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  1. 1. Overview of Rare C oagulation D eficiencies Factor VII Factor XI Glanzmann Thrombasthenia Nathalie Aubin The Montreal Children’s Hospital McGill University Health Centre
  2. 2. F actor VII <ul><li>Trace protein in blood produce d in the liver and vitamin K dependant </li></ul><ul><li>TF combined with activated Factor VII triggers the coagulation cascade resulting in the generation of thrombin and fibrin clot </li></ul>
  3. 3. Adapted by MW King. The Medical Biochemistry page Intrinsic Pathway (PTT) Surface HK PK XII XIIa XI XIa Ca 2+ HK XI XIa X Xa Ca 2+ PL VIII VIIIa Extrinsic Pathway (PT) VII VIIa + TF Ca 2 X Vascular injury V Va Ca 2+ PL Prothrombin Thrombin Fibrinogen Fibrin monomer Fibrin polymer Cross-linked fibrin polymer XIIIa XIII Common Pathway
  4. 4. Inheritance P attern & Incidence <ul><li>Autosomal recessive disorder </li></ul><ul><li>Equally frequent in male and female </li></ul><ul><li>Disorder more pre valent in countries where consanguineous marriage occurs </li></ul><ul><li>1/300 , 000 and 1/500 , 000 </li></ul><ul><li>Bleeding problems observed in homozygous individuals and rarely in heterozygous individuals </li></ul>
  5. 5. Diagnosis <ul><li>Often referred for increase d bruising, recurrent epistaxis, increase d bleeding after a dental extraction </li></ul><ul><li>Family history </li></ul><ul><li>Incidental finding following a pre-op workup (  PT) </li></ul><ul><li>Blood work: Prothrombin time (PT) is prolonged (  PT,  INR), Factor VII assay *aPTT normal* </li></ul>
  6. 6. Symptoms <ul><li>Differs from classical hemophilia </li></ul><ul><li>Residual level of Factor VII is a predictor of bleeding symptoms; patients with Factor VII level of 1-2% are sometimes asymptomatic </li></ul><ul><li>Very variable spectrum of bleeding problems </li></ul>
  7. 7. Symptoms (Severe Factor VII Deficiency) <ul><li>Intracranial hemorrhage </li></ul><ul><li>Up to 16% of patients will experience a CNS bleed. Often present shortly after birth </li></ul><ul><li>Hemarthrosis </li></ul><ul><li>Var ies considerably amongst patient s </li></ul><ul><li>Easy bruising and soft tissue hematomas </li></ul><ul><li>Muscle bleed </li></ul><ul><li>Rare event </li></ul><ul><li>Mucosal bleeding </li></ul><ul><li>Most common manifestation: epistaxis, meno r rhagia, dental, melena, hematuria </li></ul>
  8. 8. Management <ul><li>Half-life of Factor VII is between 2½ hours and 5-6 hours </li></ul><ul><li>To achieve normal hemostasis: 15 -30 % level of Factor VII is enough even when the patient undergoes surgery </li></ul>
  9. 9. Management <ul><li>1. Fresh - Frozen Plasma: Content of Factor VII in normal plasma is 1 unit/ml Volume overload can be a problem </li></ul><ul><li>2. Factor VII C oncentrates: 1 unit/kg will increase the Factor VII in the blood by 1 . 7% Prophylaxis dosing: 10-50 unit/kg 1 - 3 times/week </li></ul><ul><li>3. Recombinant Factor VIIa: Dosing: 20mcg/kg </li></ul><ul><li>4. Prothrombin C omplex </li></ul>
  10. 10. Case P resentation <ul><li>Parents are first cousins from Pakistan </li></ul><ul><li>3 rd child of the family </li></ul><ul><li>Shortly after birth a circumcision was performed: oozing +++ </li></ul><ul><li>Fresh frozen plasma was given </li></ul><ul><li>Blood work: PT >100 sec. Factor VII < 1% </li></ul><ul><li>Both parents were heterozygous with levels of 40% </li></ul>
  11. 11. Case P resentation <ul><li>Patient was started on prophylaxis with Factor VII concentrates 50 units/kg because of the risk of spontaneous CNS hemorrhage </li></ul><ul><li>No bleeding complications since the start of prophylaxis </li></ul>
  12. 12. Factor XI D eficiency <ul><li>Also known as Hemophilia C </li></ul><ul><li>Trace protein found in the blood and is synthesis in the liver </li></ul><ul><li>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 </li></ul>
