Bleeding Disorders

HOPE

Maram Al-anbar

9 - 9 - 2014
Maram Alanbar Bleeding Disorders Hope / 2010

^^ Attention Please ^^
We ( correction team of pediatric package^HOPE/2010^ ) had decided
to make one lecture of bleeding disorders in place of the two lectures
we had in our package Including the content of the previous lectures
Plus other sources to make it one organized lec. Hoping for you to get
the most benefit ,, study easily ,, and not getting distracted or
bothering yourself looking at other sources
the sources of this lecture are : “ Previous 2 lectures + Nelson +
Pediatric in Page + some youtube videos “ ...

Soo.. Let’s begin our lecture ,, Shall We ^^

** NORMAL HOMEOSTASIS **
it’s a dynamic process that occur in area of VASCULAR INJURY
composed of ::
*platelets *vascular wall *procoagulant proteins * anticoagulant
proteins

Now .. What is the sequence of events that occur in this process ?!!
Once there is injury to the vascular endothelium what happens ?? ::
1* Vasoconstriction ..
2* Primary Homeostatic mechanism (platelet plug formation) ..
3* Secondary Homeostatic mechanism (fibrin clot ,, thrombus) ..
4* Anti thrombotic and Fibrinolytic events ..

It starts with injury to vascular endothelium exposure of

subendothelial collagen confrontational changes in vWF
(von-willebrand factor) platelets bind to vWF via their receptor
GPIb in a process called ADHESION then these platelets get
activated and produce substances ex. ADP that recruit other platelets
from circulation to come then platelets bind with each other in
layers using their receptors GPIIb-IIIa using fibrinogen as a ligand
between the receptors in a process called AGGREGATION

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Maram Alanbar Bleeding Disorders Hope / 2010

forming in the end Primary Homeostatic Plug ( Platelet Plug ) that will
temporally stop the bleeding ,,

Soo ...
**Adhesion is : Platelet - Subendothelial Interaction (GP-Ib _vWF)
**Aggregation is : Platelet - Platelet Interaction ( GPIIb/IIIa _
fibrinogen_GPIIb/IIIa )

** Then comes the Secondary Homeostatic mechanism that totally aims

at the process of conversion of FIBRINOGEN into FIBRIN ( remember
the fibrinogen that served as a ligand between platelets in the plug now
we want to convert it into fibrin and organize it in a strong & stable
network (clot) that permanently stop the bleeding ) ,, and this is done by
what’s called” COAGULATION CASCADE “ and this cascade has two
pathways ::

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Maram Alanbar Bleeding Disorders Hope / 2010

** EXTRINSIC **
Shorter pathway ..
Starts with factor 7 ..
Stimulated with tissue
factor as a result of
trauma to the vessel ..
The pathway is 7 10*
*At F10 starts the common
pathway 10(in presence of
activated F5 + Ca + PF)
WARFARIN can block this
pathway (inhibiting the
production of vit.k
dependent factors
-10,9,7,2- by inhibiting the
activation of vit.k ..
Measured by PT/ INR
tests ..
** INTRINSIC **
Longer pathway ..
Starts with factor 12 ..
Stimulated with inflammatory
mediator as a result of
inflammation ..
12 11 9(in presence of
activated F8 + Ca + PF) 10*
2 1 details below
HEPARIN can block this
pathway (stimulating
antithrombine III that inhibits
thrombin(F2) & factors
-11,10,9- ..
Measured by aPTT test ..

Cascade means in a step wise manner where the active form of the
factor acts as an Enzyme ,, where as the inactive form acts as a
Substrate Ex. FXIIa act as an enzyme ,, FXI act as a substrate ...

‫أفضل تعريف لذاتك أنك لست أفضل من أحد ولست كأي أحد ولست أق ل‬
... ‫من أحد‬

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Maram Alanbar Bleeding Disorders Hope / 2010

Now how this cascade occur ?!!

