(1BC and iron studies
• severe microcytic anemia (Hb <60 g/L)
• peripheral blood film:teardrop,target, hypochromic,microcytic
• Hb electrophoresis
• HbA:0-10% (normal >95%)
• HbA 2 >2.5%
• HbT: 90-100%
Treatment
• lifelong regular transfusions to suppress endogenous erythropoiesis
• iron chelation (e.g. deferoxamine, deferasirox, and deferiprone) to prevent iron overload in organs and
the formation of free radicals(which promote tissue damage and fibrosis)
• folic acid supplementation if not transfused
• allogeneic BM transplantation (potentially curative) or cord blood transplant
• gene therapy (to encode adult Hb A) or CRISPR-Cas 9 gene editing (to allow for increased fetal Hb
production) understudy
• splenectomy (now performed less frequently)
Hemochromatosis
m
Clinical Features
ABCDH
Arthralgia
Bronte skin
Cardiomyopathy.Cirrhosis ol liver
Diabetes(pancreatic damage)
Hypogonadism (anterior pituitary
damage)
r -1
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p-Thalassemia Intermedia
Definition
• clinical diagnosis in patients whose clinical manifestations are too mild to be classified as
P-thalassemia major, but too severe to be classified as p-thalassemia minor
Clinical Features
• wide variety of clinical phenotypes
• in most cases of p-thalassemia intermedia, both P-globin genes affected
• three main mechanisms account for the milder phenotype compared to p-thalassemia major:(1)
subnormal (vs. absent) p-chain synthesis,(2) increased number of y chains, and (3) coinheritance of
a-thalassemia (in some cases)
• complications more commonly seen in p-thalassemia intermedia than p-thalassemia major include
extramedullary hematopoiesis, leg ulcers,gallstones, thrombosis, pulmonary hypertension, and
growth retardation
Treatment
• most patients only require periodic transfusions, although regular transfusions may eventually be
necessary in adulthood (third to fourth decade of life)
• folic acid supplementation if not transfused
• iron chelation therapy is required since iron overload develops due to ineffective erythropoiesis and
subsequent hepcidin downregulation
a-Thalassemia
Definition
• defect(s) in a genes
• similar geographic distribution as P-thalassemia, but higher frequency among Asians and Africans
Clinical Features
• I defective a gene (aa /a-): clinically silent; normal Hb, normal MCV
• 2 defective a genes (cis: aa/-- or trans:a-/a-): normal Hb, decreased MCV
• N.B. cis 2-gene deletion more common in Asia vs. trans 2-gene deletion more common in Africa -
thisleads to increased risk of fetal hydrops in offspring of patients from Asia vs. Africa
• 3 defective a genes (a-/--): HbH (
P4 ) disease; presents in adults, decreased Hb, decreased MCV, and
splenomegaly
• 4 defective a genes (—/—):Hb Barts (y4) disease (hydrops fetalis); usually incompatible with life
Investigations
• CBC and iron studies (for iron overload)
• peripheral blond film -screen for HbH inclusion bodies with supravital stain
• Hb electrophoresis can be used to identify HbH disease, but may miss I - or 2-gene deletions;definitive
diagnosis with UNA genotyping
Treatment
• referral for genetic/prenatal counselling
• depends on degree of anemia
1 or 2 defective a genes: no treatment required
• HbH disease:similar to p-thalassemia intermedia
Hb Barts: no definitive treatment - majority of pregnancies terminated (fetal/maternal mortality
risk), intrauterine transfusion,stem cell transplants ^
Blood flow
slows I
t blood Sickle Cell Disease viscosity ipO,
Distortedt
RBC 1
sickle cells
Definition
• autosomal recessive sickling disorders are most commonly caused by a Glu -> Valsubstitution at
position 6 of the p-globin chain (chromosome 11) resulting in HbS variant, rather than HbA (normal
adult Hb)
increased incidence of HbS allele in patients with Sub-Saharan African, Indian, Middle liastern,
or Mediterranean heritage (thought to be protective against malaria)
• SCO occurs when an individual has two HbS genes (homozygous, HbSS) or one HbS gene * another
mutant P-globin gene (compound heterozygote)
- most commonly HbS-P-thal and HbSC disease
Pathophysiology
• at low pO’
, deoxyHbS polymerizesleading to rigid crystal-like rods that distort membranes-> ‘sickles’
• the pO:level at which sickling occurs is related to the percentage of HbS present
• sickling is aggravated by acidemia,increased C02, increased 2,3-DPG, fever, and increased osmolality
