GYN GENETICS: Inheritance of Coagulation Disorders

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GYN GENETICSInheritance of Coagulation Disorders

• Jeff Seale, M.D.
• Department of Obstetrics and Gynecology
• University of Tennessee, Memphis

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Creog Objective

• Describe the inheritance of coagulation disorders.

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Inherited Thrombophilia

• Antithrombin III Deficiency
• Protein C Deficiency
• Protein S Deficiency
• Activated Protein C Resistance (Factor V Leiden)
• Plasminogen Deficiency

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Congenital Antithrombin III Def.

• Antithrombin III acts as an anticoagulant by
  directly binding and inactivating the serine
  proteases ( Factors XI, Ixa, Xa, and Thrombin).
• Heparin increases Antithrombin III activity.

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Congenital Antithrombin III Def.

• Inheritance usually autosomal dominant
• Most patients are heterozygous.
• Types
• Type 1 (Classic) There is reduced synthesis
  of the Antithrombin III molecule
• Type 2 The level of Antithrombin III is
  normal but the protein is dysfunctional.

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Congenital Antithrombin III Def.

• Types
• Type 1 (Classic) There is reduced synthesis
  of the Antithrombin III molecule
• Type 2 The level of Antithrombin III is
  normal but the protein is dysfunctional.
• Type 3 Normal quantity and quality of
  molecule but it lacks the receptor for heparin
  and therefore can not be accelerated.

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Congenital Antithrombin III Def.

• Clinical Features
• Increased risk of DVT and PE.
• Thrombosis events begin in mid-late teenage
  years.
• Events occur with 40-60 of normal activity.
• Homozygous is fatal in utero.
• May be precipitated by OCP, surgery, trauma,
  pregnancy or infection.

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Congenital Protein C Def.

• Protein C is a Vitamin K-dependent protein and is
  an inhibitor of the procoagulant system.
• It is synthesized in the liver as an inactive
  form. The activated protein functions to
  inactivate Factors Va and VIIIa,
• The activity is enhanced by its cofactor Protein
  S.

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Congenital Protein C Def.

• Inherited as an autosomal dominant disorder and
  may account up to 5-10 of patients with early
  clotting problems.
• Heterozygous individuals have levels 30 to 60 of
  normal.
• Homozygous have little to no Protein C.

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Congenital Protein C Def.

• Types
• Type 1 Decreased levels of Protein C.
• Type 2 Normal level of molecule but decreased
  functional activity.

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Congenital Protein C Def.

• Clinical Features
• Increased risk for DVT and PE.
• Thrombosis events begin in mid-late teenage
  years. Homozygous often die in early infancy.
• May be precipitated by OCP, surgery, trauma,
  pregnancy or infection.

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Congenital Protein C Def.

• Protein S is also a Vit. K-dependent factor.
• It functions as a cofactor to Protein C in the
  inactivation of Factors Va and VIIIa.
• In the circulation, it exists in two forms free
  form and bound form to complement proteinC4b.

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Congenital Protein C Def.

• Inheritance is autosomal dominant.
• Two Types
• Type 1 Decreased free Protein S, but adequate
  bound levels.
• Type 2 Decreased free and bound levels of
  Protein S.

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Congenital Protein C Def.

• Clinical features
• Similar to Protein C Def.
• 50 will have 1st thrombosis event before age 25.
• 44 will have other provocations, while the
  remaining 56 will have spontaneous thrombosis.

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Activated Protein C Resistance (Factor V Leiden)

• Factor V is a proenzyme that is activated to
  Factor Va, whose function is to catalyze the
  activation of prothrombin to thrombin.
• Remember, activated Protein C along with Protein
  S inactivates both Factor Va and VIIIa.

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Activated Protein C Resistance (Factor V Leiden)

• Inheritance is autosomal dominant.
• Both homo. and heterozygous individuals with the
  mutation can develop thrombosis.
• Homo. have 91 times increase in thrombosis
  events.
• Mean onset for homo. is age 31.
• Mean onset for hetero. is age 44.

