Transcript TTW module 5

Module 5: Understanding
coagulation
Transfusion Training Workshop
KKM 2012
Components of Haemostasis

Vessel wall

Platelets

Coagulation Factors

Fibrinolytic factors

Inhibitors
Damage to the vessel wall
EC
TF
vWF
vWF - collagen and TF exposed
M. Laffan
Primary haemostasis
EC
platelets
TF
vWF
Platelets adhere to vWF-collagen
M. Laffan
Secondary haemostasis
X
Xa
EC
VIIa
TF
TF-VIIa triggers Xa production
Thrombin generation proceeds on PL (platelet) surface
M. Laffan
Stable clot formation
fibrin
platelets
Stable fibrin-platelet clot is formed
M. Laffan
After clot formation
T-AT
TAFI
Pgn
APC
P
tPA
TM
Thrombin
Thrombin binds to TM and activates PC and TAFI
Excess thrombin is neutralized by AT
Fibrinolysis is activated by plasmin (P)
M. Laffan
No good test for haemostasis
The “coagulation screen”
Clotting
PT
APTT
TT
Fibrinogen
FBC
platelet count
Coagulation screen

Practical but unphysiological

Has limited sensitivity & specificity

Tests a very limited portion of haemostasis
A good bleeding history is
the best screening test
A significant bleeding history

Epistaxis not stopped by 10 mins compression or
requiring medical attention

Cutaneous haemorrhage or bruising without
apparent trauma (esp. multiple/ large)

Prolonged (>15 mins) bleeding from trivial wounds,
or in oral cavity or recurring spontaneously within 7
days

Post-operative bleeding

Menorrhagia (esp. from menarche)
Bleeding in the hospitalised patient

Bleeding prolonged, delayed or recurrent; or
more rapid than normal?

Single site or several sites?

Appropriate to injury?

Past h/o bleeding?

Medications?

Diseases?

Family history?
Bleeding

Immediate bleeding
 Defects in primary haemostasis
 Vascular abnormality

Delayed bleeding
 Defects in secondary haemostasis
The “coagulation screen”
Clotting
PT
APTT
TT
Fibrinogen
FBC
platelet count
HMWK
CONTACT
PK XII
APTT
XI
PT
VIIa
TF
VIII IX
V X
TT
IIa
Fibrinogen
II
Fibrin
Prolonged PT
HMWK
CONTACT
PK XII
XI
VIIa
TF
VIII IX
V X
PT
II
Fibrinogen
Fibrin
17.3 (9.6-11.6)
APTT 28
(26-32)
TT
(15-19)
16
Prolonged PT

Factor VII deficiency
Prolonged APTT
HMWK
CONTACT
PK XII
XI
VIIa
TF
VIII IX
V X
PT
II
Fibrinogen
Fibrin
10.6 (9.6-11.6)
APTT 65
(26-32)
TT
(15-19)
16
Prolonged APTT

Deficiency factor VIII, IX, XI, XII and contact
factors

Inhibitor


Specific (FVIII)
Non-specific (LA)
Prolonged PT and APTT
HMWK
CONTACT
PK XII
XI
VIIa
TF
VIII IX
V X
PT
II
Fibrinogen
Fibrin
26
(9.6-11.6)
APTT 54
(26-32)
TT
(15-19)
16
Prolonged PT and APTT

Deficiency of X or V

Multiple deficiencies


Warfarin
Factor V and VIII deficiency
Prolonged TT
HMWK
CONTACT
PK XII
XI
VIIa
TF
VIII IX
V X
PT
II
Fibrinogen
Fibrin
10.6 (9.6-11.6)
APTT 29
(26-32)
TT
(15-19)
23
Prolonged TT

Thrombin inhibitor


Direct (hirudin)
Indirect (UFH, LMWH)

Low fibrinogen (<0.8g/L)

Dysfibrinogenemia


Congenital
Acquired

Hypoalbuminemia

Elevated FDPs
All prolonged
HMWK
CONTACT
PK XII
XI
VIIa
TF
VIII IX
V X
PT
II
Fibrinogen
Fibrin
25
(9.6-11.6)
APTT 38
(26-32)
TT
(15-19)
23
All tests prolonged

Inhibitor of thrombin- heparins

DIC

Synthetic failure - liver
Bleeding disorders not detected by
routine coagulation screen

Mild factor deficiencies

von Willebrand disease

Factor XIII deficiency

Platelet disorders

Excessive fibrinolysis

Vessel wall disorders

Metabolic disorders (e.g. uraemia)
Pre-operative coagulation screening
tests


BCSH guideline 2008

PPV of abnormal tests 0.03-0.23

No significant increase in bleeding associated
with abnormal tests
Routine pre-op screening is NOT
RECOMMENDED
Chee, BCSH guideline 2008
A good bleeding history is
still the best screening test
Case 1

En KZ, 45 year-old man

Admitted for ureteric colic

US: Large R ureteric stone with hydronephrosis

Planned for stenting

PT, APTT sent
Case 1 – cont’d

APTT 98 sec
PT 12s

Procedure cancelled

Referred to hematologist

APTT mix with normal plasma corrected

FXII assay: 15%
Case 1

FXII deficiency is not associated with bleeding
or clotting (no clinical significance)

