Secondary thrombophilic states
and drug induced thrombophilia
Acquired risk factors of thrombosis
• Specific risk factors
• Aging
• Long-lasting immobilization
• History of thromboembolism
• Overweight
• Varicosity
• Heart failure
• Stroke
• Hip & leg fractures
• Infections of colon
• Nefrotic syndrome
• Oestrogens
• Malignancy
Indication for anticoagulant therapy
- heparins, coumarins
• venous thrombosis and embolism
• atrial fibrillation
• heart valve replacement
• artificial surfaces – HD,
extracorporeal circulation
• antiphospholipid syndrome
• DIC
Risk of VTE in surgery
• Cathegory Pelvic Proximal Fatal PE
• High 40-80% 10-30% 1-5%
(large orthopedic surgery, urologic surgery (age >40), history of VTE,
extensive pelvic & abdominal surgery for malignancy)
• Intermediate 10-40% 2-10% 0,1-0,8%
(common surgery & age >40 & duration > 30 minutes, surgery &
contraceptives, urgent sectio Cesarea)
• Low < 10% <1% <0,01%
(small surgery, young patient, no risk factors)
The classification of risk profile
• Low risk
• Non-complicated surgery lasting <30 min in a patient aged < 40 years
• Intermediate risk
• Surgery in a patinet aged 40-60 years without any risk factor
• Larger surgery in a patient aged > 40 years without any risk factor
• Small surgery in patients with risk factor/s
• High risk
• Larger surgery in a patient aged >60 years without risk factors
• Larger surgery in patient aged 40-60 years with risk factor/s
• The highest risk
• Large surgery in a patient aged >40 years with history of VTE and/or
recent malignancy
• Hypercoagulable states, polytrauma, heroic surgery
Indication of antithrombotic
prevention according to the risk
• Low risk – bandage (other according to the
circumstancies)
• Intermediate risk
– (common & chest surgery, gynecological surgery)
– LMWH, LD UH
• High risk
• Elective total hip replacement LMWH, anti-IIa, anti-Xa
• Elective knee replacement LMWH, amti-Iia, anti-Xa
• Hip fracture LMWH
• Polytrauma LMWH
• Acute posttraumatic paralysis LMWH
Occurence of postoperative VTE
depending on time interval after
high risk surgery
9
16
13
9
4
0
0
2
4
6
8
10
12
14
16
0 - 7. 8. - 14. 15. - 21. 22. - 28. 29. - 35. 36. - 42. dny
Pregnancy:
 PS
 Fbg, FVII, FVIII, vWF
OC:
Fbg, FVII, FVIII, vWF
 PS, AT III
Stress:
Fbg, FVII, FVIII, vWF
tPA
2AP, Plg
Inflamation
 Fbg, FVII, FVIII, vWF
 1AT, PAI-1, tPA, 2MG, Plg
Sepsis
• Demage of endothelium
• Activation of monocytes, granulocytes, expression
of TF
• Activation of platelets
• DIC
•  fibrinogen, procoagulation factors and
inhibitors of coagulation
•  platelets
Acq. thrombophilia
• Defect of inhibitors (AT, PC, PS, APCR)
• Elevation of FVIII, fibrinogen
• Elevation of PAI - 1
• Hyperhomocysteinemia
Antiphospholipid antibodies
• heterogenous auto-antibodies against
proteins bound to negatively charged
phospholipids on cell membranes
Antiphospholipid antibodies -
mechanism
• inhibition:
– release of prostacyclin from the endothelium
– protein C activation
– fibrinolysis activation by complex prekalikren+FXII
• stimulation:
– activation of platelets
– activation of FX on platelet surface
• other effects outside haemostasis
Antiphospholipid syndrome
clinical criteria
Thrombosis:
• venous or arterial
• proven only histologically
• but not superficial thrombophlebitis
Antiphospholipid syndrome
clinical criteria
Pregnancy disorders:
• three or more subsequent spontaneous abortions
