New Trends In The Management Of Bleeding Disorders

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New Trends In The Management Of Bleeding Disorders

• Galila Zaher
• MRCPath
• Consultant Hematologist
• KAUH

2
Congenital Bleeding disorders

• VWD
• Hemophilia A
• Hemophilia B
• Other congenital factor deficiency
• Bernard Solier syndrome
• GlanzmanThrombathenia
• Storage pool defect

3
Acquired Bleeding Disorders

• Coagulation Factor
• Liver Disease
• DIC
• Consumptions Coagulopathies
• Vitamin K deficiency
• Platelets defects
• ITP
• Renal impairment
• Myelo-proliferate Disorders

4
Hemophilia

• A F VIII deficiency
• B F IX deficiency
• Affects one in 6000 males
• A is 5 X gt B
• Mild gt5,Moderate 2 -5, severe lt 2
• Levels remain stable throughout life
• Both HA HB are X linked

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Clinical presentation

• lt 2 years joint bleeds
• Rare
• Only bruising or mouth bleeds are seen
• Head injuries are a major concern
• gt 2 years
• Joint and muscle bleeds become more common

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Indication For Replacement

• All joint bleeds Pain, swelling ,warmth or loss
  of movement .
• Muscle bleeds severe pain or are in a dangerous
  location
• Bruises usually dont need treatment

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Treatment

• Keep weight off of joint
• Ice pack
• Factor replacement - the sooner the better
• Amicar or tranexamic acid mouth bleed

8
Factor replacement

• Derived from pooled human plasma
• Derived from pig (porcine) plasma
• Recombinant products

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Factor VIII (AHF)

• Mechanism of action
• No tool to predict the efficacy
• Allergic reactions
• Transient (short t ½)
• Expensive.
• Risk of transmission of infection

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Biotech Development of Recombinant Factors
Amplification
Human FVII gene
hF Gene
Single copyof gene isolated
Liver gene library
hF gene

Activation and Purification
Expression ofrF in culture medium
BHK cells
hF human factor
BHK baby hamster kidney
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Recombinant Factors

• Advantages
• Safe and stable source of the agent
• When sources are scarce
• Problems
• Contaminating proteins Infectious or immunogenic
  agent
• Expensive

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Genetic Study

• Study the development of inhibitors.
• Gene Transfer Sustained therapeutic production
  of factors with No stimulation of an immune
  response .

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The Tools of Genetic Engineering

• DNA gene fragment of interest
• Endonucleases
• Plasmid
• Ligase
• Host that is capable of accepting DNA
• Insertion into the genetic machinery
• Confirm that the gene is inserted.
• Purify the protein of interest

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Gene Transfer Clinical Trials

• 5 trials approved in the States .
• Retroviral vector B-domain deletion
• Non-viral approach reduction factor use
  spontaneous bleeding episodes.
• Gutless adenovirus eliminate immune response

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Results Of Clinical Trials

• Long-term therapeutic expression not achieved,
  but data are encouraging.
• Detectable factor levels observed.
• The subjective decreased bleeding .
• No evidence of inhibitor.
• Hepatic toxicity , thrombocytopenia.
• Decline expression .

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Shortcoming Of Treatment Modalities

• Short T 1/2
• Coast
• Infections Immunologic
• Hepatic toxicity ,low platelets
• Decline expression.
• Owing to the shortcoming of treatment Modalities
  prompted the need for anew hemostatic agent.

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Initiation of Haemostasis
prothrombin
X
VIII/vWF
VIIIa
VIIa
TF
Xa
V
Va
thrombin
Va
TF-bearing cell
XI
XIa
VIIa
IX
Fibrinogen
platelet
prothrombin
IXa
X X
XIa
thrombin
Fibrin
IXa
VIIIa
Xa
Va
activated platelet
IX
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• TFindependent mechanism of rFVIIa enhanced
  hemostasis

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Rational

• Thrombin crucial role in haemostasis.
• Any agent that enhances the thrombin generation
  'general haemostatic agent'.
• rFVII enhances thrombin generation on activated
  platelets
• Compensates for lack of FVIII and FIX.
• Normalize fibrin clot permeability

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Pharmacokinetic

• t½ 2.7 h
• Inter-subject variability.
• Rapid clearance in children gt adults.
• No readily available assays
• The haemostatic levels remains uncertain.
• Frequent bolus injections, IVI potential to
  minimize usage.

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Potential Use

• Increases thrombin generation on activated
  platelet
• Hemophilia (FVIII/FIX deficiency)
• Acquired hemophilia.
• Platelet disorders qualitative and quantitative
• Diffuse bleeding triggered by surgery and trauma.
  
