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‫سورة طه اآلية (‪)114‬‬
Hypercoagulable states
By
Hany A. AbdelWahab
(M.Sc. Cardiology)
physiological hemostasis
The major components of the hemostatic
system are :
1. The vessel wall.
2. Platelets (and other blood elements).
3. Plasma proteins (coagulation and
fibrinolytic factors).
Vascular Phase
Subendothelial matrix
Endothelial cell
Platelet Activation Pathways
COLLAGEN
THROMBIN
ADP
Aggregation
GpIIb/IIIa
GpIIb/IIIa
Adrenaline
Platelet
Adhesion
vWF
Endothelium
Exposed Collagen
Coagulation Factors
I.
II.
III.
IV.
V.
VII.
VIII.
IX.
X.
Fibrinogen.
Prothrombin.
Thromboplastin.
Calcium.
Proaccelerin (Labile factor).
Proconvertin (Stable factor).
Antihemophilic globulin A.
Christmas factor.
Stuart- Prower factor.
XI. Plasma thromboplastin antecedent.
XII. Hageman factor.
XIII. Fibrin Stabilizing factor.
Risk factors for Thrombosis
•
In 1856, Rudolf Virchow postulated a
triad of factors that leads to
intravascular coagulation :
1. Local trauma to the vessel wall.
2. Hypercoagulability (Thrombophilia).
3. Stasis.
A) Stasis:
•
•
•
•
•
Immobility.
Paralysis (e.g. CVA).
Obesity.
Postoperative & casting.
Heart & Respiratory Failure.
B) Endothelial injury :
• Trauma & major syrgery.
• Central venous catheters.
C) Hypercoagulable states
(Thrombophilias) :
•
•
► Definition:
Conditions that predispose to an
increased risk for thrombosis either
venous (most common), arterial or
both.
These conditions are being identified
more frequently and may be
classified as inherited or acquired.
• Inherited
Venous
Arterial and venous
Factor V Leiden mutation
Homocystinuria
Prothrombin G20210A
Hyperhomocystinemia
Protein C & Protein S
deficiency
Dysfibrinogenemia
Antithrombin deficiency
Elevated Factor VIII
activity
• Acquired
Venous
Arterial and venous
Age
Malignancy
Previous thrombosis
Antiphospholipid
antibodies syndrome
Immobilization
Hormonal therapy (CCP)
Major surgery
Polycythemia vera
Pregnancy & Puerperium Essential thrombocythemia
Hospitalization
Hyperhomocystinemia
Activated Protein C
Paroxysmal nocturnal
hemoglobinuria.
Factor V Leiden and prothrombin
gene mutation
• Factor V Leiden mutation is the most
common inherited thrombophilia.
• Normally, Activated protein C
inactivates factors Va and VIIa and is
one of the mechanisms that maintains
a balance between clotting and
bleeding.
• This autosomal dominant disorder
results from single mutation in the
factor V gene (G1691A) which results in
replacement of arginine amino acid 506
with glutamine.
• This renders the abnormal protein
factor V Leiden resistant to inactivation
by activated protein C.
• It is more prevalent in persons of
European and Scandinavian ancestry.
• Both homozygous and heterozygous
states are at an increased risk for
venous thrombosis with a 50- to 100fold increase in the homozygous state
and a 3- to 7-fold increase in the
heterozygous state.
• Factor V Leiden doesn’t appear to be a
risk factor for stroke or M.I. (supported
by large cohort studies and metaanalysis evaluated 18 studies).
• The prothromin gene mutation G20210A
is also inherited as an autosomal
dominant mutation and leads to a higher
plasma level of prothrombin probably by
increase in mRNA and confers a 2.8-fold
increased risk for venous thrombosis.
• The risk of recurrence and for arterial
thrombosis is controversial .
• Factor V Leiden and prothrombin gene
mutation has been found to be associated
with venous thrombosis during
pregnancy and oral contraceptive use.
• Factor V Leiden mutation can be
identified by evaluating for activated
protein C resistance in the plasma or by
gene analysis using polychromase chain
reaction (PCR). The prothrombin gene
mutation is identified by genetic analysis.
• There are no clear evidence-based
guidelines for managing patients with
these mutations.
• In general, acute thrombosis should be
managed by the standard fashion.
• Patients with asymptomatic disease
should receive prophylaxis in high risk
situations.
