Inherited Coagulation Disorders - PowerPoint PPT Presentation

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Inherited Coagulation Disorders

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Title: Inherited Coagulation Disorders


1
Inherited Coagulation Disorders
  • Dr Galila Zaher
  • Consultant Hematologist
  • KAUH

2
BLOOD CLOTTING
  • Blood clotting interactions
  • Plasma protein clotting factors
  • Platelets Vascular
    endothelium

3
Hemostasis
Hemostasis
Subendothelial matrix
Subendothelial matrix
Hemostatic plug
Hemostatic plug
Endothelial cell
Endothelial cell
WBC
WBC
WBC
WBC
Fibrin
RBC
Platelets
Fibrin
RBC
Platelets
4
COAGULOPATHIES
  • Bleeding
    Thrombosis
  • Clotting factors Natural
    anticoagulant
  • platelets

5
Clot formation
  • Platelet activation Primary
    hemostasis
  • No count
    (immediate)
  • Fibrin generation
  • plasma clotting Secondary
    hemostasis
  • factors
    (delayed)

6
Platelet Activation Pathways (1)
COLLAGEN
THROMBIN

ADP
GpIIb/IIIa
Platelet
GpIb
Adrenaline
Adhesion
7
Clotting factor production
  • Liver source of plasma clotting factors except
    VWF
  • Factor VIII produced by liver endothelium
  • VWF endothelial cells megakaryocytes
  • Vitamin K dependent clotting factors are
  • II, VII, IX, X

8
COAGULATION PATHWAYS
  • Intrinsic extrinsic pathways
  • conclude in the common pathway
  • Intrinsic pathway clotting factors
  • Extrinsic pathway clotting factors
  • Common pathway clotting factors

9
NORMAL COAGULATION PATHWAYS
  • Intrinsic pathway clotting factors
  • Factor XII Factor IX
  • Factor VIII Factor XI
  • Extrinsic pathway clotting factors
  • Tissue factor (TF)
  • Factor VII
  • Common pathway clotting factors
  • Factor X
  • Factor V
  • Factor II Prothrombin
  • Factor I Fibrinogen

10
Intrinsic pathway XII ---gt XIIa
v XI---------XIa
v IX --------gt IXa
VIII v X----------------------gt
Xa Common pathway
v Xa V prothrombin
-------------gt thrombin
v fibrinogen--------------gt fibrin
11
Fibrin XIIIa Cross-linked fibrin
12
Defect Time Clinical
Platelet disorders function or number immediate (mins) Mucosal bruising,petechia, epistaxis, childhood menorrhagia, post-op
Coagulation factor delayed (hrs - days) joint (hemarthrosis), muscle, skin (soft tissue hematomas)
fibrinolytic disorders
13
Deficiencies of
  • Factor XII
  • High molecular weight kininogen
  • Prekallikrein
  • - Do NOT produce bleeding diatheses

14
COAGULATION TESTS
  • Platelet tests
  • lt150,000 thrombocytopenia
  • gt400,000 thrombocytosis
  • Tests of clotting factors

15
Platelet tests
  • Test Comment
  • Platelet count Part of routine
    CBC,
  • normal count
  • 150,000 - 400,000/uL
  • Mean platelet volume MPV Some analyzers
  • provide MPV
  • measurement in
  • healthy individuals,
  • MPV varies inversely
  • with platelet count
  • Platelet aggregation Not routine tests,
  • and secretion tests used only in special
  • circumstances

16
Tests of clotting factors
Test Abbreviation Comment
Prothrombin time PT extrinsic common pathways Functional test VII X, V, II, I
Partial thromboplastin PTT intrinsic common pathways Functional test prekallikrein, HMWK XII, XI, IX, VIII X, V, II, I
Thrombin time TT Fibrinogen concentration Quantitative test
17
Hemophilia
  • A Factor VIII deficiency
  • B Factor IX deficiency
  • Affects one in 6000 males
  • A is 5 X gt B
  • Mild gt 5 normal amount of factor
  • Moderate 2 - 5 , severe lt 2
  • Levels remain stable throughout life

18
Inheritance
  • Both HA HB are X linked
  • Only men can have the disease
  • Women are carriers

19
Clinical presentation
  • lt 2 years joint bleeds
  • Rare
  • Only bruising or mouth bleeds are seen
  • Head injuries are a major concern
  • gt 2 years
  • joint and muscle bleeds become more common

20
Clotting factor deficiencies
21
Laboratory Diagnosis
  • Isolated prolongation of APTT
  • Microcytic hypochromic anemia
  • Normal platelets count
  • Mixing studies corrected.

22
When to treat
  • All joint bleeds Pain, swelling ,warmth or loss
    of movement .
  • Muscle bleeds that cause severe pain or are in a
    dangerous location
  • Bruises usually dont need treatment
  • When in doubt .