• Impaired initial hemostasis
• FVII-deficiency
• Liver disease
• Oral anticoagulant therapy

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Hemophilia with inhibitors

• FDA Approved Feb 1999
• Bleeding during or prior to ITI therapy.
• Control bleeding during surgery.
• Safe and effective in 92 hemophilia research
  society registry
• Inhibitor titres are not boosted.
• Home treatment mild-moderate episodes.
• Recommended dose 60-120 ug/kg q 2 -6 h or IVI.

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Acquired Hemophilia

• Rare but potentially life-threatening condition
  mortality rate 20.
• Auto-antibodies against the deficient factor.
• rFVIIa is effective in major bleeding
• Induces haemostasis independent of the presence
  of FVIII or FIX.
• Well tolerated in these patients

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Liver Disease

• Reduction in the synthesis of factors involved in
  coagulation and fibrinolysis.
• Moderate thrombocytopenia.
• Upper gastrointestinal tract.
• Vitamin K .
• FFP
• PCCs thromboembolic complications.

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rFVII Liver Disease

• Acute hepatic trauma, liver biopsy, chronic
  liver disease ,cirrhosis, and liver
  transplantation.
• Experimental studies seems to be safe and
  effective.
• No evidence of thrombosis .
• Cirrhosis , achieved hemostasis in 74
  
• 
  Jeffers et al

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The Risk Of Thrombosis In LIVER Patients

• No evidence of dose relationship
• Many events have an alternative aetiology
• Few events within the first day after dosing
• No increase in events as compared with background
  transplant population

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Drug-Induced Coagulopathy

• Oral anticoagulant treatment ? hemorrhage 0.6/
  m .
• Vitamin K, FFP or PCCs
• rFVIIa in healthy volunteers 50 drop of INR
  Girard et al
• An open, multicenter pilot trial is underway to
  determine the efficacy
• Fondaparinux. normalized PT, aPTT, and TT.
  
• 
  Bijsterveld et al

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Glanzmanns Thrombasthenia

• Refractory to platelet transfusion
• Increases the initial thrombin generation,
  thereby compensating for defective platelet
• Effective in 60 during surgery .
• No adverse effects of rFVIIa
• International registry data relatively safe and
  effective when used in GT.
• Blood 1999 94 (11)
  3951-3953

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Thrombocytopenia

• Increased thrombin generation on activated
  platelets compensate for the low platelet number.
• Reduction in bleeding time in 52.4 of 105
  patients .
• 
  Kristensen et al
• No major adverse

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Surgical Trauma patients

• Effective and safe in the management of
  uncontrolled surgical in patients not known to
  have inherited coagulopathy.
• Trauma surgical intervention failed to stop
  life- threatening bleeding.
• Significant decrease to 2 packed RBC
• Shortening of PT aPTT
• Adjunctive hemostatic treatment
• Theoretical risk of TED ,none observed
  

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Building Strong Scientific Evidence

• Clinical area Status on project
• Liver transplantation Ph 2 study
• Upper GI bleeds Ph 2 study
• Liver resection Ph 2 study
• BMT Ph 2 study
• Reversal of OAC Ph 2 to be started
• Traumatology Ph 2 to be started

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Questions more than answers

• Optimal dosage.
• Dosing interval.
• Adjunctive hemostatic treatment .
• General haemostatic agent.
• Thromboembolic events .
• Coat analysis studies.
• Need for evidence-based guidelines

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Local experience

• Acquired Hemophilia
• Fresh PR bleeding
• FFP. Cryoppt,FVIII conc
• In preparation for molar root extract
• FVIII conc 100IU/Kg
• rFVII 30IU
• Normal hemostasis
• Tranexamic acid

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Thank You
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Amount of thrombin formed in the initial burst is
critical to assure

• assembly of a thick, strong fibrin plug
• activation of FXIII to cross link fibrin
• activation of TAFI to makefibrin plug resistant
  to fibrinolysis

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RNA repair

• Pre-messenger RNA (pre-mRNA) repair.
• splicing mechanisms to correct a portion of the
  defective RNA.
• The advantage large genes or genes that contain
  large regulatory elements.
• Injection of a plasmid encoding a pre-mRNA
• Useful for the treatment of autosomal dominant
  disorders.

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Inhibitors Gene Transfer

• Inhibitors 20 HA patients and 3 of HB
  patients.
• Antibodies inactivate the factor by changing
  conformation.
• Depends on type of genetic mutation.
• A large deletion ? incidence of inhibitor .
• Bleeding episodes are difficult to manage

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FEIBA
Human/porcine factor VIII
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