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Coagulation Disorders and Anti-Coagulant Therapy

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Michael Henry

on 20 July 2017

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Transcript of Coagulation Disorders and Anti-Coagulant Therapy

Coagulation Disorders and
Anticoagulant Therapy

Michael Henry, MD
Center for Cancer and Blood Disorders
Phoenix Children's Hospital

This is what a clot looks like...
Let's explore this process together.
By the end of this ILM, you will be able to:

Provide an overview of the coagulation cascade
Understand platelet endothelial interactions
Discuss the genetics of hemophilia
Describe testing used to diagnose bleeding and clotting disorders
Describe treatments for bleeding disorders
Understand the basis for current anticoagulant therapy
Understand the basic mechanism of clot lysis
Let's do it!
Simplified View of Hemostasis:
But how does this happen?
First, the
Primary Phase


It occurs in three parts:
1. Adhesion:
platelet binding to the subendothelium
2. Activation:
release of platelet contents and exposure of platelet surface glycoprotein IIb/IIIa
3. Aggregation:
enlargement of the platelet plug
Next is the
Secondary Phase:
Formation of cross-linked fibrin
And here is how it all looks
It is important to remember...
The these processes do NOT occur in linear fashion!
In reality...all processes are occurring at once, like this:
CONFUSED?
Just wait...it gets
more
confusing!
Why do some patients who are deficient in factor XII, HMWK, or PK have a long PTT but no bleeding?
And why do patients who are deficient in factor VIII or IX have an equally long PTT and exhibit serious bleeding?
The truth is that no one is really sure!
Let's get some definitions out of the way...
Here's a memory aid for you:
PTT
measures the
intrinsic
system
: PITT
PT
measures the
extrinsic
system
: PET
Now that we have that out of the way, let's start talking about bleeding and bruising!
What causes purpura?
Lots of things!!!
Bleeding history: features of abnormal bleeding include…


Epistaxis unrelieved by 15 minutes of pressure
Menstrual bleeding lasting longer than 7 days
Bleeding from dental procedures lasting beyond the day of the procedure or requiring a blood transfusion
Ecchymoses inconsistent with the degree of reported trauma
Medical history is the key!
Time of onset of symptoms

Acute onset is suggestive of acquired disorder
Longer duration (i.e., since birth) = congenital disorder
Mild bleeding disorders may not become apparent until a patient experiences a challenge to their hemostatic system
Medical history
Type of bleeding

