Congenital Clotting Factor Disorders

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					Disorders of Coagulation: A Review

Hereditary Disorders of the Vascular System

I. Hereditary Hemorrhagic Telangectasia

  A. Osler-Weber-Rendu Disease
  B. Autosomal Dominant, most commonly seen of the congenital vascular disorders
  C. Clinical Symptoms:
    1.     family history of hemorrhage, epistaxis
    2.     flat, red lesions on mucous membranes, palms and soles of the feet. On autopsy, may be
           found in any organ.

    3.     lesions are composed of dilated capillaries and small venules, cause unknown
    4.     telangiectases (lesions) develop in childhood and become more pronounced with age.
    5.     may develop hypochromic, microcytic anemia due to chronic blood loss
    6.     Bleeding Time- Normal or Prolonged
    7.     Tourniquet Test- Abnormal
    8.     normal platelet function

II. Ehlers-Danlos Syndrome (Rubberman syndrome)

    1.     autosomal dominant
    2.     decreased subendothelial connective tissue, particularly collagen
    3.     extreme vessel fragility due to lack of support tissue
     4.       skin and subcutaneous hemorrhage due to vessel rupture
     5.       degree of symptoms vary
     6.       epistaxis (nosebleeds)
     7.       Bleeding Time- Prolonged

Acquired Disorders of the Vascular System

1. Senile Purpura -          degeneration of collagen with age and exposure to sunlight leads to small
                             ecchymoses (bruises).

2. Scurvy -                  deficiency of Vitamin C. This vitamin is needed for collagen synthesis.
                             Bleeding around gums and hair follicles is characteristic. Bleeding time is
                             normal. Treatment is oral Vitamin C.

3. Allergic Purpura-         usually occurs in children over the age of two. Usually follows a previous
                             infection. Sudden onset, self-limited. Immune component thought to play a
                             role. GI symptoms accompany the appearance of the lesions.

4. Infection -               Many different organisms may be causative.     Damage to vessels thought to
                             be immune in nature.
5. Drug Induced -
 6. Purpura Simplex -         "Easy Bruising", usually occurs in young women, most laboratory testing is
                                    inconclusive, 30-40% of patients have anti-platelet antibodies.

                                            Platelet Disorders

I. Quantitative Platelet Disorders

  A. Thrombocytopenia plt count [< 150,000]
    1. 5 major classes
          a.        increased destruction
                   1. immune
                   2. non-immune
          b.       decreased or ineffective production
          c.       increased splenic sequestration
          d.       multifactoral causes

     2. Thrombocytopenia due to Immune type Destruction
            a.    idiopathic (Idiopathic Thrombocytopenic Purpura)

                    1) Chronic ITP
                             a. affects women more than men
                             b. history of petechiae, epistaxis, abnormal bleeding
                             c. history of recent viral infection
                             d. therapy: corticosteroids or splenectomy
                    2) Acute ITP
                             a. found in children
                             b. abrupt onset
                             c. 50% occur after viral infection, usually in winter or spring
                             d. male/female incidence the same
                             e. 85% spontaneous recovery
                    3) Platelet destruction by immune IgG autoantibody, PAIg.
              4) Abundant megakaryocytes in marrow
              5) Lymphadenopathy/splenomegaly, maybe
       b.     transplacental autoimmune thrombocytopenic purpura (seen in infants of mothers
       c.     Alloantibodies due to transfusion or pregnancy
       d.     Drug Induced
       e.      Secondary to infectious viral, and bacterial diseases

3. Thrombocytopenia Due to Decreased Production
       a.    Megakaryocyte Hypoplasia
             Chemotherapy & Radiation Therapy
             Aplastic Anemias
       b.    Replacement of Normal Marrow
             Leukemias, Preleukemias
             Other Neoplastic Disease, Fibrous Tissue, or Granulomatous Tissue
       c.    Ineffective Megakaryopoiesis
             Megaloblastic Anemia
       d.    Hereditary Thrombocytopenias
             May-Hegglin Anomaly
     4. Thrombocytopenia due to Increased Splenic Sequestration
           a.     seen with splenomegaly and hypersplenism

     5. Thrombocytopenia due to Dilution
           a.     seen in patients receiving large quantities of banked blood transfusions.
           b.     platelets in these patients may be replaced through the infusion of platelet

     6. Multiple Factor Causes of Platelet Deficiency
            a.      Alcohol -defects of aggregation and release / also affects platelet number
            b.      Cirrhosis- hypersplenism
            c.      Lymphoproliferative disease w/bone marrow infiltration
           d.       Cardiopulmonary Bypass Surgery with extracorporeal circulation- mechanical
                    damage, intravascular coagulation

   B. Thrombocytosis [plt increased >350,000]
    1. Primary Thrombocytosis
           a.     Chronic Myeloproliferative Disease
           b.     Essential thrombocythemia
           c.     Variable Bleeding Dysfunction
    2. Secondary Thrombocytosis
           a.     following acute hemorrhage or surgery
           b.     after splenectomy
           c.     rebound thrombocytosis in recovering alcoholics or patients on chemotherapy
           d.     malignant disease, especially lung carcinoma
           e.     chronic inflammatory disease, such as RA
           f.     patients with iron deficiency anemia

II. Qualitative (functional) Disorders of Platelets

    A.       Hereditary Disorders of Platelet Function
             [Disorders of Adhesion]

             1.      Bernard-Soulier Disease
                     a.     autosomal recessive trait
                     b.     lifelong bleeding tendencies
                     c.     defect is decreased amount of fractions of membrane glycoprotein 1b. This
                            defect prevents interaction of the platelets with vWf, and prevents adhesion to
                     d.     bleeding time is abnormal
                     e.     clot retraction is normal
                     f.     aggregation testing is normal, EXCEPT for aggregation with ristocetin, which
                            requires an intact vWf/glycoprotein 1b complex. Aggregation is not
                            corrected by the addition of vWf to the reaction, but is corrected in the
                            aggregation deficit seen in Von Willebrand's Disease.
                    g.      also called Giant Platelet Syndrome due to the large platelets seen on the
                            peripheral blood smear.

