Hypo-coagulation disorders
P. Smejkal
Department of Hematology, Faculty Hospital Bohunice
Etiology of coagulation disorders
According to the heredity:
• Herediraty – defect of synthesis
- dysproteinemias
• acquired - defect of synthesis
- increase turnover
- consumption
- antibodies
- loss
According to the phenotype:
• bleeding disorders
• thrombotic states
Etiology of hereditary bleeding disorders
• Vessel wall (Ehler-Danlos, Rendu-Osler)
• trombocyto–
penia (TAR, Wiskot-Aldrich, Grey platelet sy)
– patia (Glanzmann, Bernard- Soulier)
• plasma coagulation (focus on today):
– hemophilia
– von Willebrand disease
– defects of the others plasma coagulation factors
– hyperfibrinolysis: defect of alpha2-antiplazmin, PAI-1
?
Hemostasis
 primary
vasoconstriction immediately
platelets adhesion seconds
platelets aggregation seconds to minutes
minuty
 secondary (coagulation)
coagulation ff. Activation seconds to minutes
Fibrin formation minutes
 fibrinolysis
activation minutes
blood clot lysis hours
Bleeding manifestation
prim. hemostasis coagulopathy
petechias typical seldom
deep
hematomas
seldom typical
joints seldom typical
mucosal spontaneous after trauma
delayed seldom typical
from wounds typical minimal
bleed start promptly delayed
Primary hemostasis
Laboratoty tests of hemostasis
• Coagulation: aPTT, PT, fibrinogen, (TT)
– Specific factors assays
• Primary hemostasis:
– CBC - thrombocytopenia
– Bleeding time, PFA-100, VWF:RCo
– Assay of platelet function:
• Aggregation
• Retraction
• Flowcytometry
• Electron microscope
• Thrombelastometry
• Thrombin generation assay
Hemophilia – X-recessive heridity
Hemophilia - prevalence
• Sporadic phenotype (25 - 30%)
– Women carrier only:
• Mostly without bleeding symptoms
– New mutation
• Hemophila A (FVIII) 1/5000 – 10000 boys
• Hemophila B (FIX) 1/30000-50000 boys
Hemofílie – nemoc králů
Hemophilia – the royal disease
Hemophila A, B - diagnosis
• bleeding: - joints, muscles, deep bruises
• severe < 1% FVIII / FIX
- spontaneous bleedeng frequent (1x monthly)
• moderate 1 - 5% FVIII / FIX
- spont. bleeding seldom, after injury, surgery
• mild 5 - 40% FVIII / FIX
- bleeding after injury, surgery
Hemophila - diagnosis
hemophila von Willebrand disease
• aPTT   - N
• PT (Quick) N N
• Bleeding time N N  
• PFA-100 N  
• assay FVIII/FIX VWF, FVIII
Hemophila – prenatal diagnosis
• Chorion villus sampling:
– at 11–13 gestation week
• Amniocentesis:
– at 15–18 gestation week
• 40% of severe hemophilia A:
– Inversion of intron 22
• Foetal cell-free DNA in maternal blood:
– from gestation week 7 – 9
– 4% inconclusive results
• Preimplantation genetic diagnosis
– a single cell is removed from a two-day zygote (8 cells)
Hemofilie A – léčba:
stimulace uvolnění endogenního FVIII
• DDAVP - 0,3 µg / kg i.v. á 12 - 24 hod., max. 5 dnů
(150 - 300 µg i. n.)
- elevace: - VWF 2- 4x t1/2 5 - 10 hod.
- FVIII 2- 4x t1/2 8 - 12 hod.
• Výchozí FVIII ≥ 15 %, aby byla šance dosáhnout
hemostatické hladiny FVIII 40-50 %
DDAVP 1-desamino-8-D-arginin vasopressin
• Increase of VWF 2-3x:
– releasing from endothelial cells
– monocytes » secretion of PAF » VWF from endothelial cells
• Increase of FVIII 2-3x:
– direct releasing from the site of synthesis
• Dosage:
• 0,3 µg/kg i.v., s.c.,
• 300 µg (50 kg 150 µg) i. nasálně:
– á 12 - 24 h.
