10. • Tissue-factor-pathway inhibitor (TFPI)
– inhibit TF-factor 7a complex
• ADAMTS-13: cut VWF into pieces
• Thrombomodulin(TM)：和thrombin結合，
activate protein C(形成APC)
• Protein C system: activated protein C + protein
S(為co-enzyme)：deactivate factor 5,8
• Anti-thrombin(AT)
– quenches factors not forming complex(2,9,10)
– more efficient when binding to heparin
21. acquired inherited
Urea [5M]
solubility
test
Usually
acquired
disease
Trauma Hx( bone
fracture)
Also Consider mild
deficiency of F VIII,IX,XI
( around sen 30-40%)
and dysfibinogenemia
Pts with mild bleeding
disorder and normal
aPTT; cause aPTT did
not dected the mild
deficiecy of F VIII,IX,XI
一定有
answer
Drugs: Cpz,
fortum,
22. Coagulation Factor (1)
• All factor including protein C,S synthesis by
liver cells except FVIII( endothelial cells)
– Only Hypofibrinogen may rare from deficiency
liver biosynthesis
– Filling with vit K did not compensate the
FII,VII,IX,X prove the hapatocyte cell inj in
main cause
• Half life
– Shortest: VII(4-6 hr)
– Longest: XIII 168hrI=frbrinogen (120 hr)
23. Coagulation Factor (2)
• Cofactor
– V , VIII, tissue factor, HMWK, protein S, thrombomodulin, EPCR
• Protease : others
• Not in liver “cell” product: VIII
• Vit K dependent : II,VII,IX,X,C,S,Z
• Level newborn= adult
– Factor I, V, VIII, XIII, vWF
• Molecular weight
– > 300K : factor I, V, VIII, XIII, vWF
– < 50 K : Tissue factor, VII
24.
25. 1. A Jew patient had minimal bleeding tendency and
occasional surgical bleeding since childhood, the
most possible factor deficiency is
(A) V (B) VIII (C) XI (D) XII (E) X
Ans: C
2. Which of the following diagnosis may be compatible with the following
coagulation profile: normal prothrombin time and platelet count, prolonged
activated partial thromboplastin time ?
(1) Deficiency or inhibitor of factor VIII, IX or XI
(2) von-Willebrand’s disease
(3) Heparin induced
(4) Fibrinogen deficiency
Ans: 1,2,3
3. Which the following coagulation factors has the longest in-vivo half-life?
(A)factor II (B)factor V (C)factor VII (D)factor VIII (E)factor XIII
Ans : E
26. 3. A patient with congenital bleeding tendency, his
APTT is normal, but PT is prolonged, which factor
deficiency is most likely?
(A) XII (B) XIII (C) VII (D) V (E) X
Ans : C
4. Which of the following factor deficiencies would be
expected to result in prolongation of both the
prothrombin time and partial thromboplastin time ?
(A) Factor XI (B) Factor X (C) Factor IX (D) Factor VIII
(E) None of above
Ans : B
5. If a patients has congenital factor XIII deficiency, which screening test is useful for
detection?
