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Disoders of secondary hemostasis. Disorders of plasma clotting factors. Disorders of Secondary Hemostasis. Disorders of the proteins of fibrin formation Disorders of proteins associated with fibrinolysis Symptoms of secondary hemostatic disorders Delayed bleeding

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disoders of secondary hemostasis

Disoders of secondary hemostasis

Disorders of plasma clotting factors

disorders of secondary hemostasis
Disorders of Secondary Hemostasis
  • Disorders of the proteins of fibrin formation
  • Disorders of proteins associated with fibrinolysis
  • Symptoms of secondary hemostatic disorders
    • Delayed bleeding
    • Deep muscular bleeding
    • Spontaneous joint bleeding
    • Symptoms common to primary and secondary hemostatic disorders
      • Ecchymoses
      • GI bleeding
      • Hematuria
      • Hypermenorrhea
      • Gingival bleeding
      • Increased bleeding after tooth extraction
      • Intracranial bleeding
      • Epistaxis
disorders of proteins of fibrin formation
Disorders of Proteins of Fibrin Formation
  • Hereditary vs acquired
  • Quantitative vs qualitative deficiencies
    • Laboratory screening tests (PT, APTT)
      • Does not differentiate quantitative vs qualitative disorders
    • Qualitative abnormal proteins will
      • Prolong clotting test
      • Be recognized by immunologically-based procedures
  • Activity assays
    • Essential when screening for deficiencies
von willebrand disease
von Willebrand Disease
  • Inherited hemorrhagic disorder
    • Genetically and clinically heterogeneous
    • Caused by a deficiency/dysfunction of VWF
    • Most common hereditary bleeding disorder
  • VWF
    • Multimeric blood protein
    • Performs two major roles in hemostasis
      • Mediates adhesion of platelets to sites of vascular injury
      • Is a carrier protein for F-VIII
  • Inherited defects in VWF may
    • Interfere with biosynthetic processing or disrupt specific ligand binding sites
    • Cause bleeding by impairing either platelet adhesion or blood clotting
  • Three major categories of VWD
    • Type 1 VWD – partial quantitative deficiency of VWF
    • Type 2 VWD – qualitative deficiency of VWF
      • Divided into 4 variants
      • Type 2A – ↓ platelet-dependent function
        • Absence of high-molecular weight VWF multimers
      • Type 2B – ↑ affinity for platlet GPIb
      • Type 2M – ↓ platelet-dependent function
        • Not caused by the absence of HMW multimers
      • Type 2N – Markedly ↓ affinity for F-VIII
    • Type 3 VWD – total deficiency of VWF
    • Types 1 and 2 – autosomal dominant inheritance
    • Type 3 – autosomal recessive inheritance
  • Diagnosis
    • Specific tests
      • Quantify VWF and F-VIII activity
vwd clinical manifestations
VWD – Clinical Manifestations
  • Hemorrhagic tendency is highly variable
    • Depends on the type and severity of disease
    • Patients with Type 1 and 2 disease
      • May have mild bleeding symptoms
      • Characterized by hemorrhage from delicate mucocutaneous tissues
      • Epistaxis, easy bruising, GI bleeding, menorrhagia
      • Hematoma and hemarthroses, characteristic of hemophilia A, are not prominent
    • Patients with severe type 3 VWD
      • Severe hemorrhagic tendency
      • Spontaneous hemorrhage
        • Mucous membranes, GI tract
        • Can be frequent and may be life threatening
      • Low F-VIII level
        • Deep hematomas
        • Joint hemorrhages – similar to hemophilia
vwd therapy
VWD – Therapy
  • Goal
    • Correct both bleeding time and coagulation abnormalities
      • Raise both F-VIII and VWF to normal levels
        • Desmopressin acetate (DDAVP) stimulates release of vWF from endothelial cells – won’t work for type 3
        • Intermediate purity factor VIII which contains intact vWF
  • Hemophilia A
    • Factor VIII Deficiency
      • AntihemophilicFactor
      • X-linked recessive disorder
      • Most common type of hemophilia
  • Hemophilia B
    • Factor IX Deficiency
      • Christmas Factor (from family of first patients diagnosed with the disorder)
      • X-linked recessive disorder
  • Hemophilia C
    • Factor XI Deficiency
    • Autosomal recessive disorder seen primarily in the Ashkenazi Jewish population
    • Symptoms range from mild to severe
  • Insufficient generation of thrombinby
    • F-IXa/VIIIa complex through the intrinsic pathway of coagulation cascade
    • Bleeding severity complicated by excessive fibrinolysis
  • Clinical severity corresponds with level of factor activity
  • Severe hemophilia
    • Factor coagulant activity <1% of normal
