Basics of hemostasis Christiane Thienelt, MD Assistant Professor of Medicine Hematology/Oncology...
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Transcript of Basics of hemostasis Christiane Thienelt, MD Assistant Professor of Medicine Hematology/Oncology...
Basics of hemostasis
Christiane Thienelt, MD
Assistant Professor of Medicine
Hematology/Oncology
DVAMC/UC Denver
2014
Objectives
1. Overview of coagulation 2. Basic coagulation tests 3. Bleeding disorders
What is Hemostasis? Hemostasis=injury to blood vessel triggers a
series of reactions Formation of fibrin-platelets plugs Bleeding stops
1. vascular phase 2. platelet phase (primary hemostasis) 3. coagulation phase (secondary hemostasis) 4. Regulation of extension of clot by coagulation
factor inhibitors and by Fibrinolysis 5. remodeling and repair after arrest of bleeding
Hemostasis
Platelet plug forms=primary hemostasis
Stabilization by fibrin formation(clotting cascade)=secondary hemostasis
Extension of clotlimited by:
Natural anticoagulants
Fibrinolysis
What is Thrombosis?
Uncontrolled pathological clotting Propagation of a clot to occlude
normal blood flow Ironically, the generation of a
NORMAL hemostatic plug and the formation of an ABNORMAL thrombus are basically the same mechanisms!
Importance of Coagulation in Medicine
Good hemostasis=Good Surgery
Clot Busting ( Thrombolysis)= Cardiovascular Medicine, life-threatening PE ( pulmonary embolism)
Components of hemostasis
1. Endothelium-vessel wall 2. Platelets 3. Coagulation factors
Vessel Wall
Normal Endothelium: -inhibits coagulation -prevents platelet aggregation -promotes clot breakdown -provides barrier to reactive
elements in the vessel wall
Vessel WallPrevent blood from leaking out holes
in blood vessels
Vascular phase-Vessel Wall injury
Injury of blood vessel leads to VASOCONSTRICTION diverting
blood flow Collagen, Tissue factor and von
Willebrand factor (vWF) are exposed Platelet adhere, aggregate and
activate blood coagulation
Platelet Phase: Physiology
Megakaryocyte in bone marrow: precursor for platelets derived from hematopoietic stem cellsUp to 2000 plateletsBud off, circulate 7-10 daysSpleen: 1/3 of plateletsTPO: thrombopoietin main growth and maturation factor for megakaryocytes
Platelet adhesion: Blood Flow
From: Mechanisms in Hematology
Formation of a Platelet Plug
There are 4 events in the formation of a platelet plug:
Platelet adhesionPlatelet activationPlatelet aggregationFibrin formation and support of local coagulation
Smooth discoid shape of resting platelets
Spiny spheric shape of activated platelets
From: Mechanisms in Hematology
Lack /dysfunction of vWF=von Willebrand Factoris von Willebrand disease
Platelet Adhesion: Main mechanisms
=Platelets adhere to the injured surface and build a temporary clot (primary hemostasis)
Exposed platelets change shape (pseudopods)
Temporary bond between GPIb and vWF
Stimulated platelets expose membrane glycoproteins IIb and IIIa
IIb and IIIa bind fibrinogen and vWF
more platelets are recruited and aggregated
Platelet Adhesion
Binding of GPIIbIIIa to 1. subendothelial vWF secures stable platelet
adhesion to the vessel wall while its
2. binding to fibrinogen facilitates platelet Aggregation
Platelet Aggregation
Aggregation:Platelets are laced together through fibrinogen bridgesLocally thrombin converts the fibrinogen to fibrin stabilizing the platelet plug
Platelet Activation
Ligand-Receptor interactions Leads to intracellular signalling Exposure of GpIIb/IIIa
Release of dense and alpha granules
Platelet AGONISTSCalciumSerotoninADP/ATPThromboxane A2
vWF, fibrinogen, clotting factors Anticoagulants (protein S)Anti-heparins ( PF4)
Platelet Activation
