble is quite harmless.
3. What is the recommended injection site for Innohep®?
We recommend that Innohep® should be injected into the abdominal fat layer.
4. What are the registered brand names of tinzaparin?
Worldwide the LEO registered brand name for tinzaparin is innohep®.
5. Should used Innohep® multidose vials be stored in a refrigerator?
Not necessarily.
6. What is the shelf-life of an Innohep® multidose vial after the first perforation?
We recommend that the contents of the Innohep® multidose vials should be used within 14 days after the first perforation of the septum, provided correct handling of the vial when the solution is withdrawn into a syringe.
7. Can Innohep® syringes which has been frozen by accident still be used after thawing?
Yes - Innohep® syringes can still be used, but it depends on the temperature at which the syringes were frozen.
8. Anticoagulation in haemodialysis explained
The process of coagulation in the body is an important and complex issue.
9. The dialysis circuit
Access to the bloodstream in haemodialysis In order to initiate haemodialysis treatment, access to the patient's bloodstream must be gained by one of the following routes....
10. Role of anticoagulation in haemodialysis
Why does coagulation occur during haemodialysis? Under physiological conditions the coagulation process - the coagulation cascade - is inititaed by blood coming into contact with collagen in a damaged blood vessel wall.
11. Anticoagulants: unfractionated heparins versus low molecular weight heparins
How do heparins work? Heparin is, in fact, a family of naturally occuring anticoagulants made up of many molecules, all with different lengths.
12. Innohep® in haemodialysis
Wide range of presentations - Innohep® (tinzaparin sodium) is available in several presentations to facilitate convenient dosing...
13. REFERENCES
14. GLOSSARY
QUESTION
1. To which classification does Innohep® belong?
ANSWER
Innohep® is an injectable anticoagulant belonging to the following therapeutic groups:
Therapeutic group (IMS): B01 B2 (Low molecular weight heparin)
Therapeutic group (ATC): B01 AB (Antithrombotic agents - Heparins)
BACKGROUND
In markets where LMWH is not launched or only recently has been introduced, the product can be found in B01 B1 (conventional heparin).
QUESTION
2. Should the air bubble be removed before injection of the prefilled DVT prophylaxis syringes?
ANSWER
It is not necessary to remove the air bubble from the prefilled syringe before the injection as injection of the small air bubble is quite harmless.
Avoiding the removal of the air bubble saves nursing time and helps avoid injection fluid on the tip of the needle, which might cause pain during injection.
BACKGROUND
During the filling of the prefilled syringes a small air bubble - 5 mm - is included in all syringes to facilitate control of filling.
The air bubble corresponds to less than 0.1 ml air in the prefilled synringes for DVT prophylaxis.
Even though - like other LMWH companies - we recommend not to remove the air bubble, many nurses still discuss this matter but there is a consensus emerging, helped by the heparin suppliers, that this is not necessary.
QUESTION
3. What is the recommended injection site for Innohep®?
ANSWER
We recommend that Innohep® should be injected into the abdominal fat layer.
Administration should be avoided within 5 cm of the umbilicus and should be alternated between the left and right side.
A skin fold should be held between the thumb and forefinger and the entire length of the needle inserted at an angle of 90 degrees into the skin fold. The skin fold should be held during the injection and the solution slowly and fully injected.
It is recommended not to pull back the syringe plunger to check for blood - aspiration - as excessive needle manipulation may increase the risk of haematoma.
Other sites of injection can be used without problems. Some doctors/nurses prefer to inject into the femur in connection with major abdominal surgery.
The perpendicular injection - 90 degrees - should be used to avoid superficial injections which might cause bruising. Some companies have previously recommended an angled injection technique - 45 degrees - employing longer needles.
BACKGROUND
Some of the reasons supporting the recommendation of injections in the anterior abdominal wall are the available depth of subcutaneous fat and a large surface area over which injections can be rotated.
REFERENCES
31. Fahs PSS & Kinney MR, Nurs Res 1991;40:204-207.
32. Patel KS., BJCP Spring 1991;45:26-27.
33. Wooldridge JB & Jackson JG, Heart & Lung 1988;17:476-482.
QUESTION
4. What are the registered brand names of tinzaparin?
ANSWER
Worldwide the LEO registered brand name for tinzaparin is innohep®.
In some markets tinzaparin is available as Logiparin® by Novo Nordisk and the sales of tinzaparin might be continued by LEO under this brand name, if the brand is established.
The brand names 'Lowhep' and 'Brevihep' are registered in some European countries.
BACKGROUND
Tinzaparin was developed in cooperation between LEO Pharma and Novo Nordisk. This development cooperation resulted in a licence agreement according to which LEO has the rights to produce and market tinzaparin worldwide, with the exception of Japan.