• fragile sickle cells then cause injury in two main ways
1. fragile sickle cells hemolyze (nitric oxide depletion)
2. occlusion of small vessels (hypoxia, ischemia-reperfusion injury)
Deoxy HbS
T H'
1*
CO,
HbS '
polymers
Impaction
Infarction
Figure 8. Pathophysiology of sickling
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• Functional Asplenism:increased
susceptibility to infection by
encapsulated organisms
• S. pneumoniae
. N. meningitidis
• H. influemae
• Salmonella (osteomyelitis)
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H22 Hematology Toronto Notes 2023
$
Clinical Features
• sickle cell trait (HbAS): patient will be asymptomatic except during extreme hypoxia or infection
increased risk of renal medullary carcinoma
. SCD-SS (HbSS)
chronic hemolytic anemia
« jaundice in the first year of life
retarded growth and development ± skeletal changes
splenomegaly in childhood;splenic atrophy in adulthood
• SCD-SS often presents with acute pain episode
1. aplastic crises
toxins and infections (especially parvovirus B19) transiently suppress B\1
2.splenic sequestration crises
usually in children;significant pooling of blood in spleen resulting in acute Hb drop and
shock
uncommon in adults due to asplenia from repeated infarction
3. vaso-occlusive crises(infarction)
may affect various organs causing ischemia-reperfusion injury (especially in back, chest,
abdomen, and extremities),fever,and leukocytosis
can cause a stroke or a silent M1
precipitated by infections, dehydration,rapid change in temperature, pregnancy, menses, and
alcohol
4. acute chest syndrome
acute illness characterized by fever and/or respiratory symptoms
new pulmonary infiltrate on chest x-ray
precipitated by pulmonary infection, fat embolism, and pulmonary infarction
• SCD-SC (HbSC): most common compound heterozygote
I in 833 live births in African-Americans, common in West Africa
milder anemia than HbSS
similar complications as HbSS but typically milder and less frequent (exception is proliferative
sickle cell retinopathy,glomerulonephritis, and avascular necrosis)
spleen not always atrophic in adults
Investigations
• sickle cell prep (detects sickling of RBCs under the microscope in response to 0:lowering agent):
determines the presence of a HbS allele, but does not distinguish HbAS from HbSS
• Hb electrophoresis distinguishes HbAS, HbSS, HbSC, and other variants
• all newbornsin developed countries typically screened for SCD
Organs Affected by Vaso-Ocdusive
Crisis
Organ Problem
Brain Ischemic or hemorrhagic
stroke, vascnlopathy
Hemorrhage, blindness
Infarcts.DUO syndrome
Acute chestsyndrome,longterm pulmonary hypertension
Eye
liver
Lung
Gallbladder Slones
Heart Hyperdynamic How murmurs
Spleen Enlarged (child):atrophic
[adult]
Kidney Hematuria, loss of renal
concentrating abiity.
proteinuria
Intestines Acute abdomen
Placenta Stillbirths
Penis Priapism
Digits Dactylitis
Bone Infarction, inlection,avascular
necrosis (femoral and humeral
head)
Skin leg ulcers(ankle)
Table 13, Investigations for Sickle Cell Disease
HbAS HbSS
Increased reticulocytes, decreased Hb,and
decreased Hct
Sickled cells
No HbA, only HbS and HbF (proportions change
with age); normal amount of HbA 2
CBC Normal
Peripheral Blood
Hb Electrophoresis
Normal; possibly a few target cells
HbA fraction of 0.6S|6S%)
HbS lraction ol 0.35 (35%|
Treatment
• genetic counselling
• HbAS: no treatment required
• HbSC:treatment as per HbSS, but is dictated by symptom severity
. HbSS
Hydroiyurea (Hydroxycartamide) forSickle
Cell Disease
C ochrane Dd Syst ter 2017:4X0002202
Purpose: Io assessI he effectsol hydroiyurea
therapy in patientsol any age and genotype with
sickle cel disease (SCO).
Study Selection: Randomised andquasirandonised controlled trials >1month comparing
hydroiyurea with placebo,standard therapy or other
interventions.
Results 8RCTswere included. 889 total patients
(bothadoltsand children with SCO).When compared
lo placebo,hydroxyurea was associated with
statisticallysignificant improvements in pain
alteratioo (pain crisisfrequency,duration,intensity,
hospital admissions and opioid use),measures of
fetal hemoglobin and neutrophil coonts and fewer
occurrences of acute chestsymdroene and blood
transfusions. Differences in quality ol life and adverse
events(including serious or life-threatening events)
were not statistically significant.
