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Flashcards in Inherited Bleeding Disorders Deck (12):
1

What is the diagnostic approach to a patient with a possible bleeding disorder?

  • Ask about previous bleeding problems
  • Easy bruising can be a clue, though many who do not have a hemorrhagic disorder will have easy bruising
  • Inquire whether any excessive bleeding occurs with menses or after surgical procedures; e.g. dental extraction, tonsillectomy, etc.
  • Inquire about any past bleeding with trauma or daily activities.
  • Ask about medications - particularly aspirin, over-the-counter medications, use of herbals.
  • Inquire about a family history of a bleeding disorder or bleeding symptoms
  • Laboratory tests for coagulation disorders:
    • Prothrombin time (PT)
    • Activated Partial Thromboplastin Time (PTT)
    • PT or PTT mixing study
    • Thrombin time
    • Specific clotting factor activity assays
    • Genetic sequencing of specific clotting factor genes

2

What are the major types of vascular purpuras?

  • Anatomic malformations
    • Hemangiomas
      • may be extensive in the newborn
      • if small and confined to skin, only a cosmetic problem
      • In organs such as gut or brain, may be associated with bleeding, abscesses
    • Hereditary Hemorrhagic Telangiectasia
      • Etiology: mutations in endoglin or ALK1 genes result in dysregulated transforming growth factor-b
      • Autosomal dominant inheritance
      • Dilated vascular channels in dermis, recurrent epistaxis, gastrointestinal bleeding, organ dysfunction due to lesions in lung & liver
      • Develop severe iron deficiency anemia
      • Management: iron replacement, occasionally estrogens, anti-fibrinolytics
  • Connective tissue disorders
    • Ehlers-Danlos Syndrome
      • mutations in genes coding for collagen type III cause weak-walled arteries resulting in aneurysms, dissections, ruptures
      • clinically, hyperextensibility of joints, thin skin, poor wound healing

3

What are the bleeding vs. nonbleeding clotting factor disorders? How are they differentiated?

  • The non-bleeding disorders are recognized by a prolonged aPTT test, but patients are asymptomatic
    • Specific assays are available to distinguish the various types
  • Bleeding:
    • factor XI
    • factor IX
    • factor VIII
    • von Willebrand factor
  • Non-bleeding:
    • non-bleeding
    • factor XII
    • pre-kallikrein
    • high molecular-weight
    • kininogen

4

What is the incidence of the bleeding disorders due to clotting factor deficiency?

  • Factor VIII deficiency
    • 1/5000 live male births
  • Factor IX deficiency
    • 1/30000 live male births
  • Factor XI deficiency
    • Rare, except ~9% Ashkenazi Jews carry mutation
  • Von Willebrand Disease
    • Up to 1/1000 persons

5

What are some causes of hemophilia A and B?

  • Characteristics of Classical (factor VIII or IX) Hemophilia:
    • X-linked disorder – Gene is on X chromosome. 
  • Half of the severe FVIII type is due to inversion & translocation of exons 1-22 away from exons 23-26 due to homologous recombination between the F8A gene in intron 22 and one of the extragenic F8A copies 400 kb 5’ to the FVIII gene
    • Other causes of FVIII hemophilia and FIX hemophilia are due to gene deletions, point mutations, etc.

6

What is the role of factors VIII and IX in the clotting cascade?

  • Factors VIII and IX, when activated in the presence of phospholipid and calcium, form the tenase complex which activates factor X: a critical step in coagulation
  • Although factor X may be activated by tissue factor-factor VIIa complex, only small amounts are formed and these are quickly inactivated by the tissue factor pathway inhibitor (TFPI) and the Z-protease inhibitor (ZPI)
  • Activated factors VIII and IX greatly augment factor Xa production and this greatly enhances thrombin generation and fibrin formation
    • Thus, defects in factors VIII or IX are associated with impaired thrombin generation and clinically important bleeding

7

What affects the severity of hemophilia A and B? What are the clinical presentations?

  • Severity of Disease:
    • Clotting factor activity determines whether it is clinically mild (>5%), moderate (1%-5%), or severe (<1%)
  • Clinical Features of Severe Hemophilia A or B:
    • In infancy they may present with:
      • bleeding from circumcision
      • bruising
      • bleeding from frenulum
    • When an infant starts to crawl or walk then they can present with bleeding into the large joints
    • Spontaneous joint bleeds (hemarthroses) occur most often in those with severe disease, and sometimes in those with moderate disease
    • Potentially fatal bleeding can occur from injuries, especially to the head or abdomen
    • Persistent oozing after dental extractions may also be present
    • Sometimes those with mild disease are not diagnosed until they are adults when they have a traumatic injury or undergo surgery or an invasive procedure

8

What is the treatment protocol for hemophilia A and B?

  • Replacement of the missing clotting factor quickly prevents or controls bleeding
    • However, clotting factor concentrates must be infused intravenously
    • These are either high purity concentrates made from plasma, or proteins prepared by recombinant DNA technology
    • They may be given on demand - that is, to treat a bleeding episode, or as prophylaxisto prevent bleeding
  • If a patient with hemophilia is bleeding, or suspected to be bleeding, the appropriate clotting factor (FVIII or FIX) is given immediately and then studies are performed to determine the extent and location of bleeding
    • If prophylaxis is required, FVIII concentrates must be given at least every other day because the half-life of FVIII is only 12 hrs
    • FIX has a half-life of up to 20 hrs so may be given twice weekly
    • The two major problems are providing long term venous access, and the high costs of the products. 
  • Transmission of infectious agents is very infrequent now because of the high purity and viral inactivation procedures used to make concentrates, although prion particles and some non-enveloped viruses such as hepatitis A and parvovirus may resist inactivation steps

9

What are some complications of treatment for hemophilia A and B?

  • As many as 25% of patients with FVIII mutations may develop antibodies (known as inhibitors) to FVIII concentrates, rendering them resistant to treatment
  • Less than 5% of those with FIX deficiency develop such antibodies
  • There is some success in inducing immune tolerance in patients with antibodies

10

What is the etiology, presentation, and management of factor XI deficiency?

  • Factor XI activates factor IX to augment factor Xa production and thereby increase thrombin generation
  • Thrombin forms a complex with thrombomodulin that activates the thrombin activatable fibrinolysis inhibitor (TAFI)
  • Factor XI deficiency results in less thrombin and less TAFI, promoting more active fibrinolysis
  • Bleeding associated with increased fibrinolytic activity is usually from mucous membranes and onset delayed
  • Genetics: Autosomal inheritance
    • Type II and III molecular defects occur in Ashkenazi Jews
    • Type II is more severe, and ⅓ develop antibodies when treated with plasma
  • For all types, severity of bleeding is poorly correlated with factor XI levels
  • Replacement therapy with fresh frozen plasma is necessary for serious bleeding/surgery

11

What are the presentation of factor XIII deficiency?

  • Very rare, recessive bleeding disorder
  • Characterized by delayed, recurrent bleeding from wounds and poor wound healing

12

What are some deficiencies of the extrinsic and common pathways?

  • Congenital deficiencies of these factors (I, II, V, VII, X) are quite rare, but all result in bleeding
  • Fibrinogen (factor I) – Abnormalities include:
    • afibrinogenemia
    • hypofibrinogenemia
    • dysfibrinogenemia
  • Severity of bleeding is variable and is most severe in those with afibrinogenemia