Presentation

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



• 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



• 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

Documents

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