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Bleeding Disorders

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Platelet count = normal count ? Skin Bleeding Time (BT) =Normal; 2-10min ... Amyloid infiltration of blood vessels. Bleeding. disorders. Vascular. abnormalities ... – PowerPoint PPT presentation

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Title: Bleeding Disorders


1
Bleeding Disorders
2
Objectives
  • Normal
  • Laboratory tests
  • Vessel wall
  • Platelets
  • Coagulation pathways
  • Pathology
  • Types
  • Disorders of Hemostasis

3
Laboratory tests
  • Platelet count normal count ?
  • Skin Bleeding Time (BT) Normal 2-10min
  • Prolonged in Platelet disorders
  • Tests of coagulation
  • On citrated platelet poor plasma
  • PTT normal 3-50 sec.
  • Prolonged in deficiency of intrinsic pathway
    factors
  • Used to monitor heparin therapy
  • PT normal 10 -15 sec
  • Measure of extrinsic pathway
  • Used to monitor oral anticoagulants such as
    warfarin

4
  • Normal

5
Vascular wall ( Endothelium)
  • Antithrombotic properties
  • Antiplatelet effects
  • Anticoagulant properties
  • Fibrinolytic properties
  • Prothrombotic properties
  • Von Willebrand factor
  • Tissue factor
  • Fibrinolysis inhibitors

6
Platelets
  • Adhesion to the extracellular matrix after
    vascular injury with vWF ( vWF - glycoprotein
    Ib association) and undergo shape change
  • Secretion or release reaction of granule
    contents soon after adhesion.
  • Release of calcium and ADP.
  • Calcium is for coagulation cascade
  • ADP mediates platelet aggregation
  • Aggregation with platelets via glycoprotein IIb/
    IIIa forms the primary hemostatic plug. With
    platelet contraction, a secondary, irreversible
    plug is formed. Fibrin cements the plug

7
Coagulation pathway
  • Two pathways for fibrin clot formation
  • Intrinsic
  • Initiated by negatively charged surface
  • Extrinsic
  • Initiated on tissue injury
  • Both pathways converge on a final common pathway
  • Prothrombin ? Thrombin (Most critical step )
  • Fibrinogen Fibrin ? Clot
  • The pathways are complex and involve many
    different proteins (called blood clotting factors)

8
Coagulation Cascade - continued
  • Control of coagulation
  • Antithrombins (e.g., antithrombin III)
  • Proteins C and S
  • Fibrinolytic cascade
  • Plasminogen ? plasmin ? fibrin break down
    products (FDP or FSP) d-dimer is most
    important of the FDPs

FDP / FSP Fibrin degradation products / Fibrin
split products
9
Pathology
10
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11
Vascular abnormalities
  • Causes
  • Infections
  • Meningococcemia, Rickettsioses , Infective
    endocarditis
  • Drug reactions
  • Hereditary hemorrhagic telangiectasia
  • Autosomal dominant
  • Cushing syndrome
  • Henoch - Schönlein Purpura
  • systemic hypersensitivity disease of unknown
    cause
  • polyarthralgia, and acute Glomerulonephritis
  • Palpable purpuric rash, colicky abdominal pain
  • Scurvy and the Ehlers-Danlos syndrome
  • Amyloid infiltration of blood vessels

12
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13
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14
Platelet disorders
  • Thrombocytopenia Reduced platelet number
  • Causes
  • Decreased production of platelets
  • vitamin B12 or folic acid deficiency
  • Decreased platelet survival
  • Immunologic or Nonimmunologic etiology
  • Sequestration- Hypersplenism
  • ameliorated by splenectomy
  • Dilutional
  • Massive transfusions

15
Immune Thrombocytopenic Purpura (ITP)
  • Cause
  • Antiplatelet antibodies
  • Antigen - platelet membrane glycoprotein
    complexes IIb-IIIa and Ib-IX
  • Morphology
  • Peripheral Blood
  • thrombocytopenia, abnormally large platelets
    (megathrombocytes or Giant platelets),
  • Marrow
  • Normal or Increased magakaryocyte
  • Diagnosis - by exclusion
  • Bleeding time - prolonged, but PT PTT - normal

? Marrow magakaryocyte - your Diagnosis of ITP
is ?????
16
ITP
17
ITP
18
Drug induced thrombocytopeniaHeparin induced
thrombocytopenia (HIT)
  • Seen in 3-5 of patients treated with
    unfractionated heparin
  • thrombocytopenic after 1-2 weeks of Rx
  • Caused by IgG antibodies against platelet factor
    4/heparin complexes on platelet surfaces
  • Exacerbates thrombosis, both arterial and venous
    (in setting of severe thrombocytopenia)
  • Antibody binding results in platelet activation
    and aggregation.
  • Rx - cessation of heparin

Other drugs???
19
HIV associated Thrombocytopenia
  • MC hematological feature in HIV infection
  • Mechanisms
  • CD4 is on T cells and Megakaryocytes
  • B cell hyperplasia ? Autoantibodies (antigen GP
    IIb-IIIa) ? splenic phagocytosis