Let’s take the Intrinsic pathway :: 1st we have inflammatory mediator
that activates FXII from inactive into active form FXIIa
XII XIIa (then this will activates XI)

XI XIa(then this activates IX)

IX IXa (then this with VIIIa +Ca +PF

activates X )
X Xa (then this with Va +Ca +PF
activates prothrimbin II into thrombin IIa )

II IIa(here thombin convert

fibrinogen I into FIBRIN I * the final product that we need )

I Ia

NOW fibrin Ia is stabilized with FXIII for clot formation ^^

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Maram Alanbar Bleeding Disorders Hope / 2010

Now let’s talk about thrombin and the imp. Functions that performs ::
1* conversion of fibrinogen into FIBRIN ..
2* activation of FXIII( fibrin stabilizing factor ) that will bind fibrin
and stabilize it into a CLOT ..
3* act as platelet AGONIST ( attracts more and more platelets ) ..
4* activates plasminogen into PLASMIN ( which is fibrinolytic
enzyme )
5* activates factors V , VIII , XI ..

** Imp Note “” all coagulation factors are made in the liver except
FVIII made in vascular endothelium and bound with vWF “”

** another Note :
“” Deficiency of FVIII , FIX lead to sever bleeding disorder “”
“” Deficiency of FXI lead to mild bleeding disorder “”
“” Deficiency of FXII is asymptomatic “”

AND the last stage after the thrombus(clot) has been formed and the
bleeding has been stopped now we want to :
** prevent further thrombotic events by anti thrombotic enzymes ex.
Anti-thrombin III ,, protein C ,, protein S ...
** Dissolve the thrombus and resume the blood flow by fibrinolytic
enzymes ex. Plasmin ..

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Maram Alanbar Bleeding Disorders Hope / 2010

Soo we’ve just finished the normal process of homeostasis ^^hoping

that it was clear enough so that we start with the imp. part of the lec.

:: BLEEDING DISORDERS ::

They can be classified into :

1- Platelet disorders ..
2- Coagulation disorders ..
3- Blood vessel disorders :
** Congenital ex. Ehler-danlos Syndrome ,,
Osler-Weber-Rendu Syndrome ..
**Acquired ex. Senile Purpura ,,
HSP (henoch schoenlein purpura ) ..

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Maram Alanbar Bleeding Disorders Hope / 2010

Clinical presentation :: Lab tests we order ::

** superficial bleeding ** in
1-skin in form of *petechia(pinpoint 1- Platelet count (CBC) :
rash <3mm) ,, NL (150-400)x1000/microL” ..
*purpura(adjoining petechia
3-10mm) ,, 2- Bleeding time (time needed for
bleeding to stop)
*ecchymosis( >1cm)..
NL “3-10 minutes”..
2-mucous membranes as in
epistaxis ,, menorrhagia ..
** Immediate bleeding **
immediately after injury ..

Platelets disorders

Can be classified into ::

Qualitative disorders Quantitative disorders

” where the platelet count is ” where the platelet count is low
normal but abnormal ( thrombocytopenia ) “ ::
function”:: ** Decreased marrow production :
1- Aplastic Anemia ..
** Inherited : 2- BM infiltration ex. Leukemia ..
1- Bernard soulier syndrome
(BS) .. ** Excess Destruction :
2- Glanzmann thrombasthenia 1- ITP ( idiopathic thrombocytopenic
(GT) .. purpura )
3- von-Willebrand disease 2- TTP ( thrombotic thrombocytopenic
(vWD) .. purpura )
3- HUS ( hemolytic uremic syndrome )
** acquired : 4- DIC ( disseminated Intravascular
1- Uremia (renal failure ).. Coagulopathy )
2- Aspirin .. 5- HIT ( heparin induced
3- Alcohol .. thrombocytopenia )

** Sequestration :Hypersplenism ..

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Maram Alanbar Bleeding Disorders Hope / 2010

Now let’s talk about some of the Quantitative disorders ::

ITP
>> I stands for :
**Idiopathic ( unknown reason )
**Immune ( involvement of auto antibodies)
**Isolated ( cuz only Thrombocytopenia is present No Anemia ,, No
Leukopenia )
>> T stands for Thrombocytopenic ( cuz it’s quantitative disorder with
low platelet count )
>> P stands for Purpura ( cuz the usual presentation is purpuric rash )

Etiology
>> it’s thought to be auto immune with auto antibodies ( IgG , IgM )
that bind with platelet membrane ,, signaling them for destruction by
macrophages in Spleen ..
>> it affects young children more likely ..
>> can be divided into *Acute ( last < 6 months ,, affect young children )
and *Chronic (last > 6 months,, affect young adults mainly females )..
Clinical
presentation

>> superficial bleeding ex. Petechia ,, epistaxis ,, easy bruising ..