    • Frequent spontaneous bleeding into joints and soft tissues
    • Prolonged bleeding with trauma or surgery
  • Moderate hemophilia
    • Factor coagulant activity 1-5% of normal
    • Occasional spontaneous bleeding
    • Excessive bleeding with surgery or trauma
  • Mild hemophilia
    • Factor coagulant activity >5% of normal
    • Usually no spontaneous bleeding
    • Excessive bleeding with surgery or trauma
hemophilia clinical presentation
Hemophilia – Clinical Presentation
  • Readily diagnosed
    • In severe disease and patients with prior family history
  • Diagnosis based on
    • Unusual bleeding symptoms early in life
    • Age of first bleeding varies with severity of disease
    • Family history
    • Physical exam
    • Laboratory evaluation
hemophilia treatment
Hemophilia – Treatment
  • Replacement of clotting factor to achieve hemostasis
    • Annual cost for patient with severe hemophilia
      • $20,000-100,000
  • Various products available
    • Plasma-derived low, intermediate and high purity products
    • Plasma-derived ultrapure products
    • Ultrapure recombinant products
  • Replacement products – benefits vs risks
    • Blood-born pathogens
      • Hepatitis A, B, C, G; HIV, Parvovirus B-19
      • Thrombotic complications with some F-IX concentrations
      • Development of alloantibody inhibitors
        • Neutralize coagulant effects of replacement therapy
acquired disorders
Acquired Disorders
  • More common than hereditary disorders
    • Usually involve defects of multiple hemostatic factors
    • Bleeding often simultaneously from >1 site
    • May occur in response to another disease process
    • Can be produced by a variety of mechanisms
disseminated intravascular coagulation
Disseminated Intravascular Coagulation
  • Normal balance of hemostasis is altered
  • Results in the uncontrolled inappropriate formation and lysis of fibrin within the blood vessels
  • Activation of coagulation occurs systemically
    • Rather than locally at site of injury
  • Fibrin is deposited diffusely within capillaries, arterioles and venules
  • Clotting proteins, inhibitors and platelets are consumed faster than they are synthesized
    • Acquired deficiency of multiple hemostatic components
    • Fibrinolysis follows fibrin formation
    • Patient generally bleeds spontaneously at the same time that disseminated clotting is occurring
dic pathophysiology
DIC - Pathophysiology
  • Fibrin strands within small vessels result in
    • Traumatic destruction of RBC
      • Microangiopathic hemolytic anemia
      • Formation of schistocytes
  • Fibrin deposition in and obstruction of microvasculature
    • Tissue anoxia/microinfarcts
    • Renal failure, liver failure, respiratory failure, shock and death
  • HELLP syndrome
    • High blood pressure
    • Elevated liver enzymes
    • Low platlets
    • Occurs in pregnancy and is life-threatening
    • If the CBC of a woman in labor shows schistocytes and low platlets alert the physician immediately – the baby must be delivered immediately to save the mom!
dic laboratory diagnosis
DIC – Laboratory Diagnosis
  • Laboratory diagnosis is difficult
    • Available tests are nonspecific
    • No single test can establish the definitive diagnosis of DIC
    • PT, APTT, TT prolonged
    • Fibrin degradation products are (+)
    • Platelet count ↓; platelet function tests abnormal
    • Schistocytes, thrombocytopenia on peripheral blood smear
dic therapy
DIC – Therapy
  • Eliminate underlying cause, if possible
    • Acute DIC is often self-limited
      • Will disappear when fibrin is lysed
    • Replacement therapy
      • Platelets, RBC, Cryoprecipitate or fresh frozen plasma
vitamin k deficiency
Vitamin K Deficiency
  • Precursor proteins synthesized by hepatocytes
    • Not γ-carboxylated
    • Ca++-binding sites are nonfunctional
    • Induced functional deficiencies of all vitamin-K dependent proteins
    • Causes of vitamin K deficiency in adults
      • Malabsorptive syndromes
      • Biliary tract obstruction
      • Prolonged broad-spectrum antibiotics
  • Most often seen in newborns
    • Hemorrhagic disease of the newborn
      • Due to newborn hepatic immaturity
acquired pathologic inhibitors
Acquired Pathologic Inhibitors
  • Circulating anticoagulants
    • Usually IgG or IgM immunoglobulins
    • Inhibitors of single factors
      • Patients with inherited factor deficiencies
        • After treatment with replacement concentrates
      • Associated with other conditions
        • Diseases, drugs
      • Occasionally seen in otherwise healthy individuals
      • Interfere with or neutralize clotting factor activity
      • Prolonged screening test not corrected by 1:1 mixture with normal plasma