Required for contact activation for in-vitro
laboratory testing

A laboratory nuisance

Waste of time and money investigating a
prolonged APTT
Routine pre-op PT, APTT screening
is not recommended
A good bleeding history is the best
screening test
Case 2

1o year old boy with chronic tonsillitis

Planned for tonsillectomy

FBC, PT, APTT sent

Mother c/o that son has easy bruising and
recurrent epistaxis and she herself has
menorrhagia

Hb 12 Plt 243

PT 12.5s (12- 16s) APTT 38s (30- 42s)
Case 2 – cont’d

Since platelet count and PT, APTT all normal

Mother reassured and proceeded with
tonsillectomy

During surgery, excessive bleeding noted but
controlled with local measures

2 hours post-op, further significant bleeding
Case 2 – cont’d

Returned to OT, cauterization done

2 Packed RBC and 2 FFP transfused; bleeding
controlled

Repeat PT, APTT the following day – normal

Refer hematologist
Case 2 – cont’d

Further bleeding history taken

Mother’s blood sample sent

FBC normal PT 13s (12-16) APTT 40s (30- 42)

FVIII 34% (40-150) vWF 30% (50-150)

Son’s results similar to mum’s (on f/u)

Diagnosis: von Willebrand disease type 1
Limited investigation of a patient
with a bleeding history
is as inappropriate as
Extensive investigation of a
patient with no bleeding history
This has led to unnecessary
transfusion of blood and blood
components
Just think if this was your own child
Normal screening tests results
in a false sense of security
Limitations of PT, APTT

Lack sensitivity and specificity

Tests a very limited portion of haemostasis

Can only detect factor levels below 30%
Bleeding disorders not detected by
routine coagulation screen

Mild factor deficiencies

von Willebrand disease

Factor XIII deficiency

Platelet disorders

Excessive fibrinolysis

Vessel wall disorders

Metabolic disorders (e.g. uraemia)
Case 3

En AP, 58 year-old man

Admitted for CCF

Noted LA thrombus on ECHO

PT 35s

PT repeated 5x still prolonged

Diagnosis: liver disease or patient on warfarin
INR 2.5
APTT 30s
Case 3 – cont’d

Anticoagulation not started in view of
prolonged PT hence ‘auto-anticoagulated’

Patient had a cardiac arrest and died

Sample sent over to haemostasis laboratory

FVII 5%

Diagnosis: mild FVII deficiency
Isolated prolonged PT

Can only be FVII deficiency
Case 4

En LK, 49 year-old man

Known alcoholic liver disease

Admitted for chronic cough

CXR: RUL cavities and R pleural effusion

Planned for pleural tap and biopsy

PT 19s (INR 1.5) APTT 45s

Request for 2 FFP
Liver disease

PT, APTT only measures the pro-coagulant
function

In liver disease, there is parallel reduction in
both pro-coagulant factors and anti-coagulant
proteins

PT, APTT is not a reliable test to assess bleeding
risk in patients with liver disease
Tripodi A, NEJM 2011
INR (International Normalised Ratio)

Was devised and validated to standardise
across laboratories the PTs in patients receiving
warfarin

Should only be used for monitoring warfarin
therapy

Cannot be used for patients with chronic liver
disease (unless a different calibration based on plasma
from patients with liver disease is developed)
Idem. The INR, J Thromb Haemost 2008
Case 4 – cont’d

Patient underwent pleural tap and biopsy
without FFP cover

Outcome: no bleeding complications
Case 5

PL, 35 year-old lady

Known case of APLS with h/o stroke and L DVT

Admitted for elective ovarian cyst removal

Warfarin stopped x 5 days

Switched to LMWH

APTT 79s PT 12.5s
(as requested by anaesthetist)
Case 5 – cont’d

Seen by haematologist

Explained that APTT prolongation is due to the
lupus anticoagulant (inhibitor)

Despite this, 2 units FFP was transfused

Patient developed urticaria

Repeat APTT 98s

Op cancelled
Isolated prolonged APTT

FVIII deficiency or severe vWD

FIX deficiency

FXI deficiency

FXII deficiency (nuisance)

Lupus anticoagulant

Inhibitors to FVIII
Inappropriate transfusion of
blood/ blood components
must be discouraged
The next time you decide
to transfuse
Stop, think and ask yourself …
Is it really necessary?
Be aware of the risks of transfusion and the
morbidity/ mortality associated with it!

Febrile/ non-febrile transfusion reactions

Wrong blood

Bacteremia

Transfusion-related acute lung injury (TRALI)

Transfusion-transmitted infections (TTI)
Almost the end
Thrombophilia testing

Tests the phenotype

Will not identify or exclude a thrombophilic
genetic defect completely

Finding a low level of the natural anticoagulant
is not diagnostic of a deficiency

A normal result does not exclude a deficiency
Thrombophilia testing

There may be many other genetic factors that
have not been identified

Negative tests cause a false sense of security

Positive tests cause unnecessary anxiety

Prolonging anticoagulation increases risk of
haemorrhage
So why do clinicians request for
thrombophilia testing?

