BLEEDING DISORDERS

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• BLEEDING DISORDERS
• Dr.Nazzal Bsoul
• Hematologist
• Al Bashir Hospital

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HEMOSTASIS-1

• In health hemostasis ensures that the blood
  remains fluid and contained in the vasc.system.
• If a vessel wall is damaged,a number of
  mechanisms are activated promptly to limit
  bleeding,involving
• 1-Endothelial cells.
• 2-Platelets.
• 3-Plasma coag.factors.
• 4-Fibrinolytic system.

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HEMOSTASIS-2

• These activities are finely balanced between
  keeping the blood fluid and preventing
  intravasc.thrombosis.
• 1-Pimary hemostasis vasoconstriction and
  platelet adhe-
• sion and aggregation leading to the
  formation of the
• platelet plug.
• 2-Secondary hemostasis involves activation of
  coag.sys-
• tem leading to the generation of fibrin
  strands and
• reinforcement of the platelet plug.
• 3-Fibrinolysis activation of fibrin-bound
  plasminogen resulting in clot lysis.

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ROLE OF ENDOTHELIAL CELLS IN HEMOSTASIS

• Blood vessels are lined with endothelial
  cells,which synthesize and secrete various
  agents,that regulate hemostasis.
• 1-Procoagulant(prothrombotic) agentstissue
  factor,von Willebrand factor,F V ,F VIII.
• 2-Anticoagulant (antithrombotic) agents
• prostacyclin,nitric oxide,endothelin-1.

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ROLE OF PLATELETS IN HEMOSTASIS

1. Each megacaryocyte produces 1000-2000
   platelets,which
2. remain in the circulation for about 10 days.
   
   
   
   
3. Releasing of hemostatic proteins.
4. Platelet adhesion.
5. Platelet aggregation.

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COAGULATION FACTORS

• Coag.factorsare plasma proteins synthesized in
  the liver which,when activated lead to the
  deposition of fibrin.
• 1-Initiation phaseleads to the formation of the
  complex TF-VIIa.
• 2-Amplification phaseleads to the formation of a
  small amount of thrombin from prothrombin.
• 3-Propagation phaseleads to the formation of
  much larger amounts of fibrin.

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INHIBITORS OF COAGULATION

• Are proteins that inhibit activated
  procaog.enzymes and prevent excessive
  intravasc.coagulation
• Raised levels are not associated with
  bleeding.
• Reduced levels may predispose to thrombosis.
• Antithrombin.
• Protein C,Protein S.
• Tissue Factor Pathway Inhibitor (TFPI).

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FIBRINOLYSIS

• Small amouns of fibrin are constantly deposited
  within the vascular system and are removed by the
  fibrinolytic system
• Plasminogen Plasmin
• Fibrin
  FDPs

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ASSESSMENT OF BLEEDING SYMPTOMS

• 1-Careful and full clinical history and
  examination.
• 2-Appropriate lab.investigations.
• 3-Other investigations.

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HISTORY

• 1-Site of bleeding.
• 2-Duration of bleeding.
• 3-Precipitating cause.
• 4-Surgery.
• 5-Family history.
• 6-Systemic illnesses.
• 7-Drugs.

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Clinical Features of Bleeding Disorders

• Platelet Coagulation disorders factor
  disorders
• Site of bleeding Skin Deep in soft tissues
• Mucous membranes (joints, muscles)
• (epistaxis, gum,
• vaginal, GI tract)
• Petechiae Yes No
• Ecchymoses (bruises) Small, superficial Large,
  deep
• Hemarthrosis / muscle bleeding Extremely
  rare Common
• Bleeding after cuts scratches Yes No
• Bleeding after surgery or trauma Immediate, Delaye
  d (1-2 days),
• usually mild often severe

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Coagulation factor disorders

• Inherited bleeding disorders
• Hemophilia A and B
• vonWillebrand disease
• Other factor deficiencies

• Acquired bleeding disorders
• Liver disease
• Vitamin K deficiency/warfarin overdose
• DIC

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• HEMOPHILIAS

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Definition

• Hemophilias are a group of related bleeding
• disorders that most commonly are
  inherited.
• When the term hemophilia is used, it most
• often refers to the following two
  disorders
• 1- Factor VIII deficiency hemophilia A
• 2- Factor IX deficiency hemophilia B
• (Christmas
  disease)
• Factor XI deficiency hemophilia C.

