BLEEDING_DISORDERS

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BLEEDING_DISORDERS Powered By Docstoc
					Hemostasis:
BV Injury
Tissue Factor

Neural

Blood Vessel Constriction

Platelet Aggregation Primary hemostatic plug

Coagulation Cascade

Reduced
Blood flow

Platelet Activation

Fibrin formation

Stable Hemostatic Plug

Haemostasis

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Coagulation cascade
Intrinsic system (surface contact) XII
XI XIIa

Extrinsic system (tissue damage)
Tissue factor

XIa

IX

IXa VIII
X

VIIa

VII

VIIIa
Xa

Vitamin K dependant factors

V
II

Va IIa
(Thrombin) Fibrin

Fibrinogen

Coagulation Cascade:
Intrinsic Path (XII,XI,IX,VIII) (aPTT) (Factor X) Common Path (V,II)
(Thrombin)

Extrinsic Path (VII) (PT)

(TT)

Fibrinogen  Fibrin

(Fibrin & FDP)

Platelets:
• • • • • Contractile, adhesive, cell fragments. Bone marrow –Megakaryocytes Store coagulation factors & enzymes Surface Binding sites for fibrinogen Surface Glycoprotein Antigens.

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Disorders of Hemostasis
• Vascular disorders
– Scurvy, easy bruising

• Platelet disorders
– Low number or abnormal function

• Coagulation disorders
– Factor deficiency.

• Mixed/Consumption: DIC

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Bleeding: Clinical Features
1. 2. 3. 4. • • Local - Vs - General, spontaneous . Hematoma & Joint bleed - Coagulation Skin/Mucosal Petechiae & Purpura – PLT wound / surgical bleeding – Immediate - (PLT) Delayed - (Coagulation)

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Platelet
Petechiae, Ecchymoses

Coagulation
Joint bl.
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Petechiae & Echymoses -Platelet count

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Sub Conjuctival Haemorrhage

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Clinical Features of Bleeding Disorders
Platelet
Site of bleeding Skin
Mucous membranes (epistaxis, gum, vaginal, GI tract)

Coagulation
Deep in soft
tissue (joints,muscles)

Petechiae Ecchymoses (“bruises”) Hemarthrosis / muscle bleeding
Bleeding after cuts & scratches Bleeding after surgery or trauma

Yes Small, superficial Extremely rare
Yes Immediate, usually mild

No Large, deep Common
No Delayed (1-2days), often severe
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BLEEDING DISORDERS

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Investigations
• Platelet count • Bleeding time 2-9 minutes is time taken by a standard skin puncture to stop bleeding prolonged – defect in platelet number or function

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Coagulation cascade
Intrinsic system (surface contact) XII
XI XIIa

Extrinsic system (tissue damage)
Tissue factor

XIa

IX

IXa VIII
X

VIIa

VII

VIIIa
Xa

Vitamin K dependant factors

V
II

Va IIa
(Thrombin) Fibrin
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Fibrinogen

• Prothrombin time 11-15sec Prolonged – deficiency of factor VII, X, V, Prothrombin, Fibrinogen (Extrinsic and common pathway) • Activated Partial thromboplastin time 32-46sec Prolonged- of factor V, VIII, IX, X, XI, XII, Prothrombin, Fibrinogen (Intrinsic and common pathway)

• Factor assays

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Special Investigations:
• Specific Factor Assays • Platelet function studies
• Bone marrow examination – plt
– Aggregometry – Adhesion studies

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Vessel wall abnormalities
• • • • • • Petechiae,purpura BT,PT,APTT-Normal Infections Drugs Scurvy , Ehlers-Danlos , Cushing Henoch-Schonlein purpura

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Thrombocytopenia
• Platelet count below the lower limit of the reference range( 100 x 10 9/ l ) • Symptomatic < 50 x 10 9 / l • < 30 x 10 9 / l menorrhagia, petechiae, spontaneous bruising

• < 10 x 10 9 / l severe spontaneous bleeding including CNS
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Classification of thrombocytopenia
1.Decreased production
Generalised disease of bone marrow Aplastic anemia, marrow infiltration, Disseminated Carcinoma Selective impairment of platelet production Drugs, Infections Megaloblastic anemia

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2.Increased destruction
• Immune thrombocytopenia Autoimmune disorders platelet destruction due to antiplatelet antibodies • Idiopathic or primary • Secondary SLE, Viral Drug-Quinidine,Heparin,Sulfa • Non immune

