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    Fibrinolytic Disorders

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    Chelly Jimeno
    1. Congenital disorders of fibrinolysis that cause bleeding include increased plasminogen activator activity and plasminogen activator inhibitor-1 (PAI-1) deficiency. PAI-1 deficiency leads to excessive fibrinolysis and bleeding after trauma or procedures. 2. Alpha-2 antiplasmin deficiency also causes excessive bleeding through reduced inhibition of plasmin activity and fibrinolysis. Homozygotes present with severe bleeding while heterozygotes often have mild bleeding. 3. While increased fibrinolysis is associated with bleeding, diminished fibrinolysis has been linked to various thrombotic disorders but the significance is uncertain and requires further large prospective studies.

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    Fibrinolytic Disorders

    Uploaded by

    Chelly Jimeno
    230 views29 pages
    1. Congenital disorders of fibrinolysis that cause bleeding include increased plasminogen activator activity and plasminogen activator inhibitor-1 (PAI-1) deficiency. PAI-1 deficiency leads to excessive fibrinolysis and bleeding after trauma or procedures. 2. Alpha-2 antiplasmin deficiency also causes excessive bleeding through reduced inhibition of plasmin activity and fibrinolysis. Homozygotes present with severe bleeding while heterozygotes often have mild bleeding. 3. While increased fibrinolysis is associated with bleeding, diminished fibrinolysis has been linked to various thrombotic disorders but the significance is uncertain and requires further large prospective studies.

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    1. Congenital disorders of fibrinolysis that cause bleeding include increased plasminogen activator activity and plasminogen activator inhibitor-1 (PAI-1) deficiency. PAI-1 deficiency leads to excessive fibrinolysis and bleeding after trauma or procedures. 2. Alpha-2 antiplasmin deficiency also causes excessive bleeding through reduced inhibition of plasmin activity and fibrinolysis. Homozygotes present with severe bleeding while heterozygotes often have mild bleeding. 3. While increased fibrinolysis is associated with bleeding, diminished fibrinolysis has been linked to various thrombotic disorders but the significance is uncertain and requires further large prospective studies.

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    Download as pptx, pdf, or txt
    230 views29 pages

    Fibrinolytic Disorders

    Uploaded by

    Chelly Jimeno
    1. Congenital disorders of fibrinolysis that cause bleeding include increased plasminogen activator activity and plasminogen activator inhibitor-1 (PAI-1) deficiency. PAI-1 deficiency leads to excessive fibrinolysis and bleeding after trauma or procedures. 2. Alpha-2 antiplasmin deficiency also causes excessive bleeding through reduced inhibition of plasmin activity and fibrinolysis. Homozygotes present with severe bleeding while heterozygotes often have mild bleeding. 3. While increased fibrinolysis is associated with bleeding, diminished fibrinolysis has been linked to various thrombotic disorders but the significance is uncertain and requires further large prospective studies.

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    • Is the system whereby the

    temporary fibrin clot systematically


    and gradually dissolved as the
    vessel heals in order to restore
    normal blood flow.
    Abnormalities in the fibrinolytic system may
    be associated with thrombosis or bleeding.
    Congenital fibrinolytic abnormalities are
    uncommon, but acquired abnormalities in
    this system are not unusual.
    PATHOPHYSIOLOGY
    • Formation of a fibrin clot occurs in
    response to vascular injury
    • Fibrinolytic system breaks down fibrin
    clot, converting fibrin to soluble
    degradation products
    • Components of the fibrinolytic system –
    plasminogen, plasminogen activators,
    plasminogen activator inhibitors, and
    alpha-2-antiplasmin
    • Fibrinolysis is precisely regulated by
    these activators, inhibitors, and
    cofactors
    1.) Plasminogen
    A. Pathophysiology
    • Synthesized in the liver and converted to its active
    form (plasmin) by plasminogen activators
    • Plasmin degrades fibrin (and fibrinogen), forming
    soluble fibrin degradation products
    • Excessive plasmin formation may result in
    increased fibrinolysis and bleeding
    B. Deficiency
    a. Inherited
    • Incidence – <1/million (rare)
    • Inheritance – autosomal recessive
    • Clinical presentation – ligneous
    conjunctivitis; similar ligneous lesions in
    gingiva, ear, respiratory tract, and
    female genitourinary tract; altered
    wound healing; pseudomembrane
    function
    b. Acquired
    • May be due to liver disease, disseminated
    intravascular coagulation
    C. Thrombotic Risk
    • Heterozygotes – do not appear to have increased
    risk of thrombosis
    • Homozygotes – risk of thromboses remains unclear
    2.) Tissue plasminogen activator
    (tPA)
    A. Pathophysiology
    • Plasminogen activator is synthesized
    by endothelial cells and released in
    response to endothelial cell
    stimulation
    • tPA converts plasminogen to plasmin,
    which subsequently degrades fibrin
    (and fibrinogen), forming soluble
    fibrin degradation products
    oLow concentrations of circulating
    tPA are found in the blood
    B. Clinical Presentation
    • Increased tPA results in increased fibrinolysis and
    bleeding
    otPA is an acute phase reactant and may be
    elevated in patients with metabolic syndrome,
    cancer, surgery, pregnancy, sepsis, or other
    inflammation