New platelets stick to activated platelets and are themselves activated through release of compounds that further amplify platelet activation
These include (a) Products of oxidation of arachidonic
acid by the cyclooxygenase pathway that includes thromboxane A2 (this pathway is blocked by aspirin=Cox 1 inhibitor)***
(b) ADP released from dense granules
From: Mechanisms in Hematology
-Resultant intracellular signaling events lead to platelet activation -Binding of GPIIbIIIa to subendothelial vWF secures stable platelet adhesion to the vessel wall while its binding to fibrinogen facilitates platelet aggregation
Summary of Platelet Plug Formation
Adhesion Platelets adhere to damaged vessel wall directly via collagen
or indirectly via von Willebrand factor
Activation Excitatory agonists (collagen, thromboxane A2, etc) cause a
conformational change in platelet to expose Glycoprotein IIbIIIa binding sites for fibrinogen
Aggregation Platelets are laced together through fibrinogen bridges
Fibrin formation Locally thrombin converts the fibrinogen to fibrin stabilizing
the platelet plug
Platelet Plug-primary hemostasis
Platelet plug forms
Prevention of Bleeding:
Scaffold for secondary hemostasis
Coagulation phase: Clotting factors
Through two different pathways, the clotting cascade is activated and fibrinogen is converted into fibrin
Secondary hemostasis
Coagulation Phase
Clotting factors fill in gaps(clotting cascade makes fibrin,
the “glue” of a clot)
Prevention of Bleeding:
Clotting factors
Usually referred to by number (except prothrombin and fibrinogen)
Numbers written as Roman numerals
13 known procoagulants
Coagulation Cascade
Series of enzymatic reactions Activated when collagen, tissue
factor or negatively charged surfaces are exposed
Key reaction: production of thrombin Thrombin converts fibrinogen to
fibrin
THE CLOTTING MECHANISM
INTRINSIC EXTRINSIC
PROTHROMBIN THROMBIN
FIBRINOGEN
FIBRIN(II) (IIa)
(I) V
X
Tissue ThromboplastinCollagen
VII
XII
XI
IX
VIII
COMMON PATHWAY
Hemophilia B
Hemophilia A
Common Pathway
Xa with V, Calcium and phospholipid convert prothrombin (II) to thrombin (IIa)
“Prothrombinase complex” occurs on platelet surface
Thrombin has many substrates both procoagulant ( positive feedback loop) and anticoagulant ( negative feedback)
THE CLOTTING MECHANISM
INTRINSIC EXTRINSIC
PROTHROMBIN THROMBIN
FIBRINOGEN
FIBRIN (clot)(II) (IIa)
(I)V
X
Tissue Thromboplastin=
Tissue Factor (TF)
Collagen
VII
XII
XI
IXVIII
Extrinsic Pathway
Precipitating event is exposure of tissue factor to blood
Tissue factor is a membrane protein which acts as cofactor for VIIa
Phospholipid, tissue factor and VIIa cleaves X Xa
Intrinsic System
Independent of VII
Contact activation of XII activates XI=contact to negatively charged surfaces
(kaolin, celite, silica) XIa activates IX
IXa with VIII can activate X
THE CLOTTING MECHANISM
INTRINSIC EXTRINSIC
PROTHROMBIN THROMBIN
FIBRINOGEN
FIBRIN (=clot)(II) (IIa)
(I)V
X
Tissue ThromboplastinCollagen
VII
XII
XI
IXVIII
Formation of a Fibrin Clot-last step
Thrombin binds to fibrinogen and liberates fibrinopeptides A and B
Fibrin monomers form polymers by overlapping and interact laterally to form fibrin strands and sheets
Factor XIII cross links fibrin for a stable clot
Role of Vitamin K Factors II, VII, IX and X undergo vitamin K dependent gamma carboxylation
Reaction occurs in the liver
The anticoagulants protein C and S also are carboxylated
Fibrinogen FibrinThrombin
Fibrinogen FibrinThrombin
Prothrombin
XaVa
Fibrinogen FibrinThrombin
Prothrombin
XaVa
VIIa
TF
Extrinsic Pathway
Fibrinogen FibrinThrombin
Prothrombin
XaVa
VIIa
TF
Extrinsic Pathway
IXa
VIIIa
XIa
XIIa
Intrinsic pathway
Fibrinogen FibrinThrombin
Prothrombin
XaVa
VIIa
TF
Extrinsic Pathway
IXa
VIIIa
XIa
XIIa
Intrinsic pathway
