Diagnosis of the
bleeding patient
Diana Oelofse
• Descriptions of “bleeders” date back a few
centuries.
• The first modern description of haemophilia,
as an example of a bleeding disorder likely
came from the American physician John Otto
in 1803.
• This description is the first in which the
inheritance pattern is clearly stated.
• And the first instance of what we now know as
X-linked inheritance in any disorder.
• “Otto clearly recognized both that the
bleeding disorder was limited to males and
the possibility of its transmission by healthy
female relatives.”
• We know now however that bleeding
disorders can be hereditary or acquired.
• And that females can also be affected by
hereditary bleeding disorders, in some
instances as often as males for e.g. VWD.
• The evaluation of the patient with a suspected bleeding
diathesis has the potential to provoke much diagnostic
uncertainty.
• A severe bleeding disorder is generally a relatively
straightforward diagnostic process.
• But in contrast the work-up for minor bleeding disorders
can be complicated.
• There is currently no test available that serves as a reliable
screening test for global haemostasis.
• (that includes the bleeding time - which does not predict
bleeding)
• In addition some patients have multiple acquired
abnormalities in their haemostatic systems.
• This may also be the case in hereditary bleeding disorders –
where for e.g. VWD with Haemophilia A or B can co-occur, or
concurrent Factor V deficiency and Haemophilia A.
• Screening tests may point to the possible presence of
defects in primary haemostasis or a factor
deficiency.
• Specific diagnosis : requires more detailed testing.
• Laboratory studies have limitations including preanalytical errors, false negatives, long distances to
reference laboratories for tests that cannot be done
locally and costs involved.
• In Port Elizabeth we are able to do basic
screening tests and some of the more
specialized tests. (with Livingstone NHLS
being our regional reference laboratory for
urgent tests)
• Non-urgent specialized tests are often done in
larger centralized labs.
• Some specialized tests are however only
available on site at certain universities in
South Africa (for e.g. LPA)
Pre-analytic errors
• Problems with citrate
vacutainers
• Biological effects
– Partially filled tubes
– Vacuum leak and citrate
evaporation
– Hct ≥55 or ≤15
– Lipemia,
hyperbilirubinemia,
hemolysis
• Problems with phlebotomy
• Divers laboratory errors
–
–
–
–
–
Heparin contamination
Wrong label
Slow fill
Under-fill
Too vigorous shaking
– Delay in testing
– Prolonged incubation at
37°C
– Freeze/thaw deterioration
Aims when investigating a
patient/family with suspected
bleeding disorder / bleeding risk
Determine likelihood that patient (family) has a
haemorrhagic disorder, using the medical history and
then confirmed by laboratory investigations.
Is there implications for family members and
potential offspring?
• Attempt to estimate risk.
• Establish a management plan for future
problems and/or to at least reduce risk for
invasive procedures.
Stages in normal coagulation
• Initiation phase :
vasconstriction, platelet adhere to site
(VWF), exposed collagen interaction with platelets and interaction
between TF and FVII = TF/FVIIa
: activation X and IX.
• Amplification phase : thrombin activation of platelets and
activation of procoagulant cofactors Va and VIIIa. (on a primed
platelet surface)
• Propagation : Burst of thrombin generation on platelets
through the more stable platelet surface generated Xa
(via IXa ), + Va : Thrombin = leading to fibrin formation.
• Localization : TFPI, ATIII, Thrombomodulin, Prot C and C and
fibrinolysis.
Reproduced with permission from Sysmex
http://www.healthcare.siemens.com/hemos
tasis/hemostasis-onlinecampus/interactive-hemostasis-cascade
The extent of laboratory investigations for an
obvious, or possible bleeding diathesis is
strongly informed by the “bleeding history”
and also guided by clues from the physical
investigation and context of the presentation.
• Extensive work-up mandatory in major bleeds – these
patients are relatively few.
• (Possible) Minor bleeders problematic.
• They may be normal or have mild to moderate bleeding
disorders. (platelet secretion defects or mild VWD)
• Tosetto et al. defines a bleeder as a patient
with an increased bleeding rate. Number of
bleeding episodes occurs within a defined
time frame in the patients life.
• Bleeding rate = Number haemorrhages/time
Bleeding History
• Bleeding symptoms are often reported by otherwise healthy
subjects.
• Trivial (non-relevant) is considered part of the human
phenotype.
• Trivial bleeding never interferes with daily activities or
requires medical attention.
• Minor bleeding severe enough to interfere with daily activities
• Major bleeding may cause permanent damage or be life threatening.
• Various established scoring systems / Bleeding assessment
tools available.
https://bh.rockefeller.edu/ISTH-BATR
Other indicators that may be derived
from the history:
•
•
•
•
Bleeding localized / diffuse.
Spontaneous vs provoked.
Mucocutaneous vs. joint bleeds.
Delayed onset bleeding.
Factor XIII deficiency
A2 antiplasmin deficiency
Plasminogen activator inhibitor-1 deficiency
• Bleeding in male and female members of a family.
• Consanguinity.
Physical examination
• Skin : petechiae, ecchymoses, perifollicular haemorrhages,
telangiectasia around mounth (HTS),distribution,
oculocutaneous albinism, hepatosplenomegaly and
lymphadenopathy,stigmata of liver disease
• Joint hypermobility and skin hyper-elasticity in Ehlers-Danlos
Syndrome
• Aortic Stenosis in acquired VWD.
• Large tongue, carpal tunnel syndrome peri-orbital purpura in
amyloidosis – several acquired factor deficiencies.