23
Treatment
  • Keep weight off of joint
  • Ice pack
  • Factor replacement - the sooner the better
  • Amicar or tranexamic acid mouth bleed
  • CVL s Frequent bleeds or factor given on a
    regular basis
  • Port-a-catheters

24
Dose Duration
  • 1 IU/kg of factor VIII increases the level by 2
  • 1 IU/kg of factor IX increases the level by 1
  • Every 12 hours the level decreases by half

25
Prophylaxis
  • To prevent bleeds
  • Started after developing a target joint
  • Usually it is administered 3/week
  • Stepwise approach Initially 1/week, increasing
    to 2-3/week if needed
  • Goal is to prevent long-term joint damage

26
Team Approach
  • We all work together
  • Child and parents
  • Doctor and nurses
  • Physiotherapy
  • Social work
  • Everyone has an essential role
  • The aim is to get life to be as normal as
    possible

27
Factor VIII Replacement
  • Mechanism of action activate FX
  • Mode of administration IV
  • Monitoring no predict the effectiveness of
    treatment
  • Indications HA HB
  • Severe surgical bleeding
  • Factor VII deficiency

28
Factor VIII
  • Derived from pooled human plasma
  • Derived from pig (porcine) plasma
  • Recombinate products

29
Porcine factor VIII
  • HyateC
  • Apparently no pig viruses present
  • Can replace human Factor VIII in clotting cascade
  • Minimal cross reactivity with AHF antibodies
  • Minimal von Willebrand factor present

30
von Willebrand Factor (V W F)
  • VWF bridges platelets to collagen exposure from
    blood vessel injury
  • VWF contributes to primary hemostasis
  • Factor VIII circulates bound to VWF .
  • VWD clinically similar to platelet disorders
  • Most common inherited bleeding disorder

31
VWD
  • Inherited as a dominant or recessive .
  • Most common congenital bleeding disorder
  • Affecting 1-3 of the population.
  • Personal and family bleeding history.
  • Highly heterogeneous
  • Ranging from asymptomatic to a life threatening
    bleeding.
  • The most common bleeding symptoms ever were
    epistaxis, bruising
  • Menorrhagia is one of the most important and
    frequent complications in women

32
Platelet disorders
33
DIAGNOSIS
  • The condition is caused by a quantitative or
    qualitative deficiency of vWF.
  • Prolonged bleeding time (BT) activated partial
    thromboplastin time (APTT)
  • iron deficiency anemia .
  • type 1 vWD

34
Managment
  • The aim of treatment is to correct the dual
    defect of hemostasis ( low VIIIC prolonged
    bleeding time).
  • DDAVP is the treatment of choice for the mild
    forms of type 1 and 2 VWD
  • Unresponsive to DDAVP, plasma virally inactivated
    concentrates of factor VIII
  • Tranexamic acid

35
Increased PT
  • Deficient, function or inhibition
  • Liver disease production/ vit K
    malabsorption
  • vit. K antagonists warfarin (blocks
    carboxylation)
  • Heparin the PTT is a more sensitive test
  • FDPs inhibits coagulation
  • lupus anticoagulant PTT is a better test
  • (LA)

36
Increased PTT
  • Heparin unfractionated heparin
  • inhibits Xa and IIa
  • vit K antagonists PT is a more sensitive
  • fibrin/fibrinogen inhibits coagulation
  • degradation products
  • lupus anticoagulant PTT is a better than
  • PT

37
TT increased
  • Congenital disorders
  • afibrinogenemia homozygous def.
  • hypofibrinogenemia heterozygous def.
  • dysfibrinogenemia dysfunctional
    fibrinogen
  • Acquired disorders
  • hypofibrinogenemia liver disease,
    (disseminated
  • intravascular
    coagulation),
  • thrombolytic therapy
  • dysfibrinogenemia liver disease, hepatic
    malignancy
  • Fibrin degradation inhibits coagulation
  • products
  • Heparin inactivates IIa

38
Fibrinogen level hypofibrinogenemia)
  • Liver disease decreased production
  • Consumption disseminated intravascular
  • coagulation (DIC)
  • Thrombolytic therapy
  • Congenital def. afibrinogenemia homo. def.
  • hypofibrinogenemia hetero.

39
Fibrinogen assay
quantitative immunoassay Functional
immunologic or antigenic fibrinogen
Increased Estrogen Pregnancy Acute phase response Estrogen Pregnancy Acute phase response
decreased hypofibrinogenemia) hypofibrinogenemia) also - dysfunctional fibrinogen (dysfibrinogenemia
40
Problem solving
  • PT PTT TT
  • Incr. NL NL _____________
  • NL Incr. NL _____________
  • Incr. Incr. NL _____________
  • Incr. Incr. Incr. _____________

41
Actions of thrombin
---gt VIIIa
---gt Va
v XIII ---gt XIIIa v cross-linked fibrin
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