Bleeding Disorders

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Bleeding Disorders
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Objectives

• Normal
• Laboratory tests
• Vessel wall
• Platelets
• Coagulation pathways
• Pathology
• Types
• Disorders of Hemostasis

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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

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• Normal

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Vascular wall ( Endothelium)

• Antithrombotic properties
• Antiplatelet effects
• Anticoagulant properties
• Fibrinolytic properties
• Prothrombotic properties
• Von Willebrand factor
• Tissue factor
• Fibrinolysis inhibitors

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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

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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)

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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
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Pathology
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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

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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

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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 ?????
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ITP
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ITP
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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???
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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

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Thrombotic Microangiopathies

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

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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?
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Thrombotic Microangiopathies
Feature
HUS
TTP
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Platelet functional disorders
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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

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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

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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?

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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

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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

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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

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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

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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.

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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?