– max. 5 days
• For haemophilia A with FVIII:C ≥ 15 %
• to have chance to achieve haemostatic level about 40-50 %
Hemophila treatment – substitution of FVIII/IX
(plasma derived, recombinant)
• FVIII:C 1 IU / kg increase 2% t2 = 12 h
• FIX:C 1 IU / kg increase 1% t2 = 18 h
Prophylaxis:
• Primary: after 1st joint bleed and till age 2 years
• Secondary: started later
• Temporary: after surgery, severe bleeding
On demand:
• When bleeding has occured
• Perioperative substitution
Hemophilia - prophylaxis
Goal: to keep factor VIII/IX plasma level > 1 - 2%
Dosage:
• HA: FVIII 25 – 40 IU/kg 3 x weekly
• HB: FIX 25 – 40 IU/kg 2 x weekly
• Tailored:
– 50 IU/kg 1 x weekly
– 30 IU/kg 2 x weekly
• Low: 25-35 IU/kg 1x weekly – lower risk of inhibitor
– Start before the first joint bleeding
Effect - lower risk:
– Life-threatening bleeding
– Joint bleeding – joint demage
Hemophilia – treatment of bleeding
(WFH – Guidelines for the Management)
no resource constraint FVIII (FIX) resource constraint
 joints:
 40- 60%
 1 – 2 days, sometimes longer
 muscles:
 40 – 60%
 2 – 3 days, sometimes longer
 Musculus iliopsoas:
 80 – 100% (60-80%) 1 – 2 days
 30 – 60% 3 – 5 days
 prophylaxis
 hematuria:
 50% (40%) 3 – 5 days
 Deep laceration
 50% (40%) 5 – 7 days
 10 – 20%
 10 – 20%
 20 – 40% (15 – 30%)
 10 – 20%
 20 – 40% (15 – 30%)
 20 – 40% (15 – 30%)
Hemophilia – treatment of bleeding
(WFH – Guidelines for the Management)
no resource constraint FVIII (FIX) resource constraint
 CNS:
 80 – 100% (60 – 80%) day 1 – 7
 50% (30%) day 8 – 21
 GIT:
 80 – 100% (60 – 80%) day1 – 6
 50% (30%) day 7 – 14
 Surgery
 80 – 100% (60 – 80%) during surgery
 60 – 80% (40 – 60%) day 1 – 3
 40 – 60% (30 – 50%) day 4 – 6
 30 – 50% (20 – 40%) day 7 - 14
 50 – 80% day 1 – 3
 30 – 50% day 4 – 7
 20 – 40% day 8 –14
till day 21
 30 – 50% day 1 – 3
 10 – 20% day 4 – 7
 60 – 80% (50 – 70%)
 30 – 40% day 1 – 3
 20 – 30% day 4 – 6
 10 – 20% day 7 - 14
Hemophilia – dental surgery - extraction
During extraction and next 6-12 h:
• Desired plasma level:
– FVIII 50-100%: FVIII 50 IU / kg
– FIX 50-80%: FIX 80 IU / kg
• + antifibrinolytic drug p.o. 8 - 10 days
– Tranexamic acid (Exacyl)
• 3 x 25 mg / kg or 4 x 15-20 mg / kg /day
Ageing hemophilic population – co-morbidities
Dosage
Desired level
FVIII/IX (IU)
ASA therapy
FVIII 25-40 IU/kg alternate day
FIX 25-50 IU/kg 2-3x weekly
 5%
Dual antiplatelet
therapy
FVIII 15 IU/kg á 12 h
FIX 15 IU/kg á 12 h
 25%
Thrombolysis
Therapeutic dose of
heparins
FVIII 40 IU/kg + 20 IU/kg á 12 h
FIX 80 IU/kg + 30 IU/kg á 12 h
80%
50%
Warfarin therapy
FVIII 15 IU/kg á 12 h
FIX 15 IU/kg á 12 h
 25%
Trombocytopenia
 30 000 / l
FVIII 10 IU/kg daily
FIX 20 IU/kg alternate day
 5%
Liver biopsy
FVIII 50 IU/kg, FIX 70 IU/kg
FVIII, FIX 25 IU/kg á 12 h
during procedure 70%
next 2 (4) days  50%
*Mannucci PM. Blood 2009:5256-63 *Schutgens REG. Haemophilia 2009:952-58
*Mauser-Bunschoten EP. Aging with haemophilia 2007
Hemophila – gene therapy
restoration of FVIII/FIX synthesis by gene transfer:
 In vivo:
 i.v., i.m., s.c.
