Q: I am A+ secretor and take warfarin due to incidents of spontaneous DVTs (I have the Factor V Leiden gene deficiency). As such, I've had to lay off my beloved green tea and generally be careful of other supplements. I would like to begin taking A-friendly supplements from NAP, but am wondering if there are things I should avoid or watch for? Thanks for your help, Elizabeth



Venous Thromboembolism (VTE) is when a blood clot has formed in a blood vessel and then dislodges from its site of origin, blocking a vein. Blood clot formation may result from injury, or be associated with infections. In the US the incidence of VTE is more than 1 in 1000. Of these, 30% die within 30 days; one-fifth suffer sudden death due to pulmonary embolism. Independent risk factors for VTE in the US include increasing age, male gender, surgery, trauma, hospital or nursing home confinement, malignancy, neurological disease with arm or leg paralysis, prior superficial vein thrombosis and varicose veins; among women, risk factors include pregnancy, oral contraceptives and hormone replacement therapy. About 30% of surviving cases develop recurrent VTE within ten years. Independent predictors for recurrence include increasing age, obesity, malignant neoplasm, and arm or leg paralysis (1).

Deep Vein Thrombosis (DVT), a type of VTE usually in the deep veins of the legs or pelvis, may occur in people recovering from childbirth, surgery, or other conditions requiring prolonged bedrest, or after long haul flights; the clotting mechanism is thought to be impaired when the legs are immobilised. A danger is that a clot originating in the leg vein may dislodge and travel to the lung (pulmonary embolism). Redness, warmth, pain, swelling or tenderness of the leg can all be signs of DVT, but may not all be present. Doppler ultrasound may confirm the presence of a DVT.

Factor V is a clotting factor protein, whose normal role is to help blood to clot when an appropriate trigger is present. Like all steps in the clotting cascade however, Factor V is subject to regulation to keep it under control, preventing clots from forming too easily or too quickly. Factor V Leiden (FVL) is a genetic variant form of the Factor V clotting protein, where the inactivating protein APC cannot work to prevent excessive clotting by Factor V.

FVL is the most common hereditary blood coagulation disorder, affecting 5% of Caucasians in the US, and about 2 to 4% of the Dutch population, 7% of the Swedish population and 8% of the German population. FVL increases the risk of VTE 3-8 times for heterozygous (FVL gene inherited from one parent), and substantially more, 30-140 times, for homozygous (FVL gene inherited from both parents) individuals within the population as a whole (2).

Other genetic polymorphisms can affect blood clotting, the most common being an individual's sex and ABO and Lewis blood group (secretor status) (3,4).

Being blood group A or AB (and to a lesser extent , puts that person at greater risk of blood clotting due to an increase in plasma concentration of the clotting factors von Willebrand factor antigen (vWf) and Factor VIII. An estimated 30% of the genetically determined variance in plasma concentration of vWf is directly related to ABO blood group. Also ABH non-secretors, and in particular Lewis negative individuals have a higher tendency to blood clotting. These genetic factors can multiply together, increasing risk of VTE:

"ABH non-secretors are reported to have shorter bleeding times and a tendency toward higher factor VIII and vWf. This relationship appears to be another example of blood type synergy between ABO and Secretor/Non-secretor phenotypes. In fact, secretor genetics appear to interact with ABO genetics to influence as much as 60 percent of the variance of the plasma concentration of vWf, with secretors (Le(a-b+)) having the lowest vWf concentrations" (4).

As it is expression of the H antigen that mediates the ABO effect on plasma vWF concentration, it will make a difference as to whether an individual’s blood group A phenotype consists of a genotype of A1A1, which has higher levels than in A1O genotype, which has higher levels than in A2O genotype (3). Knowing your parents’ blood groups and getting a test for the A1/A2 subgroup may give further clarification of genotype and related risk factor.

Age-related difference in ABO-relative risk of VTE decreases with advancing age (6). It has also been suggested that high plasma homocysteine (Hcy) levels may also be a significant risk factor for VTE, particularly with those under 60 (7), as Hcy tends to increase with age. For individuals high Hcy levels, a supplement such as NAP Methyl B12 Plus may help to reduce Hcy.

Hormone replacement therapy and the contraceptive pill both increase the risk of VTEs, but women heterozygous for FVL on either type of hormonal intervention the risk is increased between two and six times, and monozygotes for FVL between fifteen and thirty times (8,9).

Statin drugs, and therefore natural statin mimetic substances such as red rice yeast may also decrease the risk of VTE, but aspirin therapy alone does not significantly reduce the risk (10).

