Disorders of Hemostasis

(Hemorrhagic and Thrombotic)

Path 548w
Pharm D

bakul.dalal@vch.ca
Objectives
In these two sessions, you will ….

 Revisit the physiology of hemostasis

 Name major events, and components of each event

 Know the principles of the laboratory tests for hemostatic disorders

 Develop conceptual understanding of hemorrhagic and thrombotic

disorders

 Brief outline of
 hemophilia
 Immune thrombocytopenic purpura
 von Willebrand’s disease
 hereditary thrombophilia
Physiology of Hemostasis
 Hemo = blood and stasis = stopping
 Keep blood moving under normal circumstances
 Stop bleeding following injury
 Restart the flow as soon as possible

 Hemostasis involves

 4 major components
 4 major events…
Physiology of Hemostasis
Four Major Components
 Blood flow
 Blood vessel
 Endothelium, muscle wall, outer wall (adventitia - collagen).
 Platelets
 Membrane, cytoplasm and granules
 Plasma proteins:
 Coagulant proteins – factors I - XIII
 Anticoagulant proteins – AT, C, S
 Thrombolytic proteins – Plasminogen system
Physiology of Hemostasis
Four Major Events
 Vasoconstriction: Stops/slows bleeding

 Platelets adhesion-activation-aggregation: Forms a temporary, loose

platelet plug

 Fibrin mesh (clot) formation: Sticky tight mesh, entraps platelets,

RBCs and WBCs, and stops bleeding

 Clot restriction and dissolution: Normal blood flow can resume

Component 1: Blood Flow
 Blood should keep flowing:
 Why: Small amounts of pro-coagulant proteins are continually
released from WBCs and endothelium, but washed away by rapid
blood flow, thus preventing blood clotting.
 When: Postop DVT, Prolonged airplane travel
 Blood should keep flowing smoothly:
 Directional blood flow is necessary to prevent clotting.
 e.g. prosthetic heart valves, atherosclerosis
Component 2: Blood Vessel
 Muscle layer contracts to produce Vasoconstriction
 Exposed outer layer contains collagen, that binds to von Willebrand
factor to which platelet adhere
 Endothelium initiates external pathway of clotting with membrane
bound tissue factor
 Endothelium restricts the extension of clot by inactivating
coagulation factors and inhibiting platelet aggregation
 thrombomodulin (through APC) - Proteolysis of Va and VIIIa
 heparin-like molecule - Inactivates II, IXa, Xa
 PGI2, NO, ADP - Inhibit platelet aggr
 Endothelium helps in clot dissolution by releasing t-PA and urokinase
 Which drugs inhibit fibrinolysis? How?
 EACA (Amicar), Tranexamic acid
 Inhibits plasminogen
 Aprotinin (serine protease inhibitor)
 Inhibits plasmin
Component 3: Platelets
 Platelet contain various components in membrane, granules and in
cytoplasm.
 Platelet adhesion to adventitial collagen via vWF bridge
 Platelet aggregation to each other by fibronectin and fibrinogen
 Platelets contain coagulation cascade proteins from granules and
from membrane
Which of the following causes
irreversible inhibition of platelet
aggregation?

 Aspirin
 Dipyridamole
 Clopidogrel
 Abciximab
 Ticlodipine

 How long after discontinuation does the effect last? Why?

