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Congenital thrombophilia

Factor V Leiden mutation = APC resistance
Thrombophilia is a condition in which the blood exhibits increased coagulability, tending to the occurrence of thrombosis.

What is the coagulation system?
Our coagulation system has various components. The blood contains certain proteins that are formed in the liver and enable the blood to coagulate, or clot. They are called clotting factors. When the body has been injured in some way, these factors step in and produce fibrin. Fibrin joins with thrombocytes (platelets) in the blood to form a thrombus, or plug (Fig. 1).

 

The coagulation system needs to be regulated as it would otherwise perpetually produce too many small thrombi. The clotting factors have what are termed antagonists: anti-coagulation agents that are able to cleave (split) certain of them. Following cleavage of the clotting factors by anticoagulants, they can no longer form fibrin. The system of clotting factors and their antagonists is in a delicate balance. If the clotting factors predominate or there is a deficit of inhibitors, the equilibrium shifts towards increased thrombus formation, with its consequent risk to the patient.

The make-up of clotting factors may be changed such that they are no longer cleaved by their antagonists, or are cleaved only slowly. This is what happens in factor V Leiden mutation.

 

Where does the name Leiden come from?
This thrombophilia was first described in 1994 at the University of Leiden in the Netherlands

What has changed?
The mutation (an exchanged protein) is located in an important blood clotting factor (factor V). As a result of this mutation, an important intrinsic anticoagulant (activated protein C = APC) can cleave factor V only slowly, as the factor V cleavage site has changed. The coagulation equilibrium shifts towards greatly increased coagulability of the blood, which is termed “hypercoagulability”.

Factor V is thus rendered resistant to cleavage by APC. “APC resistance” is a term used to denote this state. APC resistance is therefore due almost entirely to this qualitative change in factor V, which is genetically pre-determined. If the result of the APC resistance test is too low, it must always be followed by mutation analysis in the factor V gene using a technique of molecular biology. (Fig. 2 and Fig. 3.)

 

 

What was that about “genetically pre-determined”?
Humans have 46 chromosomes in each cell nucleus. They carry genetic information. There are 22 sets of paired chromosomes, half of each pair coming from the mother and the other half from the father; plus two sex chromosomes that determine whether we are male or female (male: 1 X chromosome + 1 Y chromosome; female: 2 X chromosomes). (Fig. 4)

 

The defect is found on the No. 1 chromosome. As all human chromosomes come in pairs, either one No. 1 chromosome can be affected (heterozygous carrier, Fig. 5) or both No. 1 chromosomes (homozygous carrier, Fig. 6). APC resistance is a genetic defect affecting males and females equally (autosomal dominant trait). First degree blood relatives (children, parents, brothers and sisters) have a 50% chance of also carrying the trait. A familial investigation is therefore often useful, especially an investigation of the female family members prior to any planned hormone therapy or pregnancy; or into female family members suffering from thrombosis, as a prelude to the institution of appropriate therapy.

As thrombosis usually first occurs after puberty, children should only be examined in late kindergarten age or school age, and before any planned operations, when it is easier to collect blood samples.

What are the implications for me?
Heterozygous carriers have a five to ten-fold increased risk of thromboembolism, homozygous carriers an 80-fold risk. In risk situations, which here means in particular when a person is taking oestrogens in tablet form (the pill, certain menopausal preparations) and in pregnancy, the chance of thrombosis occurring again rises sharply. Heterozygous female carriers on the oestrogen-containing pill have a 35-fold increased risk. Further risk situations are operations, lengthy confinement in bed (immobilization), leg dressings and casts (e.g. plaster casts, Unna’s paste dressing, splints) long flights and car journeys where leg space is restricted, malignant diseases, diseases associated with fluid loss (diarrhoea, etc.).

Also described is an increased rate of pregnancy complications, so that pregnant women require special monitoring and, in some cases, heparin given by injection.

