Blood Disorders

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Questions Received:

  1. We are looking for information on how to thin blood. The patient is on dialysis and also has a heart condition. At the moment we are discarding lines of dialysis twice weekly and is not coming down. Is there any other way we can thin the blood as it is too thick...

  2. A friend of mine is taking a blood thinner, coumadin, to thin his blood, but it is not working. My question is why is it not working? Is the blood really that thick?

  3. What is the cause of blood platelet reduction?

  4. I have been told I have slightly enlarged red blood cells - can you advise me what causes this?

  5. What is antithrombin III deficiency?

  6. Could you send me some information on Factor V Leiden positive? It is a rare blood disorder. My cousin has this disorder, but now her hair is falling out. She has been told it may never grow back. Surely there must be something that can be done?

  7. What is an INR test in association with Warfarin?

Responses:

We are looking for information on how to thin blood. The patient is on dialysis and also has a heart condition. At the moment we are discarding lines of dialysis twice weekly and is not coming down. Is there any other way we can thin the blood as it is too thick...

21st May 1999

It would appear that the patient’s blood is clotting when it comes into contact with the materials from which the dialysis equipment is made. Normally a system involving extracorporeal circulation (circulation of blood outside the body) requires the administration of anticoagulants to prevent this happening. Heparin is generally the preferred anticoagulant and is given as a loading dose at the commencement of dialysis with smaller doses given during the procedure. For most people this is an effective solution to the problem of blood clotting within the dialysis lines.

However, there is now clinical and experimental evidence that heparin on its own does not control platelet activity effectively, with the result that blood clotting can still occur in some people undergoing dialysis. Fortunately, there are now several ways of overcoming this problem. A promising technique is to temporarily inactivate the platelets by administering prostaglandins, usually in conjunction with the heparin (Addonizio et al, 1981; Langenecker et al, 1994; Kozek-Langenecker, 1999). This approach also reduces the risk of the bleeding complications associated with heparin use. Newer anticoagulants such as dermatan sulfate and hirudin have been used in dose-finding studies in haemodialysis, although long-term experience with these substances is lacking (Beijering et al, 1997). Some patients are not able to tolerate heparin at all, and for them it is necessary to use anticoagulants such as argatroban, which is a thrombin inhibitor (Matsuo, Koide, and Kario, 1997).

Presumably a full assessment of the patient's haematological status has taken place and advice from a consultant haematologist obtained. It will be worthwhile to review with the medical team and hospital pharmacist the anticoagulant(s) in use.

References

A friend of mine is taking a blood thinner, coumadin, to thin his blood, but it is not working. My question is why is it not working? Is the blood really that thick?

1st June 1999

Anticoagulants do not "thin" the blood in the sense that paint can be thinned by adding either water or spirit. Coumarin (oral warfarin) reduces the production of clotting factors by the liver either by inhibiting vitamin K or interfering with its resynthesis, and thus reduces the tendency of the blood to clot too readily.

Different people require different dose-levels of anticoagulants when they are being treated for blood clotting disorders. The person’s response depends on the concentration of the anticoagulant reached in the liver. This will be influenced both by the dose administered and the way the drug is absorbed and metabolised by the individual (Grahame-Smith and Aronson, 1992). Fine tuning of the maintenance dosage is often required in the early stages of anticoagulant drug therapy.

Several hours may elapse before the full effect is obtained. This is because the clotting factors already in the blood before treatment begins have quite long half-times (eg: factor VII - 6 h; factor IX - 24 h; factor X - 40 h; factor II - 60 h) and therefore take time to diminish.

The anticoagulant effect of the treatment is monitored by using a clotting test known as the (accelerated) prothrombin time. In this test, tissue thromboplastin is added to a sample of the patient’s blood in vitro. The result is expressed as a ratio (BCR) in which the prothrombin time for clotting to occur is compared to that in a normal person who is not being treated with an anticoagulant (about 12 secs). Alternatively the commercially available Thrombotest reagent may be used, in which case the results are expressed as the percentage of normal prothrombin activity.

Prior to drug therapy a control prothrombin time needs to be established. Then an initial dose of 10 mg warfarin is given daily and the prothrombin time is measured regularly. A change to a maintenance dose occurs when the prothrombin time has changed to a BCR value of about 1.5-2.0 times the control value. The total initial dose required to produce this effect is usually 20-30 mg, but some patients may require more drug as may be the case with your friend. Thereafter a maintenance dose is employed which should aim to keep the BCR in the range of 2.0-4.5. (Warfarin, 3-9 mg daily should normally achieve this.) Loading and maintenance dose schedule tables for anticoagulant administration are available to clinicians to enable them to closely tailor the dose of drug required to the observed BCR values over a period of 4 days, thus minimizing any risk of adverse bleeding which is the major problem with anticoagulant therapy.