Conclusion:Ev, fence suggeststhat hydroxyurea can
effectively decrease the frequency nf pain episodes
and other acute complications m patients with SCD.
However, data on the long-term henetts and risks ol
hydroxyurea isstill Insufficient.
1. folic add to prevent folate deficiency
2. hydroxyurea to enhance production of Hbl;
mechanism of action:stops repression of Hb-y chains and/or initiates differentiation of stem
cells expressing this gene
presence of HbF in the sickle cell RBCs decreases polymerization and precipitation of HbS
short term harms(within 6 mo):dose-related leukopenia, thrombocytopenia, anemia, and
decreased reticulocyte count; decreased sperm production, mucositis,skin ulcers
long-term harms: birth defects in offspring of people receiving the drug, growth delays in
children receiving the drug, and cancer in both children and adults who receive the drug
3. treatment of vaso-occlusive crisis
supportive care:oxygen,hydration (reduces viscosity),correct acidosis, analgesics/opiates
indication for exchange transfusion:Hb <50-60 g/L, SCD complications (acute chest
syndrome, aplastic crisis, hepatic or splenic sequestration, and stroke), prevention of
complications, preoperative
less routinely:antimicrobialsfor suspected infection
4.prevention of crises
establish diagnosis
avoid conditions that promote sickling (hypoxia, acidosis,dehydration,and fever)
vaccination in childhood (S, pneumoniae, N. meningitidis,and H. influenzae type b)
prophylactic penicillin (age 3 mo-5 yr)
good hygiene, nutrition, and social support
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H23 Hematology Toronto Notes 2023
5.screen for complications
regular blood work (CBC, reticulocytes, iron indices, BUN, LFTs, and creatinine)
urinalysis annually (proteinuria and glomerulopathy)
transcranial doppler annually until 16 yr (stroke prevention)
retinal examinations annually from 8 yr (screen for retinopathy)
echocardiography once in late childhood/earlv adulthood (screen for pulmonary
hypertension)
6. future therapies
gene therapy
voxelotor
crizanlizumab
Stroke WilliTransfusions (hanging to
Hydroxyurea (SWiTCH)
Bood 2012;119:3925-32
Purpose: Tocompare standard treatment
(transfrrsionsfchelation)to alternative treatment
(hydroiyureafphlebotomy)lor children withMine tell
anemia (SCA). stroke,and non overload.
Methods:133 pediatric patients were randombedto
(1) continuation of monUtly erythrocyte transfusions
with oral delerasiroi (28.2- 6.0 mgfkgJd) or (2)
initiation on hydroxyurea (20 mgikgfd escalated
tomanmum tolerateddose (HTD)*26.2 •4.9 mg/
kgd) with discontinuationof transfusions atMID.
and monthly phlebotomy (5-111 ntUkgi'mo|for iron
overload.
Primary Outcome:Secondary stroke recurrence rale
and quantitative liver iron content.
Results: Stroke recurrence rate was significantly
lower in patients on transfusionsldeferasiror
as compared to those initiated on hydroxyurea/
phlebotomy (0% vs.10V P'
0.05).Differences in
Over ironcontent between the two treatmentaims
were not statistically different(16.6 mgfg dry weight
liver intransfusions/deferasirox vs.15.7 mg'g in
hydroiyurea
'
phtebotomy).
Conclusion: Iransfuvo-s and chelation remain
the preferred management strategies lor pediatric
patients with SCA. stroke and ironoverload.
Autoimmune Hemolytic Anemia
Table 14. Classification of AIHA
Warm (75-90% cases) Cold
Ab Allotype IgG IgM
Agglutination Temperature 37°C
Direct Coombs Test
(direct antiglobulin test)
Etiology
4-37
’
C
Positive lor IgG t complement Positive for complement
Idiopathic
Secondary to lymphoproliferative disorder
(e.g.Cll,Hodgkin lymphoma)
Secondary to autoimmune disease (e.g.Sit)
Pregnancy
Drug-induced (e.g.penicillin,quinine,
methyldopa)
Sphcrocytcs
Treat underlying cause
Folic acid
Corticosteroids (Ist-line)
Folic acid
Rituximab|2nd-line to steroids)
Immunosuppression
Splenectomy
Idiopathic
Secondary to infection
(e.g.mycoplasma pneumonia.F6V. HCV.syphilis)
Secondary to lymphoprohlciatlvc disorder
(e.g.macroglobulinemia.Cll)
BloodFilm
Management
Agglutination
treat underlying cause
Folic acid
Warm patient/avoid cold
Rituximab regimen (Ist-line)
Plasma exchange (2nd-line for high IgM levels)
low dose alkylating agents (chlorambucil,cyclophosphamide)
or interferon maybe useful but less effective
Microangiopathic Hemolytic Anemia/Thrombotic
Microangiopathy
Definition
• hemolytic anemia due to intravascular fragmentation ofRBCs
Etiology
• see '
lhrombotic thrombocytopenic Purpura and Hemolytic Uremic Syndrome, H3I
• see Disseminated Intravascular Coagulation, H34
• eclampsia, HI:LLP syndrome, AI'
LP
• malignant hypertension
• vasculitis
• malfunctioningheart valves
• metastatic carcinoma
• drugs (calcineurin inhibitors,quinine,simvastatin)
• infections (severe CMV or meningococcus)
• catastrophic APS
Investigations
• blood film:schistocytes
• hemolytic workup (CBC, reticulocyte count, LDH, haptoglobin, indirect bilirubin)
• Coombs test: negative
• urine: hemosiderinuria, hemoglobinuria
Schistocyte
Vessel
wall
6
o
6
o
8
r <o .