Blood groups A and AB appear to be associated with increased risk estimates for both DVT and pulmonary embolism compared with blood group O during and after pregnancy (11).

Warfarin is a standard treatment for thinning the blood to break up clots and prevent new clots from forming. Generally accepted side effects of warfarin include haemorrhage, hypersensitivity, rash, alopecia, diarrhoea, unexplained drop in haematocrit, ‘purple toes', skin necrosis, jaundice, hepatic dysfunction; also rarely reported are nausea, vomiting, and pancreatitis. Some other reported side effects include: hair thinning, hair loss, fatigue, taking longer to recover from cuts or bruises, sunburn or sensitivity to light, depression.

There are alternatives to Warfarin such as fish oils, gingko biloba and garlic tablets, but as with Warfarin, supplement intake and blood clotting time must be monitored regularly and supervised by a physician, preferably a naturopath.

Other factors that prevent DVT include the following:

Keep moving your legs, don't take sleeping pills (these cause immobility), wear loose-fitting clothing, keep the legs uncrossed, keep hydrated by drinking normally, avoid alcohol to prevent dehydration, wear graduated compression stockings.

Excess caffeine may cause dehydration, but green tea, which is traditionally brewed for less than a minute, contains relatively low levels of caffeine, and should not cause dehydration if drunk in moderation as well as water.

--

References:

(1) Heit JA, Silverstein MD, Mohr DN, et. al. The epidemiology of venous thromboembolism in the community. Thromb Haemost. 2001 Jul;86(1):452-63. PMID: 11487036

(2) Folsom AR, Cushman M, Tsai MY, et. al. A prospective study of venous thromboembolism in relation to factor V Leiden and related factors. Blood. 2002 Apr 15;99(8):2720-5. PMID: 1192975

(3) Robinson WM, Roisenberg I. Venous thromboembolism and ABO blood groups in a Brazilian population. Hum Genet. 1980;55(1):129-31. PMID: 7450749

(4) D’Adamo PJ, Kelly GS. Metabolic and Immunologic Consequences of ABH Secretor and Lewis Subtype Status Altern Med Rev 2001;6(4):390-405 PMID: 11578255

(5) O’Donnell J, Boulton FE, Manning RA, Laffan MA Amount of H Antigen Expressed on Circulating von Willebrand Factor Is Modified by ABO Blood Group Genotype and Is a Major Determinant of Plasma von Willebrand Factor Antigen Levels Atherosclerosis. 1976 Jan-Feb;23(1):141-2. PMID: 11834538

(6) Allan TM. ABO blood groups and age groups in surgical venous thromboembolism. Atherosclerosis. 1976 Jan-Feb;23(1):141-2 PMID: 1078393

(7) Ray JG. Meta-analysis of hyperhomocysteinemia as a risk factor for venous thromboembolic disease. Arch Intern Med. 1998 Oct 26;158(19):2101-6. PMID: 9801176

(8) Herrington DM, Vittinghoff E, Howard TD, et. al. Factor V Leiden, hormone replacement therapy, and risk of venous thromboembolic events in women with coronary disease. Arterioscler Thromb Vasc Biol. 2002 Jun 1;22(6):1012-7 PMID: 12067913

(9) Spannagl M, Heinemann LA, Schramm W. Are factor V Leiden carriers who use oral contraceptives at extreme risk for venous thromboembolism? Eur J Contracept Reprod Health Care. 2000 Jun;5(2):105-12. PMID: 10943572

(10) Lacut K, Oger E, Le Gal G, et. al. Statins but not fibrates are associated with a reduced risk of venous thromboembolism: a hospital-based case-control study. Fundam Clin Pharmacol. 2004 Aug;18(4):477-82. PMID: 15312155

(11) Larsen TB, Johnsen SP, Gislum M, et. al. ABO blood groups and risk of venous thromboembolism during pregnancy and the puerperium. A population-based, nested case-control study. J Thromb Haemost. 2005 Feb;3(2):300-4. PMID: 15670036

(12) Ursavas A, Ozyardimci N. Travel and pulmonary thromboembolism Tuberk Toraks. 2004;52(1):98-102. PMID: 1514338

The consequences of severe human zinc deficiency have been known since the 1960s, but only more recently have the effects of milder degrees of zinc deficiency, which are highly prevalent, been recognized. Trials have shown that zinc supplementation results in improved growth in children, lower rates of diarrhoea, malaria, and pneumonia, and reduced child mortality. In total about 800 000 child deaths per year are attributable to zinc deficiency (1).