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History

• Hemophilia has featured prominently in
• European royalty and thus sometimes
• known as the royal disease.
• Queen Victoria passed the mutation for
• hemophilia B to her son Leopold, and
• through some of her daughters, to
• various royals across the continent,
• including the royal families of Spain,
• Germany, and Russia.

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Clinical Manifestation

• They exhibit a range of clinical severity
• that correlates well with factor levels.
• Severe disease factor activity less than
• 1
• Moderate disease factor activity 1-5
• Mild disease factor activity more than 5

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Incidence and Inheritance-1

• The combined incidence of hemophilia A
• and B is 1 in 5000 live male births.
• Approximately 80 have hemophilia A,2/3
• of whom have severe disease.
• Hemophilia A is the second most common
• inherited bleeding disorder.
• Severe cases among patients with hemophilia
• B are less common (about ½)
• Hemophilia A and B are X-linked recessive
• diseases.

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Incidence and inheritance-2
Slide 18
Slide 18

• Factor VIII and IX are localized on X
  Chromosome
• Haemophilia A and B are caused by a defect on
  the X chromosome
• Affect almost exclusively men
• Affect equally all races and ethnic groups

Male
Female
Carrier female
Male with Haemophilia
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X-Linked Recessive Inheritance
Father With Haemophilia Father With Haemophilia Father With Haemophilia
X Y
X XX XY
X XX XY
Healthy Father Healthy Father Healthy Father
X Y
X XX XY
X XX XY
Healthy Mother
Carrier Mother
50 of daughters will be carriers 50 of sons
will have hemophilia
All daughters will be carriers All sons will
be healthy
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Initial presentation-1

• The majority of patients are known to have
• hemophilia because of the family
• history.
• The majority of newborns with severe
• hemophilia traverse delivery and the
• first few months of life without
• detection.
• Early bleeding occurs commonly in association
• with circumcision.

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Initial presentation-2

• The majority of newborns with severe
• hemophilia become symptomatic during
• the first 2 years of life.
• Mean age at diagnosis of severe hemophilia
• 9 months,moderate disease 22 months.
• Moderate and mild hemophilia may,in the
• absence of informative family history,go
• undetected for signficant periods of time
  (age
• 14-62 years).

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Sites of bleeding

• As children begin to ambulate,bleeding episodes
• occur more often and begin to involve
  joints
• and muscles,as well as other systems
• 1-Hemarthrosis is a painful,debilitatin
  g
• manifestation of hemophilia.
• 2-Skeletal musclehematoma formation
  most
• affects quadriceps,iliopsoas,and
  forearm.
• 3-CNSintracranial hemorrhage.

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Hemarthrosis (acute)
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Diagnosis

• Family history mainly on the maternal
• side of the family.
• Screening tests.
• Specific factor assay, genetic testing.

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Family history

• The patients mother is a known carrier.
• Negative family history in about 1/3 of patients.
• Lack of a family history is of little value in
  excluding the possibility of hemophilia.
• 1-spontaneous mutation which occurs
• 25-33 of cases.
• 2-Neonatal deaths or a passage of the
• trait through a succession of female
  carriers

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Screening tests

• Initial tests to be done in patients with a
• bleeding diathesis of unknown etiology
• 1-Platelet count
• 2-Prothrombin time (PT).
• 3-Activated partial thromboplastin time
• (aPTT).
• A normal platelet count,normal PT,and a
• prolonged aPTT is characteristic of
  hemophilias, and heparin therapy.