20
Thrombotic Microangiopathies
  • Thrombotic thrombocytopenic Purpura (TTP)
  • Hemolytic-Uremic syndrome (HUS)

21
Thrombotic Microangiopathiescommon for both
disorders
  • Mechanism hyaline (platelets) thrombi in the
    microcirculation
  • Pathogenesis Systemic endothelial cell damage
  • Clinically Fever, Thrombocytopenia, Renal
    failure, Hemolytic anemia

How to differentiate them from DIC?
22
Thrombotic Microangiopathies
Feature
HUS
TTP
23
Platelet functional disorders
24
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25
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26
Clotting factor abnormalities
  • Congenital disorders
  • Von Willebrand disease MC with minimal bleeding
  • Factor VIII Deficiency - Hemophilia A or Classic
    Type
  • Factor IX Deficiency Hemophilia B
  • Acquired disorders
  • Vit. K deficiency Due to deficient carboxylation
    of factors II, VII, IX X
  • Oral anti-coagulants
  • Coumarin derivatives warfarin inhibit Vit. K
    factors
  • Liver diseases ? synthesis of factors

27
Von Willebrand Disease
  • MC inherited bleeding disorder with mild bleeding
  • Autosomal dominant
  • TYPE I Most common (70 of all cases)
  • Prolonged bleeding time but normal platelet count
  • ?Plasma vWF levels
  • Secondary ? in Factor VIII levels

28
Hemophilia A
  • MC hereditary disease with serious bleeding
  • X-linked recessive
  • In 30 No family history (new mutations)
  • 15 of severe cases develop factor VIII
    inhibitors
  • ? amount or activity of factor VIII
  • factor VIII cofactor for activation of factor X
    in the coagulation cascade
  • Symptoms usually develop in severe cases (factor
    VIII lt1 of normal) hemoarthrosis, bruising,
    hemorrhage after trauma or surgery
  • Best lab test to Diagnose patients?
  • Lab test most useful to monitor the patients ?
  • What are the chances of Heterozygous female
    having disorder?

29
Hemophilia B
  • Factor IX deficiency
  • X-linked recessive
  • Much less common
  • Clinically indistinguishable from Hemophilia A
    with Similar lab findings
  • Diagnosis by factor IX levels
  • Treat with recombinant IX

30
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31
Disseminated Intravascular Coagulation
  • Characterized by activation of the coagulation
    sequence? systemic micro- thrombi
  • Sequelae tissue hypoxia due to microinfarcts
    (Thrombotic) or bleeding problems
  • Triggering Pathways
  • Release of tissue factor / thromboplastic factors
    into circulation
  • Widespread endothelial injury
  • MechanismActivated monocytes? release IL-1 and
    TNF a ?? expression of tissue Thromboplastic
    factor on endothelial cells decrease
    Thrombomodulin
  • Mechanism Consumption of coagulation factors ,
    platelets, and activation of fibrinolytic pathways

32
Disseminated Intravascular Coagulationcontd
  • Sources of thromboplastic substances
  • Leukemic cell granules
  • Placenta in obstetric complications
  • Carcinomas- (Mucin - secreting adenocarcinomas)
  • Bacterial endo and exotoxins
  • Endothelial injury can also be Caused by
  • Antigen-antibody complexes S.L.E.
  • Temperature extremes Heat stroke or burns
  • MicroorganismsRickettsae, meningococci

33
Disseminated Intravascular Coagulationcontd
  • Plasmin ?Fibrinolysis ? formation of fibrin
    degradation products (FDP)
  • D-Dimer most important of FDPs
  • Organ damage due to Micro thrombi
  • Kidney microinfarcts in the renal cortex
  • In severe cases bilateral renal cortical
    necrosis
  • Adrenals bilateral adrenal hemorrhage
  • resembles waterhouse - Friderichsen syndrome
  • Brain Microinfarcts surrounded by foci of
    hemorrhage
  • Heart and anterior pituitary show Similar
    changes

34
Disseminated Intravascular Coagulationcontd
  • Clinically Bleeding tendency in presence of
    widespread coagulation
  • Acute D.I.C. dominated by a bleeding
  • seen in obstetrical complications and trauma
  • Chronic D.I.C. presents with Thrombotic
    complications
  • seen in cancers
  • Manifestations variable
  • Minimal to profound shock, renal failure,
    dyspnea, cyanosis, convulsions, and coma
  • Hypotension is characteristic.

35
Disseminated Intravascular Coagulationcontd
  • Lab PT And PTT Are typically prolonged.
  • Thrombocytopenia
  • low Fibrinogen
  • Elevated plasma Fibrin split products
  • Prognosis Highly variable
  • Depends upon
  • Underlying disorder
  • Degree of intravascular clotting
  • Activity of mononuclear phagocytic system
  • Amount of Fibrinolysis
  • Treatment of the underlying disorder is most
    important!!

How to differentiate DIC form HUS/TTP using lab
parameters?
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