    C. Thrombotic Risk
    • Deficiency has potential for but
    uncertain association with thrombosis
    3.) Plasminogen activator inhibitor-1 (PAI-1)
    A. Pathophysiology
    • Released primarily by the liver and adipose tissue
    • Levels are regulated by metabolic factors such as
    triglycerides, cholesterol and insulin
    • Binds to and inhibits plasminogen activators such
    as tPA, forming inactive complexes that are cleared
    by the liver
    • PAI-1 is found in its active form in blood, as well as
    in an inactive form (primarily in platelets), and in
    complexes with plasminogen activators
    • PAI-1 is an acute phase reactant and may be
    elevated in patients with metabolic syndrome,
    cancer, surgery, pregnancy, or sepsis or other
    inflammation
    • Most PAI-1 assays are designed to identify elevated
    PAI-1 concentrations rather than PAI-1 deficiency
    • Low concentrations may not be accurately
    quantified
    B. Deficiency
    a. Inherited
    • Incidence – rare (in U.S., most common in the Old
    Order Amish community)
    • Inheritance – autosomal recessive
    • Clinical presentations:
    • Heterozygotes – usually do not present with
    bleeding disorders
    • Homozygotes – moderate to severe bleeding
    • Bleeding is usually post-traumatic rather than
    spontaneous
    C. Thrombotic Risk
    • Elevated levels may be associated with venous or
    arterial thrombosis, although routine testing of
    thrombophilic patients for this disorder is not
    recommended
    • Inherited polymorphism – single guanosine
    nucleotide deletion/insertion polymorphism
    (4G/5G) at -675 bp of the SERPINE1 gene is the
    major genetic determinant of PAI-1 expression
    C. Thrombotic Risk
     Inherited polymorphism
    • Clinical presentationIndividuals with 4G/5G and
    4G/4G genotypes, especially those with other
    thrombophilic risk factors, have increased risk for
    venous thromboembolism
    • 4G/5G and 4G/4G genotypes are associated with
    increased risk of myocardial infarction
    • Some studies have associated the 5G/5G genotype
    with elevated risk of ischemic stroke (IS)
    4.) Alpha-2-antiplasmin
    A. Pathophysiology
    • Secreted by the liver
    • Binds to and inhibits plasmin

    B. Deficiency
    a. Inherited
    • Incidence – rare
    • Inheritance – autosomal recessive
    B. Clinical Presentation
    • Heterozygotes – usually mild mucosal bleeding or
    asymptomatic
    • Homozygotes – may manifest with severe
    bleeding episodes resembling
    congenital hemophilia
    • Umbilical cord bleeding
    • Hemarthroses
    • Postoperative and post-trauma excessive
    bleeding
    C. Thrombotic Risk
    • Elevated alpha-2-antiplasmin has not been reported
    to be associated with increased risk for thromboses
    •Congenital disorders of
    fibrinolysis which cause
    bleeding include
    increased plasma
    plasminogen activator
    activity and deficiency of
    alpha-2 antiplasmin.
    • PLASMINOGEN ACTIVATOR INHIBITOR-1
    DEFICIENCY:
    • A bleeding diathesis that begins in childhood due
    to hyperfibrinolysis as a result of decreased PAI-1
    activity.
    • Leads to excessive tissue plasminogen activator
    activity resulting in excessive plasmin activity.
    Characterized by:
    • Abnormal prolonged bleeding
    • After trauma
    • Tooth extraction
    • Surgical procedures
    • Rebleeding following initial hemostasis
    • Euglobulin Clot lysis Time
    • used to evaluate increased fibrinolytic
    activity.

    • Euglobulin Fraction
    • consist of fibrinogen, plasminogen and the
    activators of plasminogen.
    • Relatively free of fibrinolytic inhibitors.
    • ALPHA-2 ANTIPLASMIN DEFICIENCY:
    • When alpha-2-antiplasmin is absent or low
    concentrations, excessive bleeding may occur.
    • Diminished activities of alpha-2 are found in
    hyperfibrinolysis, which can occur as a
    complication of disseminated intravascular
    coagulation (DIC) or in operations on organs with
    a high content of plasminogen activators.
    • May due to a disturbance in synthesis(for
    example severe liver cell damage) as well as the
    additional assessment of problematic cases in
    fibrinolytic activity.
    • Homozygotes will have <10% of activity and present
    with mucosal membrane bleeding particularly in
    the GI tract, subcutaneous hematomas,
    spontaneous bruising and severe bleeding in
    trauma.
    • Heterozygotes are usually asymptomatic but may
    have mild bleeding tendencies.
    • Inhibiting plasmin results in excess fibrinolysis and
    causes lysis of fibrin thrombi at sites of vascular
    injury.
    • Liver Cirrhosis
    • Amyloidosis
    • Acute Promyelocytic Leukemia
    • Some solid tumors
    • and certain snake envenomation
    syndromes
    • Increased fibrinolysis is important to
    recognize because epsilon-aminocaproic
    acid (EACA) may be required to prevent or
    control bleeding.

    • Diminished fibrinolytic activity has been


    associated with a variety of thrombotic
    disorders, but a direct cause-and-effect
    relationship has yet to be established.
    • Diminished fibrinolysis has also been reported
    in
    a.) "idiopathic" venous thrombosis
    b.) oral contraceptive-induced and post-operative
    venous thrombosis
    c.) coronary artery disease
    d.) cerebrovascular disease
    e.) systemic lupus erythematosus
    f.) thrombotic thrombocytopenic purpura

    but the significance of abnormal fibrinolysis in


    these disorders is uncertain.
    Large, prospective studies of fibrinolytic
    variables as risk factors for vascular and
    thrombotic disease are needed to determine
    whether pharmacologic augmentation of
    impaired fibrinolysis could be useful in the
    prevention or treatment of these disorders.

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