BLEEDING DISORDERSBLEEDING DISORDERS

Dr.Nazzal BsoulDr.Nazzal BsoulHematologistHematologist

Al Bashir HospitalAl Bashir Hospital

HEMOSTASIS-1HEMOSTASIS-1 In health hemostasis ensures that the blood In health hemostasis ensures that the blood remains fluid and contained in the vasc.system.remains fluid and contained in the vasc.system.

If a vessel wall is damaged,a number of If a vessel wall is damaged,a number of mechanisms are activated promptly to limit mechanisms are activated promptly to limit bleeding,involving:bleeding,involving:

1-Endothelial cells.1-Endothelial cells.

2-Platelets.2-Platelets.

3-Plasma coag.factors.3-Plasma coag.factors.

4-Fibrinolytic system.4-Fibrinolytic system.

HEMOSTASIS-2HEMOSTASIS-2These activities are finely balanced between keeping the These activities are finely balanced between keeping the blood fluid and preventing intravasc.thrombosis.blood fluid and preventing intravasc.thrombosis.

1-Pimary hemostasis: vasoconstriction and platelet adhe- 1-Pimary hemostasis: vasoconstriction and platelet adhe-

sion and aggregation leading to the formation of thesion and aggregation leading to the formation of the platelet plug.platelet plug.2-Secondary hemostasis: involves activation of coag.sys-2-Secondary hemostasis: involves activation of coag.sys- tem leading to the generation of fibrin strands and tem leading to the generation of fibrin strands and reinforcement of the platelet plug.reinforcement of the platelet plug.3-Fibrinolysis: activation of fibrin-bound plasminogen 3-Fibrinolysis: activation of fibrin-bound plasminogen

resulting in clot lysis.resulting in clot lysis.

ROLE OF ENDOTHELIAL ROLE OF ENDOTHELIAL CELLS IN HEMOSTASISCELLS IN HEMOSTASIS

Blood vessels are lined with endothelial Blood vessels are lined with endothelial cells,which synthesize and secrete various cells,which synthesize and secrete various agents,that regulate hemostasis.agents,that regulate hemostasis.

1-Procoagulant(prothrombotic) agents:tissue 1-Procoagulant(prothrombotic) agents:tissue factor,von Willebrand factor,F V ,F VIII.factor,von Willebrand factor,F V ,F VIII.

2-Anticoagulant (antithrombotic) agents: 2-Anticoagulant (antithrombotic) agents: prostacyclin,nitric oxide,endothelin-1.prostacyclin,nitric oxide,endothelin-1.

ROLE OF PLATELETS IN ROLE OF PLATELETS IN HEMOSTASISHEMOSTASIS

1.1. Each megacaryocyte produces 1000-2000 Each megacaryocyte produces 1000-2000 platelets,which platelets,which

2.2. remain in the circulation for about 10 days. remain in the circulation for about 10 days.

3.3. Releasing of hemostatic proteins.Releasing of hemostatic proteins.

4.4. Platelet adhesion.Platelet adhesion.

5.5. Platelet aggregation.Platelet aggregation.

COAGULATION FACTORSCOAGULATION FACTORS

Coag.factors:are plasma proteins synthesized Coag.factors:are plasma proteins synthesized in the liver which,when activated lead to the in the liver which,when activated lead to the deposition of fibrin.deposition of fibrin.

1-Initiation phase:leads to the formation of the 1-Initiation phase:leads to the formation of the complex TF-VIIa.complex TF-VIIa.

2-Amplification phase:leads to the formation of a 2-Amplification phase:leads to the formation of a small amount of thrombin from prothrombin.small amount of thrombin from prothrombin.

3-Propagation phase:leads to the formation of 3-Propagation phase:leads to the formation of much larger amounts of fibrin.much larger amounts of fibrin.

INHIBITORS OF COAGULATIONINHIBITORS OF COAGULATION

Are proteins that inhibit activated Are proteins that inhibit activated procaog.enzymes and prevent excessive procaog.enzymes and prevent excessive intravasc.coagulationintravasc.coagulation

Raised levels are not associated with bleeding.Raised levels are not associated with bleeding.

Reduced levels may predispose to thrombosis.Reduced levels may predispose to thrombosis.

Antithrombin.Antithrombin.

Protein C,Protein S.Protein C,Protein S.

Tissue Factor Pathway Inhibitor (TFPI).Tissue Factor Pathway Inhibitor (TFPI).

FIBRINOLYSISFIBRINOLYSIS

Small amouns of fibrin are constantly Small amouns of fibrin are constantly deposited within the vascular system and deposited within the vascular system and are removed by the fibrinolytic systemare removed by the fibrinolytic system

Plasminogen PlasminPlasminogen Plasmin

Fibrin FDPsFibrin FDPs

ASSESSMENT OF BLEEDING ASSESSMENT OF BLEEDING SYMPTOMSSYMPTOMS

1-Careful and full clinical history and 1-Careful and full clinical history and examination.examination.