Mucosal/petechiae: think platelet disorder or von Willebrand disease

Muscle/joint: factor deficiency
Medical history is the key!
When a child has had previous surgery or dental extractions without bleeding complications, it is unlikely there is an underlying congenital hemorrhagic disorder
Rule of thumb
especially
Tonsillectomies,
Circumcisions,
&
Dental extractions
The physical examination is just as important!
http://www.baby-medical-questions-and-answers.com/images/Petechiae.jpg
Petechiae and involvement of mucosal membranes are suggestive of platelet-related bleeding
http://www.thetwistedgypsy.com/images/bruise.jpg
Bruising in places other than the anterior shins and elbows may be indicative of a bleeding tendency
http://content.answers.com/main/content/wp/en/thumb/3/36/180px-Bruises.jpg
Bruising that appears excessively large for degree of reported trauma may be indicative of a bleeding tendency
http://www.danphillips.com/personal/korg_meetings_5_03/display/Jon_picking_his_nose.jpg
Nasal excoriations and damaged vessels may be indicative of trauma (digital or otherwise)
http://www.accessmedicine.com/loadBinary.aspx?name=licha&filename=licha_XI.050t.jpg
Swelling or limited range of motion of any joint without a history of significant trauma is definitely abnormal
The possibility of physical abuse must be considered in the evaluation of any child with unusual patterns of bruising or bleeding
http://img3.buzznet.com/assets/users9/gojackarmy12/default/gallery-msg-1129302694-2.jpg?91888173
Is this abuse or a bleeding disorder?
Hemophilia A (factor VIII deficiency)
Hemophilia B (factor IX deficiency)
Von Willebrand disease
Now let's talk about
common bleeding disorders:
X-linked inheritance
New mutations occur approximately 30% of time
Life-long bleeding disorder
Hemophilia genetics
Pain
Stiffness
Swelling
Redness
Warmth
Signs and symptoms of bleeding
What can we
do
for a patient with these symptoms?
One unit FVIII/kg raises plasma FVIII activity by 2%
Half-life of FVIII is 8-12 hours
25 units/kg for minor bleeding episodes
50 units/kg for life or limb-threatening bleeding episodes
FVIII replacement
Intracranial
So, what is a
life-threatening bleed?
Retroperitoneal
Pharyngeal
One unit FIX/kg raises plasma FIX activity by 1%
Half-life of FIX is 18-24 hours
30-40 units/kg for minor bleeding episodes
100-120 units/kg for life or limb-threatening bleeding episodes
Now let's discuss
factor IX
replacement:
Never
waste any factor!
Always
give whole vial!
Factor concentrates!
How do we give
factor
to a patient?
This is all well and good, but it sounds too easy...
We are injecting
recombinant foreign proteins
into our patients! This leads to an immune response to the factor products, which in turn, leads to the development of...
FACTOR INHIBITORS
Inhibitors are
antibodies
with specificity against either factor VIII or factor IX
Approximately 15% of people with severe hemophilia A
Rarely in hemophilia B
Onset usually before age 5 years
Tend to be
familial
http://www.koate-dvi.com/images/inhibitors_r1.jpg
http://www.koate-dvi.com/images/iti_r1.jpg
An
inadequate
response to treatment (little or no change in the PTT after administration of factor concentrate) suggests the presence of an inhibitor
How we do know when inhibitors are present?
One method of dealing with inhibitors is
immune tolerance therapy (ITI)
There are
other treatments
as well
http://www.feiba.com/us/HCP/images/abt_img2.jpg
FEIBA
http://www.feiba.com/us/HCP/images/abt_img3.jpg
FEIBA
NovoSeven
OK, now let's discuss von Willebrand disease!
The most common congenital bleeding disorder, affecting 1-3% of the population

Inherited in autosomimal dominant manner, affecting both sexes and all ethnicities
von Willebrand disease
Due to a
quantitative
or
qualitative
defect in vWF, resulting in:
decreased ability to form initial platelet plug
decrease half-life of circulating factor VIII
http://www.vtheart.org/imagelibrary/platelet.jpg
Laboratory evaluation
CBC usually
normal
PTT may be prolonged, but not necessarily
Von Willebrand panel
von Willebrand factor (vWF) antigen
Ristocetin cofactor
Factor VIII activity
vWF multimers
Blood type (vWF levels are lower in blood type O patients)
von Willebrand disease
Pruthi, R. A Practical Approach to Genetic Testing for von Willebrand Disease. Mayo Clin Proc. 2006;81(5):679-691.
Von Willebrand Multimers
Laboratory evaluation

Not very reliable if:

Patient is taking OCPs (false positives with estrogen)
Patient is less than 6 months of age (maternal estrogens)

Both of these conditions cause elevation of endogenous VWF levels – unless patient has
type 3 vWD
http://www.invasivecardiology.com/files/imagecache/normal/photos/kytab1.jpg
http://www.werlhof-institut.de/kennenlernen/Leistungen/Labor-Dateien/conten8.jpg
http://www.mclno.org/webresources/pathman/BT_web/bt_paper.jpg
New way: platelet function analysis
Old way: bleeding time
Von Willebrand Disease Testing
How do we
treat
vWD?
DDAVP
(oral, IV, or intranasal)
Causes
release of vWF
stored in endothelial cells and platelets
Half-life of released vWF approximately
12 hours
Tachyphylaxis
after 2-3 doses because no further stored vWF available
Von Willebrand factor concentrate
Humate-P
80 units of RCoF activity/kg will increase vWF activity by 100%
Antifibrinolytics: aminocaproic acid
AKA: Amicar
Plasminogen activator inhibitor: Inihibits breakdown of previously formed clots
Useful in mucosal membrane bleeding only  epistaxis, dental procedures, menorrhagia
Oral birth control pill
Estrogen increases circulating levels of vWF
Useful for menorrhagia
Not to be used in conjunction with Amicar  increased risk of thrombosis
Causes
hemorrhagic disease of the newborn
Early
(0-24 hours): caused by maternal drugs
Classic
(1-7 days): caused by lack of Vit K at birth or maternal drugs
Late
(2 weeks – 6 months): dietary, diarrhea, liver disease
Major cause of
coagulopathy in patients with liver disease
later in life
Decreased synthesis of vitamin K dependent factors (II, VII, IX, X)
Resultant
portal hypertension and splenomegaly traps coagulation factors
and platelets
Let’s not forget about Vitamin K deficiency!
http://www.nature.com/tpj/journal/v5/n4/images/6500313f1.jpg
Platelet glycoprotein IIb-IIIa
Platelet glycoprotein Ib-IX (collagen receptor)
Coagulation testing is abnormal
Caveat #1
: a 2-3 second prolongation of the PT or PTT does not cause a bleeding disorder
Caveat #2
: von Willebrand labs are acute phase reactants (can give false negatives)
May have to repeat these labs
Caveat #3
:
developmental hemostasis
must be taken into account
When to refer to a hematologist
What is
developmental hemostasis
?
Andrew M, Monagle PT, Brooker, L (2000). Thromboembolic Complications During Infancy and Childhood. BC Decker: Hamilton.
Developmental Hemostasis
Note that the PTT decreases over time due to slow increase in liver's production of clotting factors
Journeycake JM, Buchanan GR: Coagulation disorders. Pediatr Rev 24:83-91, 2003
Putting it all together...
Let’s switch gears…
...and talk about
thrombotic
disorders
http://images.healthcentersonline.com/heart/images/article/Heart_attack.jpg
Thrombotic disorders
Symptoms
Pain
Paresthesias
Color change (darker)
Swelling