 Ex vivo:
 to the cells ex vivo and their implantation
Vectors:
 Viral:
 retrovirus - s.c.: tumor risk
 adenovirus - i.m.: virus elimination by immune systeme
 adeno-asociated virus – i.m.: only small gene – hemophilia B
 Non-viral - use naked plasmid DNA transferred by:
 liposoms, nanoparticles
 elektroporation
 direct injection
Gene therapy approaches for hemophilia by
direct administration of AAV8
Journal of Thrombosis and Haemostasis
pages S133-S142, 19 JUN 2015 DOI: 10.1111/jth.12926
http://onlinelibrary.wiley.com/doi/10.1111/jth.12926/full#jth12926-fig-0001
Local cell‐based therapy for hemophilic arthropathy
by MSCs expressing coagulation factor
Journal of Thrombosis and Haemostasis
pages S133-S142, 19 JUN 2015 DOI: 10.1111/jth.12926
http://onlinelibrary.wiley.com/doi/10.1111/jth.12926/full#jth12926-fig-0002
Gene therapy – haemophilia B
 for severe: FIX < 1 %
 AAV8
 1/3 of patients has má neutralizing antibodies
 hore than 50 patients from 2011:
 2x1011 vg/kg - 2x1012 vg/kg
 for 3-4 years FIX plasma level 1-6 %
  LT week 6-12
 destruction of hepatocytes by T-lymphocytes
 Padua mutant FIX (p.R338L):
 5-10x  coagulation activity
 FIX plasma level 18-80 %
*Dolan G.Eur J Haematol. 201799(Suppl.87): 3-9
*Nathwani AC. Human Gene Therapy 2017;28: 1004-12
Gene therapy – haemophilia A
 larger gene: 7 kb
 from 2015
 AAV5, 15 patinets:
 Deletion of B-domain (4,4 kb)
 7: 6x1013 vg/kg: after 1 year FVIII > 50 %
 6: 4x1013 vg/kg: after 1 year FVIII > 50 % 3x, 3x > 5 %
 3: 6x1012 vg/kg a 2x1013 vg/kg: without increase of plasma FVIII
 Lentivirus
 Possibility to transfer of large gene
*Nathwani AC. Human Gene Therapy 2017;28: 1004-12
Concentrate with modified FVIII / FIX molecule
Prolongation of plasma half-life:
 Pegylated
 Fusion with albumin Approved for treatment
 Fc fragment fusion a
EHL rFVIII:
 T1/2 1.5 x  (18-19 h)
EHL rFIX:
 T1/2 3-5x  (60-90 h)
Ortopaedic procedures in management
of hemophilic arthropathy
• Synoviorthesis (synovectomy):
– chemical (small joints)
– radioactive (elbows, knees, ankles)
• Surgical synovectomy:
– elbows, knees, ankles
• Total joint arthroplasty:
– knees, hips
• Arthrodesis:
– Joint is fused without further motion, without pain
Hemophila – FVIII/FIX inhibitor
• allo-antibodies
– neutralized factor clotting activity
– mostly class IgG
• 1 Bethesda U:
– amount of inhibitor that destroys half the factor in the
mixture of normal and patient´s plasma after 2 h incubation
• 20-30% patients with severe HA,  4% with HB
– median detection is 10-15th ED (exposure day)
Inhibitor type
responder "Low" "High"
• Response to
infused FVIII/IX without rise of rise of inhibitor titre
inhibitor titre
• Inhibitor titre < 5 BU/ml > 5 BU/ml
• Incidence cca 1/3 cca 2/3
Treatment of bleeding episodes with inhibitor
• High dose of FVIII/IX concentrates (< 5 BU/ml)