Defects in the natural
anticoagulants :
• Protein C (PC).
• Protein S (PS).
• Antithrombin (AT).
Sites of action
of the major
antithrombotic
pathways
• Deficiency of any of the three natural
anticoagulants is associated with an
increased risk for venous thrombosis.
• They are inherited as AD defects.
• PS is bound to C4 binding protein in
the plasma and acts as a cofactor in the
inactivation of factors Va and VIIIa by
activated PC.
• Levels of PC & PS are lowered in
conditions such as DIC, inflammatory
states, acute thrombosis and liver
diseases.
• Pregnancy and oral contraceptive pills
can also decrease the levels of PS.
• Levels of PC & PS are lowered by
warfarin therapy So, initiation of
warfarin therapy without concomitant
anticoagulant therapy may lead to
warfarin induced skin necrosis
(manifested by painful skin necrosis
primarily in the fatty areas), ttt includes
stopping warfarin, administer vitamin K
and plasma to replete levels, and using
an alternative anticoagulant.
• AT is produced by the liver and
endothelial cells, and functions by
inactivating thrombin, factor Xa and
factor IXa.
• Homozygous states are extremely rare
and incompatible with life.
• Levels are also low in DIC, sepsis, liver
disease, nephrotic syndrome, the use
of oral contraceptives, and during
pregnancy.
• In patients with AT deficiency, there
may be resistance to heparin (i.e.
failure to prolong the aPTT) as heparin
exerts its anticoagulant effect through
AT.
• AT concentrates are available and can
be used to correct this deficiency.
Homocysteine
• It is derived from sulfur containing
amino acid methionine and metabolized
through pathways associated with folic
acid, vitamin B6 and B12 as cofactors.
• Elevated plasma homocysteine levels >
15 μmol/L confer an independent risk
factor for vascular disease (the relative
risk for stroke and M.I. is double normal
& for PVD is triple normal).
• Causes of Hyperhomocystenemia :
1. Deficiencies in the cofactors for its
metabolism.
2. Defects in the genes for 5,10-methylene
tetrahydrofolate reductase (MTHFR) (rare),
cystathionine B-synthetase (0.5%),
homocysteine methyl transferase and
methionine synthetase (rare).
3. Secondary causes: age, male sex, menopause,
liver and renal impairment, hypothyroidism,
smoking and drugs (e.g. niacin, oral CCP,
phenytoin, methotrexate and theophyllin).
• Possible mechanisms are that
hyperhomocysteinemia may impair
release of NO from endothelial cells,
stimulates proliferation of atherogenic
smooth muscle cells and contribute to
thrombogenesis through activation of
protein C kinase and  expression of
vascular adhesion molecule 1.
• Patients with enzymatic deficiency
especially cystathionine β-synthetase
with marked elevations of
homocysteine plasma level (> 100
μmol/L) suffer from premature
atherosclerosis, arterial and venous
thrombosis.
• homocysteinuria (homozygous Cβs
deficiency) is very rare and manifested
by mental retardation, skeletal
anomalies and ectopia lenses.
• Therapy includes folate therapy
(400 µg : 2 mg/day).
• Second line therapy 10 : 25 mg/day of
pyridoxine (Vit. B6) with or without 400
µg of vit. B12/day (if there is vit. B12
deficiency).
• No data are available to establish the
vascular benefits of reducing
homocysteine values.
Heparin induced thrombocytopenia
(HIT)
• Two distinct types of HIT are known:
1- The more common form, which may
occur in up to 15% of patients receiving
therapeutic doses of heparin is a benign
and self limiting side effect.
This type is non immune mediated,
rarely causes severe thrombocytopenia
and usually doesn't require heparin
discontinuation.
2- In contrast the immune type of HIT may cause
serious arterial as well as venous thrombosis.
Its pathogenesis involves the formation of
antibodies (usually IgG) against the heparin-
platelet factor 4 (PF 4) complex. The HIT Abs
trigger procoagulant effect through platelets and
endothelial cell activation, as well as thrombin
generation leading to both micro- and
macrovascular thrombosis.
• The incidence of HIT is about 3-5% in
patients exposed to UFH, the incidence
is much lower with the use of LMWH.
• In patients with de novo exposure to
heparin a fall in the platelet count in
those with HIT occurs between day 5
and 14.