.1 Thrombus §
a
R&C
r “v Figure 9. Schistocytosis L.J
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H24 Hematology Toronto Notes 2023
Hereditary Spherocytosis
Definition/Etiology
• most common type of hereditary hemolytic anemia
t abnormality in KBC membrane proteins (c.g.spectrin)
• autosomal dominant (variable penetrance), can also be autosomal recessive or de novo
• presents with hemolytic anemia, jaundice,splenomegaly
Investigations
• CBC and differential blood film (showsspherocytes)
• KBC dehydration and membrane loss result in elevated MCHC
• osmotic fragility (increased)
• molecular analysis for spectrin gene
• ultrasound (splenomegaly and gallstones(pigment))
Treatment
• genetic counselling
• in severe cases,splenectomy and vaccination against S. pneumoniae, N.meningitidis,and H.
influenzae type b (avoid splenectomy in early childhood)
Macrophao .
Hereditary Elliptocytosis Spherocytc ©
Figure 10. Spherocytosis secondary
toAIHA Definition/Etiology
• abnormal interactions between spectrin and other membrane proteins
• autosomal dominant
• 25-75% elliptocytes
• hemolysis is usually mild
Treatment
• genetic counselling
• ifsevere hemolysis:splenectomy, folate supplementation, and immunization
Glucose-6-Phosphate Dehydrogenase Deficiency
Definition/Etiology
• deficiency in G6PD leads to a lack of reduced glutathione and increased KBC sensitivity to oxidative
stress
• X-linked recessive, prevalent in individuals of African,Asian,and Mediterranean descent
Clinical Features
• frequently presents as episodic hemolysis precipitated by:
oxidative stress
• drugs (e.g.sulfonamide,antimalarials,and nitrofurantoin)
infection
food (fava beans)
• in neonates:can present as prolonged, pathologic neonatal jaundice
Investigations
• neonatal screening
• G6PD assay (may not be useful if result is normal)
should not be done in acute crisis when reticulocyte count is high (reticulocytes have high G6PD
levels)
• blood film
Heinz bodies
bite cells (consistent with oxidative hemolysis; generated by passage through spleen)
Treatment
• genetic and prenatal counselling
• folic acid
• stop offending drugs and avoid triggers
• transfusion in severe cases
to; HiO
J-2GSH GSSG
Glucose NADP- NADPH l
Pentose Phosphate
Lactate
Figure 11. G6PDdeficiency
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H25 Hematology Toronto Notes 2023
Macrocytic Anemia
. MCV >100 fL
• see l
-
'
igure 2, H6
Causes of Macrocytic Anemia Table 15. Comparison Between Megaloblastic and Non-Megaloblastic Macrocytic Anemia
Megaloblastic A8CDEF
Alcoholism (liver disease)
B'
jdeficiency
Compensatory reticulocytosis
Drugs (cytotoxic, azidothymidine)/
Dysplasia
Endocrine (hypothyroidism)
Folate deficiency/Fetus (pregnancy)
Non-Megaloblastic
Laige.oval, nucleated IIBC precursor
Hypetsegmenled neutrophils
Failure of DMAsynthesis resulting in asynchronous
maturation of R8C nucleus and cytoplasm
large round RBC
Normal neutrophils
Reflects membrane abnormality with abnormal cholesterol
metabolism
Morphology
Pathophysiology
Note:MDS is a non.megaloblastic macrocytic anemia Dial commonly presents with oval macrocytosls
Vitamin B12 Deficiency
Characteristics of Megaloblastic
Macrocytic Anemia
• Pancytopenia
• Hypersegmented neutrophils
• Megaloblastic BM
•B12 (cobalamin)
•binds to intrinsic factor (IF) secreted by gastric parietal cells
•absorbed in terminal ileum
•total body stores sufficient for 3-4 yr
Etiology
Table 16. Etiology of Vitamin B12 Deficiency
Diet Gastric Intestinal Absorption Genetic
Strict vegan
More likely to present in
paediatric population
Vegetarian in pregnancy
Malnutrition
Malabsorption
Crohn's, celiac disease,pancreatic
insufficiency.H.pylori
Stagnant bowel
Blind loop,stricture
Fish tapeworm
Resection of ileum
Drugs
Neomycin, biguanides. proton pump inhibitors.