  13. 13. Intrinsic Pathway (PTT) Extrinsic Pathway (PT) Adapted by MW King. The Medical Biochemistry page Surface HK PK XII XIIa XI XIa Ca 2+ HK XI XIa X Xa Ca 2+ PL VIII VIIIa VII VIIa + TF Ca 2 X Vascular injury V Va Ca 2+ PL Prothrombin Thrombin Fibrinogen Fibrin monomer Fibrin polymer Cross-linked fibrin polymer XIIIa XIII Common Pathway
  14. 14. Inheritance P attern & I ncidence <ul><li>Autosomal recessive disorder </li></ul><ul><li>Will affect both male and female equally </li></ul><ul><li>Very uncommon in the general population but recognized in all ethnic groups </li></ul><ul><li>Ashkenazi Jews: most prevalent genetic defects in this population (8-9%) </li></ul>
  15. 15. Diagnosis <ul><li>Often referred for: epistaxis, easy bruising and bleeding after circumcision </li></ul><ul><li>Incidental finding in pre-op assessment </li></ul><ul><li>Family history </li></ul><ul><li>Blood work: activated partial thromboplastin (aPTT) is prolonged. Factor XI level </li></ul><ul><li>*PT normal* </li></ul>
  16. 16. Classification <ul><li>Normal levels of Factor XI activity range from 70-150% </li></ul><ul><li>1. Severe deficiency (level < 15%) </li></ul><ul><li>Homozygous individuals </li></ul><ul><li>2. Partial deficiency (level 20-70%) </li></ul><ul><li>Heterozygous individuals </li></ul><ul><li>***coinheritance of Factor XI deficiency along with Von Willebrand disease as also been observed in patients with bleeding symptoms .*** </li></ul>
  17. 17. Symptoms <ul><li>The bleeding risk is variable within an individual </li></ul><ul><li>There is a poor correlation between the degree of plasma FXI deficiency and the bleeding tendency </li></ul><ul><li>Most patient s do not suffer from spontaneous bleeding , but are at risk of bleeding following trauma or surgery </li></ul>
  18. 18. Symptoms <ul><li>Most common symptoms: </li></ul><ul><li>Mucosal bleeding </li></ul><ul><li>Menorrhagia and postpartum hemorrhage </li></ul><ul><li>Bruising </li></ul><ul><li>Bleeding with surgical intervention </li></ul>
  19. 19. Management <ul><li>Patient s do not need prophylaxis for routine daily activity , but do need treatment following dental extraction, major surgery or trauma </li></ul><ul><li>The half-life of Factor XI is estimated to be between 50 - 80 hours </li></ul><ul><li>Hemostasis is achieved t h rough level of 30% of normal activity </li></ul>
  20. 20. Management <ul><li>1. Fresh-frozen plasma: </li></ul><ul><li>Effective in raising FXI level but requires the use of large amount (risk of fluid overload) </li></ul><ul><li>2. FXI concentrates: </li></ul><ul><li>High purity concentrates </li></ul><ul><li>Effective and easy to administer rapidly </li></ul><ul><li>R isk of thrombosis associated with this product </li></ul>
  21. 21. Management <ul><li>3. DDAVP( Desmopressin): </li></ul><ul><li>Used for heterozygous patients but the efficacy of DDAVP remains unclear </li></ul><ul><li>4. Antifibrinolytic agents: </li></ul><ul><li>H elps preventing bleeding in tissues with high fibrinolytic activity </li></ul><ul><li>Used with women experiencing menorrhagia </li></ul>
  22. 22. Case P resentation <ul><li>41 year old m a n </li></ul><ul><li>Mild Factor XI deficiency </li></ul><ul><li>Diagnose d following a hemorrhage after a tonsillectomy as a child </li></ul><ul><li>Extensive bleeding history: Hemarthrosis following a knee injury, bleeding complications following 2 spinal surgeries , etc </li></ul>
  23. 23. Case P resentation <ul><li>Cervical s pine surgery planned in 2005 </li></ul><ul><li>Blood work: </li></ul><ul><ul><li>Factor XI: 29% </li></ul></ul><ul><ul><li>v on Willebrand profile: </li></ul></ul><ul><ul><ul><ul><li>FVIIIc: 51% </li></ul></ul></ul></ul><ul><ul><ul><ul><li>vW ant: 45% </li></ul></ul></ul></ul><ul><ul><ul><ul><li>vW risto: 73% </li></ul></ul></ul></ul><ul><ul><li>Blood group: O+ </li></ul></ul>