2-Appropriate lab.investigations.2-Appropriate lab.investigations.

3-Other investigations.3-Other investigations.

HISTORYHISTORY

1-Site of bleeding.1-Site of bleeding.

2-Duration of bleeding.2-Duration of bleeding.

3-Precipitating cause.3-Precipitating cause.

4-Surgery.4-Surgery.

5-Family history.5-Family history.

6-Systemic illnesses.6-Systemic illnesses.

7-Drugs. 7-Drugs.

Clinical Features of Bleeding Clinical Features of Bleeding DisordersDisorders

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, Delayed (1-2 days), usually mild often severe

Coagulation factor disordersCoagulation factor disorders

Inherited bleeding Inherited bleeding disordersdisorders1.1. Hemophilia A and BHemophilia A and B

2.2. vonWillebrand vonWillebrand diseasedisease

3.3. Other factor Other factor deficienciesdeficiencies

Acquired bleeding Acquired bleeding disordersdisorders1.1. Liver diseaseLiver disease

2.2. Vitamin K Vitamin K deficiency/warfarin deficiency/warfarin overdoseoverdose

3.3. DICDIC

HEMOPHILIASHEMOPHILIAS

DefinitionDefinition

Hemophilias are a group of related bleedingHemophilias are a group of related bleeding

disorders that most commonly are inherited.disorders that most commonly are inherited.

When the term ”hemophilia” is used, it mostWhen the term ”hemophilia” is used, it most

often refers to the following two disorders:often refers to the following two disorders:

1- Factor VIII deficiency: hemophilia A1- Factor VIII deficiency: hemophilia A

2- Factor IX deficiency: hemophilia B2- Factor IX deficiency: hemophilia B

(Christmas disease)(Christmas disease)

Factor XI deficiency: hemophilia C.Factor XI deficiency: hemophilia C.

HistoryHistory

Hemophilia has featured prominently inHemophilia has featured prominently in European royalty and thus sometimesEuropean royalty and thus sometimes known as “the royal disease”.known as “the royal disease”.

Queen Victoria passed the mutation for Queen Victoria passed the mutation for hemophilia B to her son Leopold, andhemophilia B to her son Leopold, and through some of her daughters, tothrough some of her daughters, to various royals across the continent,various royals across the continent, including the royal families of Spain,including the royal families of Spain, Germany, and Russia.Germany, and Russia.

Clinical ManifestationClinical Manifestation

They exhibit a range of clinical severity They exhibit a range of clinical severity that correlates well with factor levels.that correlates well with factor levels.

Severe disease: factor activity less than Severe disease: factor activity less than 1%1%

Moderate disease: factor activity 1-5%Moderate disease: factor activity 1-5%Mild disease: factor activity more than 5%Mild disease: factor activity more than 5%

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

Write Presentation Title in FooterWrite Presentation Title in Footer Slide Slide 1818

•• Factor VIII and IX are localized Factor VIII and IX are localized on X Chromosomeon X Chromosome

•• Haemophilia A and B are caused Haemophilia A and B are caused by a defect on the X chromosomeby a defect on the X chromosome

•• Affect almost exclusively menAffect almost exclusively men

•• Affect equally all races and Affect equally all races and ethnic groupsethnic groups

Incidence and inheritance-2Incidence and inheritance-2Slide 18Slide 18

Male Female Carrierfemale

Male with Haemophilia

X-Linked Recessive Inheritance

He

alt

hy

Mo

the

r

Ca

rrie

r M

oth

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•50% of daughters will be carriers•50% of sons will have hemophilia

Father With Haemophilia

X•Y

XXX•XY

XXX•XY

•All daughters will be carriers•All sons will be healthy

Healthy Father

XY

X•XX•X•Y

XXXXY

Initial presentation-1Initial presentation-1

The majority of patients are known to haveThe majority of patients are known to have hemophilia because of the familyhemophilia because of the family history.history.

The majority of newborns with severeThe majority of newborns with severe hemophilia traverse delivery and thehemophilia traverse delivery and the first few months of life without first few months of life without detection.detection.

Early bleeding occurs commonly in associationEarly bleeding occurs commonly in association with circumcision.with circumcision.

Initial presentation-2Initial presentation-2

The majority of newborns with severeThe majority of newborns with severe hemophilia become symptomatic duringhemophilia become symptomatic during the first 2 years of life.the first 2 years of life.

Mean age at diagnosis of severe hemophiliaMean age at diagnosis of severe hemophilia 9 months,moderate disease 22 months.9 months,moderate disease 22 months.