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Specific assays

• Factors that can produce an isolated
• prolonged aPTT are F VIII,F IX,and FXI
• Genetic analysis of F VIII and F IX.
• Prof.Abbadi did genetic studies to the all
• Jordanian patients with hemophilia and
• identified new novel mutations among
• Jordanians with hemophilia A and B.

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Hemophilia in females

• Symptomatic hemophilia has been well-
• documented in females.
• Three possible explanations for this
• 1-X-chromosome inactivation in early
• stage of embryogenesis.
• 2-Mating between an affected male and
• a carrier female produces homozygous
• disease in ½ of female offspring.
• 3-Abnormal karyotype (Turner syndrome)

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Late complications

• 1-Joint destruction due to hemarthroses,
• leading to a number of orthopedic
• abnormalities (hemophilic osteo-
• arthropathy).
• 2-Transmission of blood-borne infections.
• 3-Development of inhibitor antibodies.

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Hemophilic arthropathy

• Multiple factors may contribute to synovitis and
• joint destruction in patints with
  hemarthroses.
• 1- Tissue deposition of iron
• 2- Dense fibrosis of the joint with
• contractures,pain,and limitation
  of
• motion.
• Primary prophylactic treatment with factor
• concentrates can markedly reduce the risk
• of subsequent arthropathy.
• Synovectomy pharmacological synovectomy.
• radioactive
  synovectomy.

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Infection

• Patients treated with older factor VIII and IX
• concentrates were at high risk for
  infection
• with hepatitis A,B,C,and D and with
  HIV.
• The risk of infection has been reduced markedly
• by improvement in donor screening and
• virucidal techneques and the
  development
• of recombinant products.

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Inhibitors

• Antibodies are primarily IgG.
• Occur in 25 of severe hemophilia A,and
• 3-5 of those with severe hemophilia B.
• Much less common in patients with mild or
• moderate disease.
• Increased risk of bleeding.
• Maturational delays.

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Management-1

• Complex, and should include
• 1-Preventive and comprehensive care.
• (routine immunizations,circumcision,
• dental care,counselling and
• education,exercise and athletic
• participation)
• 2-Replacement therapy (treatment
• and prophylaxis)
• 3-Other therapies gene therapy.

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Therapies other than replacement therapy

• Ice.
• Immobilization.
• Steroids.
• Physiotherapy.
• Analgesia aspirin and NSAIDs are
  contraindicated, paracetamol or codeine can be
  used.
• Desmopressin.
• Antifibrinolytic therapy tranexamic
  acid,epsilon
• aminocaproic acid.

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Treatment of hemophilia A

• Intermediate purity plasma products
• Virucidally treated
• May contain von Willebrand factor
• High purity (monoclonal) plasma products
• Virucidally treated
• No functional von Willebrand factor
• Recombinant factor VIII
• Virus free/No apparent risk
• -No functional von Willebrand factor

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Dosing guidelines for hemophilia A

• Mild bleeding
• Target 30 dosing q8-12h 1-2 days (15U/kg)
• Hemarthrosis, oropharyngeal or dental, epistaxis,
  hematuria
• Major bleeding
• Target 80-100 q8-12h 7-14 days (50U/kg)
• CNS trauma, hemorrhage, lumbar puncture
• Surgery
• Retroperitoneal hemorrhage
• GI bleeding
• Adjunctive therapy
• Tranexemic acid or DDAVP (for mild disease only)

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Treatment of hemophilia B

• Agent
• High purity factor IX
• Recombinant human factor IX
• Dose
• Initial dose 100U/kg
• Subsequent 50U/kg every 24 hours

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Treatment of patients with inhibitors-1

• Components of therapy
• 1-Treatment of active bleeding.
• 2-Inhibitor ablation via immune
• tolerance induction (inhibitor
• eradication).

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Treatment of patients with inhibitors-2

• Inhibitor bypassing products
• 1-Prothrombin complex concentrates,
• FIEBA are associated with a lot
• of complications.
• 2-Recombinant activated factor VII
• ( r FVIIa) no anamnestic antibody
• response.Not associated with
• increased risk of DIC due to its
• localized effect.
  

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• THANK YOU ?