It has been shown that in people with zinc deficiency, activity of serum thymulin (a thymus specific hormone involved in T cell function) is decreased, an imbalance between T helper cell (Th1) and Th2 function develops, and lytic activity of natural killer cells (destructive action on enemy cells) is decreased (2).



Zinc has been used effectively to treat Wilson's disease, hepatic encephalopathy, sickle cell disease, and the common cold. Zinc is an essential part of metalloproteins and transcription factors involved in gene expression of various proteins. Zinc activates nuclear factor-kappa B in T helper cells and in zinc deficiency binding of nuclear factor-kappa B to DNA is decreased, leading to decreased gene expression of interleukin 2 and its production (2).



Zinc deficiency commonly coexists with other micronutrient deficiencies including iron, making single supplements inappropriate. Authors of a paper in the British Medical Journal now suggest: "Until the results of trials of multiple micronutrient interventions are available, zinc supplements should be given to children with infections" (3).



As zinc is essential in the activation of the enzyme intestinal alkaline phosphatase (IAP) as demonstrated in the IAP of calves (4), it is particularly important for ABH salivary non-secretors to maintain adequate zinc levels due to their lower levels of IAP (5).



If taken in doses greater than 15 mg per day, zinc supplementation should be supervised by a physician.

--

References:

1. BLACK, R.

Micronutrient deficiency: an underlying cause of morbidity and mortality.

Bull World Health Organ. [online]. 2003, vol.81, no.2, p.79-79.

Available from: . ISSN 0042-9686.



2. Prasad AS.

BMJ. 2003 Feb 22;326(7386):409-10.

Zinc deficiency.





3. Shrimpton R, Gross R, Darnton-Hill I, Young M

Zinc deficiency: what are the most appropriate interventions?



BMJ, Feb 2005; 330: 347 - 349.



4. Yan S, Liu Y, Tian X, Zhang Y, Zhou H.

Effect of extraneous zinc on calf intestinal alkaline phosphatase.

Protein Chem. 2003 May;22(4):371-5.

PMID: 13678301



5. Matsushita M, Irino T, Stigbrand T, Nakajima T, Komoda T.

Changes in intestinal alkaline phosphatase isoforms in healthy subjects bearing the blood group secretor and non-secretor.

Clin Chim Acta. 1998 Sep 14;277(1):13-24.

PMID: 9776042

Recent research (1) shows a significant difference in the prevalence of osteoporosis in postmenopausal women, suggesting that bone resorption is more active in women with non-O blood types during the post-menopausal period compared to women with blood type O. Further, osteoporosis was more frequently observed in blood type AB than in other blood types, particularly osteoporosis of the hip. The proximal femurs of AB women were 2.3 times more likely to have osteoporosis than that those belonging to women with O blood type. The findings are consistent with that of previous research (2), (3) cited in the Complete Blood Type Encyclopedia,which suggests that the reason blood types O and B are less susceptible to osteoporosis is due to a lower level of intestinal alkaline phosphatase.



For consistency, all the women were rhesus positive, and none were smokers or suffering from chronic obstructive pulmonary diseases and none were taking HRT (all of which factors can affect bone mineral density).



This study openly recognises the influence of ABO blood group and secretor status on disease incidence, and seeks to add to the wealth of information in this area. In this study the researchers admit that they could not measure objectively the behavioural habits, personality traits, or duration and intensity of physical exercise. This may be significant, as Physical activity, which is closely associated with personality and behavior patterns, is widely accepted as a favourable factor influencing bone mineral metabolism, and individuals with blood phenotype O show a significantly lower incidence of obsessional personality traits, compared to the blood types AB, A, and B. What the researchers failed to mention is the dietary habits of the South Korean women in the study, and whether their typical dietary intake may be more appropriate to the digestive capabilities of blood type O and less to those of blood type AB.



The researchers state that further research is needed to see if such findings are observed in elderly men or premenopausal women. Future studies might also find determination of secretor status, comparison of intestinal alkaline phosphatase levels and dietary intake useful markers in addition to ABO blood type, in determining the risk factors for osteoporosis, although at present it appears to be beyond the remit of scientists to think in these terms.



References:



1. Choi JW, Pai SH. Associations between ABO blood groups and osteoporosis in postmenopausal women. Ann. Clin. Lab. Sci., March 1, 2004; 34(2): 150-3. PMID: 15228226



2. Kolodchenko VP. ABO, rhesus and MN system blood groups and spinal osteochondrosis. Tsitol Genet. 1979 Mar-Apr; 13(3):232-3.

