Hyperhomocyst(e)inemia and Thrombophilia

• A major point of consensus was that no causal role of hyperhomocyst(

• e)inemia in venous or arterial thrombosis is not yet established

• Homocysteine is a non–protein-forming sulfhydryl amino acid

• Dietary methionine Homocysteine (Intracellular demethylation)

• Homocysteine methionine (remethylation)

• is derived from the reduction of• 5,10-methylene-tetrahydrofolate

Methyltetrahydrofolate (MTHFR). • Methionine excess homocysteine may

enter the transsulfuration pathway.

• Hyperhomocystinemia :marked increase in atherothrombotic CVD and VTE.

• 25% : vascular occlusive event by age 16 year & 50% by age 29 years.

• Of these events, 32% are CVA, 4% are MI , 11% are peripheral arterial

• occlusions, and 51% are VTEs.• The event rate is reduced by vitamin

therapy in B6-responsive individuals.

• The gene for MTHFR is located on chromosomal region 1p36.

• Thermolabile mutant. • 12% of the population in the United

States is homozygous• Estrogen-containing medications

result in lower plasma homocysteine levels

New Concepts inCongenital Thrombophilia

Galila Zaher(November 1999)

Congenital thrombophilia

Inherited thrombophilia can be defined as a

genetically determined tendency to venous

thromboembolism.

Genetic risk factors are now identified in 30-

50% of affected individuals.

Table 1. Risk factors for inherited thrombophilia: prevalence and relative risk for venous theombosis

Risk factorYear describe

d

Prevalence in the general population

)%(

Relative risk

for VTE*

Antithrombin deficiencyProtein C deficiency

Protein S delivery (free PS)APC resistance

HyperhomocysteinaemiaFactor VIII levels > 150 IU/dlProthrombin gene G20210A

variant

1965

1981

1984

1993

1994

1995

1996

0.181

0.24

1.35

<156***

53

113

2.33

5.03**

6.53

2.45

6.63

2.53

4.83

2.83

Hyperhomocystinaemia

Homocysteine is a sulphur containing A A.

It is derived from methionine EAA.

Homocysteine metabolism:

Re methylation pathwayMTHFRTrans sulphuration pathwayC sTrans methylation pathway

Hyperhomocystinaemia

Interest in homocysteine as a risk factor for

vascular disease came from the earlyobservations that such diseases are

commonin cases of classical homocystinuria.

Hyperhomocystinaemia

Neural tube defects (NTPs)

Arterial vascular disease

Venous thromboembolism

HyperhomocystinaemiaNTDs.

Neuronal tube defects occur in 1/1000 birth in USA.

It has a complex trait interacting with environmental factors.

Homozygousity for TL-MTHFR has been clearly

shown to be a risk factor for spina bifida in 12% of the cases.

Pre conceptional supplementation of folic acid could preventup to 70% of NDTs.

Folic acid 4 mg reduces the recurrence of NTDs(MRC vit study research gp)

(Czei Zel, N Eng] Med 1992)

HyperhomocystinaemiaArterial vascular disease

Potential mechanismsOxidative damage to endothelial cells.

Enhanced plt adhesion to endothelial cellsEnhanced plt aggregation

Plt accumulation and the formation of plt rich thrombous

Inhibition of TM expressionIncreased procoagulant activity and reduced natural

Anticoagulant(Wetch. N. Eng] Med 1998)

HyperhomocystinaemiaArterial vascular disease

Metanalysis of published studies revealed that

elevation in total plasma homocysteine were

found to be an independent risk factor for all

forms of arterial vascular disease.

(Perry Advances in Haem. 1999)

HyperhomocystenaemiaArterial vascular disease

*15-40% of patients with conorary, cerebral of peripheral arterial disease have high

plasma level of homocysteine > 20 moL/L.

*The odd ratio for IHD is 1.4 for every 5 moL/L more than homocysteine median

fasting adult males.

*C677T mutation is a major cause of mild hyperhomocystinenia, but the mutation per

se does not increase cvs disease risk

Hyperhomocystinaemiavenouss thromboembolism

There is accumulating data to suggest that hyperhomocystinemia is a risk factor for VTE

that is independent of coexisting abnormalities of the naturally occurring

Anticoagulant.Homozygosity TL-MTHFR together

with low folate level confers moderate risk factor.Hyperhomocystinaemia defined as plasma level

>95% of control (18 M mol IL) was found in 16% ofcases.

HyperhomcystinaemiaLaboratory evaluation

Intra individual variability

Inter Laboratory variabilityELISAHPLCEIA

HyperhomocystinaemiaLaboratory evaluation

There is an urgent need to improve analytical

impression and decrease the difference amongmethods.

An ideal homocysteine reference range based

on targeting subject with highest serumFolate level is preferable to the population base

range.

HyperhomocystinaemiaLaboratory evaluation

Fasting total plasma homocysteine level

Methionin loading dose.

Serum Folate and B12 PevelPCRC677T

HyperhomocystinaemiaLowering vit dose

Plasma ThCY response to folic acid and Pyridoxin hydrochlorid

The optimal homocysteine lowering vitamin dose

and target ThCY are currently unknown.

Proposed does.Folic acid 500-650 gPyridoxin 100 mg

B 120.4 mg.

Issues to be addressed

What is the minimum dose of folic acid to prevent

NTDs?

Would grain fortification adapted in USA reduce

NTDs, protects against arterial vascular disease?

What is (are) the best test (s) to evalaute hyper homocystinemia?

Concluding Remarks

.1Folate supplementation reduces the occurance and recurrence of NTDs.

.2Elevated fasting plasma homocysteine is an independent risk factor for all forms of

arterial vascular disease.

Concluding Remarks(Continue)

.3Homozygonosity for TL-MTHFR is not a significant risk factor for VTE per se

.4There is currently no strong argument to include MTHFR C677T genotyping during routine thrombophilia screen.

.5Combination of hypercystinaemia and FvL abnormality significantly increase

the risk for VTE.

Thanks