QUESTION
5. Should used Innohep® multidose vials be stored in a refrigerator?
ANSWER
Not necessarily.
The contents of the Innohep® multidose vials should be used within 14 days after the first perforation of the septum, provided correct handling of the vial when the solution is withdrawn into a syringe.
The recommended storage temperature is 15°C - 25°C (59°F - 77°F) (room temperature).
BACKGROUND
The Innohep® multidose vials contain benzyl alcohol as a preservative.
QUESTION
6. What is the shelf-life of an Innohep® multidose vial after the first perforation?
ANSWER
We recommend that the contents of the Innohep® multidose vials should be used within 14 days after the first perforation of the septum, provided correct handling of the vial when the solution is withdrawn into a syringe.
The recommended storage temperature is 15°C - 25°C (59°F - 77°F) (room temperature).
BACKGROUND
The Innohep® multidose vials contain benzyl alcohol as a preservative.
QUESTION
7. Can Innohep® syringes which has been frozen by accident still be used after thawing?
ANSWER
Yes - Innohep® syringes can still be used, but it depends on the temperature at which the syringes were frozen.
We have data for the 20,000 tinzaparin syringe (without conservation) - which shows that the solution can stand/tolerate temperatures from -20oC to +25oC.
The recommended storage temperature is, however, still 15oC to 25oC (room temperature) and you should never encourage your customers to freeze the syringes.
QUESTION
8. Anticoagulation in haemodialysis explained
ANSWER
The process of coagulation in the body is an important and complex issue. Consequently, understanding anticoagulation and its role in haemodialysis is also complicated. The following questions offers you an overview of the dialysis circuit as well as easy-to-understand background information on anticoagulation in the body.
QUESTION
9. The dialysis circuit
ANSWER
Access to the bloodstream in haemodialysis
In order to initiate haemodialysis treatment, access to the patient's bloodstream must be gained by one of the following routes:
- An A/V (arteriovenous) fistula.
- A graft made of synthetic material.
- A central venous catheter.
The most commonly used access is an A/V fistula made by a vascular surgical operation in which an artery and a vein are connected. This generates an arterial flow in the vein connected to the artery. After a so-called "maturing" period of at last 3 weeks, the vein develops a thicker vascular wall and the bloodflow increases. This means that the vein can stand the repeated cannula punctures that take place during dialysis.
The arterial and the venous side of the extracorporeal circuit
The "arterial side" and the "venous side" are expressions often used in connections with haemodialysis treatment. These phrases have nothing to do with the patient's arteries and veins. They are used by the dialysis personnel to refer to the blood's route through the tubes and dialysis filter during treatment. The "arterial" side denotes the extracorporeal circuit before the filter and the "venous" side is the extracorporeal circuit after the filter.
Consider the arterial side covering the distance from the first cannula's site of entry in the patient to the filter; and the venous side being from the filter back to where the second cannual is inserted in the patient.
Dialysis circuit (graph) (Note: click on the bottom right corner to expand photo)
KEY POINTS
Bloodflow and contact with the dialyser membrane cause clotting.
Platelets become activated and Factory XII initiates the coagulation cascade.
Anticoagulation is needed in haemodialysis to prevent obstruction of the extracorporeal circuit (ECC).
QUESTION
10. Role of anticoagulation in haemodialysis
ANSWER
Why does coagulation occur during haemodialysis?
Under physiological conditions the coagulation process - the coagulation cascade - is inititaed by blood coming into contact with collagen in a damaged blood vessel wall. During haemodialysis, two conditions can precipitate clotting:
Contact of blood with the foreign surface of the dialyser membrane (similar to contact with collagen).
Bloodflow conditions within the dialyser circuit.
Activated platelets and Factor XII, both present in blood, bind to the dialyser membrane and initiate the clotting mechanisms.
Anticoagulation is routinely performed in haemodialysis to prevent the aggregation of clotting agents such as fibrin and platelets that could build up within the artificial kidney and obstruct the extracorporeal circuit (ECC). If haemodialysis was performed without anticoagulation it would be necessary to flush the system frequently with saline and introduce a high bloodflow to avoid recurrent blood clotting.
The ideal anticoagulant should prevent clotting, be simple to use and should not increase the risk of bleeding complications.
The coagulation cascade
Haemostasis is the physiological mechanism that prevents bleeding following vascular damage. When a blood vessel is damaged, a cascade of events occurs that leads to the formation of a fibrin clot, which forms a protective layer of "plug" preventing bloodflow while the healing process takes place. The coagulation cascade consists of a number of clotting factors and co-factors.
