New Trends In The Management Of Bleeding Disorders Galila Zaher MRCPath MRCPath Consultant Hematologist KAUH.

New Trends In The New Trends In The Management Of Management Of

Bleeding DisordersBleeding DisordersGalila ZaherGalila Zaher

MRCPathMRCPathConsultant Hematologist Consultant Hematologist

KAUH KAUH

Congenital Bleeding Congenital Bleeding disordersdisorders

VWDVWD Hemophilia AHemophilia A Hemophilia BHemophilia B Other congenital factor deficiencyOther congenital factor deficiency Bernard Solier syndromeBernard Solier syndrome Glanzman’ThrombatheniaGlanzman’Thrombathenia Storage pool defectStorage pool defect

Acquired Bleeding DisordersAcquired Bleeding Disorders Coagulation Factor Coagulation Factor Liver DiseaseLiver Disease DICDIC Consumptions CoagulopathiesConsumptions Coagulopathies Vitamin K deficiencyVitamin K deficiency Platelets defectsPlatelets defects ITPITP Renal impairment Renal impairment Myelo-proliferate DisordersMyelo-proliferate Disorders

HemophiliaHemophilia

A = F VIII deficiencyA = F VIII deficiency B = F IX deficiencyB = F IX deficiency Affects one in 6000 malesAffects one in 6000 males A is 5 X > BA is 5 X > B Mild >5,Moderate 2 -5, severe < 2 %Mild >5,Moderate 2 -5, severe < 2 % Levels remain stable throughout lifeLevels remain stable throughout life Both HA & HB are X linkedBoth HA & HB are X linked

Clinical presentationClinical presentation

< 2 years: joint bleeds < 2 years: joint bleeds – RareRare– Only bruising or mouth bleeds are seenOnly bruising or mouth bleeds are seen– Head injuries are a major concernHead injuries are a major concern

> 2 years> 2 years– Joint and muscle bleeds become more Joint and muscle bleeds become more

commoncommon

Indication For ReplacementIndication For Replacement

All joint bleeds: Pain, All joint bleeds: Pain, swelling ,warmth or loss of swelling ,warmth or loss of movement .movement .

Muscle bleeds : severe pain or Muscle bleeds : severe pain or are in a dangerous locationare in a dangerous location

Bruises usually don’t need Bruises usually don’t need treatmenttreatment

Treatment Treatment

Keep weight off of jointKeep weight off of joint Ice packIce packFactor replacement - the sooner Factor replacement - the sooner

the betterthe betterAmicar or tranexamic acid : Amicar or tranexamic acid :

mouth bleedmouth bleed

Factor replacementFactor replacement

Derived from pooled human Derived from pooled human plasma plasma

Derived from pig (porcine) plasma Derived from pig (porcine) plasma Recombinant productsRecombinant products

Factor VIII (AHF)Factor VIII (AHF)

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

Biotech Development of Biotech Development of Recombinant FactorsRecombinant Factors

Human FVII geneHuman FVII gene

BHK cellsBHK cells

Liver gene Liver gene librarylibrary

Single copySingle copyof gene isolatedof gene isolated

Expression ofExpression ofrF in culture mediumrF in culture medium

hFhFgenegene

hFhFGeneGene

ActivationActivationand Purification and Purification

®®

AmplificationAmplification

hF = human factor BHK = baby hamster BHK = baby hamster kidneykidney

Recombinant FactorsRecombinant Factors

Advantages Advantages :: Safe and stable source of the agentSafe and stable source of the agent When sources are scarce When sources are scarce

Problems :Problems : Contaminating proteins :Infectious or Contaminating proteins :Infectious or

immunogenic agentimmunogenic agent ExpensiveExpensive

Genetic StudyGenetic Study

Study the development of inhibitors. Study the development of inhibitors. Gene TransferGene Transfer

Sustained therapeutic production of Sustained therapeutic production of factors with No stimulation of an immune factors with No stimulation of an immune response . response .

The Tools of Genetic The Tools of Genetic EngineeringEngineering

DNA gene fragment of interest DNA gene fragment of interest EndonucleasesEndonucleases Plasmid Plasmid Ligase Ligase Host that is capable of accepting DNA Host that is capable of accepting DNA

Insertion into the genetic machinery Insertion into the genetic machinery Confirm that the gene is inserted.Confirm that the gene is inserted. Purify the protein of interestPurify the protein of interest

Gene Transfer Clinical TrialsGene Transfer Clinical Trials

5 trials approved in the States .5 trials approved in the States . Retroviral vectorRetroviral vector :B-domain deletion :B-domain deletion Non-viral approachNon-viral approach :reduction factor :reduction factor

use & spontaneous bleeding episodes.use & spontaneous bleeding episodes. Gutless adenovirusGutless adenovirus : eliminate : eliminate

immune response immune response

Results Of Clinical TrialsResults Of Clinical Trials

Long-term therapeutic expression Long-term therapeutic expression not achieved, but data are not achieved, but data are encouraging.encouraging.