When the prothrombin time is stable, then the BCR need only be measured every 2 weeks or less often. If after initial stabilisation a change in dosage is made, then it takes about 5 days for the prothrombin time to stabilise again and dosages should generally not be altered further during that time.

Vitamin K can be used to reverse the effects of warfarin.

Reference

What is the cause of blood platelet reduction?

21st May 1999

(The following information is based largely on Haslett et al, 1999)

A reduced platelet count is called thrombocytopenia and may arise by one of three mechanisms:

The causes of thrombocytopenia include:

The platelets play an important homeostatic role by their ability to:

The normal platelet count is - 150 - 400 x109/L.

Reference

I have been told I have slightly enlarged red blood cells - can you advise me what causes this?

22nd February 2000

Enlarged red blood cells are referred to as macrocytic, and can be either megaloblastic or non-megaloblastic. This distinction depends on whether or not the enlarged cells are derived from megaloblasts, which are precursor cells sometimes found in the bone marrow. The underlying causes are different in each type.

Enlarged red cells derived from megaloblasts are a consequence of a deficiency of vitamin B12 or folic acid. Vitamin B12, also known as extrinsic factor, is present in dietary components such as liver, kidney, milk, eggs, cheese and meats. For adequate amounts of vitamin B12 to be absorbed from the digestive tract, a substance known as ‘intrinsic factor’ must be present also. Intrinsic factor is a glycoprotein first identified by Castle in 1929. It is produced by specialised parietal (argentaffin) cells in the stomach wall. Even if there is adequate vitamin B12 in the diet, a lack of intrinsic factor will result in the person experiencing a B12 deficiency because of their inability to absorb it. The term pernicious anaemia is given to this condition. Pernicious anaemia tends to occur in older people due to the gradual loss of parietal cells, or after major gastric surgery, and as a preventive measure regular intramuscular injections of vitamin B12 (usually in the form of hydroxocobalamin) are administered. The other important substrate for normal red cell production is folic acid, also a member of the B family of vitamins. Folic acid is found in leafy vegetables, cereals, liver, kidney and yeast. As you will have heard, supplementation of folic acid is recommended during pregnancy to meet the extra demands made on the mother's reserves by the baby - this strategy has been shown to reduce the risk of neural tube defects.

Enlarged red cells are not always derived from megaloblasts. For example, an increased rate of red cell production can result in a higher proportion of young red cells in the blood, and these tend to be somewhat larger than normal. And conditions such as hypothyroidism (that means an underactive thyroid gland) and liver disease can also be accompanied by enlarged red cells. In these cases, deficiencies of vitamin B12 and folic acid are not the underlying causes.

Your doctor will be able to determine which, if any, of these situations applies to you and how best to deal with it.

What is antithrombin III deficiency?

5th March 2000

Antithrombin III is a single-chain glycoprotein in plasma usually at a concentration of 112-140 mg/L (Mammen, 1998). Antithrombin is synthesized in liver parenchymal cells, and is capable of neutralizing most of the enzymes generated during activation of the blood clotting cascade including thrombin. Thus it inhibits the clotting process.

A deficiency of antithrombin increases the risk of the widespread formation of blood clots within the circulatory system. The deficiency may be present at birth due to a genetic defect, or it can be induced later in life by a variety of factors (Risberg, 1998).

Congenital

This is an autosomal dominant condition in which there is decreased synthesis of antithrombin or synthesis of a dysfunctional version of the molecule. The incidence is estimated to be 20-50 per 100 000 (Linch, 1990). Affected individuals have functional antithrombin levels of only 40-70% of normal. The disease typically presents with venous thromboses in early adulthood. Thromboses are particularly common after starting the contraceptive pill, during pregnancy or following surgery. Heparin is usually given in the short term, but is less effective here than in other situations since it may may cause the antithrombin level to fall further. For these reasons, antithrombin or fresh frozen plasma are given in the acute stages. Long-term oral anti-coagulants reduce the incidence of recurrent thromboses and the circulatory levels of antithrombin may improve.

Acquired

Acquired anti-thrombin deficiency can occur when there is sepsis or after major trauma and surgery. In such cases, there may or may not be disseminated intravascular coagulation (DIC) (Risberg, 1998). When DIC is present, clotting factors and inhibitors are consumed faster than they can be synthesised, and the low levels of antithrombin increase the risk of multiple organ failure. The administration of antithrombin in these situations can be beneficial (Okajima and Uchiba, 1998). There is evidence that antithrombin promotes the endothelial production of prostacyclin (Nielsen, 1998; Risberg, 1998), which has a marked anti-inflammatory effect. Prostacyclin moderates the activities of neutrophils, monocytes and platelets and inhibits the formation of blood clots.

Antithrombin levels may also fall with severe proteinuria, thereby contributing to the thrombotic tendency in the nephrotic syndrome. Antithrombin synthesis is also reduced in liver disease, but bleeding rather than thrombosis is usually the problem in this situation.