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Idiopathic thrombocytopenic purpura

Acute Chronic

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Molecular Mimicry:
VZV

Platelet
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MHCII

Macrophage (APC)
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1.
Phagocytosis
MHCII

Macrophage (APC)
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2. 1.
Phagocytosis

Destruction

MHCII

Macrophage (APC)
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Infection, Cytokines (e.g. TNF, IFN)

APC Activation
Destruction

2. 1.
Phagocytosis

MHCII

Macrophage (APC)
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Infection, Cytokines (e.g. TNF, IFN)

APC Activation
Destruction

2. 1.
Phagocytosis

Altered processing

MHCII

Macrophage (APC)
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Infection, Cytokines (e.g. TNF, IFN)

APC Activation
Destruction

2. 1.
Phagocytosis

Altered processing

Peptides

MHCII

3.
Macrophage (APC)
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Infection, Cytokines (e.g. TNF, IFN)

APC Activation
Destruction

2. 1.
Phagocytosis

Altered processing

Peptides

MHCII

3.
Macrophage (APC)
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4.
Abnormal Presentation
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Infection, Cytokines (e.g. TNF, IFN)

APC Activation
Destruction

2. 1.
Phagocytosis

Altered processing

CD4+ T cell Activation MHCII TcR

Peptides

3.
Macrophage (APC)
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4.
Abnormal Presentation of a platelet autoantigen
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Acute ITP
• Most often in children 2 – 6 yrs • Most often 1 – 3 wks after viral infection eg; chicken pox, rubella, CMV, viral hepatitis • Platelet count < 20 x 10 9 / l • Abrupt onset of bleeding • Self limited • Therapy- none steroids ( severe thrombocytopenia)
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Chronic ITP
• • • • • • Adults 20 – 40 yrs F: M = 3 : 1 Onset insidious Antecedent infection unusual Platelet count 30-80 x 10 9 / l .BT-prolonged Therapy- Steroids Splenectomy Spontaneous remission uncommon

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Clinical features
• Bleeding into skin,mucous membrane bleeding into CNS rare • Easy bruising • Splenomegaly & lymphadenopathy rare

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Lab findings
• Platelet count -low • Bone marrow Megakaryocytes- increased immature forms+ • BT Prolonged • PT & PTT normal

Thrombotic microangiopathies
TTP • Fever,thrombocytopenia Microangiopathic hemolytic Anemia,neurologic deficits, renal failure • Hyaline thrombi • PT,APTT-Normal • Platelet transfusion is contraindicated • vWF metalloprotease absent
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HUS
• Microangiopathic HA, Thrombocytopenia • Renal failure • GI bleed • E.coli

Thrombocytopenia

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Defective platelet function
• Bernard-soullier syndrome – gp Ib-IX • Glanzmann’s thrombasthenia- IIbIIIa

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COAGULATION DISORDERS
• Acquired Vitamin K deficiency –factors II,VII,IX,X -Liver disease DIC • Hereditary Deficiency of Factor VIII (Haemophilia A) Deficiency of Factor IX (Christmas Disease/Haemophilia B)
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Haemophilia
• Congenital deficiency -Factor VIII(A) or IX(B) • Bleeding – Haematoma, joint. • Gene on X chromosome.
– (Carrier females, Males suffer)

• Prolonged PTT but normal PT. • FFP or Factor replacement – Life long.
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Hemophilia A
• Reduction in the amount or activity of factor VIII • X linked recessive disorder • Males, homozygous females

Pathogenesis Factor VIII gene on long arm of X Deletion / point mutation Decreased VIII levels

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• Clinical severity is related to the concentration of deficient factor • Severe < 1 % of normal Moderate- 2-5% of normal Mild 6-50% of normal In severe cases symptoms commences by 2 yrs of age mild cases-adolescences

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Clinical features
• • • • • Hemarthrosis - commonly knee joint, muscle atrophy pain + destruction of joint & deformities easy bruising & massive haemorrhage after trauma Petechiae absent
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Investigations
• Bleeding time, platelet count, P T – normal • Prolonged PTT • Definitive diagnosisSpecific factor assay

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Treatment
• Fresh blood, fresh plasma • Recombinant Factor VIII concentrate