Laboratory Investigations
• FBC, U/E and Creatinin, LFTs
• Clotting Screen
Prothrombin time : Extrinsic ( F 2 5 10 + 7 )
liver pathology, warfarin therapy
PTT Intrinsic ( F12 11 9 8 + 2 5 10)
Trombin Time and Fibrinogen (Common path)
DIC , Heparin therapy and dysfirbinogenaemia
Bleeding time : Result depends on integrity of blood vessels, platelet
function, VWD. Not standardised. Ivy template method 3 – 8min
PFA - 100
D-Dimers :DIC
• Corrections studies and Factor assays
• Von Willebrand Disease screen
(often needs to be repeat and can be complex)
• LTA (light transmission aggregometry)
• Electron microscopy platelets
• Evaluation of fibrinolysis
Two stage approach
First Stage
• FBC
• PT
• PTT
• Fibrinogen
• TT
• BT / PFA-100
• VWF assays
• FVIII
• ABO blood group
Second Stage
(Depending on results of first stage)
• Specific coagulation
factors
• Mixing tests
• VW:Collagen binding
assay
• VWFM
• LTA
• FXIII
• Antiplasmin
• Fibrinolysis exploration
Coagulation tests in context of
simplified clotting cascade
Intrinsic
Pathway
(F12,11,9,
Extrinsic
Pathway
F8
)
(TF and F7)
F10
PTT
PT/INR
F5
Correction studies
Correction studies
Common
Pathway
Thrombin
time
Thrombin (F 2)
F13
Clauss
Fibrinogen
Clot lysis time,
α2 antiplasmin
Fibrinogen → Fibrin
D-Dimers
FDPs
A quick and accurate
method for measuring
fibrinogen in plasma
J. Lab. Clin.
Med. 1961 Sep; 58; 477-88
Ellis BC, Stransky A.
Coagulation factor disorders
• Inherited bleeding
disorders
– Hemophilia A and B
– vonWillebrands disease
– Other factor
deficiencies
• Acquired bleeding
disorders
– Liver disease
– Vitamin K
deficiency/warfarin
overdose
– DIC
– Acquired inhibitors to
factors
Platelet problems can be
congenital or acquired platelet
abnormalities,
and quantitative and qualitative
Blood Vessels in Hemostasis:
•
•
•
•
•
Initial phase of hemostasis.
Simple easy bruising – women
Senile purpura – atrophy,
Scurvy – vit C deficiency, collagen def.
Steroid induced purpura
• Henoch-Schonlein purpura – children.
( *Acquired F 13 deficiency)
Patient - 1
Abnormal PT
Abnormal PTT
Repeat
with
50:50
mix
50:50 mix is
abnormal
Test for inhibitor activity:
Specific : Factors V, X, Prothrombin,
fibrinogen (rare)
Non-specific:
anti-phospholipid (common)
50:50 mix is
normal
Test for factor deficiency:
Isolated deficiency in common pathway: Factors V, X,
Prothrombin, Fibrinogen
Multiple factor deficiencies (common)
(Liver disease, vitamin K deficiency, warfarin, DIC)
Patient - 2
Normal PT
Abnormal PTT
Repeat
with
50:50
mix
50:50 mix is
abnormal
Test for inhibitor activity:
Specific factors: VIII,IX, XI
Non-specific
(anti-phospholipid Ab)
50:50 mix is
normal
Test for factor deficiency:
Isolated deficiency in intrinsic pathway
(factors VIII, IX, XI)
Multiple factor deficiencies (rare)
Patient - 3
Abnormal PT
Normal PTT
Repeat
with
50:50
mix
50:50 mix is
abnormal
Test for inhibitor activity:
Specific: Factor VII (rare)
Non-specific:
Anti-phospholipid (rare)
50:50 mix is
normal
Test for factor deficiency:
Isolated deficiency of factor VII (rare)
Multiple factor deficiencies (common)
(Liver disease, vitamin K deficiency, warfarin, DIC)
Evaluation of a Bleeding Patient 4
normal PT
normal PTT
Abnormal
Urea
solubility
Factor XIII
deficiency
Normal
Consider evaluating for:
Mild factor deficiency
Monoclonal gammopathy
Abnormal fibrinolysis
(a2 anti-plasmin def)
Elevated FDPs
Platelet disorder
Vascular disorder
To conclude with Dr Otto:
And now 210 years later…..
Thank you !
References
1.
Key,Makris et al. Practical Haemostasis and Thrombosis, Second
edition. Pg1
2. Hayward, Moffat 2013. Laboratory testing for bleeding disorders,
uses of high and low-yield tests IJLH
3. Tosetto, Castaman et al. 2013. Bleeders, bleeding rates and bleeding
score. JTH
4. Schulman, Angeras et al.2010.Definition of major bleeding in clinical
investigations of antihemostatic medicinal products in surgical
patients. JTH
5. Redeghiero, Michel et al. 2013. Standardization of bleeding
assessment in ITP from the IWG. Blood.
6. The Medical Research Council`s General Pratice Research
Framework. Thrombosis prevention trial. 1998 Lanset
7. Ridker,Cook et al . A Randomised trial of low dose aspirin in the
primary prevention of CVD in women. 2005. NEMJ
8. http://www.genmedhist.info/articles-and-papers/
9. https://bh.rockefeller.edu/ISTH-BATR
10. De Moerloose et al. Diagnosis of mild bleeding disorders.
11. Diagnosis and management of mild bleeding disorders.Hayward. ASH