XIIIa
Soft clot
FibrinHard clot
Fibrinogen FibrinThrombin
Prothrombin
XaVa
VIIa
TF
Extrinsic Pathway
IXa
VIIIa
XIa
XIIa
Intrinsic pathway
XIIIa
Soft clot
FibrinHard clot
VVIII
++
+
Control of Coagulation Normal balance towards
anticoagulation
Fibrinolysis=clot breakdown
Antithrombin III=natural anticoagulant
Proteins C and S=natural anticoagulants
Natural Anticoagulants: AT III, protein C, S
TFPI TF+ VIIa
IX+VIII
X+V
II +
Fibrinolysis CLOT
Antithrombin
Protein C and
Protein S
Heparin
Degradation of Factors V, VIII
Thrombin
Natural Anti-Coagulants
Natural anti-clotting factors(Protein C, Protein S, Antithrombin)
Spreading clot beyond where it is needed- limited by “anti-clotting” factors
Fibrinolysis
Clot breakdown system(fibrinolysis)
Extra clot and old clot “cleaned-up”by factors that “chew up” clot
Fibrin Fibrin Split Products (FSP)Plasmin
Fibrinolysis
Fibrinolytic phase
Lysis (=breakdown) of clot allows repair of vessel wall/tissue injury and normalizes flow through vessel
Fibrin is degraded by plasmin Plasmin originated from
plasminogen Plasminogen is activated by tissue
plasminogen activator (TPA) Fibrinolysis is inhibited by
plasminogen activator inhibitors and alpha2-antiplasmin
Fibrin Fibrin Split Products (FSP)D-Dimer
Plasmin
Plasminogen
tPA
Fibrinolysis
INHIBITORS of PLASMINOGENPlasminogen activator inhibitor (PAI-1) inhibits PlasminogenAlpha 2 antiplasmin
Commonly Used Pharmacologic Agents in
BleedingHemostatictranexamic acid (Cyklokapron):
5% mouthwash for prolonged bleeding in dentistry, antifibrinolytic
aminocaproic acid (Amikar): inhibits plasmin, antifibrinolytic, oral rinse, iv or tablets
Aprotonin(Trasylol), antifibrinolytic, withdrawn from Market
Activated factor VII, recombinant, bypasses intrinsic system
Summary Hemostasis
Depends on -vessel wall integrity -adequate platelet number -adequate Platelet function -adequate factor levels -adequate fibrinolysis
Objectives
1. Overview of coagulation 2. Basic coagulation tests 3. Bleeding disorders
Basic coagulation tests
1. Platelet count 2. Bleeding Time/Platelet function
testing 3. Prothrombin time (PT)/INR 4. aPTT (activated partial
Thromboplastin time) 5. Thrombin Time (TT) 6. Factor assay 7. D-Dimer
SEVERITY OF THROMBOCYTOPENIA
Normal >150,000/mm3
Mild 90-150,000/mm3
Moderate 20-90,000/mm3
Severe 5-20,000/mm3
Very Severe <5,000/mm3
Thrombocytopenia (=low platelet count)
Normal platelet count between 150,000-400,000/ul
Platelets 20–50,000: may see spontaneous hemorrhage and increased risk of hemorrhage with trauma or surgery So safe platelet count for surgery is
generally 50,000 or higher Platelets <10,000-20,000: can see
life-threatening spontaneous hemorrhage
Copyright ©2008 American Society of Hematology. Copyright restrictions may apply.
Maslak, P. ASH Image Bank 2008;2008:8-00089
Figure 1. This picture demonstrates petechiae in dependent areas of a thrombocytopenic patient with AML
Basic coagulation tests
1. Platelet count 2. Bleeding Time/Platelet function
testing 3. Prothrombin time (PT)/INR 4. aPTT (activated partial
Thromboplastin time) 5. Thrombin Time (TT) 6. Factor assay 7. D-Dimer
Bleeding Time/Platelet function analyzer
Bleeding time measures platelet function, vessel wall and skin integrity
A template device makes a cut on the forearm and time to clot (2-9 minutes) is measured
Platelet function analyzer (PFA) can determine an in vitro bleeding time with agonists
Bleeding time
Old test to screen for vW Disease or other platelet function disorder Operator dependent, not
reproducible Elevated in patients with uremia and
liver disease-little prognostic value Also prolonged in patients taking
ASA or NSAIDS Does not correlate with bleeding
complications Not helpful-please do not order!