• The clinical diagnosis requires a fall in
platelet count by 50% following heparin
exposure or a fall by 30% in a setting of
new thrombosis on heparin use.
• The clinical spectrum ranges from
isolated HIT to HIT (T), where there is
associated thrombosis that may be
arterial (Stroke, MI, PAD) or venous in
nature.
• Other manifestation include
hypotension from adrenal hemorrhage
secondary to adrenal infarction, skin
necrosis or venous limb gangrene.
• Lab diagnosis includes functional
assays of such as heparin induced
platelet aggregation, serotonin release
assay, immunoassays such as
antibodies to heparin-PF 4 complexes.
• The serotonin release assay has the
highest sensitivity and specificity for
the diagnosis of HIT.
• TTT includes stopping Heparin and
starting an alternative anticoagulant
unless C.I.
• Direct thrombin inhibitors including
Lepirudin and Argatorban are approved
for the use in ttt of HIT (N.B. There are
no available agents that reverse the
effects of these drugs).
• As argatorban falsely  INR, it should
not be discontinued until the INR is > 4.
• Platelet transfusion should be avoided
if possible as it may worsen the
situation.
• Once the platelet count is > 100.000/CC
warfarin may be started at low dose.
• It is reasonable to continue
anticoagulation for at least a month in
the absence of contraindications
because the highest incidence of
thrombosis occurs within the 1st
month.
Antiphospholipid Antibodies
Syndrome
• They are heterogeneous group of
autoantibodies that in clinical practice
can be divided into two large groups :
(a) Anticardiolipin antibodies.
(b) Lupus anticoagulants.
• They are either not associated with an
autoimmune disorder (1ry APS) or very often
associated with autoimmune conditions (e.g.
SLE) (2ry APS) and can cause recurrent
pregnancy loss, as well as arterial or venous
thrombosis.
• APA have also been reported in conjunction
with idiopathic autoimmune hemolytic anemia,
malaria, Q fever, infections by mycobacteria,
Pneumocystis carinii, cytomegalovirus, and
human immunodeficiency virus (HIV), and after
exposure to drugs such as neuroleptics,
quinidine, and procainamide.
•
It has been reported that there is about
fivefold increase in risk for thrombosis
with lupus anticoagulant.
Two mechanisms were proposed whereby
antiphospholipid Abs promote thrombosis :
1. Interfering with the phospholipid dependant
anticoagulant pathways.
2. Binding to cell surfaces and inducing cell
activation.
• Anticardiolipin antibodies are detected
and quantified using an enzyme-linked
immunosorbent assay and may be IgG,
IgM, or IgA. IgG titers have been
correlated with thrombosis.
• Lupus anticoagulants prolong
phospholipids-dependent blood
clotting times.
• Once a thrombotic event occurs, long-term
therapy with warfarin must be considered
(Recurrence rate of thrombosis up to 70%).
• A higher target INR is used (approximately
3.0) as this may be superior to normal target
INR of 2.0 to 3.0 in preventing recurrent
events.
• Another strategy is to correlate the INR to a
factor II and factor X level of 20% to 30 %.
Malignancy
• Many malignancies induce a
hypercoagulable state and in patients
with idiopathic thrombosis, a search for
age- and gender- specific malignancies
is necessary.
Hormonal Therapy
• Hormonal therapy carries increased
risk for VTE, and the risk may be
increased significantly in thrombophilic
women.
• HRT and CCP increase the risk of
thrombosis 2-4 folds.
• The pathogenesis of hormone induced
thrombosis is not clear.
• Estrogens have many different effects
on the coagulation system including 
in procoagulant factors,  protein S
and antithrombin and acquired protein
C resistance.
• It inceases the fibrinolytic activity but
doesn’t counterbalance this
procoagulant effect.
Other Conditions
• Elevated factor VIII levels, deficiency of
plasminogen or tissue plasminogen
activator (the fibrinolytic system),
dysfibrinogenemia, and factor XIII
polymorphism are emerging risk
factors for hypercoagulability.
Stepwise Approach For
Management of Thrombophilias
(A) When to suspect ?!
•
•
•
•
•
Idiopathic (i.e., spontaneous) VTE.
VTE at young age ( <45 years old).
Recurrent VTE.
VTE in unusual sites (e.g. U.L.)
