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وقل رب اآلية زدنى علما طه سورة
(114)
By
Hany A. AbdelWahab(M.Sc. Cardiology)
Hypercoagulable statesHypercoagulable states
physiological hemostasisphysiological 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(.
Subendothelial matrix Endothelial cell
Vascular Phase
Platelet Activation Pathways
Adhesion
ADP
Adrenaline
PlateletGpIb
Exposed Collagen
Endothelium
vWFAdhesionAdhesion
THROMBIN
GpIIb/IIIaGpIIb/IIIa Aggregation
COLLAGEN
Coagulation Factors
I. Fibrinogen.II. Prothrombin.III. Thromboplastin.IV. Calcium.V. Proaccelerin )Labile factor(.VII. Proconvertin )Stable factor(.VIII. Antihemophilic globulin A.IX. Christmas factor.X. 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
VenousArterial and venousFactor V Leiden mutationHomocystinuria
Prothrombin G20210AHyperhomocystinemia
Protein C & Protein S deficiency
Dysfibrinogenemia
Antithrombin deficiency
Elevated Factor VIII activity
• Acquired
VenousArterial and venousAgeMalignancy
Previous thrombosisAntiphospholipid antibodies syndrome
ImmobilizationHormonal therapy )CCP(
Major surgeryPolycythemia vera
Pregnancy & PuerperiumEssential thrombocythemia
HospitalizationHyperhomocystinemia
Activated Protein CParoxysmal nocturnal hemoglobinuria.
Factor V Leiden and prothrombin Factor V Leiden and prothrombin gene mutationgene 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 100-fold 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 meta-analysis 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 Defects in the natural anticoagulants :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.
HomocysteineHomocysteine
• 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 Heparin induced thrombocytopenia (HIT)(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 Antiphospholipid Antibodies SyndromeSyndrome
• 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 %.
MalignancyMalignancy
• Many malignancies induce a
hypercoagulable state and in patients
with idiopathic thrombosis, a search for
age- and gender- specific malignancies
is necessary.
Hormonal TherapyHormonal 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 ConditionsOther 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.
Screening TestsConfirmatory 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.
Confirmatory tests for lupus
Anticoagulants )Include at least one of the following: platelet neutralization procedure, hexagonal phase phospholipids, Textarin / Ecarin test, platelet vesicles, DVV Confirm.(
Screening tests for lupus anticoagulants )sensititve aPTT, aPTT mixing studies, dilute Russell viper venom time(
Anticardiolipin antibody testing by ELISA.
Fasting total plasma homocysteine level.
Recommended Laboratory Evaluation for Patients Suspected of Having an Underlying Hypercoagulable State
(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 high-
risk 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 low-
molecular-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 )anti-
factor 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.
SummarySummary• 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.
Recommended