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.