Platelet function screen Replaces the
bleeding time as a test of platelet function
PFA-100; ordered as “platelet function screen”
Blue top tube
Measures the time it takes for blood to block membrane coated with platelet agonists ( either collagen/epinephrine or collagen/ADP)
Basic coagulation tests
1. Platelet count 2. Bleeding Time/Platelet function
testing 3. Prothrombin time (PT)/INR 4. aPTT (activated partial
Thromboplastin time) 5. Thrombin Time (TT) 6. Factor assay 7. D-Dimer
Prothrombin time (PT) Measures extrinsic pathway Useful for measurement of VII, X, V and II
and fibrinogen Calcium and thromboplastin (extract of
tissue) added to citrated plasma and time to clotting is measured in seconds
PT is sensitive to decreased levels of Vitamin K-dependent factors (exception factor IX), useful for monitoring oral anticoagulants (WARAFRIN)
Test results expressed in seconds
THE CLOTTING MECHANISM
INTRINSIC EXTRINSIC
PROTHROMBIN THROMBIN
FIBRINOGEN
FIBRIN(II) (III)
(I)V
X
Tissue ThromboplastinCollagen
VII
XII
XI
IXVIII
Measured by PT
INR
For monitoring oral anticoagulants (warfarin, coumadin) expressed as INR (International Normalized Ratio)
Devised to correct for variations in instrumentations and reagents ( tissue thromboplastin)
Normal INR is 1.0 Therapeutic anticoagulation is 2-3
( for A fib, DVT, PE), occasionally 2.5-3.5 ( for artificial valves)
INR equation
[Patient PT/Mean Normal PT]ISI=INR
ISI=international sensitivity indexINR=international normalized ratio
Basic coagulation tests
1. Platelet count 2. Bleeding Time/Platelet function
testing 3. Prothrombin time (PT)/INR 4. aPTT (activated partial
Thromboplastin time) 5. Thrombin Time (TT) 6. Factor assay 7. D-Dimer
THE CLOTTING MECHANISM
INTRINSIC EXTRINSIC
PROTHROMBIN THROMBIN
FIBRINOGEN
FIBRIN(II) (III)
(I)V
X
Tissue ThromboplastinCollagen
VII
XII
XI
IXVIII
Measured by PTT
Activated Partial thromboplastin time (aPTT) Measures the intrinsic pathway Surface activating agent and
phospholipid is added to citrated plasma
Activated plasma is then recalcified and time to clotting measured in seconds
aPTT
Measures the activity of the entire clotting pathway except Factor VII ( because Factor VII is extrinsic pathway)
Useful to detect Factor VIII, IX, XI, XII deficiencies
Sensitive to inhibition by heparin and fibrin split products
Basic coagulation tests
1. Platelet count 2. Bleeding Time/Platelet function
testing 3. Prothrombin time (PT)/INR 4. aPTT (activated partial
Thromboplastin time) 5. Thrombin Time (TT) 6. Factor assay 7. D-Dimer 8. Bleeding Time/Platelet function
testing
Thrombin Time
Excess thrombin is added to plasma Measure the rate of conversion of
fibrinogen to fibrin upon the addition of thrombin to plasma
Prolonged in the presence of heparin, low or abnormal fibrinogen and fibrinogen/fibrin degradation products
THE CLOTTING MECHANISM
INTRINSIC EXTRINSIC
PROTHROMBIN THROMBIN
FIBRINOGEN
FIBRIN(II) (III)
(I)V
X
Tissue ThromboplastinCollagen
VII
XII
XI
IXVIII
COMMON PATHWAY
Basic coagulation tests
1. Platelet count 2. Bleeding Time/Platelet function
testing 3. Prothrombin time (PT)/INR 4. aPTT (activated partial
Thromboplastin time) 5. Thrombin Time (TT) 6. Factor assay 7. D-Dimer
Factor assay
Each of the factors is individually assayed using modifications of the PT or PTT test
Pooled normal plasma is defined as 100% activity
Factor levels vary tremendously from person to person ( normal is 50-150 % activity)
Basic coagulation tests
1. Platelet count 2. Bleeding Time/Platelet function
testing 3. Prothrombin time (PT)/INR 4. aPTT (activated partial
Thromboplastin time) 5. Thrombin Time (TT) 6. Factor assay 7. D-Dimer
Fibrinogen FibrinThrombin
Prothrombin
XaVa
VIIa
TF
Extrinsic Pathway
IXa
VIIIa
XIa
