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.

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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