• aPCC - activated prothrombin complex concentrate (FVIIa,
FII, FIX, FX) FEIBA®
– 50-100 IU/kg á 6-12 h
– Limitation: maximum 200 IU/kg per day
• rFVIIa NovoSeven®
– 90 g/kg á 2-3 h
– Single dose 270 g/kg
• Plasmapheresis with immunoadsorption
Immune tolerance induction - ITI
• Bonn protocol:
– FVIII/IX 200-300 IU / kg / day
– High responders
– Inhibitor eradication: 85%
• low dose protocol:
– FVIII/IX ≤ 50 IU / kg / day (3 x weekly)
– Low responders
– Inhibitor eradication: 67%
• Malmö protocol:
– Plasmapheresis with immunoadsorption of IgG
– Immunosupresive treatment – cyclophosphamide
– FVIII/IX substitution – neutralize inhibitor and rise level  30%
– Inhibitor eradication: 50%
•
FVIII-mimetic function of bispecific antibody
Emicizumab – dosage and plasma level
• Dosage 1x weakly s.c.:
– group 1: 0,3 mg/kg
– group 2: 1 mg/kg
– group 3: 3 mg/kg
„Trough level“ week 12:
• 10 µg ~ 3 % FVIII
• 30 µg ~ 9 % FVIII
• 90 µg ~ 27 % FVIII
• 30-50 µg ~ 10-15% FVIII
• Recommended dosage: 3 mg/kg s.c. 1x weakly for 4 weeks
• next 1,5 mg/kg 1x weakly or 3 mg/kg á 2 weeka or 6 mg/kg á 4 weeks
*Shima M. et al. N Engl J Med 2016;374:2044-53
von Willebrand disease
• is the most common hereditary bleeding disorder
– Low level of VWF: 1%
– Disease 1.000-3.000 / 1.000.000
• Severe type 3 / 1.000.000
• caused by quantitative or qualitative defect of VWF
– multimeric structure glycoprotein
– synthesized in endothelial cells and megakaryocytes
– carrier of FVIII
– promoting
• platelet adhesion to subendothelium
• platelet aggregation
*Reininger AJ. Haemophilia 2008;14 (Suppl.5):11-26
Multimer structure + electrophoretically separated bands
*Reininger AJ. Haemophilia 2008;14 (Suppl.5):11-26
*Siedlecki ChA. Blood 1996;88:2239-50
No shear 35 Dyn/cm2
Shear induced VWF changes and imobilization
Primary platelet clot
Classification of von Willebrand disease
*Sadler JE, Thromb Haemost 1994; 71: 520-525
• type 1 – partial quantitative deficiency, AD
• type 2 – qualitative defects, AD, AR
– 2A – decreased VWF-dependent platelet adhesion and
deficiency of HMW multimers, AD
– 2B – increased affinity for platelet GPIb, AD
– 2M – decreased VWF-dependent platelet adhesion
without selective deficiency of HMW multimers, AD
– 2N – decreased binding affinity for FVIII, AR
• type 3 – virtually complete deficiency of VWF, AR
Changes in the classification of VWD
*Sadler JE,J Thromb Haemost 2006; 4: 2103-2114
• VWD is not restrict to VWF gene mutation
• VWD type 1 includes partial quantitative
deficiency:
– HMWH multimers of VWF are decreased only
relatively
– normal ratio of functional activities compared
with VWF:Ag
SSC-ISTH classification of VWD 2A subtypes
*Schneppenheim R.Semin Hematol 2004;42:15-28
*Gadisseur A.Acta Haematol 2009;121:128-38
Laboratory diagnosis of VWD
• Screening tests: sensitivity