Although haemostasis is essential for survival, the formation of a thrombus (an unwanted blood clot) can be life-threatening.
Platelets play a major role in the formation of a fibrin clot. They become activated or "sticky" after vascular injury and release pro-coagulant substances. This encourages other platelets to "stick" and provides a surface for certain clotting factors to interact (IX and VIII together with Factors V, X, and II) (Bartels, 2000; Walsh, 1994; De La Cadena, 1994). Current knowledge of the cascade is comprehensive but by no means conclusive.
The coagulation cascade is a complex sequence of events that terminate in the formation of a fibrin clot.
There are three pathways that interact to form the coagulation cascade:
Instrinsic pathway.
Extrinsic pathway.
Common pathway.
Each pathway is made up of a number of inactive clotting factors that become activated under certain conditions, moving the cascade forward. Activation of one, inert factor (e.g. XII) into its active form (e.g. XIIa - "a" denotes "activated") then catalyses the conversion of the next inactive factor into its active form, which catalyses formation of the next, so forth, giving rise to the cascade that culminates in the production of large amounts of fibrin (figure - click on the bottom right corner to expand graphic).
KEY POINTS
The coagulation cascade is a complex pathway with many interacting "factors"
An endogenous anticoagulant substance, antithrombin III (ATIII), prevents clotting by inhibiting certain stages of the coagulation cascade. This is a target for anticoagulants such as heparin and LMWHs.
During dialysis, Factor XII binds to the dialysis membrane and initiates the cascade, which quickly results in the production of fibrin strands that form the basis of a thrombus.
Coagulation inhibitors
Healthy vascular endothelium produces antithrombotic substance that prevent clotting. One inhibitor of the coagulation cascade is antithrombin III (ATIII). This inhibits thrombin (IIa) and Factor Xa. Another important physiological anticoagulant is tissue factor pathway inhibitor (TFPI), which inhibits coagulation by altering the Factor VIIa-tissue factor complex and enhancing the effect of heparins. When heparins are injected, TFPI is released form the endothelium and can contribute approximately one-third of the antocoagulant effect of the heparin (the remaining two-thirds being provide by ATIII) (Sandste, 2000). Table (click right bottom to expand graphic).
QUESTION
11. Anticoagulants: unfractionated heparins versus low molecular weight heparins
ANSWER
How do heparins work?
Heparin is, in fact, a family of naturally occuring anticoagulants made up of many molecules, all with different lengths.
Heparan sulphate, the naturally occurring heparin in humans, is released by healthy endothelium to prevent the formation of unwanted blood clots.
Heparins mainly inactivate the coagulation cascade in two places: Factor IIa and Factor Xa.
They do this by binding to ATIII via a unique "site" on the heparin molecule.
All heparins bound to ATIII can inactivate Xa, and longer heparin chains can bind also to IIa to cause inactivation.
Unfractionated heparin
Unfractionated heparin (UFH) has a range of different molecular weights from 5000 to 30,000 Da (Choay, 1989). For clinical use, mixtures of UFHs are extracted from bovine lung or porcine intestinal mucosa.
Mechanism of action of UFH
UFH inhibits the coagulation cascade at two stages: Factor IIa and Factor Xa (figure - click on bottom right to expand graphic). UFH binds to ATIII, via a unique site on the UFH molecule, and accelerates ATIII's inactivation of Xa, in addition to IXa, XIa and XIIa (figure - click on bottom right to expand graphic). UFH can also prevent fibrin formation as it contains molecules long enough to bind to ATIII and IIa (figure - click on bottom right to expand graphic). Therefore, the shorter heparin chains in UFH generate anti-Xa activity whilst the longer chains in UFH can generate anti-IIa activity. However, not all UFH molecules have an anticoagulant effect; this is because only 30% of UFH molecules possess the unique site.
After binding to ATIII and IIa (or Xa) UFH is released from the complex to act on other ATIII molecules.
The administration of UFH also stimulates the release of TFPI, which increases the anticoagulant effect.
KEY POINTS
UFH and LMWH amplify ATIII, which inactives thrombin (IIa) and Factor Xa, preventing thrombus formation.
Both UFH and LMWH have a unique site on the molecule that binds with high affinity to ATIII.
Pharmacokinetic and pharmacodynamic profile of UFH
UFH is administered either subcutaneously (SC) or intravenously (IV), since it is not absorbed in the gastrointestinal tract due to its size. When UFH is given IV, the start of anticoagulant activity is almost immediate. However, UFH binds strongly to plasma proteins, which can affect its bioavailability (Haines, 1995; Hirsh, 1992). When UFH is given SC, systemic absorption is slow, enabling certain cells to metabolise heparin quickly. It is on