Inherited Coagulation Disorders

Dr Galila ZaherConsultant Hematologist

KAUH

BLOOD CLOTTINGBlood clotting interactions

Plasma protein clotting factors

Platelets Vascular endothelium

HemostasisSubendothelial matrixSubendothelial matrix

PlateletsPlatelets

Hemostatic plugHemostatic plug

FibrinFibrin

Endothelial cellEndothelial cell

RBCRBCWBCWBC

WBCWBC

HemostasisSubendothelial matrixSubendothelial matrix

PlateletsPlatelets

Hemostatic plugHemostatic plug

FibrinFibrin

Endothelial cellEndothelial cell

RBCRBCWBCWBC

WBCWBC

COAGULOPATHIES

Bleeding Thrombosis

Clotting factors Natural anticoagulant

platelets

Clot formation

Platelet activation Primary hemostasis

No &count (immediate)Fibrin generation plasma clotting Secondary

hemostasisfactors (delayed)

Adhesion

GpIIb/IIIa

Platelet Activation Pathways (1)

GpIIb/IIIaGpIIb/IIIa Aggregation

ADP

Adrenaline Platelet GpIb

Exposed Collagen

Endothelium

vWF

COLLAGEN

GpIIb/IIIaGpIIb/IIIa AggregationGpIIb/IIIaGpIIb/IIIa Aggregation

AdhesionAdhesion

ADP

Adrenaline

THROMBINTHROMBIN

Clotting factor productionLiver: 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

COAGULATION PATHWAYS

Intrinsic & extrinsic pathways “conclude” in the common pathway

Intrinsic pathway clotting factors

Extrinsic pathway clotting factors

Common pathway clotting factors

NORMAL COAGULATION PATHWAYS

Intrinsic pathway clotting factorsFactor XII Factor IXFactor VIII Factor XI

Extrinsic pathway clotting factorsTissue factor (TF)*Factor VII

Common pathway clotting factorsFactor XFactor VFactor II Prothrombin Factor I Fibrinogen

Intrinsic pathway XII ---> XIIa

v XI---------XIa

v IX --------> IXa

+ VIIIv

X----------------------> Xa [Common pathway] v Xa + V

prothrombin -------------> thrombin

vfibrinogen--------------> fibrin

Extrinsic pathwayVII + TF ----->VIIa/TF

vIXase (“crossover”)Xase (minor)

Fibrin

XIIIa

Cross-linked

fibrin

Defect Time ClinicalPlatelet disorders function or number

“immediate” (mins):

Mucosal bruising,petechia, epistaxis, childhoodmenorrhagia, post-op

Coagulation factor

“delayed” (hrs - days):

joint (hemarthrosis), muscle, skin (soft tissue hematomas)

fibrinolytic disorders

Deficiencies of:

Factor XII High molecular weight kininogen Prekallikrein

- Do NOT produce bleeding diatheses

COAGULATION TESTS Platelet tests <150,000 thrombocytopenia>400,000 thrombocytosis Tests of clotting factors

Platelet testsTest CommentPlatelet 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

Tests of clotting factorsTest Abbreviation Comment

Prothrombin time PT extrinsic & common pathways

Functional test VIIX, V, II, I

Partial thromboplastin

PTT intrinsic &common pathways

Functional test prekallikrein, HMWK XII, XI, IX, VIIIX, V, II, I

Thrombin time TT Fibrinogen concentration

Quantitative test

Hemophilia

A = Factor VIII deficiency B = Factor IX deficiency Affects one in 6000 males A is 5 X > B Mild > 5 % normal amount of factor Moderate 2 - 5 %, severe < 2 % Levels remain stable throughout life

Inheritance

Both HA & HB are X linked

Only men can have the disease

Women are carriers

Clinical presentation

< 2 years: joint bleeds Rare Only bruising or mouth bleeds are seenHead injuries are a major concern

> 2 yearsjoint and muscle bleeds become more

common

Clotting factor deficiencies

Laboratory Diagnosis Isolated prolongation of APTT Microcytic hypochromic anemia Normal platelets count Mixing studies :corrected.

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 don’t need treatment When in doubt .

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

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

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

Team Approach

We all work togetherChild and parentsDoctor and nursesPhysiotherapySocial work

Everyone has an essential role The aim is to get life to be as normal

as possible

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

Factor VIII

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

Porcine factor VIII

Hyate:C Apparently no pig viruses present Can replace human Factor VIII in

clotting cascade Minimal cross reactivity with AHF

antibodies Minimal von Willebrand factor present

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

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

Platelet disorders

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

Managment The aim of treatment is to correct the dual

defect of hemostasis ( low VIII:C & 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

Increased PTDeficient, function or inhibition :Liver disease production/ vit K

malabsorptionvit. K antagonistswarfarin (blocks

carboxylation)Heparin the PTT is a more

sensitive testFDPs inhibits coagulationlupus anticoagulant PTT is a better test(LA)

Increased PTT

Heparin unfractionated heparin inhibits Xa and IIa

vit K antagonists PT is a more sensitive

fibrin/fibrinogen inhibits coagulation

degradation productslupus anticoagulant PTT is a better

than PT

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

Fibrinogen level hypofibrinogenemia)

Liver disease decreased production

Consumption disseminated intravascular

coagulation (DIC)Thrombolytic therapy Congenital def. afibrinogenemia: homo.

def.hypofibrinogenemia:

hetero.

Fibrinogen assayquantitative immunoassay:

Functional

“immunologic” or “antigenic” fibrinogen

Increased: Estrogen PregnancyAcute phase response

Estrogen PregnancyAcute phase response

decreased hypofibrinogenemia)

hypofibrinogenemia) also - dysfunctional fibrinogen (dysfibrinogenemia

Problem solvingPT PTT TTIncr. NL NL _____________

NL Incr. NL _____________

Incr. Incr. NL _____________

Incr. Incr. Incr. _____________

Intrinsic pathway XII ---> XIIa

v XI---------XIa

v IX --------> IXa

+ VIIIv

X----------------------> Xa [Common pathway] v Xa + V

prothrombin -------------> thrombin v

fibrinogen--------------> fibrin

Extrinsic pathwayVII + TF ----->VIIa/TF

vIXase (“crossover”)Xase (minor)

vXIII ---> XIIIa vcross-linked fibrin

---> VIIIa

---> Va

Actions of thrombin