Inherited Coagulation Disorders

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Inherited Coagulation Disorders

• Dr Galila Zaher
• Consultant Hematologist
• KAUH

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BLOOD CLOTTING

• Blood clotting interactions
• Plasma protein clotting factors
• Platelets Vascular
  endothelium

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Hemostasis
Hemostasis
Subendothelial matrix
Subendothelial matrix
Hemostatic plug
Hemostatic plug
Endothelial cell
Endothelial cell
WBC
WBC
WBC
WBC
Fibrin
RBC
Platelets
Fibrin
RBC
Platelets
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COAGULOPATHIES

• Bleeding
  Thrombosis
• Clotting factors Natural
  anticoagulant
• platelets

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Clot formation

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

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Platelet Activation Pathways (1)
COLLAGEN
THROMBIN

ADP
GpIIb/IIIa
Platelet
GpIb
Adrenaline
Adhesion
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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

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COAGULATION PATHWAYS

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

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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

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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
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Fibrin XIIIa Cross-linked fibrin
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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
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Deficiencies of

• Factor XII
• High molecular weight kininogen
• Prekallikrein
• - Do NOT produce bleeding diatheses

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COAGULATION TESTS

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

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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

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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
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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

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Inheritance

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

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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

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Clotting factor deficiencies
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Laboratory Diagnosis

• Isolated prolongation of APTT
• Microcytic hypochromic anemia
• Normal platelets count
• Mixing studies corrected.

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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 .

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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

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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

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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

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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

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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

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Factor VIII

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

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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

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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

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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

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Platelet disorders
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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

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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

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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)

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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

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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

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Fibrinogen level hypofibrinogenemia)

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

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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
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Problem solving

• PT PTT TT
• Incr. NL NL _____________
• NL Incr. NL _____________
• Incr. Incr. NL _____________
• Incr. Incr. Incr. _____________

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