Coagulation disorders

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  • Normal hemostasis
    • arteriolar vasoconstriction ismediated by endothelin– a potent endothelium-derived vasoconstrictor (MCQ)
    • Endothelial injury exposes highly thrombogenic subendothelial extracellular matrix (ECM), facilitating platelet adherence and activation. (MCQ)
    • Primary hemostasis
      • Activation of platelets results in a dramatic shape change as well as the release of secretory granules.
      • Within minutes the secreted products recruit additional platelets (aggregation)to form a hemostatic plug
    • Secondary hemostasis
      • Tissue factor is exposed at the site of injury
      • Also known as factor III and thromboplastin (MCQ)
      • tissue factor is a membrane-bound procoagulant glycoprotein
      • synthesized by endothelial cells. (MCQ)
      • It acts in conjunction with factor VII as the major in vivo initiator of the coagulation cascade, eventually culminating in thrombin generation.
      •  Thrombin
        • cleaves circulating fibrinogen into insoluble fibrin, creating a fibrin meshwork
        • it induces additional platelet recruitment and activation
        • This sequence, consolidates the initial platelet plug
        • Polymerized fibrin and platelet aggregates form a solid, permanent plug to prevent any further hemorrhage.
    • Endothelium
      • Normally, endothelial cells exhibit antiplatelet, anticoagulant, and fibrinolytic properties(MCQ)
      • After injury or activation they acquire numerous procoagulant activities
      • endothelium can be activated by
        • trauma , plasma mediators, and cytokines
        • infectious agents, hemodynamic forces