XIIa
Intrinsic pathway
XIIIa
Soft clot
FibrinHard clot
VVIII
++
+
D-Dimer
Fibrin monomer bind to form thrombus
Factor XIII binds their D-domains together
Fibrinolysis: Degradation fragment is called D-Dimer
D-Dimer is a fibrin split product
D-Dimer
Elevated D-Dimer levels indicate that
1) Thrombin has acted on fibrinogen to form a fibrin monomer which bonded to another monomer aided by Factor XIII
2) clot was lysed by plasmin (=fibrinolysis)
Objectives
1. Overview of coagulation 2. Basic coagulation tests 3. Bleeding disorders
Evaluation of Bleeding
Patients may consider an appropriate amount of bruising or bleeding to be excessive
Therefore, a detailed history is essential in the workup
Approach to the bleeding patient-
History is the most important tool 1. Have you ever had a nosebleed? How frequent did these
occur? Did it require a trip to the hospital? 2. Have you ever had dental work? Did it require stitching
or packing due to the bleeding? Did it bleed the next day? 3. What surgeries have you undergone? Did any of them
require transfusions? Did your surgeon comment on excessive bleeding?
4. What is the biggest bruise you ever had? How did it happen?
5. How long are your menstrual periods? Have you ever been so anemic you needed to be on iron replacement? Did you have excessive bleeding after childbirth or require a transfusion then?
6. Have you ever had bleeding when you urinated, from your stomach or from your gastrointestinal tract?
7. Do you bleed when you brush your teeth?From Hemostasis and Thrombosis; 1999Landes Bioscience
Approach to the bleeding patient
1. History/Severity of symptoms: Major vs. Minor bleeding, menorrhagia, bruising, nosebleeds (Acquired vs. inherited)
2. Prior stressors (contact sports, trauma, broken bones, surgeries, pregnancies)
3. Family History (extended, especially males) 4. Drugs (Rx plus OTC) 5. Previous coagulation parameters available? (PT, PTT,
platelet count) 6. Concurrent illnesses
Case A 40 y/o woman presents to your office for dental evaluation. She
will need extraction of several teeth. Years ago, she had wisdom teeth extraction performed and tells you that she started to bleed about 4 hrs after extraction and needed plasma transfusion to stop the bleeding. She is very apprehensive about any further extractions. You order the following labs:
CBC shows normal platelets count at 267. PT is normal at 12.3 sec, PTT is normal at 28 sec. INR is 1.0. Platelet function testing is normal.
She also tells you that she bled each time after her deliveries ( she has 4 children) where she lost enough blood to receive blood transfusions each time. She bled after her gallbladder surgery and her tonsillectomy.
You tell her:A) based on her history, she must have a bleeding disorderB) you don’t think, she has a bleeding disorder because all of her
testing has been normalC) you think, she must have had an incompetent surgeon/dentist
before and YOU will be more carefulD) you think, she needs more testing
Bleeding disorders
Inherited bleeding disorders
Von Willebrands disease
Hemophilia A and B
Other factor deficiencies
Acquired bleeding disorders
Thrombocytopenia Liver disease Vitamin K
deficiency/warfarin overdose
DIC Renal
disease/uremia Drug induced (ASA)
Bleeding disorders
1. Vessel defects 2. Platelet disorders 3. Coagulation abnormalities 4. Other
Vessel defects
1. Vitamin C deficiency 2. Bacterial/viral infections 3. Rheumatologic disorders
(vasculitis)
Vessel wall integrity
Peri-follicular hemorrhage
Scorbutic gingivitis
Bleeding disorders
1. Vessel defects 2. Platelet disorders 3. Coagulation abnormalities 4. Other
Platelet disorders
Thrombocytopenia ( decreased numbers of platelets)
Platelet function defects ( abnormal platelet function)