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Hemophilia B
• Factor IX deficiency • Less common X linked recessive Clinically indistinguishable from Hemophilia A Diagnosis by factor assay

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Von Willebrands Disease
• Deficiency of Von Willebrand factor (vWF) • Factor VIII is complexed with large multimers of vWF in circulation,and maintains its stability • Activity can be assayed by RISTOCETIN AGGLUTINATION TEST • Autosomal dominant • Autosomal recessive Rare

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Clinical features
• common inherited bleeding disorder • Spontaneous bleeding from mucous membrane, excessive bleeding from wounds, menorrhagia • BT-prolonged, platelet count-normal • vWF levels by Ristocetin activity-reduced • Secondary FVIII decrease- increased aPTT

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Nail bed - Hematoma
•Red •Blue/Grey •Brown

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Contusion - Hematoma

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Bleeding-Coagulation disorder
•Deep bleeding •Haematoma •Joint bleeds •Joint deformity

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Disseminated Intravascular Coagulation
Activation of both coagulation and fibrinolysis
Triggered by • Sepsis • Trauma
– Head injury – Fat embolism
• Obstetrical complications
– Amniotic fluid embolism – Abruptio placentae

• Malignancy

• vascular disorders • Reaction to toxin (e.g. snake venom, drugs) • Immunologic disorders
– Severe allergic reaction – Transplant rejection

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Disseminated Intravascular Coagulation (DIC) Mechanism
Systemic activation of coagulation

Intravascular deposition of fibrin

Depletion of platelets and coagulation factors

Thrombosis of small and midsize vessels with organ failure
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• three natural anticoagulants: antithrombin (AT), protein C (PC), and protein S (PS).
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Pathogenesis of DIC
Release of thromboplastic material into circulation

Coagulation
Fibrinogen
Thrombin

Fibrinolysis

Plasmin

Consumption of coagulation factors; presence of FDPs  aPTT  PT  TT  Fibrinogen Presence of plasmin FDP,D dimer, Fibrinopeptides,monomer Intravascular clot  Platelets Schistocytes
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Fibrin Monomers

Fibrin(ogen) Degradation Products

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Fibrin Clot (intravascular)

Plasmin

Thrombocytopenia

Initial Evaluation of a Bleeding Patient 1
Normal PT Abnormal PTT
Repeat with 50:50 mix
50:50 mix is abnormal Test for inhibitor activity: Specific factors: VIII,IX, XI Non-specific (anti-phospholipid Ab)

50:50 mix is normal Test for factor deficiency: Isolated deficiency in intrinsic pathway (factors VIII, IX, XI) Multiple factor deficiencies (rare)
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Initial Evaluation of a Bleeding Patient 2
Abnormal PT Normal PTT
Repeat with 50:50 mix
50:50 mix is abnormal Test for inhibitor activity: Specific: Factor VII (rare) Non-specific: Anti-phospholipid (rare)

50:50 mix is normal Test for factor deficiency: Isolated deficiency of factor VII (rare) Multiple factor deficiencies (common) (Liver disease, vitamin K deficiency, warfarin, 11/16/2008 DIC) Thrombocytopenia

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Initial Evaluation of a Bleeding Patient 3
Abnormal PT Abnormal PTT
Repeat with 50:50 mix
50:50 mix is abnormal Test for inhibitor activity: Specific : Factors V, X, Prothrombin, fibrinogen (rare) Non-specific: anti-phospholipid (common)

50:50 mix is normal Test for factor deficiency: Isolated deficiency in common pathway: Factors V, X, Prothrombin, Fibrinogen Multiple factor deficiencies (common) 11/16/2008 Thrombocytopenia Liver disease, vitamin K deficiency, warfarin, DIC

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Initial Evaluation of a Bleeding Patient 4
Normal PT Normal PTT
Urea solubility
Abnormal Factor XIII deficiency

Normal Consider evaluating for:

Abnormal fibrinolysis (a2 anti-plasmin def) 11/16/2008 Elevated FDPs

Platelet disorder Vascular disorder
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Summary:
• Haemostasis – Blood vessels+ Platelets + Coagulation • Traumatic & Spontaneous bleeding. • Disorders are Congenital or Acquired • Screening tests: BT, CT, PT, PTT, Platelet count. • Platelet disorders–Skin/Mucosa Coagulation disorders- Deep bleeds, joint.

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