Detectable factor levels observed. Detectable factor levels observed. The subjective : decreased bleeding . The subjective : decreased bleeding . No evidence of inhibitor.No evidence of inhibitor. Hepatic toxicity , thrombocytopenia.Hepatic toxicity , thrombocytopenia. Decline expression . Decline expression .

Shortcoming Of Treatment Shortcoming Of Treatment ModalitiesModalities

Short T Short T 1/21/2 CoastCoast Infections & ImmunologicInfections & Immunologic Hepatic toxicity ,low platelets Hepatic toxicity ,low platelets Decline expression. Decline expression. Owing to the shortcoming of treatment Owing to the shortcoming of treatment

Modalities prompted the need for anew Modalities prompted the need for anew hemostatic agent.hemostatic agent.

Initiation of HaemostasisInitiation of Haemostasis

X

XaVa

prothrombin

TF-bearing cell

platelet

activated platelet

VIIa

VIIaIX

IXa

VIIIa VaIXa

X X

Xa

prothrombin

thrombin

thrombin

IX

Fibrinogen

Fibrin

TF

TF

XIa

VIII/vWF VIIIa

V Va

XI XIa

TF–independent mechanism of rFVIIa TF–independent mechanism of rFVIIa enhanced hemostasisenhanced hemostasis

Rational Rational

Thrombin crucial role in haemostasis.Thrombin crucial role in haemostasis. Any agent that enhances the Any agent that enhances the

thrombin generation 'general thrombin generation 'general haemostatic agent'.haemostatic agent'.

rFVII enhances thrombin generation rFVII enhances thrombin generation on activated platelets on activated platelets

Compensates for lack of FVIII and Compensates for lack of FVIII and FIX. FIX.

Normalize fibrin clot permeability Normalize fibrin clot permeability

PharmacokineticPharmacokinetic tt½ :½ :2.7 h 2.7 h Inter-subject variability. Inter-subject variability. Rapid clearance in children > adults.Rapid clearance in children > adults. No readily available assays No readily available assays The haemostatic levels remains The haemostatic levels remains

uncertain.uncertain. Frequent bolus injections, IVI Frequent bolus injections, IVI

potential to minimize usage.potential to minimize usage.

Potential UsePotential Use

Increases thrombin generation on Increases thrombin generation on activated platelet activated platelet – Hemophilia (FVIII/FIX deficiency) Hemophilia (FVIII/FIX deficiency) – Acquired hemophilia.Acquired hemophilia.

– Platelet disorders qualitative and quantitativePlatelet disorders qualitative and quantitative – Diffuse bleeding triggered by surgery and Diffuse bleeding triggered by surgery and

trauma. trauma.

Impaired initial hemostasisImpaired initial hemostasis– FVII-deficiencyFVII-deficiency– Liver disease Liver disease – Oral anticoagulant therapy Oral anticoagulant therapy

Hemophilia with inhibitorsHemophilia with inhibitors

FDA Approved Feb 1999 FDA Approved Feb 1999 Bleeding during or prior to ITI therapy. Bleeding during or prior to ITI therapy. Control bleeding during surgery. Control bleeding during surgery. Safe and effective in 92% Safe and effective in 92% hemophilia hemophilia

research society registryresearch society registry Inhibitor titres are not boosted. Inhibitor titres are not boosted. Home treatment: mild-moderate episodes.Home treatment: mild-moderate episodes. Recommended dose 60-120 ug/kg q 2 -6 Recommended dose 60-120 ug/kg q 2 -6

h or IVI.h or IVI.

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

Liver DiseaseLiver Disease Reduction in the synthesis of factors Reduction in the synthesis of factors

involved in coagulation and fibrinolysis.involved in coagulation and fibrinolysis. Moderate thrombocytopenia.Moderate thrombocytopenia. Upper gastrointestinal tract. Upper gastrointestinal tract. Vitamin K .Vitamin K . FFPFFP PCCs : thromboembolic complications.PCCs : thromboembolic complications.

rFVII &Liver DiseaserFVII &Liver Disease Acute hepatic trauma, liver biopsy, Acute hepatic trauma, liver biopsy,

chronic liver disease ,cirrhosis, and chronic liver disease ,cirrhosis, and liver transplantation.liver transplantation.