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Activated Protein C Resistance (Factor V Leiden)

• Clinical features are similar to Antithrombin
  III, Protein C and S Def.

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Congenital Plasminogen Def.

• Fibrinolysis
• Crosslinked fibrin is the end product of the coag
  cascade.
• The fibrolytic system breaks down cross-linked
  fibers to avoid excessive thrombosis.
• Plasmin is the molecule that is directly
  responsible for degrading fibrin.
• Plasminogen activator converts plasminogen to is
  active form, plasmin.

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Congenital Plasminogen Def.

• Inheritance Autosomal dominant
• Very rare
• Two forms Absent plasminogen and dysfunctional
  plasminogen.
• Clinical features are similar to Antithrombin
  III, Protein C and S Def.
• aPT, Aptt, platelet count, thrombin time and
  bleeding time are all normal.

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Inherited Bleeding Disorders

• VonWillebrand Disease
• Factor VIII Def. (Hemophilia A)
• Factor IX Def. (Hemophilia B)
• Factor XI Def.
• Factor I Def. (fibrinogen)

• Factor II Def. (prothrombin)
• Factor V Def.
• Factor VII Def.
• Factor X Def.
• Factor XIII Def.

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VonWillebrand Disease

• VonWillebrand Factor has two main functions
• It facilitates platelet adhesion to the vessel
  wall by linking platelet membrane receptors to
  the subendothelium.
• It serves as the plasma carrier for Factor VIII
  and stabilizes the molecule.

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VonWillebrand Disease

• VonWillebrand Disease is the most common
  inherited bleeding disorder.
• Incidence 1in 100 to 1000.
• Major GYN and antepartum problems seem to be
  rare, but has high incidence of postpartum
  hemorrhage.
• Two main types.

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VonWillebrand Disease

• Most common form is inherited by autosomal
  dominance.
• Most patient are Heterozygous.
• Mild to moderate decrease in plasma levels of the
  factor.
• Most patients have mild disease with excessive
  bleeding after surgery or trauma.

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VonWillebrand Disease

• Rare form of the disease is inherited by
  autosomal recessive.
• Severe form of the disease and has bleeding
  similar to hemophilia.

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Hemophilia A (Factor VIII
Def.)

• Inheritance is x-linked recessive.
• Incidence is 1 in 5000 live male births.
• Symptoms can occur in females due to mosiacism.
• It is a quantitative def. in the synthesis of
  Factor VIII.
• Factor VIII gene is large and appears to undergo
  frequent mutations.
• One of the mutations in severe hemophilia A is an
  inversion within the gene.

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Hemophilia A (Factor VIII
Def.)

• Clinical features
• Usually male since x-linked recessive.
• Excessive bleeding at time of circumcision.
• History of extensive bleeding after trauma or
  spontaneous bleeding into joints and muscles.
• Severity of bleeding depends on level of Factor
  VIII.
• Females may have excessive bleeding during menses
  or labor/postpartum, but is rare.

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Hemophilia A (Factor VIII
Def.)

• Mild hemophilia Factor VIII 5-50 - has little
  risk for spontaneous bleeds but may bleed
  excessively after surgery or trauma.
• Moderate hemophilia Factor VIII 1-4
• Severe hemophilia Factor VIII lt1 - at risk for
  spontaneous hemorrhages and soft tissue bleeds.

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Hemophilia B (Factor IX Def.)

• Inheritance is x-linked recessive.
• Incidence is 1 in 30,000 live male births.
• It is a quantitative def in the synthesis of
  Factor IX.
• Clinical features identical to Hemophilia A.
• Bleeding in female carriers is more common that
  in Hemophilia A, including antepartum and
  postpartum hemorrhage.

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Factor XI Def.

• Inheritance is autosomal recessive
• Increased frequency in Ashkenazi Jews -
  approximately 4.
• Otherwise rare.
• Results from decreased amount of the protein and
  not from abnormal protein.