– platelets (type 2B)
– aPTT < 30%
– bleeding time < 40%
– PFA100 85 - 90%
• Specific tests:
– VWF:Ag, VWF:RCo + VWF:CBA, FVIII:C
• Discriminating tests:
– multimeric analysis of VWF, RIPA, VWF FVIII binding
capacity, VWFpp
• Molecular diagnosis
• Assay of platelet VWF
Role of the VWFpp/Ag ratio
*Gadisseur A.Acta Haematol 2009;121:128-38
• VWFpp is released after VWF secretion
• half-life:
• VWFpp: 2-3 h
• VWF:Ag 8-12 h
• diagnosis of increased clearence:
• in VWD
• in acquired VWF defects
Collagen binding assay - VWF:CBA
• more sensitive for HMW multimer deficiency:
– type 2A ,2B: vWF:CBA / vWF:Ag < 0,5
Ag
RCo
CBA
100%
50%
30%
*Favaloro EJ.Semin Thromb Hemost 2006;32:456-71
*Favaloro EJ.Semin Thromb Hemost 2006;32:566-76
A summary of the routine laboratory
findings in the various types of VWD
type RIPA RCo Ag FVIII RCo/Ag CBA CBA/Ag
1 N   N N  N
2A   N N < 0,7  < 0,5
2B N  N N < 0,7   < 0,5
2M N  N N < 0,7 N  N
2N N N  N  N N N
3         N   N 
Diagnosis of von Willebrand disease
(SSC ISTH Subcommittee on vWF, 1996)
*Sadler JE, J Thromb Haemost 2005; 3: 775-777
• confirm: a) mucocutaneous bleeding
b) family history
c) laboratory tests
VWF: RCo, VWF:Ag < 2 SD (BG 0, non-0)
• possible:
– without a) or b)
Grades of bleeding severity used in the IMS
*Tosetto A.Haemophilia 2008;14:415-22
Minimaly diagnostic criteria for clinicaly
useful diagnosis of VWD - BS
• bleeding score:
–  3 in men
–  5 in women
– requirement for high BS is less stringent in
children
*Rodeghiero F.2009;51st Congress of ASH,New Orleans
The utility of the PFA-100 in the
identification of VWD
Sensitivity:
•  98% to VWD
• types 2A, 2B, 2M, 3
• 50 – 100% to VWD type 1
• 50% - not specified cut-off
for vWF:Ag, RCo
• 85 – 90% overall
*Favaloro EJ. Semin Thromb Hemost 2006;32:537-45
Minimaly diagnostic criteria for clinicaly
useful diagnosis of VWD – tests of VWF
– MCMDM-1vWD cut off for percentil 2,5 (n=1166):
• BG 0:
– VWF:RCo 43%
– VWF:Ag 44,4%
• BG non-0:
– VWF:RCo 54%
– VWF:Ag 54%
• VWF:Ag or VWF:RCo:
–  40%
• 30 – 40% only if BS is  3 / 5 in men / females
*Rodeghiero F.2009;51st ASH,New Orleans
-  30% *Nichols WL. Haemophilia 2008;14:171-232
VWD – therapeutic weapons
• release of endogenous VWF:
– DDAVP
• VWF substitution:
– pd concentrates containing WF/FVIII
– platelet concentrates
• other forms:
– antifibrinolytics
– estrogens
DDAVP 1-desamino-8-D-arginin vasopressin
• Increase of VWF 2-3x:
– releasing from endothelial cells
– monocytes » secretion of PAF » VWF from endothelial cells
• Increase of FVIII 2-3x:
– direct releasing from the site of synthesis
• Dosage:
• 0,3 µg/kg i.v., s.c.,
• 300 µg (50 kg 150 µg) i. nasálně:
– á 12 - 24 h.
– max. 5 days
Efficacy of DDAVP in therapy of VWD
• type 1: v 90%
• typ 2: max. about 50%:
– 2A (increase of proteolysis, t2: 2- 4 h.)
– 2M (variable)
– 2N (t2: 2- 4 hod.)
