Venous and Arterial Thrombosis (blood clotting): A body user's guide

CJ Glueck MD, James E Lang MD, Cholesterol Center, ABC Building, Jewish Hospital, 3200 Burnet Ave, Cincinnati, OH 45229.

E-mail: glueckch@healthall.com or cglueck@fuse.net Fax: 513-924-8273

I. Background:

In westernized, industrialized countries, venous thrombosis occurs in ~1/1000 people
Venous thrombosis most often occurs in the leg, either in the superficial veins (superficial phlebitis), or in the deep veins (deep venous thrombosis). Thrombi in the leg may embolise to the lung, known as pulmonary embolus.
Thrombosis can also occur in other venous and linked arterial beds, although more rarely than in the leg. Venous and or arterial thrombosis in these areas tend to be severely underdiagnosed or misdiagnosed, particularly in regards to miscarriage, fetal death, and major complications of pregnancy.

cerebral sinus (brain)
retinal veins/and or arteries (eye)
veins in the arms or upper thorax (chest)
veins in the mesentery (gastrointestinal tract)
veins in bones, usually the hip or jaw, causing bone death (osteonecrosis)
veins and/or arteries in the placenta, causing placental insufficiency, miscarriage, and major complications of pregnancy including eclampsia and pre-eclampsia, abruptio placentae, and intrauterine growth retardation.

Arterial thrombi most commonly occur in the following areas:

Coronary arteries, causing myocardial infarction (heart attack)
Carotid and/or vertebral arteries, or intracerebral arteries causing ischemic stroke
Peripheral arteries, usually in the leg, causing ischemia and (eventually) gangrene.
Mesenteric arteries
Retinal arteries causing loss of vision
Placental arteries, in conjunction with venous thrombosis, causing placental insufficiency, miscarriage, and major complications of pregnancy including eclampsia and pre-eclampsia, abruptio placentae, and intrauterine growth retardation.

Risk factors for venous thrombosis differ from those for arterial thrombosis, for the most part ,but increasingly, it is clear that there may be considerable overlap. Risk factors for arterial thrombosis include smoking, hypertension, hyperlipidemia, diabetes mellitus, cholesterol emboli.

Risk factors for venous thrombosis include multiple thrombophilic (loves to clot) and/or hypofibrinolytic (can't lyse clots normally) factors, mostly inherited, and acquired risk factors (pregnancy, immediate post-childbirth period, use of oral contraceptives or estrogen replacement therapy, high dose corticosteroid therapy , immobilization/bone fracture, knee-hip-abdominal surgery, and foreign objects in the blood stream [catheters].

II. Diagnosis:

Most of the discussion which follows will focus on venous thrombosis, and risk factors for venous thrombosis, but areas of overlap will be highlighted. The following measures should be obtained, if possible, to best understand the causes of venous or, where there is overlap, with arterial thrombosis:

Thrombophilia:

cDNA-PCR assays for gene mutations and polymorphisms:

Factor V Leiden Leiden,

Methylenetetrahydrofolate reductase (MTHFR) MTHFR C677T,

Cystathionine beta synthetase (CBS) CBS T833C & G919A,

Prothrombin G20210A Prothrombin G20210A, and

platelet glycoprotein gene IIIa A1/A2 Platelet glycoprotein IIIa A1/A2.

Serologic (blood) tests:

Proteins C, S (S),

Antithrombin III,

homocysteine (homocysteine),

Factor VIII,

anticardiolipin antibodies (ACLA) IgG and IgM ACLA,

the Lupus Anticoagulant (LA) (LA).

Hypofibrinolysis:

cDNA-PCR assays for gene mutations: 4G/5G polymorphism of the plasminogen activator inhibitor-1 gene (PAI-1) PAI-1.

Serologic (blood) tests: Lp(a) Lp(a).

Figures 1 and 2 below display the estimated population prevalence for the thrombophilic and hypofibrinolytic factors, and approximations of the percentage of venous thrombi which they cause. It is important to remember that the ultimate development of a venous clot is usually multicausal, involving gene mutations/polymorphisms AND acquired risk factors.

III. Therapy

The therapy of both venous and arterial thrombosis needs to be individualized to each subject. The duration of the therapy must be individualized as well. In many cases of venous thrombosis, no anticoagulant therapy needs to be given. During pregnancy, Coumadin cannot be given, but heparin or low molecular weight heparin are safe. Folic acid and Vitamins B6 and B12 are safe during pregnancy. Statin drugs should not be given during pregnancy. In broad summary, the general approach would be as follows, by individual risk factors:

V Leiden Mutation: Acute- Heparin or low molecular weight heparin. Long term-Coumadin

Prothrombin gene mutation:

MTHFR or CBS Mutations (if accompanied by high homocysteine [>13.1 umol/L])- Folic acid 5 mg/day, Vitamin B6 100 mg/day, Vitamin B12 2000 ug/day.

Platelet glycoprotein gene IIIa A1/A2- Aspirin- 325 mg/day

4G4G homozygosity for PAI-1 gene mutation (if accompanied by high plasminogen activator inhibitor activity and fasting hyperinsulinemia [>20 uU/ml]- Metformin 850 mg three times/day.

Protein C, S, or antithrombin III deficiency- Heparin or low molecular weight heparin overlapped with Coumadin for 48 hours, then Coumadin long term.

Homocysteine >13.1 umol/L- Folic acid 5 mg, Vitamin B6 100 mg, Vitamin B12, 2000 ug/day.

Lp(a) > 35 mg/dl- No specific anticoagulant approach known, but lower LDL cholesterol to levels <100 mg/dl with statin drugs if necessary, since Lp(a) and LDL cholesterol are synergistic for the development of atherosclerotic vascular disease.

High Factor VIII- no uniform agreement as to therapy, but acute and chronic therapy, if indicated would be heparin/low molecular weight heparin and coumadin respectively.

Anticardiolipin antibodies IgG and or IgM, Lupus anticoagulant- these commonly accompany each other and are known as the antiphospholipid antibody syndrome. Acute and chronic therapy if indicated would be heparin/low molecular weight heparin and coumadin respectively.

Coagulation disorders causing miscarriage, or major complications of pregnancy: This is a special situation which can best be handled as follows:

If possible, first document the coagulation disorder in the non-pregnant state, not on oral contraceptives or estrogen therapy, since pregnancy, oral contraceptives, and estrogens can effect protein S and C levels, and can mimic resistance to activated protein C.
Monitor the time of conception as closely as possible, using serum or urine specific HCG tests. As soon as conception is verified, start therapy with low molecular weight heparin, Lovenox 60 mg/day or Fragmin, 5000 U/day.

For additional molecular diagnostic testing contact Molecular Diagnostics Laboratories (MDL)

E-mail: glueckch@healthall.com
or cglueck@fuse.net
Fax: 513-924-8273