Download Coagulation factor deficiency

Bleeding
History
• Site of bleed
• Duration of bleed
• Precipitating causes, including
previous surgery or trauma
• Family history
• Drug history
• Age at presentation
• Other medical conditions, e.g.
liver disease
Examination
There are two main patterns of bleeding:
1. Mucosal bleeding
Reduced number or function of platelets (e.g.
bone marrow failure or aspirin) or von Willebrand
factor (e.g.von Willebrand disease)
Skin: petechiae, bruises
Gum and mucous membrane bleeding
Fundal haemorrhage
Post-surgical bleeding
2. Coagulation factor deficiency
(e.g. haemophilia or warfarin)
Bleeding into joints (haemarthrosis) or muscles
Bleeding into soft tissues
Retroperitoneal haemorrhage
Intracranial haemorrhage
Post-surgical bleeding
Vessel wall abnormalities
Vessel wall abnormalities;
congenital, such as hereditary haemorrhagic telangiectasia
• acquired, as in a vasculitis or scurvy
Hereditary haemorrhagic telangiectasia(HHT)
Autosomal dominant .
Telangiectasia and small aneurysms are found on the fingertips, face and tongue,
and in the nasal passages,lung and gastrointestinal tract.
Pulmonary arteriovenous malformations (PAVMs) that cause arterial hypoxaemia
due to a right-to-left shunt. These predispose to paradoxical embolism, resulting
in stroke or cerebral abscess. =
All patients with HHT should be screened for PAVMs; if these are found, ablation
by percutaneous embolisation should be considered.
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Recurrent bleeds, particularly epistaxis, or with iron deficiency due to occult
gastrointestinal bleeding.
TREATMENT •
1-Iron replacement for IDA
2-Local cautery or laser therapy may prevent single lesions from bleeding
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Platelet function disorders
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Primary Hemostasis
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Platelet Plug formation
Dependent on normal platelet number & function
Initial manifestation of clot formation
1-Thrombocytopenia
2-Thrombasthenia
Thrombasthenia
Congenital •
Deficiency of the membrane
glycoproteins
Glanzmann’s thrombasthenia (IIb/IIIa)
Bernard–Soulier disease (Ib)
Defective platelet granules
deficiency of dense (delta) granule
(storage pool disorders)
Macrothrombocytopathies
Alport`s syndrome
Acquired •
Iatrogenic; •
Aspirin ;cyclo-oxygenase inhibitor
Clopidogrel; adenosine inhibitor
Dipyridamole;phosphodiesterase
inhibitor
Abciximab; IIb/IIIa inhibitor
Laboratory Tests for Primary
Hemostasis Function
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Platelet count
Bleeding time
Platelet Aggregation Studies
clot retraction
Flow cytometric studies for Glycoproteins
Glanzmann thrombasthenia
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Background:
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Pathophysiology:
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Thrombasthenia was first describe in 1918 by Glanzmann
when he noted purpuric bleeding in patients with normal
platelet counts
Typically, thrombasthenia is diagnosed at an early age
Autosomal recessive trait
The production and assembly of the platelet membrane
glycoprotein IIb-IIIa is altered, preventing the aggregation
of platelets and subsequent clot formation
Treatment
1-local measure.2-antifibrinolytic agent such as tranexamic acid
.3-platelet transfusion.4-Recombinant factor VII
Idiopathic thrombocytopenic purpura
Autoantibodies, most often directed against the platelet
membrane glycoprotein IIb/IIIa, which sensitise the platelet,
resulting in premature removal from the circulation by cells of the
reticulo-endothelial system.
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1-Isolated condition.
2-Association with connective tissue diseases,HIV infection,
B cell malignancies, pregnancy and certain drug therapies.
Clinical features
Classification of ITP disease phases
ITP phase Definition
Newly diagnosed
Persistent
Chronic
Within 3 months of diagnosis
3 to 12 months from diagnosis
> 12 months from diagnosis
In adults, ITP usually has an insidious onset, with no preceding
illness.
Nearly one-quarter of patients present asymptomatically and
receive a diagnosis of ITP through incidental routine blood
tests
Petechiae or purpura • Unusual or easy bruising (haematoma)•
Persistent bleeding symptoms from cuts or other injuries• Mucosal
bleeding• Frequent or heavy nose bleeds (epistaxis)
• Haemorrhage from any site (usually gingival or menorrhagia in
womenn
Purpura and
haematomas
Mucosal bleeding
Petechie
Recommended diagnostic approaches for ITP
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Patient history
Family history
Physical examination
Complete blood count and reticulocyte count
Peripheral blood smear
Quantitative immunoglobulin level measurement*
Bone marrow examination (in selected patients)
Blood group (rhesus)
Direct antiglobulin test
Helicobacter pylori
Human immunodeficiency virus (HIV)
Hepatitis C virus (HCV)
Bone marrow aspiration
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is indicated in older patients (particularly
those over 60 years of age to exclude
myelodysplastic syndrome),
in those with an atypical presentation
(e.g. abnormalities observed on
peripheral blood smear suggestive of
other haematological disorders),
in those with a poor response to first-line
therapy
and in those being considered for
splenectomy..
