Module 5: Understanding coagulation

Transfusion Training WorkshopKKM 2012

Components of Haemostasis

Vessel wall

Platelets

Coagulation Factors

Fibrinolytic factors

Inhibitors

EC TF vWF

Damage to the vessel wall

vWF - collagen and TF exposedM. Laffan

EC

Primary haemostasis

Platelets adhere to vWF-collagen

TF

platelets

vWF

M. Laffan

VIIaEC TF

PL

Xa

Secondary haemostasis

TF-VIIa triggers Xa productionThrombin generation proceeds on PL (platelet) surface

X

M. Laffan

Stable clot formation

fibrin platelets

Stable fibrin-platelet clot is formed

M. Laffan

After clot formation

Thrombin binds to TM and activates PC and TAFIExcess thrombin is neutralized by ATFibrinolysis is activated by plasmin (P)

tPA

Pgn

P Thrombin

APC

T-AT

TM-

TAFI

-

M. Laffan

No good test for haemostasis

The “coagulation screen”

Clotting

PT

APTT

TT

FibrinogenFBC

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

FibrinogenFBC

platelet count

IX

II

Fibrinogen Fibrin

PK

HMWK

XI

XII

VIIaTF VIII

XV

CONTACT

PT

APTT

TT IIa

IX

II

Fibrinogen Fibrin

PK

HMWK

XI

XII

VIIaTF VIII

XV

CONTACT

PT 17.3 (9.6-11.6)

APTT 28 (26-32)

TT 16 (15-19)

Prolonged PT

Prolonged PT

Factor VII deficiency

IX

II

Fibrinogen Fibrin

PK

HMWK

XI

XII

VIIaTF VIII

XV

CONTACT

PT 10.6 (9.6-11.6)

APTT 65 (26-32)

TT 16 (15-19)

Prolonged APTT

Prolonged APTT

Deficiency factor VIII, IX, XI, XII and contact factors

Inhibitor Specific (FVIII) Non-specific (LA)

IX

II

Fibrinogen Fibrin

PK

HMWK

XI

XII

VIIaTF VIII

XV

CONTACT

PT 26 (9.6-11.6)

APTT 54 (26-32)

TT 16 (15-19)

Prolonged PT and APTT

Prolonged PT and APTT

Deficiency of X or V

Multiple deficiencies Warfarin Factor V and VIII deficiency

IX

II

Fibrinogen Fibrin

PK

HMWK

XI

XII

VIIaTF VIII

XV

CONTACT

PT 10.6 (9.6-11.6)

APTT 29 (26-32)

TT 23 (15-19)

Prolonged TT

Prolonged TT

Thrombin inhibitor Direct (hirudin) Indirect (UFH, LMWH)

Low fibrinogen (<0.8g/L)

Dysfibrinogenemia Congenital Acquired

Hypoalbuminemia

Elevated FDPs

IX

II

Fibrinogen Fibrin

PK

HMWK

XI

XII

VIIaTF VIII

XV

CONTACT

PT 25 (9.6-11.6)

APTT 38 (26-32)

TT 23 (15-19)

All prolonged

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 INR 2.5 APTT 30s

PT repeated 5x still prolonged

Diagnosis: liver disease or patient on warfarin

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 thrombosis-prone 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

NICE guidelines 2012

1.

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

NICE guidelines 2012

2.

3.

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

Rec DVT2007, 2009

No DVT

PS 25%PS 28%

PS 28%

Rec DVT1994, 2002

Case 8 – family tree

Indications for thrombophilia testing

NICE guidelines 2012

4.

5.

Risk

Age

Thrombotic threshold

Risk from “ageing”

Genetic risk 2

Genetic risk 1

Thrombosis is Multi-Causal Arising from Interacting Genetic and Acquired Risk Factors

Cumulative riskAcquired risk

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 miscarriagesExcept 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 BP 193/93 PR 94 O2 sat 97%

Rxed with analgesics

Hb 13.0 TW 8.5 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