Easy to monitor extremity diameter in clinical setting
Just remember to measure from the same spot each time
Deep venous thrombosis
http://www.dme-direct.com/skin/frontend/dmedirect/dmedirect/images/aircast-thigh-cryo-cuff.png
http://www.vascularweb.org/graphics/evs_graphics/EVS2006%20Aortic%20thrombosi%20fig%201.jpg
Often in patients with
indwelling
arterial catheters – especially in the NICU
Medical emergency!
Treat with
fibrinolytics
– must be
within 4 hours
of diagnosis
Tissue plasminogen activator, urokinase, streptokinase
Arterial thrombosis
http://server.activeweb.pl/images/tabelka82.jpg
Antiphospholipid antibody syndrome
http://www.pharmacytimes.com/_media/_upload_image/_inDoc/apstable%20copy(1).png
History
Trauma
Indwelling catheter
Long periods of stasis
Family history
Stroke or MI before the age of 50 years
Other idiopathic thrombi
Multiple miscarriages or spontaneous abortions
My Thrombotic Workup
History
Trauma
Indwelling catheter
Long periods of stasis
Family history
Stroke or MI before the age of 50 years
Other idiopathic thrombi
Multiple miscarriages or spontaneous abortions
My Thrombotic Workup
Vessel factors:
Fasting homocysteine
Fasting lipoprotein(a)
Fasting cholesterol
Lupus anticoagulant
Anti-cardiolipin antibodies

Clot factors:
Factor V Leiden mutation
Prothrombin gene mutation
My Thrombotic Workup
Fibrinolytic system factors:
Protein C activity
Protein S activity
Protein C antigen
Protein S antigen (free and total)
Antithrombin III activity
Plasminogen activity
Tissue plasminogen activator activity
Plasminogen activator inhibitor-1 acvtivity
PAI-1 gene polymorphism

Inflammatory factors:
Factor VIII activity
D-dimer
My Thrombotic Workup
Depends on the cause
Remove the catheter!
Is there a positive family history?
Is there a history of trauma?

Start with
enoxaparin
(1 mg/kg/dose sc q12h) –
higher dose for infants
Why?
Because infants have much less ATIII than adults do!
Monitor therapy by checking
anti-Xa level must be drawn 4-6 hours after enoxaparin dose
Thrombosis therapy
Rettie AE, Tai G: The pharmacogenomics of warfarin. Molecular Interventions 6:223-7, 2006
Warfarin
http://www.cartoonstock.com/lowres/mno0074l.jpg
Thanks for watching!
Platelet function defects can arise when platelet
cell-surface receptors
are deficient
http://www.uspharmacist.com/CMSImagesContent/2007/3/anticoagulantst1.jpg
https://www.mja.com.au/sites/default/files/issues/181_08_181004/bri10225_fm-1.gif
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FYI, there is no sound in this presentation.
Full transcript