Coagulation factors in plasma:
Component 4: Plasma Proteins
Prekallikrein Fletcher factor Intrinsic
HMWK Contact activation factor Intrinsic
I  Plasma Fibrinogen
proteins are many, Both
and have either procoagulant or
II anticoagulant
Prothrombin properties Both
III Tissue Factor Extrinsic
IV  vWFCalcium
present is required Both
for platelet adhesion
V  Fibrinogen
Labile factor Both aggregation
is required for platelet
 Fibrinogen
VI (Va) Accelerin
other coagulation factors are required for clot formation
VII  Protein
Proconvertin
C, S, and AT preventExtrinsic
clot extension
VIII  Plasminogen
Antihemophiliac
system factorA
dissolves the Intrinsic
clot
IX Christmas Factor Intrinsic
X Stuart-Prower Factor Both
XI PTA Intrinsic
XII Hageman Factor Intrinsic
XIII Fibrin stabilizing factor Both
Which of the following is/are
procoagulant forces…
 Rapid blood flow
 Eddy currents
 Endothelial damage
 Thrombocytopenia
 Protein C deficiency
 Factor V mutation
Drugs Affecting Coagulation Cascade
 Heparin / low molecular weight heparin
 Promotes AT > quicker breakdown of II, X (and IX, XI XII)
 LMWH vs heparin
 Less osteoporosis, no APTT, only X, less reversible by protamine
 Warfarin (Coumadin)
 Vit K antagonist – II, VII, IX, X, C, S
 Dabigatran
 Direct II inhibitor
 Rivaroxaban
 Direct Xa inhibitor
 Apixaban
 Direct Xa inhibitor
Drugs Affecting Platelet Aggregation
 Aspirin:
 COX inhibitor, increase TXA2
 Clopidogrel
 ADP receptor inhibitor
 Dipyridamole:
 Adenosine reuptake inhibitor
 Ticlopidine:
 ADP receptor inhibitor
 Abciximab:
 Iib/IIIa inhibitor
Procoagulant Drugs
 Octaplex
 Prothrombin complex concentrate
 Beriplex
 Prothrombin complex concentrate
Platelet
Bleeding
FDPs andcount
time
D-dimers
 Count - by auto analyzers PTT: or Intrinsic pathwayPT: Extrinsic pathway


Diagnosis
Fibrin degradation
Reference range is
of<<Platelet<
150,000
Disorders
products to
manually
(FDP, ofVit-K-dependent
"fibrin split
Heparin
450,000
Hemostasis
products",
effect factors
FSP, X-Y-D-E):
 First two events – vasoconstriction and platelet adhesion-aggregation
 Produced
Increased by plasminogen
count usually dosystem,
not after
make youthe thrombus has formed.
clot
 Test for blood
 Clinical vessels,
features Measured
- platelets, vW factor in sec Warfarin effect

 Decreased
Increased
Performed counts
levels
with make you bleed
a standardized blade thatand
makes identical cutfactor
everyas
time
 hemorrhage in cavities and joints muscles Measured
favors INR
 <10
 Normal spontaneous
2-9 minutes hemorrhage
 DIC deficiency
 10-50 induced hemorrhage
 Mucosal and >Factors>>
cutaneous
thrombus hemorrhages indicate platelet problems
 Large hemorrhage
 >100 intracranial
 Tests:
 D-dimer - also an FDP,
 Component but billed
1 Blood flow: as more and
Doppler specific indicator
other of DVT.
rheologic studies
Exclusion value.
 Component 2 Blood vessel - bleeding time
 Component 3 Platelets
 Bleeding time
 Platelet count
 Morphology
 Others - EM, aggregometry
 Component 4 Plasma proteins
TT: Heparin effect
 PT, PTT, TT
Measured FDP, in sec etc
D-dimer
 Morphology
 Other - factor assays, PCR for gene mutations
 A 78-year-old man presents to the emergency room with atrial
fibrillation (treated with warfarin), hematuria (blood in the urine),
and melena (blood in the stool). He also has a history of mental
problems and erratic nutrition. The set of laboratory results MOST
likely to be seen in this patient is:

PT PTT Thrombin time

A. shortened shortened shortened
B. prolonged prolonged shortened
C. prolonged shortened prolonged
D. prolonged slightly prolonged normal
E. Normal normal normal
 A 12-year-old boy presents with a history of recurrent bleeding into
the knee joints. A blood transfusion was necessary following
extraction of a tooth when he was 9 years old.

PTT 108s (normal: <40s) PT normal BT normal

The MOST likely diagnosis for this patient is:

A. factor II deficiency
B. von Willebrand's disease (vWD)
C. factor VIII deficiency
D- factor VII deficiency
E. factor XII deficiency
 A patient has the following results:

platelets 300 x109 (normal: 150-350)/mm3;

bleeding time 12 (normal: 4—8)min.

