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Overview of Rare Coagulation Deficiencies
Factor VIIFactor XI
Glanzmann Thrombasthenia
Nathalie AubinThe Montreal Children’s HospitalMcGill University Health Centre
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
Intrinsic Pathway(PTT)
SurfaceHKPK
XII XIIa
XI XIaCa2+
HK
XI XIa
X Xa
Ca2+
PLVIII VIIIa
Extrinsic Pathway(PT)
VII
VIIa + TFCa2
X
Vascular injury
V VaCa2+
PL
Prothrombin Thrombin
Fibrinogen Fibrin monomer
Fibrin polymer
Cross-linked fibrin polymer
XIIIa
XIII
Common Pathway
Adapted by MW King. The Medical Biochemistry pagehttp://www.indstate.edu/theme/mwking/bloodcoagulation.html
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
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*
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
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
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
Management
1. Fresh - Frozen Plasma:Content of Factor VII in normal plasma is 1 unit/ml Volume overload can be a problem
2. Factor VII Concentrates:1 unit/kg will increase the Factor VII in the blood by 1.7%Prophylaxis dosing: 10-50 unit/kg 1-3 times/week
3. Recombinant Factor VIIa:Dosing: 20mcg/kg
4. Prothrombin Complex
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 < 1%
• Both parents were heterozygous with levels of 40%
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
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
SurfaceHKPK
XII XIIa
XI XIaCa2+
HK
XI XIa
X Xa
Ca2+
PLVIII VIIIa
VII
VIIa + TFCa2
X
Vascular injury
V VaCa2+
PL
Prothrombin Thrombin
Fibrinogen Fibrin monomer
Fibrin polymer
Cross-linked fibrin polymer
XIIIa
XIII
Common Pathway
Intrinsic Pathway(PTT)
Extrinsic Pathway(PT)
Adapted by MW King. The Medical Biochemistry pagehttp://www.indstate.edu/theme/mwking/blood-coagulation.html
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%)
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*
Classification
Normal levels of Factor XI activity range from 70-150%
1. Severe deficiency (level < 15%)
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.***
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
Symptoms
Most common symptoms:
• Mucosal bleeding
• Menorrhagia and postpartum hemorrhage
• Bruising
• Bleeding with surgical intervention
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
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
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
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
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+
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
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)
Platelet Adhesion & Aggregation
Source: Disorders of the platelet function, from the Canadian Hemophilia Society website
Inheritance Pattern & Incidence
• Autosomal recessive disorder
• Affects male and female equally
• Incidence 1/ 1,000,000
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
Classification
Three types of severity depending on the importance of the platelet deficiency in GlycoproteinIIb/IIIa:
1. Type 1 (Severe): level < 5% of normal
2. Type 2 (Less severe): level between 5-20% of normal
3. Type 3 (Least severe): a variant of Thrombasthenia. Level is normal but with abnormalities in the way platelets aggregate
Symptoms
• Purpura
• Mucosal bleeding: nose, mouth
• Gastro-intestinal, CNS hemorrhage (rare)
• Menorrhagia, postpartum hemorrhage
Management
1. Platelets:Effective treatment but it’s use is often limited by the appearance of antibodies that destroy the transfused platelets
2. Recombinant Factor VIIa:Useful in patient who no longer respond to platelet transfusions or to avoid the development of platelet antibodies
3. Antifibrinolytic agent
4. Hormonal therapy for women:May control menorrhagia
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
Case Presentation
• Blood work:
Platelet aggregation: 0
Bleeding time: > 30 minutes
• Hemorrhoidectomy performed and treated with:
Platelets transfusion
Antifibrinolytic therapy
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
Booklets
Booklets available:
• Fibrinogene
• Factor V
• Factor VII
• Factor X
• Factor XII
• Factor XIII
• Glanzman Disease
In Progress:
• Factor XI
• Bernard Soulier Syndrome