References

Could you send me some information on Factor V Leiden positive? It is a rare blood disorder. My cousin has this disorder, but now her hair is falling out. She has been told it may never grow back. Surely there must be something that can be done?

25th August 2000

Factor V Leiden is the name given to a blood clotting disorder in which there is an increased risk of blood clots forming in blood vessels when they should not. Usually the clots form in veins in the legs, but they may occur in any blood vessel. It is not exactly rare, since 3 to 7% of the populations in Europe and the United States are affected. The collective name for disorders of this type is thrombophilia (where 'thrombus' means clot and 'philia' means a liking for). The complications of such abnormal clot development are many, but include stroke (Zuber et al, 1996; Ludemann et al, 1998) and difficulties for a mother and her baby during pregnancy (Hatzis et al, 1999).

Factor V Leiden refers to a point mutation (guanine changed to adenine at position 1691) in the gene for the clotting factor, Factor V. Under normal circumstances, the tendency of Factor V to precipitate clot-formation is held in check by an activated protein called Protein C, which can break down Factor V. The presence of the Leiden mutation makes the Factor V molecule resistant to degradation by Protein C, leading to an increased tendency for blood to clot.

We receive one copy of the Factor V gene from our mother, and another from our father. If one of these genes has the Leiden mutation (heterozygous condition), the risk of venous thrombosis rises 3 to 8-fold, while if both genes are affected (homozygous condition) the clotting risk rises steeply to 30 to 140-fold.

A procedure called the Factor V Leiden (FVL) test has been available since 1993 to determine whether or not the mutated gene is present. As this is quite a complicated genetic test, screening usually begins with a simpler clotting test that looks for prolongation of the activated partial thromboplastin time in the presence of activated protein C. Then, if an abnormal result is obtained, the DNA analysis can be carried out.

Women with Factor V Leiden have an increased risk of venous thromboembolism when they take the contraceptive pill. Since it would be costly to screen all women for Factor V Leiden mutation, it has been suggested that only those with a personal and family history of venous thromboembolism should be offered screening (Walker, 1999).

If someone is Factor V Leiden positive, but they have not yet experienced an abnormal clotting episode, treatment with aspirin can be effective. In more severe cases, particularly when clotting has already occurred, an anticoagulant such as heparin or warfarin (Coumadin) is given for a 3-6 months period (Ridker, 1998). The problem is that thrombosis can recur when the anticoagulant is stopped, while if it is continued long term there is an increased risk of hemorrhage. It is possible that your cousin is experiencing hair loss as a reaction to Coumadin. Other side effects experienced by some people include fatigue and slower recovery from cuts or bruises. Great care in the use of prophylactic anticoagulation must be taken during pregnancy and the puerperium (Cavenagh and Colvin, 1996). Coumadin cannot be taken since it will cross the placenta and may affect the baby. An alternative treatment is low-molecular weight heparin.

There are other preventive measures. For example, an appropriate exercise regime benefits blood flow, particularly in the lower limbs, and thereby reduces the risk of thrombosis. It is also important to remember to move around regularly during long-distance travelling to reduce the risk of deep vein thrombosis.

References

What is an INR test in association with Warfarin?

23rd January 2001

Warfarin is an important drug used as the mainstay of long-term anticoagulant therapy. Warfarin has a chemical structure which is similar to vitamin K and thus competitively inhibits the enzyme epoxide reductase, so limiting the active form of the vitamin to form clotting factors, especially prothrombin.

Individual responses to warfarin therapy are varied and as the dosage for the treatment of patients is critical, it is important to determine the effect of the drug on anticoagulation for each patient. A standard coagulation test routinely performed in haematology laboratories is prothrombin time (PT), and this test is repeated until stabilisation occurs. The international normalised ratio (INR) is the widely recommended form of reporting prothrombin time when measuring warfarin effects.

Usually the patient’s PT is determined along with that for a control sample of plasma and the two values are reported as a ratio. However recent studies have indicated a degree of variability amongst different laboratories. The INR was adopted in order to standardize testing between labs. The INR is defined as the ratio of the patient’s PT to that of a control PT obtained by a standard method using a WHO standard primary thromboplastin. One practical consequence of standardization to the INR is that the notion of maintaining good anticoagulant control by prolonging the PT to 1.4 to 2.5 times normal has been replaced by more specific recommendations for each therapeutic indication for warfarin based on the INR.

Maintenance therapy should aim to keep the INR in the range of 2.0-4.5. Warfarin 3-9 mg/day (taken at the same time each day) should normally achieve this. When the dose for an individual is stable the INR need be measured only every 6-8 weeks.

The level of anticoagulation may be adjusted to match the perceived level of danger of thrombosis by the following guidelines:

References

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