THROMBOPHILIA

Dr Annabelle D Marie
JMO
Dept of Pathology
 OBJECTIVES
1. Revise hemostatic mechanisms
2. Review of Virchow's triad
3. Discuss hypercoaguable states
4. Focus specifically on the inherited
hypercoaguable conditions
5. Briefly describe the mechanism behind
each of the inherited thrombophilias
6. Review the hypercoaguable workup and
when it is appropriately done
 Back to school!
HAEMOSTASIS COAGULATION

PLATELET
PLATELET ADHESION
ACTIVATION
THROMBUS

PLATELET
AGGREGATION PRIMARY
PLATELET PLUG

CLOT
SECONDARY
EMBOLUS
PLATELET PLUG
New theory of coagulation
 Thrombophilia
Thrombophilia or hypercoagulability is
the propensity to develop thrombosis
(blood clots) due to an abnormality in the
system of coagulation
Congenital
Acquired

Syn: prothrombotic state, hypercoagulable

state, thrombogenic state
Virchow's Triad
platelets (increased activity
and or numbers)
coagulation factors
(increase)
natural anticoagulants
(decrease and/or
dysfunction)
fibrinolytic system
(decrease)
pathological conditions
(hyperhomocysteinaemia,
antiphospholipid syndrome,
contraceptive pills etc)
Causes of venous thrombosis
HEREDITARY
 When to suspect
hypercoagulability?
Thrombosis < 50years of age
Family history
Thrombosis in unusual site (mesenteric vein or
cerebral vein)
Idiopathic or recurrent thrombosis
Unexplained spontaneous abortions (more
than 3 consecutive 1st trimester pregnancy
losses without an intercurrent term pregnancy)
Massive thrombosis
 Racial difference
Asians and Africans
Protein C deficiency
Protein S deficiency
Whites
Factor V Leidon
Prothrombin gene G20210A mutation
 Factor V Leiden
Most common form of inherited thrombophilia---50% of cases
Present in 5% of whites
Discovered in Leiden, the Netherlands 1993 amongst a group of
subjects with unexplained DVT
Point mutation of Factor V gene
Mutant Leiden gene product not susceptible to cleavage by APC
Activated protein C resistance
FVA Leiden---> increased thrombin generation, decreased
anticoagulation, decreased inactivation of factor FVIIIa
Also decreases PAI inactivation so decreased fibrinolysis
Venous thrombosis and fetal wastage
Homozygous: 80x risk Heterozygous: 2-3x risk
 Protein C and S deficiency
Protein C and S are the 2
major cofactors responsible
for regulating the amplification
of the clotting cascade
Inhibit activated cofactors Va
and VIIIa respectively
Protein C is consumed and
levels are low in Vitamin K
deficiency, DIC, surgery,
trauma liver disease, warfarin,
pregnancy and OCP use
Homozygous individuals have
purpura fulminans
 Protein S deficiency
Heterozygous or
homozygous
congenital or acquired
clinical expression of
hypercoagulability variable,
and do not necessarily
correspond with absolute
concentration of protein C
Acquired protein S
deficiency may be induced
by OCPs, pregnancy or
nephrotic syndrome
 Prothrombin gene mutation
Normal prothrombin (Factor II) circulates as vitamin K
dependent cofactor with a half life of 3-5 days
Mutation discovered in 1996 as a transition (G--->A) at
nucleotide 20210 resulting in elevated plasma levels of
factor II
heterozygotes have a 30% higher plasma
prothrombin level compared to normal
Prothrombin 20210A mutation is the 2nd most common
prothrombotic mutation
causes a decrease in thrombin inactivation
Diagnosed by DNA PCR
 Antithrombin deficiency
AT is a potent inhibitor of thrombin and other
serine protease (SERPIN) of the coagulation
cascade like Factor Xa, Factor IXa
Autosomal dominant inheritence- both sexes
low incidence
Females with AT deficiency are at high risk for
VTE during pregnancy
DVT, PE, mesenteric vessel thrombosis
Resistant to UFH. Must treat with LMWH
 M
IX
E D
Hyperhomocysteinaemia
AKA homocysteinuria
Rare autosomal recessive disorder characterised by developmental delay,
osteoporosis, ocular abnormalities, VTE and severe premature CAD
5-7% of population have less marked elevation of homocysteine and have a
number of clinical factors
Cause: 1. Cystathionine beta synthase deficiency (most common)
2. Vitamin B6, B12 and folic acid deficiency
Primary atherogenic and prothrombotic properties
Odds ratio 2.5-3 for VTE
Elevated homocysteine-->
vascular endothelial injury (free oxygen radicals)
decreased protein C activation
increased factor V activity
induction of endothelial cell tissue factor activity
AQUIRED
 Pregnancy prior thrombotic
OCP or HRT event
Heparin use and heparin recent major surgery
induced thrombocytopenia
and thrombosis (HITT)
esp orthopaedic
APLS presence of a
Myeloproliferative central venous
disorders catheter
PCV, essential trauma
thrombocytopenia
Hyperviscosity syndromes immobilisation
Multiple myeloma, malignancy
Waldenstrom's
heart failure
macroglobulinaemia
 Pregnancy
Placenta: placental plasminogen activator
inhibitor type 2
Enlarged uterus---> venous stasis in the
leg
Pelvic vein injury
trauma of Caesarean section