Based on these findings, the MOST likely etiology is:

A. von Willebrand's disease (vWD)

B. idiopathic thrombocytopenic purpura (ITP)
C. factor XII deficiency
D. factor V deficiency
E. factor VII deficiency
Classification Disorders of Hemostasis
 Classify by abnormality of individual components
 Blood flow
 Blood vessel
 Platelets
 Plasma proteins

 Each one of above further sub-classify by clinical presentation

 Hemorrhagic
 Thrombotic
 Disorders of Blood
Prosthetic Flow Valves
Cardiac
Carpenter Edwards
 Hemorrhagic tendency Carpenter Edwards
St high
 Increased pressure e.g.
Aortic Judealtitude, Valsalva maneuver
Mitral
 Thrombotic tendency
 Slowing or cessation of flow e.g. immobilization, surgery
 Abnormal blood flow e.g. heart valve prostheses

Starr Edwards Hancock Medtronic

• •Stasis Purpura
Valsalva Petechiae
 • Ehler Danlos
Blood Vessel
Disorders Damage
of Blood Vessels in Infections
Syndrome
Leading to Hemorrhage • Amyloid
(the human
 Hemorrhagic tendency DIC
pretzel)
 Compromised mechanical integrity of the supporting collagen
tissue e.g. steroids, scurvy, old age
 Physical damage to blood vessels
 Thrombotic tendency
 Physically damaged endothelium promotes thrombosis -
atherosclerosis, sepsis, meningococci
Meningococ
Normal
cemia Rocky
Abnormalities Infectious Mountain
of Blood Endocarditis Spotted Fever
Vessels
Atherosclerosis
Inducing Mild Severe
Hemorrhagic or
Abnormalities of Blood Vessels Inducing
Thrombotic
Hereditary Hemorrhagic Telangiectasia
••(Osler
Senile Thrombotic Tendency
Purpura
Tendency
ScurvyWeber Rendu Disease)
 Qualitative
Disorders Platelet Abnormalities
of Platelets
 Hemorrhagic tendency:
 Quantitative - thrombocytopenia
 Qualitative – Abnormalities of membrane, granules, cytoplasm eg
MDS, Bernard-Soulier, Glanzmann
 Thrombotic tendency (rare)
 Thrombocythemia
Thrombocytopenia
 Decreased production
 Medications, chemotherapy
 Alcohol toxicity
 Sepsis
 Megaloblastic anemias
 Increased destruction
 Sepsis, HUS, TTP, DIC
 Antibody mediated - ITP, SLE
 Drug-antibody complexes on platelets - heparin, gold, sulfa,
quinine, and quinidine
 Hypersplenism - cirrhosis, rheumatoid arthritis
 Massive hemorrhage - patient getting transfused with blood but
physician forgets to give platelets
Tourniquet Test for Dengue Fever
IDIOPATHIC THROMBOCYTOPENIC
PURPURA (ITP)
 Autoimmune disorders in which platelet destruction results from the
formation of antiplatelet antibodies, most often IIb-IIIa or Ib-IX
(80% of ITP pts). Opsonized platelets are phagocytosed by
macrophages, especially in spleen. Remarkable improvement after
splenectomy
 Petechiae skin and mucosa. esp dependent areas, when confluent -
ecchymoses.
 Lab –
 Plt count
 Low.
 BT
 Prolonged
 PT
 Normal
 PTT
 Normal
IDIOPATHIC THROMBOCYTOPENIC
PURPURA (ITP) … contd
 Two subtypes – acute and chronic
 Chronic: SLE, HIV, after viral infections, and as a complication of
drug therapy. Adult women <40yrs. M:F::3:1
 Acute: Childhood, M=F, preceded by a viral illness by 2 weeks.
Self-limited, and it usually resolves spontaneously within 6
months. Steroid therapy is indicated only if thrombocytopenia is
severe. >6 months = chronic.
Disorders of Plasma Proteins
 Hemorrhagic tendency
 Coagulation factor deficiency VIII, IX, others, DIC (pan-
deficiency)
 Thrombotic tendency (thrombophilia)
 Anticoagulation factor deficiency
 Abnormal persistence of coagulation factors
Hemophilia A and B
 Hemophilia A - Deficiency of VIII, hemophilia B - Deficiency of IX
 Severe; < 2%
 Moderate; 2–5%
 Mild; > 6%
 >25% factor activity rarely bleed
 X-linked, recessive
 Hemophilia A - 10 in 100,000 males, Hemophilia B - 2 in 100,000
males
Hemophilia A and B
 Lab dx:
 Platelet count
 Normal
 PT
 Normal
 PTT
 Prolonged
 TT
 Normal
 Appropriate factors low.
 Treatment
 Hemophilia A: Recombinant or monoclonal factor VIII, or
cryoprecipitate
 Hemophilia B: Recombinant factor IX
Von Willebrand’s Disease
 Commonest hereditary clotting problem 1:100
 Autosomal dominant
 vWF lacking > no adhesion of platelets to endothelium
 Several types, depending on the specific type of molecular defect
Leiden Mutation of Factor V
PCR
 for V inLeiden
Thrombophilia
Point mutation the Factor V gene - Factor V Leiden
 Prevalence in Caucasians 2-5%
 Rare in Afro-Am/Orientals
 Increased tendency for the blood to clot
 Autosomal dominant trait
 Inherited
 Responsible
 Leidenformutation
~60% ofoffamilial thrombosis
factor V 55%
 Disrupts theChemostatic
 AT, process because
and S deficiency the V can not be inactivated and
5% each
continues to promote
 Mutated clottinggene 20%
prothrombin
 Hyperhomocystinemia
 Increased levels of VIII
 Acquired
 Smoking
 Atherosclerosis
 Female hormones - pregnancy, pills, HRT
 Immobilization, surgery
 Cancer
 Lupus anticoagulant
APCR
 Activated protein C resistance is associated with a mutation in which
of the following factors?