(A) Prothrombin time (B) Activated partial thromboplastin time
(C) Urea solubility test (D) Euglobulin lysis test
(E) Assay for fibrin degradation products
Ans : C
29. Clinical Distinction between Disorder of Vessels and Platelets and Disorders of Blood
Coagulation
Finding Disorder of Platelets or Vessels Disorder of Coagulation
Petechiae
Deep dissecting hematomas
Superficial ecchymoses
Hemarthrosis
Delayed bleeding
Bleeding form superficial
cuts and scratches
Sex if patient
Positive family history
Characteristic
Rare
Characteristic, usually small and
multiple
Rare
Rare
Persistent, often profuse
Relative more common in
females
Rare ( Except vWD and
hereditary hemorrhagic
telangiectasia)
Rare
Characteristic
Common, usually large and
solitary
Characteristic
Common
Minimal
80-90% of inherited forms
occur only in male patients
Common
How to D/D primary or secondary hemostasis
33. Positive Bleeding History
Screening Tests
CBC, (Bleeding Time) PFA-100, PT, aPTT
Coagulation Factor Deficiency
FVIII
FIX
FXI
aPTT-based
assays
FVII
FX
FV
PT-based
assays
Defects of Primary Hemostasis
vWD Platelet Disorders
vWF:Ag
vWF:RC
o FVIII:C Platelet
aggregation
test
Platelet
number &
morphology
RIPA
vWF
multimers
34. Symptom(+) Lab (+) and
Sym(-)
Screen Lab:
APTT, PT and PLt
(-)
if aPTT,PT,TT and Plt all is normal R/O F XIII
problem check urea [5M] solubility test( clot
stability test) : if abnormal F XIII resolution in
minutes( hydrogen bond peptide bond by FXIII)
(+)
See You
Confirmatory test
mixted aPTT; mixed PT 0 and 2 hour
If corrected (N+P < buffer+normal)
Factor deficiency
Or weak antibody
If not antibody
1. Anti phospholipid Ab ( no clincal importance) on 0
hr
2. Factor antibody ex: VIII ab ( delay titier: 2 hr more
long)
Condition with abnormal screening tests but
no hemorragic diathesis
Factor XII deficiency
Prekallikrein deficiency
High-molecular-weight kinogen deficiency
Mild to moderate factor VII defiency
Lupus anticoagulant
Exscess citrate anticoagulant (eg with Hct >60%)
56. PT aPTT Platelet Common causes Rare causes
Acquired FVII def.
Early liver disease.
Early vit. K deficiency
Warfarin therapy
Congenital FVII deficiency;
N N
Factor X, V, II or fibrinogen deficiency;
Dysfibrinogemia;
some case of DIC
N N
Hemophilia A or B,
Factor VIII inhibitor,
Lupus anticoagulant,
vWD; Heparin*.
* PT reagent contains polybrene
which neutralizes trace heparin.
Congenital FXI deficiency
Congenital FXII, Pre-K, HMWK def
N
Vitamin K def.
Liver disease (late stage)
Warfarin overdose
Prothrombin, FV, FX def. or inhibitor;
Fibrinogen deficiency; DIC;
Dysfibrinogenemia; primary fibrinolysis.
Heparin, Superwarfarin
DIC;
Liver disease (late stage)
Heparin-induced thrombocytopenia;
57. Sensitivity of PT and aPTT
Procoagulant Hemostasis
(要多少量的凝血因子才
能凝血止血)
Threshold for
prolonged PT
Threshold for
prolonged PTT
Common Fibrinogen 50-100 mg/dL <100mg/dL <60mg/dL
Factor 2 20-30% <50% <15%
Factor 5 >20% <50% <40%
Factor 10 >20% <60% <25%
Extrinsic Factor 7 >10% <50% NA
Intrinsic Factor 8 >40% NA <35%
Factor 9 >30% NA <20%
Factor 11 Variable NA <30%
Factor 12 0 NA <20%
60. Hemorrhagic diathesis with
normal PT +/- PTT
• ○ Plt dysfxn
• ○ vWD disease (some)
• ○ Dysfibrinogenemia
• ○ Monoclonal gammopathy
• ○ Connective tissue disease, steroid use
61. Limitations of PT and aPTT in
Clinical Decision-Making
Hemorrhagic diatheses with normal PT and/or aPTT
– Some vWD
– Platelet dysfunction
– α2-antiplasmin deficiency
– Dysfibrinogenemia
– Monoclonal gammopathy
– Factor XIII deficiency
– Vascular or connective tissue abnormalities
Conditions with abnormal screening tests but no
hemorrhagic diathesis
– Factor XII deficiency
– Prekallikrein & HMW kininogen deficiency
– Mild factor VII deficiency
– Lupus anticoagulant
National Taiwan University Hospital Department of Internal Medicine
