Overview of Rare Coagulation Deficiencies

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Overview of Rare Coagulation Deficiencies

• Factor VIIFactor XIGlanzmann Thrombasthenia

Nathalie AubinThe Montreal Childrens
HospitalMcGill University Health Centre
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Factor VII

• Trace protein in blood produced in the liver and
  vitamin K dependant
• TF combined with activated Factor VII triggers
  the coagulation cascade resulting in the
  generation of thrombin and fibrin clot

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Adapted by MW King. The Medical Biochemistry
pagehttp//www.indstate.edu/theme/mwking/bloodcoa
gulation.html
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Inheritance Pattern Incidence

• Autosomal recessive disorder
• Equally frequent in male and female
• Disorder more prevalent in countries where
  consanguineous marriage occurs
• 1/300,000 and 1/500,000
• Bleeding problems observed in homozygous
  individuals and rarely in heterozygous individuals

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Diagnosis

• Often referred for increased bruising, recurrent
  epistaxis, increased bleeding after a dental
  extraction
• Family history
• Incidental finding following a pre-op workup (?
  PT)
• Blood work Prothrombin time (PT) is prolonged
  (? PT, ?INR), Factor VII assay aPTT normal

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Symptoms

• Differs from classical hemophilia
• Residual level of Factor VII is a predictor of
  bleeding symptoms patients with Factor VII level
  of 1-2 are sometimes asymptomatic
• Very variable spectrum of bleeding problems

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Symptoms (Severe Factor VII Deficiency)

• Intracranial hemorrhage
• Up to 16 of patients will experience a CNS
  bleed. Often present shortly after birth
• Hemarthrosis
• Varies considerably amongst patients

• Easy bruising and soft tissue hematomas
• Muscle bleed
• Rare event
• Mucosal bleeding
• Most common manifestation epistaxis,
  menorrhagia, dental, melena, hematuria

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Management

• Half-life of Factor VII is between 2½ hours and
  5-6 hours
• To achieve normal hemostasis 15-30 level of
  Factor VII is enough even when the patient
  undergoes surgery

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Management

• 1. Fresh - Frozen PlasmaContent of Factor VII
  in normal plasma is 1 unit/ml Volume overload can
  be a problem
• 2. Factor VII Concentrates1 unit/kg will
  increase the Factor VII in the blood by
  1.7Prophylaxis dosing 10-50 unit/kg 1-3
  times/week
• 3. Recombinant Factor VIIaDosing 20mcg/kg
• 4. Prothrombin Complex

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Case Presentation

• Parents are first cousins from Pakistan
• 3rd child of the family
• Shortly after birth a circumcision was performed
  oozing
• Fresh frozen plasma was given
• Blood work PT 100 sec. Factor VII
• Both parents were heterozygous with levels of 40

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Case Presentation

• Patient was started on prophylaxis with Factor
  VII concentrates 50 units/kg because of the risk
  of spontaneous CNS hemorrhage
• No bleeding complications since the start of
  prophylaxis

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Factor XI Deficiency

• Also known as Hemophilia C
• Trace protein found in the blood and is synthesis
  in the liver
• Plays an important role in the amplification of
  the initial coagulation response the
  coagulation process is maintained and amplified
  through the activation of FXI by Thrombin

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Intrinsic Pathway(PTT)
Extrinsic Pathway(PT)
Adapted by MW King. The Medical Biochemistry
pagehttp//www.indstate.edu/theme/mwking/blood-co
agulation.html
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Inheritance Pattern Incidence

• Autosomal recessive disorder
• Will affect both male and female equally
• Very uncommon in the general population but
  recognized in all ethnic groups
• Ashkenazi Jews most prevalent genetic defects
  in this population (8-9)

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Diagnosis

• Often referred for epistaxis, easy bruising and
  bleeding after circumcision
• Incidental finding in pre-op assessment
• Family history
• Blood work activated partial thromboplastin
  (aPTT) is prolonged. Factor XI level
• PT normal

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Classification

• Normal levels of Factor XI activity range from
  70-150
• 1. Severe deficiency (level
• Homozygous individuals
• 2. Partial deficiency (level 20-70)
• Heterozygous individuals
• coinheritance of Factor XI deficiency along
  with Von Willebrand disease as also been observed
  in patients with bleeding symptoms.