PMID: 113917

A German health insurance company has offered all of its customers a test for a genetic disorder so that they can receive early treatment if they are affected. Four thousand customers took up the offer, and 67 were told that they were at high risk of the disease.

In cooperation with the Hanover Medical School, the Kaufmännische Krankenkasse, a health insurance company with about two million customers, offered all of its clients a test for the hereditary disease haemochromatosis, a disorder in which the body stores too much iron. The results were given exclusively to the people tested and not divulged to the company.

Haemochromatosis is an autosomal recessive disorder, which is characterised by excessive iron absorption in the gut and causes damage to the kidney, liver, and other organs, eventually leading to organ failure. Symptoms usually occur first after the age of 40. The disorder is treated by regular venesection (giving blood) to reduce the amount of iron.

At a press conference to announce the results of the initiative, Ingo Kailuweit, the company chairman, reported that out of almost 4000 voluntary participants, 67 people were identified as homozygous (carrying two copies of the faulty gene) and therefore at high risk of developing the disease. Not all people who carry two faulty genes develop the full blown disease, so some of the 67 people identified as being at high risk may remain healthy.

An opinion poll at the time of testing showed that almost 90% of the population supported genetic testing as part of a health insurance company’s programme if it provided benefit to the participants.

----------------------

Commentary:

This shows how genetic testing is being used to reduce a potential financial burden on the insurance company for treating a preventable disease, without compromising the principle that insurance covers individual risk by using contributions from the whole membership without discrimination against risks about which the individual has no control. It costs more to insure a smoker, but continuing to smoke is a choice that is made by the individual.

Since the disease is often detected in its late stages, patients identified as carrying two faulty genes for the disorder at an early stage might be spared dialysis and possible kidney and liver transplantation. The estimated cost of treating someone with the disease when it is discovered late is about €100 000 (£69 000; $130 000).

The German government is passing a law on genetic testing, which will ensure that customers will not have to disclose the results of any genetic tests to life insurance companies if they are insuring their lives for less than €250 000. Nor will they ever have to disclose such results to their employers. The law will also make it compulsory to offer counselling to all people offered genetic tests.

If people were simply told their blood group and counselled on how to act according to that information, it would benefit everyone's health, and not just a tiny minority with rare genetic conditions.

Reference:

BMJ 2004;329:1364

The European Journal of Clinical Nutrition compared the diets of 507 hospitalised Italians recovering from their first heart attack and 478 controls, and found that the more pizza eaten, the lower their risk of acute myocardial infarction (heart attack). The authors of the study could not explain the link with pizza eating, but suggest that some of the ingredients of pizza have been shown to have a favourable influence on the risk of cardiovascular disease.

In Italy most pizza is usually consumed in traditional pizzerias, and consumption of "fast food" pizza is unusual. 100 g of a traditional Italian pizza has about 50g of carbohydrates, 20 g of tomato sauce, 20 g of mozzarella cheese, 4 g of olive oil, and 2 g of yeast. In terms of being a healthy meal, a pizza on its own is not ideal, as it contains relatively few vegetables, but combined with a fresh green salad, traditional Italian pizza could score better than a lot of other commonly available restaurant meals. In analysing the contents of a basic traditional pizza, real mozzarella cheese is one of the few cheeses that is acceptable for the diets of most blood groups; the pizza base, although made from wheat, is a relatively small part of the meal when compared with a deep pan pizza or pasta, for example, and more suited to individuals of blood groups A and AB, who have higher risk of heart disease than those with blood groups O and B; tomato is neutral or beneficial for non-secretors (who are at higher risk of heart disease than secretors); olive oil is generally beneficial; and a standard Italian pizza contains about 500-800 Calories, reducing the risk of obesity from calorie consumption. Pizza eaters were classed as occasional (one to three 200 g portions a month), regular (more than one a week), and frequent (two or more a week).

N.B. This is not a recommendation to those at risk of heart disease to eat lots of pizza: the 478 controls who ate more pizza than the 507 who had had a heart attack were also in hospital, so eating pizza does not keep you out of hospital. For specific individualised health advice consult your naturopath, and read the book 'Cardiovascular Disease: Fight It With The Blood Type Diet' by Dr. Peter D'Adamo.

References:

Pizza and risk of acute myocardial infarction. Eur J Clin Nutr. 2004 Nov;58(11):1543-6. Gallus S, Tavani A, Vecchia CL. PMID: 15138460