Treatment
when to treat?
If a patient has two relapses,or primary refractory disease, splenectomy is considered.
Splenectomy produces complete remission in about 70% of patients and improvement in
a further 20–25%, so that,following splenectomy, only 5–10% of patients require further
medical therapy.
Second-line therapy with the thrombopoietin analogue romiplostim or the thrombopoietin
receptor agonist eltrombopag
Rituximab, ciclosporin and tacrolimus should be consideredin cases where the
approaches above are ineffective.
Coagulation disorders
Clinical Features of Bleeding Disorders
Platelet
disorder
Coagulation
disorders
Site of bleeding
Skin
Deep in soft tissues
Mucous membranes
(joints, muscles)
(epistaxis, gum,
vaginal, GI tract)
Petechiae
Yes
Ecchymoses (“bruises”)
Small, superficial
Large, deep
Hemarthrosis / muscle bleeding
Extremely rare
Common
Bleeding after cuts & scratches
Yes
No
Bleeding after surgery or trauma
Severity
Immediate,
usually mild
No
Delayed (1-2 days),
often severe
Haemophilia A
Clinical features
 A prolonged aPTT: a normal aPTT does not exclude mild
hemophilia A because the aPTT may not be sufficiently sensitive to
detect slightly reduced levels of FVIII-C in the approximate 20-30%
range
 Normal PT
Treatment
• Replacement of missing coagulation factor
o Clotting factor replacements
 Clotting factor concentrates (CFCs)
 Plasma-derived
 Recombinant
 FVIIa
 Cryoprecipitate in developing countries
o
Other pharmacologic agents
Desmopressin (DDAVP)
Anti-fibrinolytic agent
Tranexamic acid
8-aminocaproic acid (EACA)
o Supportive measures
 Rest
 Ice
 Compression
 Elevation
Two main Treatment Modalities
*On -demand
**Prophylaxis
Complication of clotting factor therapy
- Infection; HIV, HBV, HCV
- Anti factor VIII inhibitor in 20 % ,
treated by infusion of activated factor
VIIa OR factor VIII inhibitor bypass
activity (FEIBA)
Optimal dosage according to the site of Haemorrhag
Site of haemorrhage
Optimal factor level
Dose (U/Kg BW)
Duration (days)
Joint
30-50
15-25
1-2
Muscle
30-50
15-25
1-2
GIT
40-60
30-40
7-10
Oral mucosa
30-50
15-25
Until healing
Epistaxis
30-50
15-25
Until healing
Hematuria
30-50
15-25
Until healing
CNS
80-100
50
10-21
Retroperitoneal
50-100
30-50
7-14
Trauma/Surgery
50-100
30-50
Until healing
Haemophilia B (Christmas disease)
• Due to deficiency of factor IX .
• X-linked
• Clinical manifestation indistinguishable from
haemophilia A
• Treatment ; factor IX concentrate , indication and
dosing same as to haemophilia A.
• Complication of therapy similar to haemophilia A
regarding transmission of infection BUT the
incidence of inhibitor is < 1%.
Von Willebrand disease
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von Willebrand factor
– Synthesis in endothelium and megakaryocytes
– Forms large multimer
– Carrier of factor VIII
– Anchors platelets to subendothelium
– Bridge between platelets
Lab Studies:
Screening tests typically include
 prothrombin
time (PT)
 activated partial thromboplastin time (aPTT),
 FVIII level
 ristocetin cofactor (RCoF) activity
 vWF antigen (vWF:Ag).
Laboratory evaluation of von Willebrand disease
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Classification
– Type 1
– Type 2
– Type 3
Partial quantitative deficiency
Qualitative deficiency
Total quantitative deficiency
*Bleeding time ↑
*aPTT ↑
vWD type
Assay
vWF antigen
vWF activity
Multimer analysis
1
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Normal
2
Normal
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Abnormal
3
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Absent
Disseminated intravascular coagulation (DIC)
 DIC
is a clinicopathologic syndrome in which
widespread intravascular coagulation is induced
by procoagulant that are introduce or produce in
circulation and overcome the natural anticoagulant
mechanisms.