Experimental studies :seems to be Experimental studies :seems to be safe and effective. safe and effective.

No evidence of thrombosis . No evidence of thrombosis . Cirrhosis , achieved hemostasis in 74% Cirrhosis , achieved hemostasis in 74%

Jeffers et alJeffers et al

The Risk Of Thrombosis In The Risk Of Thrombosis In LIVER PatientsLIVER Patients

No evidence of dose relationshipNo evidence of dose relationship Many events have an alternative Many events have an alternative

aetiologyaetiology Few events within the first day after Few events within the first day after

dosingdosing No increase in events as compared No increase in events as compared

with background transplant with background transplant populationpopulation

Drug-Induced Drug-Induced CoagulopathyCoagulopathy

Oral anticoagulant treatment Oral anticoagulant treatment hemorrhage :0.6%/ m .hemorrhage :0.6%/ m .

Vitamin K, FFP or PCCs Vitamin K, FFP or PCCs rFVIIa in healthy volunteers :50% drop of rFVIIa in healthy volunteers :50% drop of

INR INR Girard et alGirard et al An open, multicenter pilot trial is An open, multicenter pilot trial is

underway to determine the efficacy underway to determine the efficacy FFondaparinux. normalized PT, aPTT, and ondaparinux. normalized PT, aPTT, and

TT. TT. Bijsterveld et alBijsterveld et al

Glanzmann’s Glanzmann’s ThrombastheniaThrombasthenia

Refractory to platelet transfusionRefractory to platelet transfusion Increases the initial thrombin generation, Increases the initial thrombin generation,

thereby compensating for defective platelet thereby compensating for defective platelet Effective in 60% during surgery . Effective in 60% during surgery . No adverse effects of rFVIIaNo adverse effects of rFVIIa International registry data :relatively safe International registry data :relatively safe

and effective when used in GT.and effective when used in GT.

Blood 1999; 94 (11): 3951-3953Blood 1999; 94 (11): 3951-3953

Thrombocytopenia Thrombocytopenia

Increased thrombin generation on Increased thrombin generation on activated platelets compensate for activated platelets compensate for the low platelet number.the low platelet number.

Reduction in bleeding time in 52.4% Reduction in bleeding time in 52.4% of 105 patients . of 105 patients .

Kristensen Kristensen et al et al

No major adverseNo major adverse

Surgical &Trauma patientsSurgical &Trauma patients

Effective and safe in the management of Effective and safe in the management of uncontrolled surgical in patients not uncontrolled surgical in patients not known to have inherited coagulopathy.known to have inherited coagulopathy.

Trauma :surgical intervention failed to Trauma :surgical intervention failed to stop life- threatening bleeding. stop life- threatening bleeding.

– Significant decrease to 2 packed RBC Significant decrease to 2 packed RBC

– Shortening of PT & aPTTShortening of PT & aPTT Adjunctive hemostatic treatmentAdjunctive hemostatic treatment Theoretical risk of TEDTheoretical risk of TED ,none observe ,none observedd

Building Strong Scientific Building Strong Scientific EvidenceEvidence

Clinical areaClinical area Status on project 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

Questions more than Questions more than answersanswers

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

Local experienceLocal experience

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

Thank YouThank You

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

1.1. assembly of a thick, strong assembly of a thick, strong fibrin plugfibrin plug

2.2. activation of FXIII to cross link activation of FXIII to cross link fibrinfibrin

3.3. activation of TAFI to makeactivation of TAFI to makefibrin plug resistant to fibrin plug resistant to fibrinolysisfibrinolysis

RNA repairRNA repair

Pre-messenger RNA (pre-mRNA) repair. Pre-messenger RNA (pre-mRNA) repair. splicing mechanisms to correct a portion splicing mechanisms to correct a portion

of the defective RNA. of the defective RNA. The advantage :large genes or genes that The advantage :large genes or genes that

contain large regulatory elements. contain large regulatory elements. Injection of a plasmid encoding a pre-Injection of a plasmid encoding a pre-

mRNAmRNA Useful for the treatment of autosomal Useful for the treatment of autosomal

dominant disorders.dominant disorders.

Inhibitors &Gene Transfer Inhibitors &Gene Transfer

InhibitorsInhibitors : :20% HA patients and 3% of HB 20% HA patients and 3% of HB patients.patients.

Antibodies inactivate the factor by Antibodies inactivate the factor by changing conformation.changing conformation.

Depends on type of genetic mutation. Depends on type of genetic mutation. A large deletion A large deletion incidence of inhibitor . incidence of inhibitor . Bleeding episodes are difficult to manage Bleeding episodes are difficult to manage

FEIBAHuman/porcine factor VIII