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Coagulation Disorders and Anti-Coagulant Therapy

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Michael Henry

on 20 March 2013

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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,
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
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
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
Color change (darker)

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
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
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 For best results, go to "full screen" FYI, there is no sound in this presentation.
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