It 0 anesthesia, metlormin
Iranscobalamin II deficiency
IF receptor defect
Mucosal atrophy
Gastritis, autoimmune
Pernicious anemia (see
below)
Postgastrectomy
Pathophysiology of Pernicious Anemia
• auto-Abs produced against gastric parietal cells leading to achlorhydria and lack of IF secretion
• IF is required to stabilize Bi
’
as it passes through the bowel
• decreased IF leads to decreased ileal absorption of B12
• may be associated with other autoimmune disorders ( polyglandular endocrine insufficiency)
• most common in Northern European White populations, usually >30 yr (median age of 60 yr)
Clinical Features
• neurological (severity of anemia and neurological sequelae depends on deficiency)
peripheral neuropathy (variable reversibility)
usually symmetrical, afi'
ccting lower limbs more than upper limbs
spinal cord (irreversible damage)
subacute combined degeneration
posterior columns:decreased vibration sense, proprioception, 2-point discrimination, and
paresthesia
pyramidal tracts:spastic weakness, ataxia
• cerebral (common, reversible with Bi > therapy)
confusion, delirium, and dementia
• cranial nerves (rare)
optic atrophy
Investigations
• CBC, reticulocyte count
anemia often severe ± neutropenia ± thrombocytopenia
• MCV >110 fL
• low reticulocyte count relative to the degree of anemia (<2%)
• serum B12 and RBC folate
caution:lower serum Bi
’
leads to low RBC folate; absence of Bi
’
results in folate polyglutamate
synthesis failure
• alternatively, can measure elevated urine metabolites (methylmalonatc, homocysteine)
• blood film
oval macrocytes, hypersegmented neutrophils
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H26 Hematology Toronto Notes 2023
•BM
• hypercellularity
nuclear-cytoplasmic asynchrony in RBC precursors(less mature nuclei than expected from the
development of the cytoplasm)
•bilirubin and LDH
• elevated unconjugated bilirubin and LDH due to breakdown of cells in BM
•Schilling test (radiolabeled B12 test,rarely done) to distinguish pernicious anemia from other causes
(e.g. anti
-IT antibody, anti
-parietal cell antibody)
Treatment
•treatment dose = vitamin B12 1000 pg1M weekly or 1000-1200 pg PO once daily if intestinal
absorption intact;route and duration depends on cause
•maintenance dose (once replete) = vitamin B 12 1000 pg1M monthly or 1000 pg PO once daily
•watch for hypokalemia and rebound thrombocytosis when treating severe megaloblastic anemia
Folate Deficiency
• uncommon in developed countries due to extensive dietary supplementation (enriched in flour)
• folate stores are depleted in 3-6 mo
• folate commonly found in green, leafy vegetables, and fortified cereals
• maternal folate deficiency is associated with fetal neural tube defects
Etiology
Table 17. Etiology of Folate Deficiency
Diet/Deficiency Malabsorption Drugs Increased Demand
Alcohol use disorder
Substance misuse
Elderly/infants
Poor intake
Celiac disease Antifolate (methotrexate)
Anticonvulsants (phenytoin)
Alcohol
Oral contraceptive
Pregnancy
Hemolysis
Prematurity
Exfoliative dermatitis/psoriasis
Hemodialysis
IBD
Short bowel syndrome
Clinical Features
• anemia, mild jaundice, glossitis, diarrhea, confusion, pallor
• consider social history, alcohol use disorder/substance misuse, very poor diet (e.g. elderly, depressed)
Investigations
• similar to B12 deficiency (CBC,reticulocytes, blood film, RBC folate, and serum B12)
• if decreased RBC folate,rule out B12 deficiency as cause
Management
• folic acid 1-5 mg PO once daily x 1-4 mo; then 1 mg PO once daily maintenance if cause is not