 DIC may cause tissue ischemia from occlusive
microthrombi as well as bleeding from both
consumption of platelet and coagulation factor and
anticoagulation effect of product of secondary
fibrinolysis
Disseminated Intravascular Coagulation (DIC)
Mechanism
Systemic activation
of coagulation
Intravascular
deposition of fibrin
Thrombosis of small
and midsize vessels
with organ failure
Depletion of platelets
and coagulation factors
Bleeding
Pathogenesis of DIC
Release of
thromboplastic
material into
circulation
Coagulation
Consumption of
coagulation factors;
Fibrinolysis
Fibrinogen
Plasmin
Thrombin
Fibrin
Monomers
Fibrin
Clot
(intravascular)
Fibrin(ogen)
Degradation
Products
Plasmin
 aPTT
 PT
 TT
 Fibrinogen
Presence of plasmin
 FDP
Intravascular clot
 Platelets
Schistocytes
MAHA
DIC
Treatment
 Treatment
of underlying disorder
 Platelet
transfusion (6-10 U plat (ideally rise to more
than 50000-100000
 Fresh
frozen plasma;1-2 unit For coagulation factor
depletion
 Hypofibrinogenaemia;
 Anticoagulation
8-10 U cryopercipitate
with heparin; unless there is a clear
contraindication
 Coagulation
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inhibitor concentrate (ATIII)
Patients with DIC should not be treated with antifibrinolytic
therapy, e.g.tranexamic acid.
Thrombotic thrombocytopenic purpura(TTP)
 thrombosis
is accompanied by paradoxical
thrombocytopenia,
 TTP
is characterised by a pentad of findings,
although few patients have all five components:
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thrombocytopenia
 • microangiopathic haemolytic anaemia(MAHA)
 • neurological sequelae
 • fever
 • renal impairment
TTP-Cont.
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It is an acute autoimmune disorder mediated by antibodies
against ADAMTS-13 (a disintegrin and metalloproteinase with
a thrombospondin type-1 motif).
It is a rare disorder (1 in 750 000 per annum), which may occur
alone or in association with drugs (ticlopidine, ciclosporin), HIV,
shiga toxins and malignancy.
It should be treated by emergency plasma exchange.
Corticosteroids, aspirin and rituximab also have a role in
management
 Untreated mortality rates are 90% in the first 10 days, and
even with appropriate therapy, the mortality rate is 20–30% at
6 months
THROMBOTIC DISORDERS
 Virchow’s
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Triad
Pathogenesis of a Thrombus
Endothelial injury
Abnormal blood flow
Hypercoagulability
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Genetic
acquired
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Signs & Symptoms
DVT:
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50% with no clinical signs
?Edematous extremity
Plethoric,Warm,Painful extremity
PE:
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Cough, SOB, Hemoptysis
Tachycardia
Thrombophilia
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Hereditary Thrombophilias
 Physiologic Inhibitors of
 Protein C pathway
coagulation
 Factor V Leiden
 Antithrombin
 Protein C deficiency
 Activated Protein C + protein S
 Protein S deficiency
 Inactivates Va and VIIIa (via
 Prothrombin G20210A
proteolysis)
mutation
 Thrombomodulin
 Antithrombin deficiency
 Binds to thrombin
 Hyperhomocystinemia
 activate Protein C
 C677T MTHFR mutation
Hereditary Thrombophilias
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None of them is strongly associated with arterial thrombosis.
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• All are associated with a slightly increased incidence of
adverse outcome of pregnancy,including recurrent early fetal
loss, but there are no data to indicate that any specific
intervention changes that outcome.
• Apart from in antithrombin deficiency and homozygous factor
V Leiden, most carriers of these genes will never have an
episode of VTE; if they do, it will be associated with the
presence of an additional temporary risk factor.
• There is little evidence that detection of these abnormalities
predicts recurrence of VTE.
• None of these conditions per se requires treatment with
anticoagulants
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Antiphospholipid Antibody
Syndrome
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Autoimmune Acquired Prothrombotic Disorder
Very High Risk for recurrent thromboembolic disease
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both venous and arterial
Indefinite duration anticoagulation recommended +/immunosuppression
Strict Diagnostic Criteria
Antiphospholipid Syndrome
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Clinical criteria (≥1 must be present):
1.Vascular thrombosis:
- ≥ 1clinical episode of, objectively confirmed, arterial, venous, or small
vessel thrombosis
2. Pregnancy morbidity:
- ≥ 1 unexplained fetal death @ ≥ 10 weeks EGA
- ≥ 1 premature birth (≤ 34th week of gestation) due to eclampsia, severe
pre-eclampsia, or placental insufficiency
- ≥ 3 unexplained consecutive spontaneous abortions @ <10 weeks EGA
Revised Sapporo/Sydney Criteria. JTH 2006;4:295-306
Antiphospholipid Syndrome
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Laboratory criteria (≥1 must be present):
 Lupus anticoagulant {LA} (+) ≥ 2 occasions, at least 12 weeks
apart, according to ISTH guidelines:
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prolonged aPTT, lack of correction with 1:1 mix, and correction with
Anticardiolipine antibody(ACLA) and/or anti-β2 glycoprotein-I
antibody:
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medium or high IgG and/or IgM isotype titer ≥ 2 occasions, at least 12
weeks apart
Standardized ELISA assays
Revised Sapporo/Sydney Criteria. JTH 2006;4:295-306