before the 10th week of gestation (excluding other
causes)
• one or more deaths of morphologically normal fetus
(documented by sonography or direct examination)
after week 10 of gestation
• one or more premature births (34 weeks and earlier)
of a healthy newborn in severe pre-eclampsia or
severe placental insufficiency
Antiphospholipid syndrome
laboratory criteria
• anticardiolipin antibodies (ACLA):
– IgG and/or IgM > 40 U/ml or > 99. percentil)
• anti--glycoprotein I antibodies:
• IgG and/or IgM > 99. percentil
• are present 12 weeks or more weeks apart
• it is examined by a standardized ELISA
Antiphospholipid syndrome
laboratory criteria
Lupus anticoagulans:
• are present 12 weeks or more weeks apart
• evidence of prolongation of the screening test (aPTT,
PT)
• there is no correction by norma plasma
• shortening after addition of excess of phospholipids
Antiphospholipid syndrome - diagnosis
• presence of at least one criterion:
– laboratory
– clinical
• the symptom has a maximum distance of 5
years from laboratory criteria
Types of APS and management
• Type I (venous) – LMWH, UFH, W
• Type II (arterial) – LMWH, LD UFH, ASA, W
• Type III (CNS, retinal) – LMWH, ASA, W,
• Type IV (combination) – LMWH, LD UFH, W
• Type V (abortions) – LMWH, ASA
• Type VI (no clinical criteria)
– in pregnancy (ASA, LD W)
– in situations at risk for thrombosis (LMWH, LD
UFH)
Heparin induced thrombocytopenia - HIT
Etiology:
• complex heparin-PF4 + antibody stimulates platelet Fc receptor
– Induce platelets aggregation
– Venous and arterial thrombosis in  50% patients with HIT
• day 4 - 10 after onset of heparin treatment
• decline of platelet count more than 50%
Scoring system of HIT diagnosis:4 T´s
*Lo et al: JTH 2006; 4: 759-765
2 points 1 point 0 points
Thr-penia;
plt count
> 50%
nadir >20 x109/l
30-50%
nadir 10-19 x109/l
< 30%
nadir < 10
x109/l
Timing 5-10D;
≤1D (H 30D before)
5-10D ? plt; >14D; ≤1D
(H 30 - 100D)
4D
Thrombosis New, skin necrosis progression,
recurrence, nonnecrotic
skin lesion
none
Thr-penia;
other reason
none possible yes
• > 3 points  laboratory examination, discontinuation of UFH or
LMWH
• 4-5 point - moderate, 6-8 points – high suspicion of HIT
HIT: diagnosis
• Clinical + laboratory:
– Decline of plt count (thrombosis, skin necrosis)
– HIPA:
• Aggregation of healthy platelets + patient‘ s PPP + heparin
• Low (50%) sensitivity, almost 100% specificity
– ELISA:
• complex heparin - PF4 antibodies
• High sensitivity, low specificity
– Release of 14*C-serotonine
• the highest sensitivity and specificity
HIT: treatment
– Cross-reactivity between UFH and LMWH:
– argatroban – IIa inhibitor (1C)
– bivalirudin – IIa inhibitor (2C)
– danaparoid – heparinoid with predominant FXa inhibition (1B)
– Fondaparinux (Arixtra®) - oligosacharid with FXa inhibition (2C)
– Warfarin after normalization of plt count 150
– If no thrombosis – prophylactic dosage for 30 days
HIT – platelets‘ count according to the risk
•  0,1%:
–  4 days
– internal and gyneacological indication:
• LMWH for  4 days
• 0,1 – 1%:
– Internal a gyneacological: - after surgery:
• UFH  4 days * LMWH  4 days
•  1%:
– After surgery:
• UFH  4 days
• heparin induced • coumarine induced
*Bichler A.J. et al: Hypersensitivity reactions to
anticoagulant drugs: diagnosis and managment option.
Allergy 2006: 61: 1432-1440
Skin necrosis
Drug induced thrombophilia - mechanins