reversible
Never give folate alone to an individual
with megaloblastic anemia because it
will mask B2 deficiency and neurological
degeneration will continue
Hemostasis
Stages of Hemostasis
1. Primary Hemostasis
• cellular defense -involves the platelet and VWI;
predominantly
• goal is rapid cessation of bleeding; main effect is on mucocutaneous bleeding
• vessel injury results in collagen/subendothelial matrix exposure
• blood flow is impeded and platelets come into contact with damaged vessel wall ( figure 12a, H27)
« adhesion:platelets adhere to subendothelium via VWT
• activation:platelets are activated resulting in integrin activation,shape change, and granule
release
• aggregation:activated GPlIbllla on platelets bindssoluble ligands, which results in aggregation
and the formation of a localized platelet plug
2. Secondary Hemostasis
• platelet plug is reinforced by production of a fibrin clot ( figure 12b, H27 )
• extrinsic (initiation) pathway:initiation of secondary hemostasis
• intrinsic (amplification) pathway: amplification once secondary hemostasis hasstarted via positive
feedback
• both the intrinsic and extrinsic pathways converge onto the common pathway, which results in
thrombin generation and fibrin formation
Phases of Hemostasis
• Primary Hemostasis
Vascular response and platelet plug
formation via VWF
• Secondary Hemostasis
Fibrin clot formation
• Fibrin Stabilization
Fibrinolysis
and release of vasoconstrictors
C ]
Check out this educational module
created bySt. Michael'
s Hospital
residents and hematology faculty:www.
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+ 3. Fibrin Stabilization
• conversion from a soluble to an insoluble, cross-linked clot
4. Fibrinolysis
• once healing isinitiated, clot dissolution is mediated by the fibrinolytic system
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H27 Hematology Toronto Notes 2023
INACTIVE ACTIVE EXTRINSIC PATHWAY INTRINSIC PATHWAY
HMWK 5
J5
Tissue Damage
- XII Xlla Antithrombin (AT) Aspirin
”
Clopidogrel
Ticlopidine
GPIIb/llla inhibitors
Dipyridamole
IHMWK
XI —i
— Xla
:
-
Tissue Factor O- H
1
ICa *
•
— IX 1 .IXa — - <s>- H
s
I Fondaparinux
LMWH
| R
'
rvaroxaban
rO- -VII -
Ls
-Vila <0
CN I
-
f
lla VIII Ilia r. o
I
i i
$
COMMON x
PATHWAY t
pO— '
Xa ®- +
BLOODVESSEL
LUMEN OF J— — thromiomodulin V
Protein C
I
Dabigatran
APC
ProteinS
I
I lla — —©
j
I
i
i (Prothrombin) (Thrombin)
l
J
h®~
Fibnnogen
Plasmin
tPA /SK/UK EXPOSED COLLAGEN FIBRESIN SUBENDOTHELIUM Warfarin Plasminogen
Tenecteplase -
J
CrosslinkedFribrin Clot
HMWK'
highmolecular
weight kininogen
PK-prekalikrein
PL -phospholipid
APC - activated protein C
tPA-tissue plasminogen activator
SK - streptokinase
UK ^ urokinase
FDPs -fibrinlogen) degradation
products
LMWH -lowmolecular weightheparin
UFH -unfractionatedheparin
inhibits
a - activated
& von Willebrand factor|VWF) fibrinogen
“
GPIb-binding domain of VWF m inactivatid Gp||b/llla u
. M activated GPIIWIIIa » inhibition
Figure 12a. Platelet activation Figure 12b. Coagulation cascade
Table 18, Commonly Used Tests of Hemostasis Tests of Secondary Hemostasis
Type of
Hemostasis
Test Typical
Reference
Range (lab
dependent)
Purpose Examples of Associated Diagnoses
PT/INR:Tennis is played outside
(Extrinsic pathway)
PTT:Table Tennis is played Inside
(Intrinsic pathway)
Platelet count 130-400 x 10®
/L To quantitate platelet number
28- 38 s
Primary Low in IIP,HUS/TTP.DIC,HIT
Secondary PH Measures intrinsic pathway (factors VIII, Prolonged in hemophilia A and 8 (if factor