62. Abnormal screening test but no
hemorrhagic diathesis
• Factor 12 deficiency (PTT severe prolong)
• Factor 7 deficiency (只要10%就能凝血, >30%
就不會)
• Lupus anticoagulant
68. Causes of Vitamin K-Deficiency
Newborn
Malnutrition
Biliary obstruction (effect
on bile salts)
Malabsorption of vit. K
– Sprue, coeliac disease
– Board-spectrum
antibiotics
Vit. K antagonists
– Warfarin (Coumadin)
– Superwarfarin
Vit. K1 Vit. K2
Source
Leafy
vegetables
Bacterial
flora
Site of
absorption
Proximal
bowel
Terminal
ileum, colon
National Taiwan University Hospital Department of Internal Medicine
69. • ● Vit K (用IV slowly push for 3 mins; SC太不
穩定)
• ○ 為油溶性, 泡在N/S或Tai5內不會溶,只會
卡在IV set中
73. Blood 2010; 116:878-885
National Taiwan University
Hospital
Department of Internal Medicine
Rebalanced Hemostasis in patients with Liver Disease
74. ↓Thrombocytopenia
↓ Platelet function
↓ Factors II, V, VII, IX,
X, XI
↓ Dysfibrinogenemia
↑Fibrniolysis
↑tPA
↓α2-antiplasmin
↓TAFI
↑FDP, D-dimer
↑FVIII + vWF
↓Anti-coagulant
↓Protein C & S
↓Antithrombin
↓Fibrinolysis
↓Plasminogen
↓PAI-1
Bleeding tendency Thrombotic tendency
Decompensation
DIC-like
Hemostatic Changes in Liver Disease
National Taiwan University Hospital Department of Internal Medicine
Rare portal vein
thrombosis
Bleeding tendency in
patients with hepatic
failure
No bleeding tendency in most
cases of liver cirrhosis
75. Factor deficiency Half-life
Minimum for
hemostasis
Dose of FFP
Factor II 60 hr 20-30% 10-20 ml/kg qd
Factor V 12-36 hr 25-30% 10-20 ml/kg q12h
Factor VII 4-6 hr >10% 10-20 ml/kg load, 5 ml/kg q4-6h
Factor IX 18-24 hr >30%
Factor X 30 hr >20% 10-20 ml/kg load, 5 ml/kg q12h
National Taiwan University Hospital Department of Internal Medicine
• For a patient with liver disease, who has active bleeding or requires surgery,
10-15 ml/kg FFP q 8-12 h is recommended.
→ complication: fluid overloading, portal hypertension
Systemic Treatment for Bleeding Tendency in Liver Diseases
76. New concepts for Perioperative management in
patients with liver disease
National Taiwan University Hospital Department of Internal Medicine
• The previous assumption of bleeding tendency in patients with liver
disease is false. The average patient is actually in a state of
"rebalanced hemostasis" that can relatively easily be tipped toward
both bleeding and thrombosis.
• There is no evidence that the use of prophylactic blood product
transfusion prior to invasive procedures reduces bleeding risk.
• Independent bleeding risk factors: poor renal function or infections.
• Increase in central venous pressure (CVP) increases the bleeding, so
during procedures, a restrictive infusion policy should be applied.
• Clinicians should be alert to the possibility of thrombosis occurring in
these patients.
Transfus Med Rev. 2014; 283:107-113;
Expert Rev Gastroenterol Hepatol. 2014 ; 26:1-12
77. Working Recommendation
National Taiwan University Hospital Department of Internal Medicine
from UVA Liver Disease Coagulation Group
• Limit concern over an elevated INR in patients with cirrhosis
• Limit repletion with FFP because of its limited effect on INR and it
results in increased portal pressure
• Transfuse platelets to a target of ≧50Kdepending on the clinical
scenario
• Control any infection to reduce endogenous heparinoids
• Control uremia to prevent further platelet dysfunction
• Use conservative replacement to maintain low volumes and avoid
exacerbating portal hypertension
• Replete with cryoprecipitate if fibrinogen <120 mg/dL when patients
are actively bleeding or as a pre-procedural therapy
• Adjunctive therapy: DDAVP or Transamin, when patients are actively
bleeding or as a pre-procedural therapy
• In case of uncontrollable hemorrhage: consider PCC or rFVIIa
Nat Rev Gastroenterol Hepatol. 2014 Jul 15 [Epub ahead of print]