– 2B (contraindication - progress of thrombocytopenia)
• typ 3: VWF/FVIII level  5-10%
• ineffective
Substitution of VWF/FVIII
• cryoprecipitate (FVIII/VWF 80 – 100 IU/1 TU)
• pd-concentrates of FVIII containing VWF:
– variable content of HMW multimers of VWF
– the highest ratio VWF:RCo/FVIII:
– Haemate P®
– labeled:
– VWF:RCo
– FVIII:C
Comparison various pd FVIII/VWF concentrates
concentrate
VWF:RCo
/ FVIII
Recovery / IU
/ kg
t1/2
(h.)
FVIII IU
/ 1 mg
Haemate P® 2,4 2% 7 2 - 6
Fanhdi® 1,2 2% 14 2,5 - 10
Wilate® 0,9 1,5 - 2% 18 - 34 ≥ 60
Willfact® ≥ 10 1,5 - 2% 8 - 14
≥ 50
VWF:RCo
High purity VWF concentrate
(Wilfactin®, Willfact®)
• Increase of FVIII:C - rate 6% per 1 h
– In acute bleed combination woth FVIII concentrate
– In case of surgery 1st dose 12 h before surgery
– t2 VWF:RCo = 12 h.
– t2 FVIII:C = 17 h.
Recommended level of VWF:RCo and FVIII:C
bleeding type
desired level
duration of substitution
VWF:RCo FVIII:C
major surgery > 50% > 50% until healing (7 - 10 days)
minor surgery > 30-50% > 30-50% until healing (1 - 5 days)
dental
extraction
> 50% > 50% for 12 h
+ antifibrinolytics 5 -10 days
bleeding
episodes
> 30-50% > 30-50%
until bleeding stops
(2 - 4 days)
vaginal delivery > 40-50% > 40-50% 3 - 4 days
*Mannucci PM.Blood Transfus 2009;7:117-26
*Nichols WL. Haemophilia 2008;14:171-232
*Nordic Guidelines on VWD 2008
Rare inherited coagulation bleeding disorders
• Heredity autosomal recessive
• Severe defects 1 / 1 000 000
(homozygot, double heterozygot)
• dysfibrinogenemia (AD, bleeds or TEN or without)
• Factors deficiency:
– fibrinogen, F II, V, VII, X, XI, XIII
• Fibrinolysis inhibitors deficiency:
– 2AP, PAI,
•
Dysfibrinogenemia
• Diagnosis:
–  thrombin time and reptilase time
– Antigen > functional activity (Clauss)
• Fenotyp (mostly AD):
– Asymptomatic 55% (A Arg 16 His)
– Bleeding 25% (A Gly 17 Val)
– Thrombosis 20% (Arg 554 cys)
• To be include in screening of thrombophilia
• More than 300 mutations
• Therapy:
– Bleeding: substitution of fibrinogen
– Thrombosis: LMWH, kumarins
– Abortions:
• LMWH
• substitution
;
Factor PT aPTT TT BT remarks
A-fbg     fbg 0
Dys - fbg    N Fbg activity , Fbg:Ag N,  rept time
II   N N < 30 %
V   N N -  < 30 %
VII  N N N < 30 %
VIII N  N N < 30 %
VWD N  - N N  - N FVIII: N - , VWF:RCo < 40-50 %
IX N  N N < 30 %
X   N N < 30 %
XI N  N N < 40 %
XII N  N N < 40 %
XIII N N N N  coagulum lysis
α2AP N N N N  coagulum lysis
PAI-1 N N N N  coagulum lysis
Coagulation tests and BT in factor deficiency
Prevalence of severe hereditary coagulation disorders
• Fibrinogen 1 : 1 000 000
• FII 1 : 2 000 000
• FV 1 : 1 000 000
• FVII 1 : 300 000 – 500 000
• FV+VIII 1 : 2 000 000
• FVIII (XR) 50 – 80 : 1 000 000 (not only severe)
• FIX (XR) 10 – 15 : 1 000 000 (not only severe)