            2.      von Willebrand Disease
                    a.     decreased production of von Willebrand Factor
                    b.     corrected by administration of vWf/VIII complex
                    c.     actually a plasma factor disorder

B. Hereditary Disorders of Platelet Function
           [Disorders of Primary Aggregation]

            1.       Glanzmann's Thrombasthenia
                    a.     rare disorder
                    b.     autosomal recessive lack of glycoproteins IIb and IIIa
                    c.     disease only apparent in homozygotes
                    d.     platelet count normal / prolonged bleeding time
                    e.     clot retraction abnormal
                    f.     abnormal aggregation of platelets, except with ristocetin

C. Hereditary Disorders of Platelet Function
           [Disorders of Platelet Secretion]

            1.      Heterogeneous group of disorders characterized by an abnormality in the platelet
                    granules, inhibiting the release of platelet factors upon stimulation
            2.      Occurs as one of the features of several autosomal recessive disorders such as:

                    a. Chediak-Higashi syndrome

                            1)   Autosomal Recessive Disorder
                            2)   Storage Pool deficiency
                            3)   Large Organelles positive for Acid Phosphatase
                            4)   Increased susceptability to pyogenic infections
                            5)   Bleeding Time- Prolonged
                            6)   Platelet Adhesion- Abnormal
        7) Platelet Aggregation- Abnormal

b. Wiscott-Aldrich Syndrome
       1) Sex-linked Recessive Disorder
       2) Storage Pool deficiency
       3) Immunologic disorder -B & T cell dysfunction
       4) Recurrent pyogenic infections
       5) Bleeding Time- Prolonged
       6) IgM low
       7) Platelet Aggregation- Abnormal
       8) Eczema
       9) Small platelets with decreased or absent dense bodies
      10) Mild to moderate bleeding
      11) Easy bruising
      12) Severe thrombocytopenia
(II, continued, Hereditary Disorders of Platelet Function)

                    c. Gray Platelet syndrome
                           1) Autosomal Recessive
                           2) Storage Pool deficiency
                           3) Absence of platelet alpha granules
                           4) Bleeding Time- Prolonged
                           5) Platelet Adhesion- Abnormal
                           6) Platelet Aggregation- Abnormal
                           7) Thrombocytopenia

D. Acquired Disorders of Platelet Function
          1. Uremia - due to buildup of toxic products within the blood
          2. Many Hematologic Disorders - leukemias
                        myeloproliferative diseases
                        multiple myeloma
          3. Drug Induced Platelet Dysfunction
                  a.       many drugs can affect platelet function
                  b.       Aspirin:
                  1.       inhibits the release mechanism
                  2.       acts as an inhibitor to cyclo-oxygenase
                  3.       prevents thromboxane A2 release
                  4.       permanently inhibits second wave aggregation and release
                  5.       prolongs bleeding time
                  6.       coagulation testing must not be done within 7 days of aspirin ingestion

Disseminated Intravascular Coagulation

    A.      Seen when the normal mechanisms of coagulation are activated and the inhibitory mechanisms
            are overwhelmed.
    B.      Results in the consumption of plasma coagulation factors and platelets.
    C.      Fibrinolytic systems are activated.
    D.      Blood becomes incoagulable.
    E.      Diffuse hemorrhage.
    F.      Tissue damage due to vascular occlusion.
    G.      Treatment involves infusion of fresh, frozen plasma.
    H.      Protamine Sulfate Test and FDP's are POSITIVE
    I.      PT, APTT, Thrombin Time - all PROLONGED
    J.      Factor Assays, Fibrinogen, Plasminogen - all DECREASED
                                                 Congenital Clotting Factor Disorders
 Disorder                    Inheritance                 Specific             PT      APTT            Bleeding               PTT Correction                         Comments
                             Mode                        Deficit                                      Time                        With
                                                                                                                         AS                   AP
 Factor I                           AR            fibrinogen                  P      P                     N             NO                   YES

Factor II                            ?            prothrombin                 P      P                    N             NO                   NO

Factor V                            AR            V                           P      P                    N             NO                                         PT correction w/BaSO4 plasma

Factor VII                          AR            VII                         P      N                    N             not applicable                             PT correction w/aged serum

Von Willebrand                      XR            VIII:vWF                    N      P                    P             NO                   YES                   cofactor deficit

Hemophilia A                        XR            VIII:C                      N      P                    N             NO                   YES

Hemophilia B                        XR            IX                          N      P                    N             YES                  NO

Factor X                            AR            X                           P      P                    N             YES                  NO                    PT is corrected w/aged serum

PTA Deficiency                      ?R            XI                          N      P                    N             YES                  YES

Factor XIII                         AR            XIII                        N      N                    N                                                        clot will dissolve in 5M urea or 1% monochloroacetic acid

      Monday, May 21, 2012

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