Moderate and mild hemophilia may,in theModerate and mild hemophilia may,in the absence of informative family history,goabsence of informative family history,go undetected for signficant periods of time (ageundetected for signficant periods of time (age 14-62 years).14-62 years).

Sites of bleedingSites of bleeding

As children begin to ambulate,bleeding episodesAs children begin to ambulate,bleeding episodes

occur more often and begin to involve jointsoccur more often and begin to involve joints

and muscles,as well as other systems:and muscles,as well as other systems:

1-Hemarthrosis: is a painful,debilitating1-Hemarthrosis: is a painful,debilitating

manifestation of hemophilia.manifestation of hemophilia.

2-Skeletal muscle:hematoma formation most2-Skeletal muscle:hematoma formation most

affects quadriceps,iliopsoas,and forearm.affects quadriceps,iliopsoas,and forearm.

3-CNS:intracranial hemorrhage.3-CNS:intracranial hemorrhage.

Hemarthrosis (acute)Hemarthrosis (acute)

DiagnosisDiagnosis

Family history: mainly on the maternal Family history: mainly on the maternal

side of the family. side of the family.

Screening tests.Screening tests.

Specific factor assay, genetic testing.Specific factor assay, genetic testing.

Family historyFamily history

The patients mother is a known carrier.The patients mother is a known carrier.Negative family history in about 1/3 of patients.Negative family history in about 1/3 of patients.Lack of a family history is of little value in Lack of a family history is of little value in

excluding the possibility of hemophilia.excluding the possibility of hemophilia. 1-spontaneous mutation which occurs1-spontaneous mutation which occurs 25-33% of cases.25-33% of cases. 2-Neonatal deaths or a passage of the2-Neonatal deaths or a passage of the trait through a succession of female carrierstrait through a succession of female carriers

Screening testsScreening tests

Initial tests to be done in patients with aInitial tests to be done in patients with a bleeding diathesis of unknown etiology:bleeding diathesis of unknown etiology: 1-Platelet count1-Platelet count 2-Prothrombin time (PT).2-Prothrombin time (PT). 3-Activated partial thromboplastin time 3-Activated partial thromboplastin time (aPTT).(aPTT). A normal platelet count,normal PT,and aA normal platelet count,normal PT,and a prolonged aPTT is characteristic of prolonged aPTT is characteristic of

hemophilias, and heparin therapy.hemophilias, and heparin therapy.

Specific assaysSpecific assays

Factors that can produce an isolatedFactors that can produce an isolated

prolonged aPTT are F VIII,F IX,and FXIprolonged aPTT are F VIII,F IX,and FXIGenetic analysis of F VIII and F IX.Genetic analysis of F VIII and F IX.

Prof.Abbadi did genetic studies to the allProf.Abbadi did genetic studies to the all

Jordanian patients with hemophilia andJordanian patients with hemophilia and

identified new novel mutations amongidentified new novel mutations among

Jordanians with hemophilia A and B. Jordanians with hemophilia A and B.

Hemophilia in femalesHemophilia in females

Symptomatic hemophilia has been well-Symptomatic hemophilia has been well-

documented in females.documented in females.

Three possible explanations for this :Three possible explanations for this :

1-X-chromosome inactivation in early1-X-chromosome inactivation in early

stage of embryogenesis.stage of embryogenesis.

2-Mating between an affected male and2-Mating between an affected male and

a carrier female produces homozygousa carrier female produces homozygous

disease in ½ of female offspring.disease in ½ of female offspring.

3-Abnormal karyotype (Turner syndrome)3-Abnormal karyotype (Turner syndrome)

Late complicationsLate complications

1-Joint destruction due to hemarthroses,1-Joint destruction due to hemarthroses,

leading to a number of orthopedicleading to a number of orthopedic

abnormalities (hemophilic osteo-abnormalities (hemophilic osteo-

arthropathy).arthropathy).

2-Transmission of blood-borne infections.2-Transmission of blood-borne infections.

3-Development of inhibitor antibodies.3-Development of inhibitor antibodies.

Hemophilic arthropathyHemophilic arthropathyMultiple factors may contribute to synovitis andMultiple factors may contribute to synovitis and joint destruction in patints with hemarthroses.joint destruction in patints with hemarthroses. 1- Tissue deposition of iron1- Tissue deposition of iron 2- Dense fibrosis of the joint with 2- Dense fibrosis of the joint with contractures,pain,and limitation ofcontractures,pain,and limitation of motion.motion.Primary prophylactic treatment with factorPrimary prophylactic treatment with factor concentrates can markedly reduce the risk concentrates can markedly reduce the risk of subsequent arthropathy. of subsequent arthropathy. Synovectomy: pharmacological synovectomy.Synovectomy: pharmacological synovectomy. radioactive synovectomy. radioactive synovectomy.