Thrombocytopenia (=low platelet count)
Normal platelet count between 150,000-400,000/ul
Platelets 20–50,000: may see spontaneous hemorrhage and increased risk of hemorrhage with trauma or surgery So safe platelet count for surgery is
generally 50,000 or higher Platelets <10,000-20,000: can see
life-threatening spontaneous hemorrhage
Causes of Thrombocytopenia
Caused by either of these mechanisms:Decreased production of platelets
Increased destruction of platelets
Distribution/Dilution disorders (Increased sequestration of platelets due to splenomegaly)
Petechiae
Do not blanch with pressure
Not palpable
Impaired/Decreased Platelet production
Bone marrow failure -nutritional deficiencies ( Vitamin B12, Folate) -ETOH -malignancies ( leukemia, lymphoma, metastatic
disease to bone marrow, myelodysplastic syndrome)
-Drug-induced (chemotherapy , antibiotics, thiazide diuretics etc)
-Radiation ( marrow in Radiation field) -Viral infections (HIV, Hep C) -congenital
Disorders causing Increased Destruction of
Platelets Thrombocytopenia occurs when platelets are rapidly destroyed and bone marrow cannot compensate
Most common cause is immune thrombocytopenia where platelets are coated with anti-platelet antibodies leading to premature removal of platelets by the spleen
Disorders: Immune thrombocytopenia (ITP) – common
cause (outpatient) DIC – rare cause (usually inpatient setting) Sepsis – rare cause (inpatient) Thrombotic thrombocytopenic purpura (TTP) –
rare cause, inpatients
Thrombocytopenia
ITP ( immune thrombocytopenic purpura)
Autoimmune disorder caused by antibodies that lead to destruction of platelets
Disorders of dilution/distribution
Active bleeding or clotting (consumption)
Massive transfusion (dilution) Hypersplenism ( sequestration of
platelets in enlarged spleen)-normally 30% of platelets stored in spleen-with increase in size, more platelets get
sequestered in spleen-most often seen in Liver disease ( Liver cirrhsois)-
>portal hypertension->splenomegaly
Abnormal platelet function (platelet number normal) 1. Drug induced ( aspirin, NSAIDs,
Plavix) -stop aspirin 5-7 days before elective
surgery 2. uremia 3. congenital platelet function
defects(Glanzman thrombasthenia, Bernard-
Soulier syndrome-missing platelet receptor proteins)
Bleeding disorders
1. Vessel defects 2. Platelet disorders 3. Coagulation abnormalities 4. Other
Hemophilia
• X-linked deficiency of Factor VIII (hemophilia A) or Factor IX (hemophilia B)
• Males primarily affected• Carrier females can be symptomatic• Elevated PTT is only abnormal
screening test
Hemophilia A and B
Hemophilia A – Factor VIII deficiency 1:5000 male births
Hemophilia B – Factor IX deficiency 1:50,000 male births
Many new mutations; negative family history does not rule out hemophilia
Diagnosis of Hemophilia Screen males with unexplained
hematomas, bruises and post surgical or traumatic bleeding
PTT ranges from high normal to very prolonged
Assay Factor activity to distinguish Hemophilia A and B-important for treatment
Hemophilia-Clinical manifestations
Clinical manifestations (hemophilia A & B indistinguishable)
Hemarthrosis (most common)Fixed joints
Soft tissue hematomas (e.g., muscle)Muscle atrophyShortened tendons
Other sites of bleedingUrinary tractCNS, neck (may be life-threatening)
Prolonged bleeding after surgery or dental extractions
Ecchymoses
(typical of coagulation factor disorders)
Coagulation Factor Testing
Pooled normal plasma is defined as 100% activity
Normals are ~50-150% activity Severe hemophilia - <1% - spontaneous
bleeds Moderate 2-5%-bleed with minor
trauma Mild hemophilia 5-10% - bleed with
severe trauma, surgery and dental procedures
Factor Level does not change significantly throughout life!