  24. 24. Case P resentation <ul><li>Management for the surgery: </li></ul><ul><ul><li>Patient admitted 48 hours prior to surgery for infusion of f resh f rozen p lasma to obtain hemostatic level of Factor XI the morning of the surgery </li></ul></ul><ul><ul><li>DDAVP 20mcg IV 2 hours prior to surgery to increase the vW protein </li></ul></ul>
  25. 25. Glanzmann T hrombasthenia <ul><li>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 relative s in this village. </li></ul><ul><li>Defect in the platelet glycoprotein IIb/IIIa w h ich is a receptor on the surface of the platelet that allow s platelet s to interact with the blood vessel wall or with other blood cells </li></ul><ul><li>Affects the ability of the blood platelets to aggregate (platelet clumping) </li></ul>
  26. 26. Platelet A dhesion & A ggregation Source: Disorders of the platelet function , from the Canadian Hemophilia Society w ebsite
  27. 27. Inheritance P attern & I ncidence <ul><li>Autosomal recessive disorder </li></ul><ul><li>Affects male and female equally </li></ul><ul><li>Incidence 1/ 1,000,000 </li></ul>
  28. 28. Diagnosis <ul><li>Often referred for: soft tissue hematomas, epistaxis, mouth bleeding, menorrhagia </li></ul><ul><li>Family history </li></ul><ul><li>Blood work: </li></ul><ul><li>Bleeding time will be prolonged </li></ul><ul><li>Platelet aggregation studies: failure of platelets to aggregate or reduced aggregation </li></ul>
  29. 29. Classification <ul><li>Three types of severity depending on the importance of the platelet deficiency in GlycoproteinIIb/IIIa: </li></ul><ul><ul><li>Type 1 (Severe): level < 5% of normal </li></ul></ul><ul><ul><li>Type 2 (Less severe): level between 5 - 20% of normal </li></ul></ul><ul><ul><li>Type 3 (Least severe): a variant of Thrombasthenia. Level is normal but with abnormalities in the way platelets aggregate </li></ul></ul>
  30. 30. Symptoms <ul><li>Purpura </li></ul><ul><li>Mucosal bleeding: nose, mouth </li></ul><ul><li>Gastro-intestinal, CNS hemorrhage (rare) </li></ul><ul><li>Menorrhagia, postpartum hemorrhage </li></ul>
  31. 31. Management <ul><li>Platelets : Effective treatment but it’s use is often limited by the appearance of antibodies that destroy the transfused platelets </li></ul><ul><li>2. Recombinant Factor VIIa : Useful in patient who no longer respond to platelet transfusions or to avoid the development of platelet antibodies </li></ul><ul><li>3. Antifibrinolytic agent </li></ul><ul><li>4. Hormonal therapy for women: M ay control menorrhagia </li></ul>
  32. 32. Case P resent a tion <ul><li>36 year old m a n from Pakistan </li></ul><ul><li>Parents were first cousins </li></ul><ul><li>Older brother died at 10 days old from circumcision hemorrhage </li></ul><ul><li>Major bleeding problem through h is life: epistaxis </li></ul><ul><li>In past year: </li></ul><ul><ul><li>bleeding hemorrhoids +++ </li></ul></ul><ul><ul><li>Admitted 2X for decreased hemoglobin </li></ul></ul>
  33. 33. Case P resentation <ul><li>Blood work: </li></ul><ul><li>Platelet aggregation: 0 </li></ul><ul><li>Bleeding time: > 30 minutes </li></ul><ul><li>Hemorrhoidectomy performed and treated with: </li></ul><ul><li>Platelets transfusion </li></ul><ul><li>Antifibrinolytic therapy </li></ul>
  34. 34. Recommendations <ul><li>Physical activit y to stay fit </li></ul><ul><li>Appropriate gear for sporting activities </li></ul><ul><li>Dental prevention </li></ul><ul><li>No ASA, Ibuprofen </li></ul><ul><li>Avoidance of herbal remedies </li></ul><ul><li>Vaccination </li></ul><ul><li>Identification (bracelet, wallet card) </li></ul><ul><li>Comprehensive care team </li></ul>
  35. 35. Booklets <ul><li>Booklets available: </li></ul><ul><li>Fibrinogene </li></ul><ul><li>Factor V </li></ul><ul><li>Factor VII </li></ul><ul><li>Factor X </li></ul><ul><li>Factor XII </li></ul><ul><li>Factor XIII </li></ul><ul><li>Glanzman Disease </li></ul><ul><li>In Progress: </li></ul><ul><li>Factor XI </li></ul><ul><li>Bernard Soulier Syndrome </li></ul>