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Factor XI Def.

• Clinical features
• Spontaneous bleeding rare.
• Hemorrhage usually occurring after trauma or
  surgery.
• Excessive postpartum bleeding not uncommon.

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Factor I Def.(Fibrinogen)

• Three types
• Afibrinogenemia
• Hypofibrinogenemia
• Dysfibrinogenemia

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Factor I Def.(Fibrinogen)

• Afibrinogenemia
• Rare, autosomal recessive disorder.
• Bleeding from umbilical cord may be 1st symptom.
• Bleeding usually occurs after surgery or trauma
  and may have menorrhagia.

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Factor I Def.(Fibrinogen)

• Hypofibrinogenemia
• Extremely rare, autosomal dominant or recessive
  disorder.
• Possibly a heterozygous state of afibrinogenemia.
• Hemorrhage is infrequent.

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Factor I Def.(Fibrinogen)

• Dysfibrinogenemia
• rare, autosomal dominant or recessive disorder.
• Qualitative defect in fibrinogen molecule.
• Bleeding tends to be mild.
• Bleeding from umbilical cord may be 1st symptom.
• Presents as menorrhagia, epistaxis, and
  hemorrhage after surgery or trauma.
• Some patients can have wound breakdown.
• High incidence of excessive bleeding with
  abortions.

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Factor II Def.(Prothrombin)

• Inheritance autosomal dominant or recessive.
• Extremely rare.
• Clinical features easily bruising, epistaxis,
  GI bleeding and rarely hemarthroses.

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Factor V Def.

• Inheritance autosomal recessive.
• Incidence 1 in 1 million births.
• Clinical features are the same as Factor II Def.

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Factor VII Def.

• Inheritance autosomal recessive.
• Incidence 1 in 500,000 births.
• Clinical features are similar to hemophilia,
  including menorrhagia.

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Factor X Def.

• Inheritance autosomal recessive.
• Incidence 1 in 500,000 births.
• Clinical features are the same as Factor II Def.

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Factor XIII Def.

• Inheritance autosomal recessive.
• Incidence 1 in several million births.
• May have severe post surgical or traumatic
  bleeding, which may be delayed for 12 to 36
  hours.
• Common presentation is bleeding from umbilical
  stump.
• Wound breakdown and abnormal scar formation may
  occur.

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Bibliography

• Nachman, Ralph MD and Silverstein, Roy MD.
  Hypercoagulable States. Annals of Internal
  Medicine. 1993119819-827.
• Cohen, Alice J. and Kessler, Craig M. Treatment
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• Bick, Rodger MD, FACP and Pegram, Mark MD.
  Syndromes of Hypercoagulability and Thrombosis
  A Review. Seminars in Thrombosis and Hemostasis.
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• Coleman, Hirsh, Marder and Salzman. Hemostasis
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  Practices Third Edition. 1994.
• Thomas, Duncan P. MD and Roberts, Harold MD.
  Hypercoagulability in Venous and Arterial
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• Davie, Earl W. et al. The Coagulation Cascade
  Initiation, Maintenance, and Regulation.
  Biochemistry. 19913010363-10370.

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Bibliography(Cont.)

• Dahlback, Bjorn, Resistance to Activated Protein
  C and Venous Thromboembolism. Journal of
  Clinical Investigation. 199494923-927.
• VonWillebrands Disease. Harrisons Principles of
  Internal Medicine Thirteenth Edition. McGraw
  Hill, Inc. New York. 1994.
• Thompson, Harker. Manual of Hemostasis and
  Thrombosis Third Edition.. 1983.
• Rosendaal, FR et al. High Risk of Thrombosis in
  patients Homozygous for factor V Leiden. Blood.
  199585(6) 1504-1508.
• Ratnoff, Forbes, Charles D. Disorders of
  Hemostasis Second Edition. 1991.

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