Transcript 24b96b07-29ca-4625-9682

BLEEDING DISORDERS
Dr.Nazzal Bsoul
Hematologist
Al Bashir Hospital
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.
HEMOSTASIS-2
These activities are finely balanced between keeping the
blood fluid and preventing intravasc.thrombosis.
1-Pimary hemostasis: vasoconstriction and platelet adhesion and aggregation leading to the formation of the
platelet plug.
2-Secondary hemostasis: involves activation of coag.system leading to the generation of fibrin strands and
reinforcement of the platelet plug.
3-Fibrinolysis: activation of fibrin-bound plasminogen
resulting in clot lysis.
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) agents:tissue
factor,von Willebrand factor,F V ,F VIII.
2-Anticoagulant (antithrombotic) agents:
prostacyclin,nitric oxide,endothelin-1.
ROLE OF PLATELETS IN
HEMOSTASIS
1. Each megacaryocyte produces 10002.
3.
4.
5.
2000 platelets,which
remain in the circulation for about 10
days.
Releasing of hemostatic proteins.
Platelet adhesion.
Platelet aggregation.
COAGULATION FACTORS
Coag.factors:are plasma proteins synthesized in
the liver which,when activated lead to the
deposition of fibrin.
1-Initiation phase:leads to the formation of the
complex TF-VIIa.
2-Amplification phase:leads to the formation of a
small amount of thrombin from prothrombin.
3-Propagation phase:leads to the formation of
much larger amounts of fibrin.
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).
FIBRINOLYSIS
Small amouns of fibrin are constantly
deposited within the vascular system and
are removed by the fibrinolytic system
Plasminogen
Plasmin
Fibrin
FDPs
ASSESSMENT OF BLEEDING
SYMPTOMS
1-Careful and full clinical history and
examination.
2-Appropriate lab.investigations.
3-Other investigations.
HISTORY
1-Site of bleeding.
2-Duration of bleeding.
3-Precipitating cause.
4-Surgery.
5-Family history.
6-Systemic illnesses.
7-Drugs.
Clinical Features of Bleeding
Disorders
Platelet
disorders
Coagulation
factor disorders
Site of bleeding
Skin
Mucous membranes
(epistaxis, gum,
vaginal, GI tract)
Deep in soft tissues
(joints, muscles)
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,
usually mild
Delayed (1-2 days),
often severe
Coagulation factor disorders
 Inherited bleeding
disorders
Acquired bleeding
disorders
1. Hemophilia A and B
2. vonWillebrand
disease
3. Other factor
deficiencies
1. Liver disease
2. Vitamin K
deficiency/warfarin
overdose
3. DIC
HEMOPHILIAS
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.
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.
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%
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
•
•
•
•
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
X
Y
X•
XX•
X•Y
X
XX
XY
50% of daughters will be carriers •
50% of sons will have hemophilia •
Healthy Mother
Carrier Mother
Healthy Father
X•
Y
X
XX•
XY
X
XX•
XY
All daughters will be carriers
All sons will be healthy •
•
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.
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).
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,debilitating
manifestation of hemophilia.
2-Skeletal muscle:hematoma formation most
affects quadriceps,iliopsoas,and forearm.
3-CNS:intracranial hemorrhage.
Hemarthrosis (acute)
Diagnosis
Family history: mainly on the maternal
side of the family.
Screening tests.
Specific factor assay, genetic testing.
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
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.
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.
Hemophilia in females
Symptomatic hemophilia has been welldocumented 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)
Late complications
1-Joint destruction due to hemarthroses,
leading to a number of orthopedic
abnormalities (hemophilic osteoarthropathy).
2-Transmission of blood-borne infections.
3-Development of inhibitor antibodies.
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.
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.
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.
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.
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
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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
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)
Treatment of hemophilia B
Agent
– High purity factor IX
– Recombinant human factor IX
Dose
– Initial dose: 100U/kg
– Subsequent: 50U/kg every 24 hours
Treatment of patients with
inhibitors-1
Components of therapy:
1-Treatment of active bleeding.
2-Inhibitor ablation via immune
tolerance induction (inhibitor
eradication).
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 it’s
localized effect.
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