VTE in the setting of a strong family
history of VTE.
• Recurrent pregnancy loss ( >3
consecutive first-trimester pregnancy
losses without an inter-current term
pregnancy).
(B) Diagnosis
• In fact, testing for an inherited
hypercoagulable state is costly & likely to
uncover an abnormality in more than 60%
of patients presenting with idiopathic
VTEs.
• Although the remaining 30% to 40% will
have unremarkable test results, this does
not imply a true absence of a
hypercoagulable state.
(Deitcher SR, 2000).
• In the absence of validated guidelines,
testing for hypercoagulable states
should be performed only in selected
patients, and only if the results will
significantly affect the management.
Recommended Laboratory Evaluation for Patients
Suspected of Having an Underlying Hypercoagulable State
Screening Tests
Confirmatory Tests
Activated protein C resistance.
Factor V Leiden PCR
Prothrombin G20210A mutation testing
by PCR.
Antigenic assays for
antithrombin, protein C, and/or
protein S
Antithrombin, protein C, and protein S
activity (functional) levels.
Factor VIII activity level.
Screening tests for lupus anticoagulants
(sensititve aPTT, aPTT mixing studies,
dilute Russell viper venom time)
Confirmatory tests for lupus
Anticoagulants (Include at least
one of the following: platelet
neutralization procedure,
hexagonal phase phospholipids,
Fasting total plasma homocysteine level. Textarin / Ecarin test, platelet
vesicles, DVV Confirm.)
Anticardiolipin antibody testing by
ELISA.
(C) Treatment
• There are no specific therapies to reverse most
hypercoagulable states.
• Recombinant factor concentrates of
antithrombin and APC do exist.
• Gene transfer to correct a particular genetic
defect is theoretically feasible but likely cost
prohibitive at this time. Attempts to eliminate
APA by plasmapheresis or immunosuppressive
therapy have not been very successful.
• Initiation of oral anticoagulation for
primary VTE prophylaxis in
asymptomatic carriers of any
hypercoagulable state has not been
advised, mainly because the annual
absolute risk of idiopathic VTE is either
low or not high enough to be favorably
balanced against the annual risk of oral
anticoagulation- related major and fatal
hemorrhage.
• However, because most VTEs (50% to
70%) in patients with a predisposition
to hypercoagulability occur following a
situational risk factor, such as major or
orthopedic surgery, aggressive VTE
prophylaxis should be prescribed to
asymptomatic carriers of
hypercoagulable states during highrisk situations (Kearon C, 2000).
• The presence of a hypercoagulable state
should not affect acute VTE treatment (i.e.,
initial anticoagulation with intravenous
unfractionated heparin or subcutaneous lowmolecular-weight heparin followed by oral
anticoagulation with warfarin) except for those
with a lupus anticoagulant. Because these
antibodies can prolong the aPTT, monitoring of
unfractionated heparin therapy in this scenario
should be performed by heparin assay (antifactor Xa activity assay).
• If such assays are not immediately
available, the use of weight-based,
subcutaneous low-molecular-weight
heparin should be considered instead
of unfractionated heparin, because the
former compounds do not require
monitoring.
• It must be emphasized that there are no
current data from prospective,
randomized controlled trials specifically
designed to address the optimal duration
of anticoagulation therapy in patients
with specific hypercoagulable states.
• Thus, any decisions regarding the ideal
duration of therapy must take into
account the estimates of VTE
recurrence for a given disorder, the
nature of the index VTE, and the risk of
bleeding associated with prolonged
oral anticoagulation.
• However, it is also reasonable to consider
long-term anticoagulation therapy for
patients with conditions known to be
associated with increased rates of VTE
recurrence. These include individuals with
documented persistent lupus anticoagulants,
homozygous factor V Leiden, and may be
patients with a deficiency of protein C or
protein S, or with double heterozygosity for
factor V Leiden and the prothrombin
G20210A mutation.
Summary
• In summary knowledge about Hypercoagulable
states is expanding. Identifying such states
may alter type or intensity of therapy in some
situations (e.g. HIT, antiphospholipid
antibodies) and the duration of therapy in other
situations.
• They should be suspected in patients who
develop idiopathic VTE, VTE at a young age,
VTE in unusual sites, recurrent VTE, and those
with a strong family history of VTE and
recurrent pregnancy loss.