Factor XI Deficiency
PTT prolonged
Post-operative bleeding
Variable bleeding history
Autosomal recessive
Variable incidence in populations
Hemophilia
Hemophilia A
Hemophilia B
Factor XI deficiency
Affected Coagulation factor
F VIII F IX F XI
Inheritance
X linked recessive
X linked recessive
Autosomal recessive
Incidence 1/5,000 males
1/50,000males
Ashkenazi Jews (5% of population
Treatment of hemophilia A:
Factor VIII concentrates Preferred agent: recombinant goal range : 30-40% factor level hemorrhagic joints 100% factor level in patients undergoing major surgery or
CNS trauma infuse as fast as possible 1 unit of factor VIII raises plasma level by 2%
(Desired Factor VIII concentration x weight in kg
2
Bleeding disorders
1. Vessel defects 2. Platelet disorders 3. Coagulation abnormalities 4. Other
Von Willebrand Disease
Most common congenital bleeding disorder
Autosomal dominant Abnormality in platelet/endothelial
interaction Clinical problems:
Mucosal bleeding Nose bleeds GI bleeds Menorrhagia Bleeding after surgery if no correction
Von Willebrand Disease:
Pathophysiology Von Willebrand’s protein is extremely large
protein in a series of forms with 2 functions
1ST FUNCTION: Adheres platelets to exposed collagen at the
site of a wound or vessel disruption
2nd FUNCTION: Carry Factor VIII Without this protein, Factor VIII has a VERY
short half-life
Von Willebrand Disease: Diagnosis
(Initial) Tests for von Willebrand’s Disease: Factor VIII level normal or decreased
(measures 2nd function of vW protein)
von Willebrand’s antigen (measures amount of vW protein) < 0.30 IU/dL
von Willebrand’s activity, aka ristocetin cofactor activity (measures function of patient’s vW protein using donor platelets) < 0.30 IU/dL
Blood Type (Type 0) has lower baseline levels)
Von Willebrand Disease Types
Type 1: Partial quantitative vWF deficiency.
(70-80% cases) Type 2: Qualitative defects – abnormal
function of vW protein(15-30% cases) Type 3: Almost complete absence vWF
(Rare)
Von Willebrand Disease Treatment - DDAVP
Need to avoid aspirin, NSAID’s, other platelet inhibiting drugs
Long term prophylaxis rarely required DDAVP (arginine vasopressin) enhances
already synthesized vWF release from endothelial stores so effective in type 1 but not type 2 or type 3 disease
Once stores depleted, will need time to make more
vW factor DDAVP is available as nasal spray
(Stimate) or intravenous form Trial in a non-bleeding state is warranted
before elective procedure to verify pt will respond with increased levels
Von Willebrand Disease Treatment – vWF Replacement Therapy
“Intermediate purity” factor VIII (also rich in vWF) concentrates are most commonly used
Mainly used in type 2 and 3 disease Indications in type 1 disease:
More severe disease, especially when severe bleeding involved
When other measures have failed Post op setting when prolonged treatment
maybe needed, because DDAVP will not work repeteadly
Case 1
A 23 y/o woman is sent to you for wisdom teeth extraction. On pre-screening form, patient reports “very heavy menses” that have always been present. She works as a hair stylist and has to take off work for her periods. What should you do next?
A) inquire about previous surgeries/extractions, i.e. obtain a bleeding history
B) Proceed with extractions and see if she bleeds
C) Send for hematology evaluationD)Tell the patient that she has a bleeding
disorder and deny her surgery.
Case 2
The same patient tells you that she had a vaginal delivery 2 years ago and bled extensively about 8 days after her delivery. She required a Blood transfusion at that time. No obstetric reason for her bleeding was found. She was supposed to see a hematologist at that time but never followed up. What would be the best way to proceed now?
A) Obtain a hematology evaluation nowB) Assume, she has hemophilia and give a factor
concentrate before the extractionC) Assume, she has von Willebrand disease and
give DDAVPD) Assume, she has a platelet disorder and arrange
for transfusion of platelets before her extraction.
Case 3
The same patient is seen by hematology and is diagnosed with von Willebrand disease, Type I, the most common type. The hematologist most likely will recommend:
A) 1 dose of DDAVP i.v. before extraction
B) 1 dose of Humate P (Factor VIII)C) Transfusion of platelets before
extractionD) Cryoprecipitate before extraction
Case 4
In a patient with von Willebrand disease, which types of bleeding would you NOT expect?
A) nosebleedsB) excessive menstrual bleeding C) joint bleeds ( hemarthrosis)D) post-procedural bleeding
Case 5
The same patient eventually undergoes tooth extraction with appropriate pre-treatment and does well. She asks you whether her now 2 y/o son could have von Willebrand disease as well?
A) yes, please explain B) no, please explain
Bleeding History Pearls***
Mucocutaneous bleeding:Platelet or von Willebrand factor defect
Soft Tissue/Joint/Deep Bleeding:
Coagulopathy (Factor deficiency=Hemophilia)
Questions?