 A. factor X
B. factor IX
C. factor V
D. factor IV
E. factor XI
Thrombophilia
 In the work-up of patients with thrombophilia (thrombotic
tendencies), which of the following is the MOST likely finding?

A. increased antithrombin
B. increased protein C
C. resistance to activated protein C
D. prolonged PT
E. loss of platelet glycoprotein (GP) Ib/IX
A previously healthy 27-year-old woman has a petechial rash. No
recent bleeding and has had no recent illness. Hemoglobin, hematocrit,
and white blood cell counts are normal. The blood film shows normal
red and white blood cells and is remarkable only for a paucity of
platelets. The most likely diagnosis in this patient is

A. Aleukemic leukemia
B. Idiopathic thrombocytopenic purpura (ITP)
C. Glanzmann’s thrombasthenia
D. Amegakaryocytic thrombocytopenia
E. Drug-induced thrombocytopenia
52-year-old man, hospitalized for 6 weeks with a bowel obstruction.
The patient has had several operative procedures, one of which
required transfusion of 3 units of packed red cells. He has been unable
to eat and has been receiving broad-spectrum antibiotics almost
continuously.
PT prolonged PTT prolonged
Mixing study: complete correction Fibrinogen normal
Thrombin time normal Platelet count normal

The most likely cause of the coagulation abnormality is

A. An acquired inhibitor
B. Dilution of coagulation factors secondary to transfusions
C. Vitamin K deficiency
D. Folate deficiency
E. Von Willebrand’s disease
Summary: Hemorrhagic Tendency
 Blood vessel
 Decreased mechanical integrity of the supporting collagen tissue
e.g. steroids, scurvy
 Physical damage to blood vessels e.g. infections etc.
 Blood flow
 Increased pressure - high altitude, Valsalva maneuver, stasis
 Platelets
 Quantitative - thrombocytopenia
 Qualitative - MDS, lazy platelet syndrome (Glanzmann), Bernard
Soulier syndrome, gray platelet syndrome
 Plasma factors
 Coagulation factor deficiency VIII, IX, vWD, others, DIC
Summary: Thrombotic Tendency
 Blood vessels
 Physically damaged endothelium promotes thrombosis -
atherosclerosis, sepsis, meningococci
 Blood flow
 Slowing or cessation of flow e.g. immobilization, surgery,
 Abnormal blood flow e.g. mechanical heart valves
 Platelets
 Thrombocythemia (very unusual)
 Plasma factors
 Anticoagulation factor deficiency
 Abnormal persistence of coagulation factors