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Vascular Damage and Blood flow

Damage to the vascular endothelium exposes

circulating blood that initiate thrombosis. Stasis by constriction of blood vessels. Elevated fibrinogen, increasing blood viscosity, initiating thrombosis.

Thrombosis may be caused by:
Increased Platelet counts Qualitative alterations in platelets (by intrinsic

platelet defects or changes in the plasma)

Causes spontaneous aggregation and increased adhesiveness.

Blood Clotting Factors

Hypercoagulable states arise from an

imbalance between the anticoagulant and prothrombotic activities of plasma. Thrombophilia can be caused by qualitative alterations or increased titer of activated clotting factors.

Factor V Leiden
Factor V Leiden thrombophilia is an inherited

disorder of blood clotting. Factor V Leiden is the name of a specific gene mutation that results in thrombophilia, which is an increased tendency to form abnormal blood clots that can block blood vessels.

Blood Clotting Factors

Factor V R50Q6 (Leiden) mutation is the most

common underlying genetic cause of thrombophilia. The mutation can cause deep venous thrombosis with a greater frequency of occurrence of thrombi in the lower limbs than in the chest.

Genetic Testing
The 3 most common assays ordered to

investigate a genetic predisposition to thrombosis are: 1. Factor V (Leiden) 2. Prothrombin mutation 3. Methylenetetrahydrofolate reductase enzyme (MTHFR)

Factor V (Leiden)
Evaluation for factor V Leiden can begin with a test for activated protein C (APC) resistance, though it is not commonly performed. About 95% of the time, APC resistance is due to a factor V Leiden mutation. If resistance is present, then

a test for the factor V Leiden gene mutation is performed on the affected person's DNA, both to confirm the diagnosis and to determine whether the person is heterozygous or homozygous for the mutation.

Prothrombin mutation
The PT 20210 mutation must be diagnosed

with genetic testing, checking directly for the gene mutation in the person's DNA and determining whether the patient is heterozygous or homozygous. Although prothrombin levels are usually moderately elevated with this mutation and could be measured, they are not clinically useful in identifying the mutation.

Methylenetetrahydrofolate reductase enzyme (MTHFR)

This enzyme plays a role in processing amino

acids, the building blocks of proteins. Methylenetetrahydrofolate reductase is important for a chemical reaction involving forms of the B-vitamin folate (also called folic acid or vitamin B9).

Methylenetetrahydrofolate reductase enzyme (MTHFR)

This enzyme converts 5,10-

methylenetetrahydrofolate to 5methyltetrahydrofolate. This reaction is required for the multistep process that converts the amino acid homocysteine to another amino acid, methionine.

Significance of Homocysteine and Methionine

Homocysteine is a chemical in the blood that

is produced when an amino acid (a building block of protein) called methionine is broken down in the body. We all have some homocysteine in our blood. Elevated homocysteine levels (also called hyperhomocysteinemia) may cause irritation of the blood vessels.

Significance of Homocysteine and Methionine

Elevated levels of homocysteine show an

increased risk for (1) hardening of the arteries (atherosclerosis), which could eventually result in a heart attack and/or stroke, and (2) blood clots in the veins, referred to as venous thrombosis.

Methylenetetrahydrofolate reductase enzyme (MTHFR) DNA testing

To evaluate the cause of

elevated homocysteine levels; sometimes to help determine your risk of thrombosis or premature cardiovascular disease (CVD).

Methylenetetrahydrofolate reductase enzyme (MTHFR) DNA testing

This test is sometimes ordered as a followup

to an elevated homocysteine test and may be occasionally ordered along with other cardiac risk tests if a person has a personal or family history of premature cardiovascular disease (CVD) or thrombosis.

Circulating Anticoagulants
Acquired inhibitors that inactivate or inhibit

the usual procoagulant activity of coagulation factors. Characterized as specific (single coagulation factor), or nonspecific (complex of coagulation factors).

Circulating Anticoagulants
majority of these inhibitors are

immunoglobulins which may arise following transfusion of blood. Specific inhibitors can be detected in patients with individual factor deficiencies. Patients with acquired specific inhibitors may exhibit hemorrhagic episodes.

