Bleeding disorders and thrombophilia

Clinical bleeding history
1. Location and type
  1. Mucosal bleeding
    1. Defect in primary hemostasis
  2. Petechiae, ecchymoses, purpura
  3. Body cavity bleeding
    1. Defect in secondary hemostasis
2. True purpura
3. Palpable purpura
4. Telangectasia
5. Symptoms highly suggestive of bleeding disorders
  1. Epistaxis but only if it lasts more than ten minutes
  2. Bruising and hematomas without trauma
  3. Prolonged bleeding after dental work (after 4-6 hours)
  4. Post-operative bleeding
  5. In women: menorrhagia (defined as bleeding during cycle period >80cc)
Thrombocytopenias
1. Thrombocytopenias with increased platelet consumption
  1. Immune pathogenesis
    1. Idiopathic acute thrombocytopenic purpura in childhood
    2. Idiopathic thrombocytopenic purpura in adults
    3. Autoimmune thrombocytopenia of pregnancy
    4. Passive alloimmune thrombocytopenia
    5. Neonatal immune thrombocytopenia
    6. Thrombocytopenia secondary to other autoimmune diseases
    7. Thrombocytopenia secondary to drug administrations
      1. Heparin-induced thrombocytopenia
  2. Not exclusively immune pathogenesis
    1. Thrombocytopenia of infectious diseases
    2. Hemolytic micro-angiopathies
      1. Thrombotic thrombocytopenic purpura (TTP)
        Mutations in the gene encoding for ADAMTS13
        Clinical manifestations
      2. Atypical hemolytic-uremic syndrome
        Occur either following an infection or it can occur in otherwise healthy people that have problems with their complement components
2. Impaired thrombocytopoiesis
  1. Alcohol-related thrombocytopenias
  2. Hereditary thrombocytopenias
  3. Acquired aplastic anemia
  4. Fanconi's anemia
  5. Secondary to hematologic neoplasms
  6. Congenital hypo-megakaryocytosis
3. Platelet sequestration
  1. Hypersplenism secondary to liver cirrhosis
4. Hemodilution
  1. Massive transfusions
  2. Thrombocytopenia of pregnancy
Platelet function disorders
1. Platelet function evaluation
  1. Aggregometry
  2. Platelet function analyzer
  3. Antibodies
  4. Flow cytometry
2. Congenital platelet membrane receptor defects
  1. Glycoprotein Ib-IXb deficiency
  2. Glycoprotein IIb-IIIa deficiency
  3. Glycoprotein VI deficiency
  4. P2Y1-P2Y12 deficiency
  5. TP deficiency
  6. PARs deficiency
3. Congenital platelet granule defects
  1. Storage Pool disease (decrease in delta granules)
  2. Grey Platelet syndrome (decrease in alpha granules)
4. Acquired platelet function disorders
  1. Glanzmann thromboasthenia (no IIb-IIIa receptor for fibrinogen)
  2. Bernard-Soulier syndrome (deficiency receptor for vWF)
Disorders of secondary hemostasis
1. Screening tests
  1. APTT – Activated Partial Thromboplastin Time
  2. PT – Prothrombin Time
2. Mixing studies
  1. Done when patients have abnormal APTT or PT values and their plasma is mixed with normal plasma
3. Congenital coagulation disorders
  1. Hemophilia A
    1. Factor VIII deficiency
    2. In order to cure it, factor VIII is synthesized and administered
    3. X-linked
    4. Different forms
      1. Severe
      2. Moderate
      3. Mild
      4. Subclinical
  2. Hemophilia B
    1. Factor IV deficiency
    2. X-linked
  3. Hemophilia C
    1. Factor XI deficiency
    2. Autosomally inherited
    3. No bleeding within joints (contrarily to A and B)
  4. Von-willebrand disease, afibrinogenemia and factor XIII deficiency
    1. Autosomally inherited
    2. Von-Willebrand disease
      1. Type 1
        Partial quantitative deficiency of vWF
      2. Type 2
        Qualitative deficiency
      3. Type 3
        Complete deficiency of vWF
      4. Diagnosis is done with a specific bleeding score
4. Acquired coagulation disorders
  1. Liver disease
    1. All clotting factors (except vWF, produced in endothelial cells) are produced by hepatocytes
    2. Liver also produces all the naturally occurring anti-coagulant factors
  2. Massive transfusion syndrome
  3. DIC
    1. Non-overt DIC
      1. Present in many cancers
      2. Increased risk of thrombosis of the microcirculation
    2. Overt DIC
      1. Decreased platelet count and with an especially prolonged PT
      2. Fibrinogen levels may be markedly reduced
      3. Sepsis is the most common underlying cause of DIC
    3. Inflammation is a reason for hypercoagulability
  4. Spontaneous inhibitors of clotting factors
    1. Some patients produce auto-Abs against all the various factors
Thrombophilia
1. Initially defined as Anti-thrombin deficiency
2. Considered in cases of:
  1. Purpura fulminans neonatalis
  2. VTE at young age (<50y) and recurrent episodes of VTE
  3. Thrombosis occurring at unusual sites (IVC, mesenteric veins, renal veins, hepatic veins, cerebral veins)
  4. Family history of VTE
  5. Idiopathic VTE
  6. Coexistence of arterial and venous thrombosis
3. Necessary but not sufficient factor for the development of thrombosis
Venous thromboembolism
Virchow's triad - thrombosis is given by:
1. Blood stasis
2. Vessel wall defects
3. Blood composition
Congenital deficiencies of natural anticoagulant system
1. Normal anticoagulant system characterized by 3 molecules:
  1. TFPI
  2. Anti-thrombin
  3. Protein C
2. Autosomal dominant transmission
  1. Anti-thrombin deficiency
  2. Protein C deficiency
  3. Protein S deficiency
    1. Type I
      1. Decrease in total amount of protein S molecules
    2. Type II
      1. Qualitative mutation of the free protein S
    3. Type III
      1. Quantitative defect by reducing the number of free protein S
Acquired deficiencies
1. Lupus anticoagulant
Gain-of-function mutations
1. Factor V Leiden
2. G20210A mutation in prothrombin gene
3. Factor IX mutation
4. Prothrombin mutation
5. Hyper-homocysteinemia

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Bleeding disorders and thrombophilia

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	Created by LewisLewis almost 11 years ago