OCP: promote liver synthesis of

coagulation factors
 Malignancy
Multifactorial risk for thrombosis
15% patients with cancer have clinical thrombosis
Esp: mucin secreting adenocarcinoma (GI or lung),
pancreatic cancer, acute promyelocytic leukaemia
venous thrombosis predominant
stasis, tumour invasion of vessels, chemoradiotherapy
effects superimposed on acquired or primary defects in
haemostasis, surgery, tranfusions, indwelling IV access
Increased production of tissue factor and cancer
procoagulant by tumours found in many patients which
can activate FX directly
 Surgery/ Trauma
Mechanisms:
1) release of tissue factor from injured
tissue
2) decreased plasma level of
anticoagulants
Particularly common in orthopaedic
surgery
Hip and knee surgery without
anticoagulant prophylaxis--> 45-70% DVT
 Antiphospholipid Syndrome
Definition Catastrophic
antiphospholid
Synonyms syndrome

Lab diagnosis
Clinical
manifestation
Treatment
Classification

Etiology Prophylaxis
 APLA Syndrome -Etiology
Asso Infections Drugs Others
diseases
SLE Syphilis Cardiac- Procainamide, Familial
quinidine, propranolol, association
hydralazine
Sjogrens HCV Neuroleptic /psychiatric - HLA
Phenytoin, associations:
chlorpromazine between aCL
RA HIV Other - Interferon alfa, ab and indivs
quinine, amoxicillin with certain
AI TCP HTLV I
HLA genes
AI HA Malaria
Psoriatic Bacterial
arthropathy septicemi
PSS a
MCTD
PMR/ GCA
 Additional risk factors for
thrombosis
Age (M-> 55 , F-> 65 )
Risk factor for CVD- HT, DM, elevated LDL or low
HDL, smoking, F/H premature CAD, BMI 30,
microalbuminuria, eGFR < 60 ml/min.
Inherited thrombophilias
OCP
Nephrotic syndrome
Malignancy
Immobilization
Surgery
 Antiphospholipid Syndrome
Antibodies
Target PL directly- cardiolipin, phosphatidylserine,
phosphatidylinositol,phosphatidylethanolamine,
phosphatidylglycerol, and phosphatidylcholine.
APAs -IgG, IgA, and IgM.
APS antibodies against protein antigens anionic
PL, forming a protein-phospholipid complex. Eg-
beta-2-glycoprotein I(2-GPI) and prothrombin.
antibodies against annexin V and protein C
associated with APLS &SLE.
 Lupus anti coagulant(LA)

Misnomer, associated with thrombosis and not

bleeding
LA inhibits formation of prothrombinase complex.
It blocks binding of prothrombin and factor Xa to
phospholipids, (conversion of prothrombin to
thrombin).
LA can be- IgG, IgA, or IgM.
LA is found in 10% of SLE.
LA commonly ass. with venous thrombosis &
occasionally arterial disease
 MANIFESTIONS
DVT and pulmonary embolism are the two
most common manifestations of the same
disease : vte
90% of cases of acute PE are due to
emboli emanating from the proximal veins
of the lower extremities: proximal DVTs
are clinically most significant due to high
morbidity and mortality
 VENOUS VS ARTERIAL
Superficial or deep Acute MI
veins Angina
Thrombophlebitis: CVA, TIA
swollen, painful Claudication
extremity
Pulmonary
embolus
 When to suspect
hypercoagulability?
Thrombosis < 50years of age
Family history
Thrombosis in unusual site (mesenteric vein or
cerebral vein)
Idiopathic or recurrent thrombosis
Unexplained spontaneous abortions (more
than 3 consecutive 1st trimester pregnancy
losses without an intercurrent term pregnancy)
Massive thrombosis
 Diagnosis
Clinical exam: unilateral leg pain and swelling, tenderness on
compression of calf muscle, HOman's sign positive, increased
circumference of at least 1cm, palpable cord over calf,
ipsilateral edema, warmth, superficial venous dilation
PE: dyspnoea, tachypoea, tachycardia, chest pain, decreased
breath sounds, haemoptysis
D- dimer: useful in low pre-test probability to exclude diagnosis
of VTE. Sensitivity and negative predictive value are high (99%)
Compression ultrasonography- gold standard
MR venography
CT
Echocardiography, VQ scanning, pulmonary angiography
 Work up for hereditary
thrombophilia
Why test:
to avoid OCP
family knowledge, screening and planning
duration of anticoagulation therapy
intensity of anticoagulation therapy and therapeutic monitoring
strategies
When: 4-6 weeks after acute thrombotic event
Consensus in Haematologic community growing to not routinely do
hypercoagulable workup
studies fail to show recurrent VTE rates associated with thrombophilia
 Treatment
Anticoagulation
UFH and LMWH
Enable anti-thrombin to accelerate manyfolds
its inactivation of thrombin
LMWH should be avoided in CKD and it is C/I
in Stage V CkD
Vitamin K antagonists (warfarin)
heparin + warfarin is more effective than
warfarin alone. All cases of VTE should be
bridged with heparin
 Should be adjusted according to PT INR
Inhibition of protein C first (6-8hours) then
inhibits other clotting factors (24-48hrs)
transient hypercoagulable state---> warfarin
induced skin necrosis
Warfarin started within 24hours after initiation
of heparin. Heparin should be given for at least
4 days and not discontinued until the INR in the
therapeutic range (2-3) for 2 consecutive days.
 Factor Xa inhibitors (fondaparinux)
Hirudins (Lepirudin)
Thrombolysis *usually reserved for
massive PE- tissue plasminogen
activators (t-PA, urokinase, alteplase)
Thrombectomy (arterial)
 Complications of treatment
Bleeding
Heparin induced thrombocytopenia
Heparin induced osteoporosis
Warfarin induced skin necrosis
Post thrombotic syndrome (venous
hypertension caused by valvular
incompetence): pain, swelling, ulceration.
 How long?
Short term treatment- help resolve initial DVT
Long term treatment: reduce risk of recurrence
Recurrences more likely during th first 3 weeks
of treatment.
positive D-dimer
post thrombotic syndrome
obesity BMI>30
older age
male
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