InfectionInfection

Patients treated with older factor VIII and IX Patients treated with older factor VIII and IX

concentrates were at high risk for infectionconcentrates were at high risk for infection

with hepatitis A,B,C,and D and with HIV. with hepatitis A,B,C,and D and with HIV.

The risk of infection has been reduced markedlyThe risk of infection has been reduced markedly

by improvement in donor screening andby improvement in donor screening and

virucidal techneques and the developmentvirucidal techneques and the development

of recombinant products.of recombinant products.

InhibitorsInhibitors

Antibodies are primarily IgG.Antibodies are primarily IgG.

Occur in 25% of severe hemophilia A,andOccur in 25% of severe hemophilia A,and

3-5% of those with severe hemophilia B.3-5% of those with severe hemophilia B.

Much less common in patients with mild orMuch less common in patients with mild or

moderate disease.moderate disease.

Increased risk of bleeding.Increased risk of bleeding.

Maturational delays. Maturational delays.

Management-1Management-1

Complex, and should include:Complex, and should include:

1-Preventive and comprehensive care.1-Preventive and comprehensive care.

(routine immunizations,circumcision,(routine immunizations,circumcision,

dental care,counselling anddental care,counselling and

education,exercise and athleticeducation,exercise and athletic

participation)participation)

2-Replacement therapy (treatment 2-Replacement therapy (treatment

and prophylaxis)and prophylaxis)

3-Other therapies: gene therapy.3-Other therapies: gene therapy.

Therapies other than replacement Therapies other than replacement therapytherapy

Ice.Ice.

Immobilization.Immobilization.

Steroids.Steroids.

Physiotherapy.Physiotherapy.

Analgesia: aspirin and NSAIDs are contraindicated, Analgesia: aspirin and NSAIDs are contraindicated, paracetamol or codeine can be used.paracetamol or codeine can be used.

Desmopressin.Desmopressin.

Antifibrinolytic therapy: tranexamic acid,epsilon Antifibrinolytic therapy: tranexamic acid,epsilon

aminocaproic acid. aminocaproic acid.

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Treatment of hemophilia ATreatment of hemophilia A

Intermediate purity plasma productsIntermediate purity plasma products– Virucidally treatedVirucidally treated– May contain von Willebrand factorMay contain von Willebrand factor

High purity (monoclonal) plasma productsHigh purity (monoclonal) plasma products– Virucidally treatedVirucidally treated– No functional von Willebrand factorNo functional von Willebrand factor

Recombinant factor VIIIRecombinant factor VIII– Virus free/No apparent riskVirus free/No apparent risk

--No functional von Willebrand factorNo functional von Willebrand factor

Dosing guidelines for hemophilia ADosing guidelines for hemophilia A

Mild bleedingMild bleeding– Target: 30% dosing q8-12h; 1-2 days (15U/kg)Target: 30% dosing q8-12h; 1-2 days (15U/kg)– Hemarthrosis, oropharyngeal or dental, epistaxis, hematuriaHemarthrosis, oropharyngeal or dental, epistaxis, hematuria

Major bleedingMajor bleeding– Target: 80-100% q8-12h; 7-14 days (50U/kg)Target: 80-100% q8-12h; 7-14 days (50U/kg)– CNS trauma, hemorrhage, lumbar punctureCNS trauma, hemorrhage, lumbar puncture– SurgerySurgery– Retroperitoneal hemorrhageRetroperitoneal hemorrhage– GI bleedingGI bleeding

Adjunctive therapyAdjunctive therapyTranexemic acid or DDAVP (for mild disease only)Tranexemic acid or DDAVP (for mild disease only)

Treatment of hemophilia BTreatment of hemophilia B

Agent Agent – High purity factor IXHigh purity factor IX– Recombinant human factor IXRecombinant human factor IX

DoseDose– Initial dose: 100U/kgInitial dose: 100U/kg– Subsequent: 50U/kg every 24 hoursSubsequent: 50U/kg every 24 hours

Treatment of patients with Treatment of patients with inhibitors-1inhibitors-1

Components of therapy:Components of therapy:

1-Treatment of active bleeding.1-Treatment of active bleeding.

2-Inhibitor ablation via immune 2-Inhibitor ablation via immune

tolerance induction (inhibitortolerance induction (inhibitor

eradication).eradication).

Treatment of patients with Treatment of patients with inhibitors-2inhibitors-2

Inhibitor bypassing products:Inhibitor bypassing products:

1-Prothrombin complex concentrates,1-Prothrombin complex concentrates,

FIEBA: are associated with a lotFIEBA: are associated with a lot

of complications.of complications.

2-Recombinant activated factor VII2-Recombinant activated factor VII

( r FVIIa): no anamnestic antibody( r FVIIa): no anamnestic antibody

response.Not associated withresponse.Not associated with

increased risk of DIC due to it’s increased risk of DIC due to it’s

localized effect. localized effect.

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