IX.XI.XII) and common pathway deficiency is below reagent threshold ol
Used tomonitor heparin and argaltoban detection)
therapy N.6.Prolonged if lupus anticoagulant
present
PI 10 -13 s Measures extrinsic pathway {factor Vll|
and common pathway
Prolonged in vitamin K deficiency, vitamin
K antagonist therapy (warfarin),factor VII
deficiency
INK 0.91.2 Used to monitor warfarin therapy and lor
assessment of hepatic Inaction
Mixing studies Normalization of coagulation time if
coagulation lactor(s) from a deficiency in deficiency of single coagulation (actor
(normalization maynol occur it multiple
Mix patient's plasma with normal plasma coagulation factors are deficient)
in1:1ratio and repeat abnormal test Lack of normalization if inhibitor present
Looks for accelerated fibrinolysis May be shortened (increased fibrinolysis)
in QIC or factor XIII deficiency
May differentiate inhibitors of
coagulation factors
Figure 13. Coagulation factors
involved in PT and PTT
Fibrinolysis Euglobulin lysis N ’
90 mm
lime
Other Fibrinogen
D-dimer
Specific factor assays|o.g.factor VIII)
lupus anticoagulant
von Willebrand tests (VWF antigen. Ristocetin colactor activity,factor VIII)
Causes of a Prolonged PTT without
Bleeding include:
1. Early contact factor (Factor XII.HMWK,
PK) deficiency
2.Lupus anticoagulant
3.Inappropriate blood draw
4.Heparin contamination
5.Erythrocytosis (laboratory artifact)
Note:INR is mathematically derived from PT
Table 19. General Rules of Thumb: Signs and Symptoms of Disorders of Hemostasis
Primary (Platelet, VWF) Secondary (Coagulation)
Surface Cuts
Onset Alter Injury
Site of Bleeding
Excessive,prolonged bleeding
Immediate
Superficial i.e.mucosal (nasal,gingival.Gl
tract, vaginal),skin
Petechiae,ecchymoses
Normal/slightly prolonged bleeding
Delayed
Deep i.e.joints,muscles lexcessive,posttraumatic)
Hemailhroses,hematomas
Consider PTT
• IV heparin,argatroban monitoring
• Hemophilia AJ'B.factor XI deficiency,
severe VWD r -»
Lesions <
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H28 Hematology Toronto Notes 2023
Table 20. Lab Values in Disorders of Hemostasis
PT PTT Platelet Court Hb
Consider PT/INR
• Warfarin
• Liver disease
• Risk factor for vitamin K deficiency
(e.g. malabsorption,cholestasis,
malnutrition)
Hemophilia A/B N K
*
t •
VWD N.
'*
N i H -
DIC t t N / «
Liver Failure N N / 4 '
t N *
IIP N I N
IIP N N »
*
*
anemia may develop from progressiveiron deficiency and/or active bleeding
Consider both PTT and PT/INR
• Suspected DIC
• Trauma patient,or requiring massive
transfusion protocol
• Bleeding patient
• Patient receiving thrombolytic
therapy
Disorders of Primary Hemostasis
Definition
• inability to form an adequate platelet plug due to:
• disorders of blood vessels
disorders of platelets:abnormal function/numbers
disorders of VW1
;
Classification
1‘
Hemostasis Disorders
V '
[PLATELETS ] [ VWD ] [VASCULAR ]
T £ 4
Hereditary
•Osler-Weber-Rendu
* Connective tissue
disorders
Acquired
•Purpura simplex
(easy bruising)
•Senile purpura
•Dysproteinemias
•HSP
•Scurvy
•Cushing's
syndrome
•Inlections
•Drugs
Low platelet count:
• Thrombocytopenia (see H7)
Nonnal platelet count
• Platelet dysfunction
Drugs Commonly Associated with
Thrombocytopenia
Irimethopriraf Heparin NSAIDs
sultanettiorarole
VaiKonpon
Bilanpai
Ettiambclcl
Amphotericin B
i r
Sequestration
• Splenomegaly
Hereditary
* Bernard Soulier
syndrome (GPIb
deticiency)
•Glanrmans
syndrome IGP
llb/llla deficiency)
Acquired
* Drugs (ASA.