Bleeding disorders related to defective platelet functions

  • Inherited disorders of platelet function can be classified into
    • defects of adhesion
    • defects of aggregation
    • disorders of platelet secretion (release reaction).
  • Bernard-Soulier syndrome(MCQ)
    • Bleeding resulting from defective adhesion of platelets to subendothelial matrix (MCQ)
    • autosomal recessive disorder(MCQ)
    • caused by an inherited deficiency of the platelet membrane glycoprotein complex Ib-IX. (MCQ)
      • This glycoprotein is a receptor for vWF
      • it is essential for normal platelet adhesion to the subendothelial extracellular matrix(MCQ)
    • Glanzmann thrombasthenia(MCQ)
      • Bleeding due to defective platelet aggregation (MCQ)
      • transmitted as an autosomal recessive trait. (MCQ)
      • deficiency or dysfunction of glycoprotein IIb-IIIa, an integrin that participates in “bridge formation” between platelets by binding fibrinogen.
      • Thrombasthenic platelets fail to aggregate in response to adenosine diphosphate (ADP), collagen, epinephrine, or thrombin (MCQ)
  • Hemorrhagic diatheses related to abnormalities in clotting factors
    • Unlike the petechial bleeding seen with thrombocytopenia, bleeding due to isolated coagulation factor deficiencies most commonly manifests as (MCQ)
      • large post-traumatic ecchymoses or hematomas
      • prolonged bleeding after a laceration or any form of surgical procedure. Bleeding into the gastrointestinal and urinary tracts
      • Bleeding into weight-bearing joints (hemarthrosis), is common.
    • All coagulation factors cause bleeding except for factor XII deficiency; presumably, in vivo the extrinsic pathway and thrombin-mediated activation of factors XI and IX compensate for the absence of factor XII. (MCQ)
    • Hereditary deficiencies typically affect a single clotting factor.
      • factor VIII (hemophilia A),
      • factor IX (hemophilia B)
      • Deficiencies of vWF (von Willebrand disease) influences both coagulation and platelet function. (MCQ)
  • Vitamin K deficiency results in the impaired synthesis of factors II, VII, IX, and X and protein C.
  • The Factor VIII-vWF Complex
    • Factor VIII and vWF
      • encoded by separate genes
      • synthesized in different cells.
    • Factor VIII
      • is an essential cofactor of factor IX, which converts factor X to factor Xa
      • particularly important sources of
        • sinusoidal endothelial cells and Kupffer cells in the liver(MCQ)
        • tubular epithelial cells in the kidney(MCQ)
    • vWF
      • produced by endothelial cells and, megakaryocytes, which are the source of the vWF that is found in platelet α-granules. (MCQ)
      • Once factor VIII reaches the circulation, it binds to vWF
      • vWF stabilizes factor VIII(MCQ)
      • it has a half-life of about 2.4 hours when free and 12 hours when bound to vWF in the circulation. (MCQ)
      • Circulating vWF exists as multimers
      • In addition to factor VIII, these multimers interact with several other proteins involved in hemostasis, including collagen, heparin, and possibly platelet membrane glycoproteins.
      • the most important function of vWF is to promote the adhesion of platelets to the subendothelial matrix.
      • This occurs through bridging interactions between platelet glycoprotein Ib-IX, vWF, and matrix components such as collagen.
      • Two sources of vWF
        • Some vWF is secreted from endothelial cells directly into the subendothelial matrix, where it lies ready to promote platelet adhesion if the endothelial lining is disrupted
        • Endothelial cells and platelets also release vWF into the circulation.
          • Upon vascular injury, this second pool of vWF binds collagen in the subendothelial matrix to further augment platelet adhesion
      • vWF multimers may also promote platelet aggregation by binding to activated GpIIb/IIIa integrins; this activity may be of particular importance under conditions of high shear stress (such as occurs in small vessels). (MCQ)
    • ristocetin agglutination test. (MCQ)
      • Used to assess vWF function
      • This assay is performed by mixing the patient’s plasma with formalin-fixed platelets and ristocetin,
      • ristocetin(MCQ)
        • a small molecule that binds and “activates” vWF.
        • induces multivalent vWF multimers to bind platelet glycoprotein Ib-IX and form interplatelet “bridges.”
      • The resulting clumping (agglutination) of platelets is measured in a device called an aggregometer
      • the degree to which patient plasma promotes ristocetin-dependent platelet agglutination is a measure of vWF activity. (MCQ)
  • Von Willebrand Disease
    • most common inherited bleeding disorder of humans
    • in most of those affected, the bleeding tendency is mild and often goes unnoticed until some hemostatic stress, such as surgery or a dental procedure, reveals its presence. (MCQ)
    • The most common symptoms are
      • spontaneous bleeding from mucous membranes (e.g., epistaxis);
      • excessive bleeding from wounds
      • menorrhagia(MCQ)
    • causes a prolonged bleeding time in the presence of a normal platelet count. (MCQ)
    • usually transmitted as an autosomal dominant disorder(MCQ)
    • Type 1 and type 3 von Willebrand disease are associated with a reduced quantity of circulating vWF. (MCQ)
    • Type 1
      • an autosomal dominant disorder
      • characterized by a mild to moderate quantitative vWF deficiency
      • accounts for about 70% of all cases. (MCQ)
      • Incomplete penetrance and variable expressivity are commonly observed
      • it generally is associated with mild disease (MCQ)
    • Type 3
      • an autosomal recessive disorder
      • associated with extremely low levels of functional vWF
      • causes severe clinical manifestations.
      • It is usually caused by deletions or frameshift mutations involving both alleles.
    • Type 2 von Willebrand disease
      • characterized by qualitative defects in vWF
      • type 2A is the most common.
      • inherited as an autosomal dominant disorder.
      • vWF is expressed in normal amounts (MCQ)
      • missense mutations are present that lead to defective multimer assembly.
      • Large and intermediate multimers, representing the most active forms of vWF, are missing from plasma.
      • accounts for 25% of all cases
      • associated with mild to moderate bleeding.
    • Laboratory
      • defects in platelet function despite a normal platelet count
      • The plasma level of active vWF, measured as the ristocetin cofactor activity, is reduced. (MCQ)
      • Because vWF stabilizes factor VIII, a deficiency of vWF gives rise to a secondary decrease in factor VIII levels.
      • This may be reflected by a prolongation of the PTT in von Willebrand disease types 1 and 3. (MCQ)
    • Except in rare type 3 patients, adverse complications typical of severe factor VIII deficiency, such as bleeding into the joints, are not seen.
    • Persons facing hemostatic challenges (dental work, surgery) can be treated with (MCQ)
      • desmopressin, which stimulates vWF release
      • infusions of plasma concentrates containing factor VIII and vWF.
  • Hemophilia A (Factor VIII Deficiency)
    • most common hereditary disease associated with life-threatening bleeding
    • caused by mutations in factor VIII
    • inherited as an X-linked recessive trait (MCQ)
    • affects mainly males and homozygous females.
    • Rarely, excessive bleeding occurs in heterozygous females, presumably as a result of inactivation of the X chromosome bearing the normal factor VIII allele by chance in most cells (unfavorable lyonization).
    • About 30% of patients have no family history; their disease is caused by new mutations.
    • clinical severity correlates with the level of factor VIII activity(MCQ)
      • less than 1% of normal levels have severe disease
      • with 2% to 5% of normal levels have moderately severe disease
      • with 6% to 50% of normal levels have mild disease.
    • Why there is varying degrees of factor VIII deficiency
      • Due to heterogeneity in the causative mutations.
      • As with β-thalassemia, the genetic lesions include
        • Deletions
        • nonsense mutations that create stop codons
        • mutations that cause errors in mRNA splicing.
      • The most severe deficiencies result from an inversion involving the X chromosomethat completely abolishes the synthesis of factor VIII.
      •  Clinical presentation and Labs
        • tendency toward easy bruising and massive hemorrhage after trauma or operative procedures.
        • spontaneous hemarthroses
        • Petechiae are characteristically absent. (MCQ)
        • typically have a prolonged PTT and a normal PT.
        • Factor VIII–specific assays are required for diagnosis.
        • Both inadequate coagulation (fibrinogenesis) and inappropriate clot removal (fibrinolysis) contribute to the bleeding diathesis in hemophilia
          • In the absence of factor VIII
            • insufficient thrombin (and fibrin) is generated to create a stable clot.
            • high levels of thrombin are required to activate TAFI (thrombin-activated fibrinolysis inhibitor), a factor that inhibits fibrinolysis. (MCQ)
        • Hemophilia A is treated with infusions of recombinant factor VIII.
        • About 15% of patients with severe hemophilia A develop antibodies that bind and inhibit factor VIII,
        • Before the development of recombinant factor VIII therapy, thousands of hemophiliacs received plasma-derived factor VIII concentrates containing HIV, and many developed AIDS (MCQ)
  • Hemophilia B (Christmas Disease, Factor IX Deficiency)
    • inherited as an X-linked recessive trait (MCQ)
    • In about 15% of these patients, factor IX is present but nonfunctional.
    • PTT is prolonged and the PT is normal
    • treated with infusions of recombinant factor IX.


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