>> these symptoms usually follow acute viral illness (1-4 weeks after)..
>> imp << it’s unusual to have splenomegaly
Diagnosis

>> Diagnosis of exclusion ..

>> 1* clinical presentation
2* CBC ( plt count is low ,, NL RBC ,, NL WBC ) ,, Bleeding time high
3* Bone Marrow biopsy (we’ll notice Increases in Megakaryocyte) it’s
actually not necessary but can be used to rule out Other Dx ex.
Leukemia ,, aplastic anemia

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Maram Alanbar Bleeding Disorders Hope / 2010

Therapy

>> therapy doesn’t affect long term outcome of ITP but rather
increase plt count in acute conditions ..
>> not necessary if plt count >30,000
>> if <30,000 it depends on severity of symptoms ::
1* IVIG ( it has the same effect of steroids but with rapid action >> WE
start with it , if it doesn’t work start steroids )
2* Corticosteroids ( before using it U should do BM biopsy to exclude
malignancy ex. Leukemia cuz steroids are contraindicated in leukemic
patients )
3* anti-RhD Ig ( for Rh +ve )
these 3 ways can decrease rate of clearance of sensitized platelets
rather than decreases antibodies production ...
4* Platelets transfusion ( not preferred cuz ITP is autoimmune so Abs
can attack the transfused platelets ) used only in sever plt reduction ...
5* Splenectomy used in *chronic type ,, and *acute type only with life
threatening bleeding ( it should be the last modality if previous ways
didn’t work )
>> 80% resolve in 6 months ..
>> 1% can develop Intra Cranial Hemorrhage ICH ..

>> Now moving into other Disorders <<

** But before that you need to know about what’s called MAHA
( Micro Angiopathic Hemolytic Anemia ) and How it Occurs ::

It starts with vascular endothelial damage this will trigger

Thrombus formation In this thrombus

Platelets are consumed Fibrin strands cause mechanical

destruction of RBCs passing in that vessel
Thrombocytopenia
Hemolytic Anemia

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Maram Alanbar Bleeding Disorders Hope / 2010

Now this MAHA happens in many conditions like what we’re concerned
with now >> HUS ,, TTP ,, DIC << ..

HUS
** H stands for Hemolytic ( hemolytic anemia which is characterized
by schistocytes <fragmented RBCs> in Blood film ) ..
** U stands for Uremic ( uremia due to acute renal failure that occurs
bcz of renal vessels being affected ) ..
** S stands for Syndrome ..

Etiology

>> 90% are caused by E.coli O157:H7 that produces verotoxin which
attacks the endothelial lining of renal vessel leading to MAHA ..
>> Childhood disease ..

Clinical
presentation

>> Kidney is the main organ involved <<

>> Bloody Diarrhea ..
>> Blood in Urine ( Hematuria ) ..
>> Signs of ARF ( Acute Renal Failure ) ..

Tests
>> CBC :: platelets ,, Hb ..
>> Blood film :: schistocytes ..
>> their may be Hematuria ,, Proteinuria ..

Therapy
>> often resolves spontaneously ..
>> Dialysis might be needed for ARF ..
>> Plasma exchange in sever persistent disease ..

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Maram Alanbar Bleeding Disorders Hope / 2010

TTP
** Thrombotic Thrombocytopenic Purpura **

Etiology

>> Genetic or Acquired deficiency of ADAMTS13 which is protease

that normally cleaves multimers of vWF soo.. These multimers causing
platelet aggregation , with fibrin strands they cause MAHA ..
>> adulthood disease

Clinical
Presentation
>> multiple organs are involved <<
>> Fever ..
>> CNS signs ( seizure ,, altered level of consciousness , ..)
>> signs of renal failure ..
>> superficial bleeding ..