EtOH, NSAIDs)
* Uremia/
chronic renal failure
* Myeloprolilerative
disorders
Decreased
production
• Aplastic
anemia
Increased
destruction
•ITP
Digoxin Acetaminophen
Amiodarone Ethanol
Ouinidine H2 antagonists
Ouinine Chemotherapy
(common)
• TTP/HUS
• HIT
HSP - Henoch-Schonlein purpura
Figure 14.Approach to disorders of primary hemostasis
Immune Thrombocytopenia
Table 21. Features for Childhood vs. Adult Immune Thrombocytopenia
Features Childhood ITP (see Paediatrics,P53) Adult ITP
Peak Age 2-6 yr 20- 40 yr
Gender
History of Recent Infection
Duration
Spontaneous Remissions
F-M F»M
Common
Usually wk
80% or more
Rare
Mo to yr
Uncommon
Terminology of ITP
• primary: isolated thrombocytopenia ( platelet count < IOO x I 0
V
/L) with no other cause of
thrombocytopenia
• secondary: thrombocytopenia associated with another condition (e.g. HIV, HCV,SLE, or CLL)
• drug-induced: drug-dependent anti-platelet Abs causing platelet destruction
Classification of Primary ITP
• acute:3 mo from diagnosis
• persistent: 3-12 mo from diagnosis
• chronic: >12 mo from diagnosis
• refractory: post-splenectomy
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H29 Hematology Toronto Notes 2023
Pathophysiology
« primary orsecondary I I P
• an acquired immune-mediated disorder (pathophysiology not completely understood)
increased platelet destruction
anti-platelet Abs bind to platelet surface -> increased splenic clearance
• helper T-cell and cytotoxic T-cell activation
impaired platelet production
Clinical Features
• variable presentation:asymptomatic,fatigue, minimal bruising, mucocutaneous bleed (e.g. purpura,
ecchymoses, petechiae, continuous epistaxis, menorrhagia), and intracranial hemorrhage
• assess for symptoms/signssuggesting a secondary cause
Investigations
• CBC:thrombocytopenia
• PT and P I T: normal
• peripheral blood film:decreased platelets,giant platelets ( rule out platelet clumping)
• H1V.HCV
• H. pylori testing (urea breath test,stool antigen,or endoscopy) vitamin Bn, ANA,C3,C4,APLA,
quantitative immunoglobulins (to rule out underlying immunodeficiency') depending on clinical
symptoms
• blood group RhD typing
• BM aspirate and biopsy:increased number of megakaryocytes
BM aspirate and biopsy should be considered pre-splenectomy or if there is suspicion of
diminished BM function (systemic symptoms,failed traditional1TP and/or abnormal blood film)
Treatment
• rarely indicated if platelets >30 x lO’/L unless active bleeding, trauma,orsurgery
• emergency treatment (active bleeding (CNS, Gl,or GU) or in need of emergency surgery)
general measures:stop drugs that reduce platelet function, control blood pressure,minimize
trauma
corticosteroids:prednisone (0.5-2 mg/kg/d) or dexamethasone (40 mg PO once daily x 4 d)
if corticosteroids contraindicated:IVIg 1 g/kg x I dose, to be repeated if necessary (raises platelet
count faster than corticosteroids)
« IVIg can be used with corticosteroids when a more rapid increase in platelet count isrequired
antifibrinolytic:tranexamic acid (I g PO T1D or 1g1V q8 h) if mucosal bleeding
platelet transfusion:for refractory,major bleeding,or need for urgentsurgery (expect that platelet
recovery will be diminished)
• emergency splenectomy: may be considered, vaccinations prior if possible (.S’, pneumoniae, N.
meningitidis,and H.in fluenzae type b)
management of intracranial bleeding:IV steroids,IVIg, platelet transfusion
• non-urgent treatment (platelet count <20-30 x 109/L and no bleeding)
Ist-line
corticosteroids(dexamethasone 40 mg PO oncedaily x 4 d x 1-4 cycles (not wk) or prednisone
(0.5-2 mg/kg/d) x 2-3wk then slow taper over6 weeks)
IVIg 1 g/kg
anti-D: appropriate for Rh+ non-splenectomized patients, but can cause hemolysis (avoid if
low Hb at baseline or if DAT is positive)
« 2nd-line
splenectomy (need vaccinations prior to splenectomy:5. pneumoniae, N.meningitidis,and H.
influenzae type b) -not preferred if within 12 months from diagnosis
thrombopoietin ( I PO) receptor agonists(romiplostim, eltrombopag) -may not be accessible
assecond line due to funding considerations
rituximab
3rd-line
immunomodulating therapy (azathioprine, cyclophosphamide,danazol, and vincristine)
Syk inhibitors(Fostamatinib) - blocks platelet clearance
Definitions of Response to Treatment
• complete response:platelet count >100 x lO’/L
« partial response: platelet count 30-100 x 10’/L
• no response:platelet count <30 x 109/L
Prognosis
• -20% will not attain a hemostatic platelet count after first and second line therapy
• fluctuating course
• life expectancy similar to general population (however, risk of mortality from bleeding/infection
increases with advancing age)
• major concern isspontaneous intracranial hemorrhage, more common in the elderly
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