• FX 1 : 1 000 000
• FXI 1 : 1 000 000 (Ashkenazi 8% heterozygotes)
• FXIII 1 : 1 000 000
• MvW (AD) 100 – 1 000 : 1 000 000 (not only severe)
Factor
Type of bleeding in severe
defect
Abnormal
assay
Desired level in
bleeding / surgery
Treatment
fbg umbilical, CNS, soft tissues PT, aPTT, TT 0,5 - 1 g / l Fibrinogen
II Soft tissues PT, aPTT 20 - 30 % PCC
V hemophilic type PT a aPTT 15 - 20 % FFP
VII <1% hemophilic type PT 15 - 20 % FVII, PCC
VIII joints, muscles aPTT 40 - 50 % FVIII
vWCH
mucous membrane, after trauma
type 3 hemophilic type
aPTT, BT 40 - 50 % vWF/FVIII
IX Joints, muscles aPTT 40 - 50 % FIX
X <1% hemophilic type PT, aPTT 15 - 20 % PCC
XI Obstetric, dental procedures aPTT 30 – 45 % FFP, (FXI)
XII no bleeding aPTT no need of treatment
XIII Umbilical , CNS, soft tissues fibrinolysis 3 - 5 % FXIII, FFP
PK no bleeding aPTT no need of treatment
HMWK No bleeding aPTT no need of treatment
a2AP hemophilic type, to bones fibrinolysis ? antifibrinolytics, FFP
PAI-1 after trauma,surgry fibrinolysis ? antifibrinolytics, FFP
Combined defects
Type:
• I FV+VIII
• II FVIII+IX
• III FII+VII+IX+X, PC, PS
– (vitamin K dependent factors)
• IV FVII+VIII
• V FVIII+IX+XI
• VI FIX+XI
aPTT – etiology of prolongation
• deficit:
– FVIII, FIX, FXI, FXII
– FII, FV, FX
• lupus anticoagulans
• heparin (  TT, normal reptilase time)
• dabigatran (   TT)
• acquired inhibitor (mostly against FVIII)
• severe hypofibrinogenemia
•  PCV (packed cell volume)
PT – etiology of prolongation
• deficit:
– FVII
– FII, FV, FX
• Warfarin therapy
• Xabans – only mild increase inconstantly
• lupus anticoagulans
• severe hypofibrinogenemia
• very seldom acquired inhibitor (FVII)
•  PCV (packed cell volume)
Procoagulation factors in new-borns
Stable level:
• fibrinogen > 1,5 g / l
• FVIII > 50%
• FV, FXIII > 30 – 40%
Low level:
• FII, FVII > 25% 40-60%
• FIX, FX, FXI, FXII > 10-15% 30-50%
- ½ year – 18 years > 50% (level is 80-85% as in adults)
- In adults > 50 -60%
Higher level:
• VWF – during the first 3 months
Koagulogram of new-born baby
• PTd1 d90 d180
< 1,6 INR < 1,26 INR < 1,2 INR
• aPTT
< 1,6 R < 1,5 R < 1,28 R
Coagulation inhibitors in new-borns
Lower level:
• AT III > 40% (60%) normalization (> 80%) in month 4-6
> 15% (40%) if born in 30 – 36 gestation week
• PC > 15% (35%)
> 30% month 3 > 40% 1/2 – 5 years
> 45% 5 – 10 year > 55% - adult
• PS > 15% (35%) > 55% after month 3
• HCII > 10% (45%) > 50% after month 6
Elevation:
• 2MG > 100% normalization in 20 years
Influence on coagulation factors:
Gestation:
 Fbg, FVII, FVIII, VWF, FIX, FX, FXII, PAI
 PS
OC:
 Fbg, FVII, FVIII, VWF, FIX, FXII, FII, X, XI
 PS, AT III
Inflamation:
 Fbg, FV, FVII, FVIII, VWF
 1AT, PAI, tPA, 2MG, Plg
Stress:
 Fbg, FVII, FVIII, VWF
 tPA
2AP, Plg