To predict VTE recurrence

To determine duration of anticoagulation

To prevent/ reduce thrombosis

The ‘in-thing’ to do
Predicting recurrence

Long-term prospective cohort outcome studies
have shown that finding a heritable
thrombophilia does not typically predict
recurrence
Baglin et al, 2003; Christiansen et al, 2005
Risk of Recurrence

In patients with deficiency of a natural
anticoagulant (AT, PC, PS) the risk of recurrence
is uncertain

Relative risks of recurrence appear to be <2.0 in
patients who are not selected from thrombosisprone families
Baglin et al, 2003; Christiansen et al, 2005;
De Stefano et al, 2006
Case 6

28 year-old female nurse

No medical illness

Weight 110 kg

c/o Fever and RIF pain x 3 days
Case 6 – cont’d

Diagnosis: acute appendicitis

Appendicectomy performed

Findings: perforated appendix

Discharged POD6
Case 6 – cont’d

Returned evening of same day

Acute SOB with reduced O2 sat

Ventilated

CT pulmonary angiogram confirmed pulmonary
embolism
CTPA – Pulmonary embolism
Case 6 – cont’d

Initial LMWH, then warfarin x 6 months

Thrombophilia test sent


PS activity 30%
Referral: ? to continue long-term ac
Indications for thrombophilia
testing
1.
NICE guidelines 2012
Case 6 – Duration of AC

Provoked

Precipitating factor- major: surgery

Predisposing factor: obesity

No family history of VTE

Duration of AC: 3 months (9th ACCP 2012)

Repeat PS act 76% (as pt was anxious & a staff nurse)
Inaccuracy of thrombophilia testing
BJH guidelines 2010
Case 7

28 year old lady doctor

c/o recurrent hemoptysis x 1 month

Investigated for PTB and started empirically on
anti-TB Rx

Noted bilateral leg swelling
Case 7 – cont’d

Doppler US confirmed bilateral DVT

CT pulmonary angiogram confirmed pulmonary
embolism

Anti-TB Rx stopped
Case 7- cont’d

Unprovoked or idiopathic

Duration of AC: at least 3 months or long term
(9th ACCP 2012)
Case 7 – cont’d


After 6 months ac

PC 86%

PS 55%

AT 90%
Referred whether to continue AC
Extending anticoagulation
BJH Guidelines 2010
Case 7 – LA screen sent

LA normalised ratio: 3.1

ACL antibody: positive

Anti-β2 GP1: positive

Diagnosis: Primary APLS

Duration of AC: long-term
Indications for thrombophilia
testing
2.
3.
NICE guidelines 2012
Case 8

28 year-old man

Spontaneous R LL
swelling

Doppler US:
thrombosis R common
femoral vein

Father also had
unprovoked DVT on
long-term ac
Case 8 – family tree
PS 28%
Rec DVT
1994, 2002
PS 28%
No DVT
PS 25%
Rec DVT
2007, 2009
Indications for thrombophilia
testing
4.
5.
NICE guidelines 2012
Thrombosis is Multi-Causal Arising from Interacting
Genetic and Acquired Risk Factors
Risk
Acquired risk
Cumulative risk
Thrombotic
threshold
Risk from “ageing”
Genetic risk 2
Genetic risk 1
Age
Laffan M, 2007
Virchow’s triad
1.
Blood
2.
Vessel
3.
Flow
No evidence that thrombophilic trait is
associated with an increase risk for
arterial thrombosis or recurrent
miscarriages
Except for lupus anticoagulant (LA)
NICE guidelines 2011
Guidelines for thrombophilia
testing
BJH Guidelines 2010
Thrombophilia testing- has
little clinical utility
Except for Lupus Anticoagulant (LA)
VTE CPG 2013
Case 9

70 yrs old man; known DM/ HT

Skidded and fell from motorbike

Fell on L side

c/o pain L hip

Unable to walk

Admitted to ward
Case 9 – cont’d

In pain

Small haematoma L temple

GCS 15

Rxed with analgesics

Hb 13.0
BP 193/93
TW 8.5
PR 94 O2 sat 97%
Plt 235
Case 9 – Fracture L pubic rami
Case 9 – D5 post-MVA

c/o chest tightness & SOB

O2 sat 90%

ECG: sinus tachy

CXR: haziness both bases

? Pulmonary embolism

Referred to medical
Case 9 – D5 post-MVA

Seen by medical

D-Dimer sent

If D-Dimer high >> CTPA

D-Dimer 3.6 ug/mL (0 - 0.5)
Causes of a high D-Dimer

DVT

Cellulitis/ infection

Haematoma or
bleeding

DIC

Pregnancy

Inflammation/ Fracture
D-dimer & DVT in hospitalised
patients
Brotman DJ, Am J Med 2003
D-dimer assays lack standardisation
Legnani C, Hematologica 2008
D-dimer: cut-off values?

Outpatient vs. hospitalised patients

Pregnant vs. non-pregnant

Old vs. young

Cancer vs. non-cancer
Legnani C, Hematologica 2008
The end
Thank you