Tests

>> same as HUS

Therapy

>> TTP is more severe than HUS with higher mortality ..

>> it’s Hematological Emergency <<
>> urgent Plasma Exchange may be life saving ..
>> steroids ,, IVIG ,, Splenectomy in non-responders ..

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Maram Alanbar Bleeding Disorders Hope / 2010

DIC
>> this disease is actually both Platelet & Coagulation disorder <<
>> it’s mostly seen in ICU patients ,, usually with shock <<

Etiology

>> their are different causes ::

* malignancy ..
* sepsis ex. Meningococcemia ..
* trauma ..
* obstetric events ..

**These causes lead to widespread activation of coagulation from the

release of procoagulants into circulation leading to ::
** clotting factors consumption & platelets consumption
Bleeding anywhere ..
** Fibrin strands in vessels destruct passing RBCs Hemolysis ..
** Fibrinolysis is also activated ..

Clinical
Presentation

>> bleeding and clotting manifestations ..

Tests
>> platelets >> bleeding time >> PT , PTT
>> fibrin degradation products(D-Dimer) ,,>> fibrinogen

Therapy
**Treatment of DIC is challenging ,, what we do is :
1- Treat the underlying cause
2- Replace *Platelets by transfusion
*clotting factors by FFP(fresh frozen plasma )
*Fibrinogen by cryoprecipitate
3- using Heparin for thrombosis is controversial

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Maram Alanbar Bleeding Disorders Hope / 2010

Now moving into Inherited Qualitative Disorders ::

Bernard-soulier (BS)

>> autosomal recessive AR

>> NL platelet count ,, AbNL ADHESION
**adhesion occur when platelet bind via it’s receptor GP-Ib with vWF **
>> here we have deficiency of GP-Ib ....

Glanzmann
Thrombasthenia (GT)
>> NL Platelet count ,, NL Adhesion ,, AbNL AGGREGATION
** aggregation occur when platelets bind with each other via their
receptor GPIIb-IIIa having fibrinogen in between as ligand **
>> here we have deficiency of GPIIb-IIIa ....

von-Willebrand Disease
(vWD)

>> Deficiency of vWF

>> this disease is both Platelet & Coagulation disorder <<
** Platelet disorder cuz vWF is part of platelet adhesion process ..
** Coagulation Disorder cuz FVIII is bound with vWF in circulation ..
>> it has 3 types ::
<> Type 1 <> - Quantitative ( partial reduction ) of vWF
- the most common one affecting around 80%
- Autosomal Dominant AD
- usually asymptomatic
<> Type 2 <>
- Qualitative defect in vWF ( can’t bind FVIII )
- “Hemophilia equivalent” cuz their will be FVIII deficiency
<> Type 3 <>
- Quantitative ( absolute reduction ) of vWF
- Autosomal Recessive AR
- v.low FVIII

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Maram Alanbar Bleeding Disorders Hope / 2010

And NOW moving into the LAST PART of the lecture

Clinical Presentation
** Deep Bleeding **
>> Hematoma ( bleeding in
tissue outside BV )
>> Hemarthrosis ( bleeding
in joints )
** Delayed Bleeding **
due to the compensatory role
of Platelets ( primary
Homeostasis )
Lab tests we order ::
** PT ( prothrombine time ) :
indicates problem in Extrinsic
pathway when prolonged ( NL value
“10-12 sec” )..
** aPTT ( activated partial
thromboplastin time ) :
indicates problem in Intrinsic
pathway when prolonged ( NL value
“25-40” ) ..
** Thrombin time : for the common
pathway ,, it tests conversion of
fibrinogen into fibrin ..