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Symptoms

• The bleeding risk is variable within an
  individual
• There is a poor correlation between the degree of
  plasma FXI deficiency and the bleeding tendency
• Most patients do not suffer from spontaneous
  bleeding, but are at risk of bleeding following
  trauma or surgery

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Symptoms

• Most common symptoms
• Mucosal bleeding
• Menorrhagia and postpartum hemorrhage
• Bruising
• Bleeding with surgical intervention

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Management

• Patients do not need prophylaxis for routine
  daily activity, but do need treatment following
  dental extraction, major surgery or trauma
• The half-life of Factor XI is estimated to be
  between 50-80 hours
• Hemostasis is achieved through level of 30 of
  normal activity

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Management

• 1. Fresh-frozen plasma
• Effective in raising FXI level but requires the
  use of large amount (risk of fluid overload)
• 2. FXI concentrates
• High purity concentrates
• Effective and easy to administer rapidly
• Risk of thrombosis associated with this product

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Management

• 3. DDAVP( Desmopressin)
• Used for heterozygous patients but the efficacy
  of DDAVP remains unclear
• 4. Antifibrinolytic agents
• Helps preventing bleeding in tissues with high
  fibrinolytic activity
• Used with women experiencing menorrhagia

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Case Presentation

• 41 year old man
• Mild Factor XI deficiency
• Diagnosed following a hemorrhage after a
  tonsillectomy as a child
• Extensive bleeding history Hemarthrosis
  following a knee injury, bleeding complications
  following 2 spinal surgeries, etc

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Case Presentation

• Cervical spine surgery planned in 2005
• Blood work
• Factor XI 29
• von Willebrand profile
• FVIIIc 51
• vW ant 45
• vW risto 73
• Blood group O

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Case Presentation

• Management for the surgery
• Patient admitted 48 hours prior to surgery for
  infusion of fresh frozen plasma to obtain
  hemostatic level of Factor XI the morning of the
  surgery
• DDAVP 20mcg IV 2 hours prior to surgery to
  increase the vW protein

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Glanzmann Thrombasthenia

• Discovered in Switzerland by a pediatrician named
  Glanzmann in 1918. Children affected with the
  disease all came from a tiny village named Le
  Valais. There were frequent marriages between
  close relatives in this village.
• Defect in the platelet glycoprotein IIb/IIIa
  which is a receptor on the surface of the
  platelet that allows platelets to interact with
  the blood vessel wall or with other blood cells
• Affects the ability of the blood platelets to
  aggregate (platelet clumping)

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Platelet Adhesion Aggregation
Source Disorders of the platelet function, from
the Canadian Hemophilia Society website
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Inheritance Pattern Incidence

• Autosomal recessive disorder
• Affects male and female equally
• Incidence 1/ 1,000,000

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Diagnosis

• Often referred for soft tissue hematomas,
  epistaxis, mouth bleeding, menorrhagia
• Family history
• Blood work
• Bleeding time will be prolonged
• Platelet aggregation studies failure of
  platelets to aggregate or reduced aggregation

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Classification

• Three types of severity depending on the
  importance of the platelet deficiency in
  GlycoproteinIIb/IIIa
• Type 1 (Severe) level
• Type 2 (Less severe) level between 5-20 of
  normal
• Type 3 (Least severe) a variant of
  Thrombasthenia. Level is normal but with
  abnormalities in the way platelets aggregate

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Symptoms

• Purpura
• Mucosal bleeding nose, mouth
• Gastro-intestinal, CNS hemorrhage (rare)
• Menorrhagia, postpartum hemorrhage

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Management

• PlateletsEffective treatment but its use is
  often limited by the appearance of antibodies
  that destroy the transfused platelets
• 2. Recombinant Factor VIIaUseful in patient
  who no longer respond to platelet transfusions or
  to avoid the development of platelet antibodies
• 3. Antifibrinolytic agent
• 4. Hormonal therapy for womenMay control
  menorrhagia

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Case Presentation

• 36 year old man from Pakistan
• Parents were first cousins
• Older brother died at 10 days old from
  circumcision hemorrhage
• Major bleeding problem through his life
  epistaxis
• In past year
• bleeding hemorrhoids
• Admitted 2X for decreased hemoglobin

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Case Presentation

• Blood work
• Platelet aggregation 0
• Bleeding time 30 minutes
• Hemorrhoidectomy performed and treated with
• Platelets transfusion
• Antifibrinolytic therapy

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Recommendations

• Physical activity to stay fit
• Appropriate gear for sporting activities
• Dental prevention
• No ASA, Ibuprofen
• Avoidance of herbal remedies
• Vaccination
• Identification (bracelet, wallet card)
• Comprehensive care team

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Booklets

• Booklets available
• Fibrinogene
• Factor V
• Factor VII
• Factor X
• Factor XII
• Factor XIII
• Glanzman Disease

• In Progress
• Factor XI
• Bernard Soulier Syndrome