SPECIFIC INHIBITORS Antiphospholipid Antibodies

1. Lupus Anticoagulant
Most common coagulant inhibitor found in SLE

patients. Interferes with phospholipid-dependent coagulation reactions in laboratory assays but does not inhibit the activity of any specific coagulation factor LA is an inhibitor that prolongs phospholipiddependent clotting tests in vitro. Most common cause of prolonged aPTT.

SPECIFIC INHIBITORS Antiphospholipid Antibodies

2. Anticardiolipin Antibodies
bind to the phospholipids cardiolipin in the presence

of beta 2-GP 1-cardiolipin complex.

LA and ACA are risk factors for thrombosis but

the MOA is unclear.

Antiphospholipid Syndrome
The APS is defined by the persistent presence

of antiphospholipid antibodies. APS is a prothrombotic disorder with a history of recurrent venous or arterial thromboembolism or a history of miscarriages. APS is an important cause of acquired thrombophilia.

Antiphospholipid Syndrome
Antiphospholipid antibodies include:
LA Anticardiolipin antibodies Anti-b2-glycoprotien-1 antibodies.

Factor VIII Inhibitor

most common specific factor inhibitors. Inhibitors of factor VIII develop in 10% to 15%

of patients with factor VIII deficiency (hemophilia A), and the majority occur in patients with severe hemophilia (those having less than 1% factor VIII activity). Nonhemophilia women have been reported to develop factor VIII inhibitors during the postpartum period, most frequently after th birth of their first child.

Factor VIII Inhibitor

Patients with underlying immunological

disorders such as:

SLE Drug allergies

Ulcerative colitis
Bronchial asthma also have an increased tendency to develop factor VIII

Factor VIII Inhibitor

Inhibitors against vWF occur in patients with

von Willebrand disease, underlying diseases such as malignancy or SLE, and in previously healthy persons.

Factor IX Inhibitor
Inhibitors are found in approximately 2% to

3% of factor IXdefi cient (hemophilia B) patients, but the incidence of inhibitors in severe hemophilia B may be as high as 12%
Although these inhibitors are predominantly a result of transfusion of blood products, spontaneous inhibitor formation

Factor V Inhibitor
rare and are not generally associated with

hereditary factor V defi ciency. exposure to streptomycin but no causal relationship has been established.

Fibrinogen, Fibrin, and Factor XIII Inhibitors

These inhibitors have occurred following

plasma transfusions or appeared spontaneously.

taking isoniazid, an antituberculosis drug.

Factor II, VII, IX, and X Inhibitors

rare The causes for factor inhibitor development

are varied and include congenital deficiencies, immune disorders, and amyloidosis

Factor XI and XII Inhibitors

Inhibitors of factors XI and XII have been

reporte infrequently in patients with:

Waldenstrm macroglobulinemia, and other disorders

as well as with chlorpromazine administration.

Clinical Presentation
The LA is the most commonly acquired Bleeding episodes in these patients are

usually the result of thrombocytopenia or another anomaly

Clinical Presentation
patients with LA are at increased risk for:
arterial and venous thromboembolism Spontaneous abortion intrauterine deaths

Nonhemophiliac patients with acquired

inhibitors of factor VIII can have major bleeding requiring transfusiomn

Clinical Presentation
Nonhemophiliac patients with acquired

inhibitors of factor VIII can have major bleeding requiring transfusion

Patients with inhibitors to vWF, factor XI, and

factor XIIc do not generally exhibit a hemorrhagic tendency.

Clinical Presentation
Inhibitors of factors XIII, II, VII, IX, and X;

fibrin; or fibrinogen can result in serious hemorrhagic events

Laboratory Findings
Prolonged PT or aPTT are classic laboratory

Incubation of patients plasma with normal

plasma at 37C (mixing study) and determination of aPTT and PT may detect the presence of an inhibitor
prolonged in the presence of an inhibitor

Laboratory Findings
Inhibitors are more time and temperature

stable than their specific clotting factors.

Bethesda assay quantitate the levels of inhibitors
most commonly used defined as the amount of antibody that will neutralize 50% of the inhibitor activity in a mixture of equal parts of normal plasma and antibody containing plasma that has been incubatedfor 2 hours at 37C.

Laboratory Findings
Detection of antiphospholipid antibody is based on

prolongation of phospholipid-dependent coagulation assays

Antiphospholipid antibody is considered one of the

most common causes of a prolonged aPTT. Assays include the:

Russells viper venom time kaolin clotting time platelet neutralizationprocedure tissue thromboplastin inhibition test