COAGULATION DISORDERS

1- Hemophilia A ,, B

2- DIC

3- vWD

4- Liver Disease

5- Vitamin K Deficiency

6- Drugs ex. Heparin ,,

warfarin

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Maram Alanbar Bleeding Disorders Hope / 2010

Hemophilia

>> vWD is the MOST common inherited bleeding disorder <<

Where as
>> Hemophilia (A+B) is the most common SEVER inherited disorder <<

Etiology
>> Hereditary Deficiency of pro-coagulant proteins ::
* F VIII in Hemophilia A
* F IX in Hemophilia B
>> both are X-Linked disorders
>> Males are mainly affected 1 : 5000 in A ,, 1 : 25,000 in B
>> Female is usually asymptomatic carrier , unless , her father is
affected and mother is carrier, turner syndrome (XO), or lionization of
chromosome X ..
>> Hemophilia A accounts for 80-85 % of cases

>>Severity of disease correlates with Degree of Deficiency ::

1* SEVER ::
* <1% of normal factor level
* spontaneous bleeding
* bleeding with minor trauma
* manifest in Infancy
2* MODERATE ::
* 1-5 % of normal factor level
* bleeding requires moderate trauma
3* MILD ::
* 6-40 % of normal factor level
* bleeding requires significant trauma
* might go unDiagnosed many years

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Maram Alanbar Bleeding Disorders Hope / 2010

Clinical
Presentation

>> Deep bleeding :: Hematoma ,, Hemarthrosis ..

>> Delayed bleeding
>> CNS bleeding may occur so should do CT scan ..
>> Intra-abdominal bleeding can occur and suspected when patient
complains of abdominal pain after minor trauma ..

Tests
>> aPTT will be High
>> specific factor assay ( to determine whether F VIII or F IX )

Therapy

>> Replacement Therapy <<

** in life threatening bleeding ::
- level of 80-100 % of factor is needed
** in mild to moderate bleeding ::
- level of 40% of factor VIII is needed
- level of 30-40 % of factor IX is needed

*** for << F VIII >> we need 0.5U/Kg to increase the level by 1%
Soo... Dose of F VIII = ( Desired level (%) * weight (kg) * 0.5 )
*** for << F IX >> we need 1.5U/Kg to increase the level by 1%
Soo... Dose of F IX = ( Desired level (%) * weight (kg) * 1.5 )

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Maram Alanbar Bleeding Disorders
Vitamin K deficiency ::
** Vit.K is synthesized by
Intestinal bacteria ..
** it’s imp for clotting factors
(10,9,7,2) ..
** deficiency due to ::
1- newborn not receiving
vit.K
2- malabsorption as in cystic
fibrosis
3- medications antagonize
vit.k like warfarin
** intrinsic pathway will be
mostly affected so
PT will be High & INR (PT
measured / PT standard ) will
be High as well ..
**aPTT can be slightly high
due to F 9 being affected ..
Hope / 2010
Liver Disease ::
** we said earlier that all
clotting factors except 8
are synthesized in the
liver so both Intrinsic &
Extrinsic pathway are
affected ..
** PT / INR ,, aPTT will
be high ..
FXIII deficiency ::
** bleeding ,, but ,,
** NL PT ,, aPTT
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Maram Alanbar Bleeding Disorders Hope / 2010

Bleeding after Umbilical bleeding Bleeding during

circumcision .. after being delivery ,, CNS bleeding
detached ,, ( cephalhematoma ) ..
or delayed
separation ..

Family Imp points in Hematoma after

history ex. IM injection like
Hemophilia .. HISTORY TAKING when vaccinated ..
when patient comes with
bleeding

onset of Site of bleeding : Drug history

bleeding : *superficial :: ex. Aspirin ,,
Immediate vs Epistaxis ,, gum warfarin ,,
delayed .. bleeding ,, bleeding after heparin ..
tooth extraction ,,
petechia ,, purpura ..
*deep ::
hematoma ,,
hemarthrosis ..

what about OSCE ??!

Example :: case of ITP :: U should be able to answer them ^^
>>> 4 YO boy presented by his mother with multiple bruises on lower
limbs and elbow >>>

Q1 what are the questions you would like to ask ??

As in the previous page + ( imp Q ) any recent viral infection ??

Q2 what are the signs you would like to examine ??

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Maram Alanbar Bleeding Disorders Hope / 2010

Q3 what are your DDx ?? And most likely Dx ??

Q4 what tests you would like to order ??

Q5 if platelets count was 5000 ,, what’s your next step ??

Q6 how does IVIG work ??

Q7 if IVIG didn’t work ,, what should you do ??

Q8 what test should be done before using steroid ?? Why ??

Q9 if all didn’t work ,, what is your final way ??

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