Certain drugs can also raise the risk of thrombosis, such as cortisone in tablet form, and certain antihormone preparations (e.g. Tamoxifen®) etc.

What is the treatment?
The gene defect itself cannot be treated. Symptomless carriers without a history of thrombosis do not need long-term medication, though they should be made aware of the aforementioned risk situations and be provided with sufficient heparin injections. Through this means it is possible to prevent thrombosis with a probability bordering on certainty, as thrombosis is rare outside the aforementioned risk situations.

Following thrombosis, administration of an anticoagulant drug (Sintrom®, Coumadin®, Marcumar®) is recommended. Treatment should last for 6-12 months depending on the severity of the condition. If, however, there have been recurrent thromboembolic events or there is a history of very severe conditions such as pulmonary embolism, or phlebothombosis in the brain or gut, life-long therapy with anticoagulants is recommended. Decisions must always be made from case to case, taking a number of points into consideration. Combined thrombophilias are no rarity and many patients have several coagulatory changes that will decide what treatment they receive.

The pill and other oral oestrogen preparations should be discontinued, except when Marcumar therapy is required anyhow, in which case the hormone preparation can continue to be taken.

Treatment with aspirin, for instance, is insufficient in the acute phase following thrombosis or as prophylaxis in risk situations.

Administration of heparin should also be discussed when the person is due to travel by air for more than 4 hours at a time. Please discuss these points with your family doctor. Patients already on oral anticoagulants do not require heparin additionally.

What about when planning to have children?
Nowadays the presence of factor V Leiden is no longer an obstacle to planned pregnancy.

Women who have already had thrombosis receive low-molecular-weight heparin once daily as soon as their pregnancy is confirmed. Women learn to inject heparin subcutaneously into the fleshy fold of the abdomen. This is not difficult. Heparin injections must be continued for up to six weeks after delivery, as thrombosis often occurs in the immediate post-delivery phase. Heparin does not harm the child as it does not cross the placenta.

The risk of bleeding is not increased during delivery.

Breastfeeding is also unproblematic as heparin is not secreted in the mother’s milk.

Women with factor V mutation without a history of thrombosis need only to be monitored during their pregnancy and be given heparin prophylactically during confinement.

Is the mutation rare?
No! In Europe about 6-8% of the population carries the mutation. This explains the relatively high incidence of vascular disease among Caucasians. In other populations (Asiatic, African) this mutation does not occur. When a genetic change occurs in more than 2% of the population, the term used is “polymorphism”.

A more accurate name for the mutation would therefore be “factor V polymorphism”.

Does it have only disadvantages?
No, not according to many studies! It has been shown that carriers of factor V mutation lose less blood following injury, during surgery and in childbirth. This has possibly been an evolutionary advantage, which explains why the trait is so widespread. So the mutation has its positive side, too!

What can I do?
There is unfortunately no dietary recommendation that can influence coagulation for the better. Over-weight persons, however, should aim to eat a healthy, vitamin-rich diet in order to lose weight. Regular exercise and sports are highly recommended for thrombosis prophylaxis (30 minutes stamina exercise 3 times a week), also in persons who have had thrombosis. When the thrombosis was recent, there should of course be a three-month pause before such activities are taken up.

Where there is a history of thrombosis, the prescribed treatment regime should be adhered to in order to prevent a recurrence. The wearing of compression hosiery is definitely recommended, as it can minimize the risk of a common unpleasant complication: so-called post-thrombotic syndrome (swelling, skin changes, ulcers). Optimally, the stockings should be worn regularly for up to 2 years following thrombosis. Elevating the legs in the evening is also a useful measure. Exposure of the legs to heat, especially prolonged exposure to the sun, should be avoided. Some patients, on the other hand, find saunas to be a pleasant experience on account of the alternating warmth/coldness. The thing to do is try it for yourself.

Dr. med. Hannelore Rott, specialist in Transfusion Medicine, Königstr. 53, 47051 Duisburg/Germany (2005)