02/21/2019

DISORDERS OF COAGULATION AND RBC SYNTHESIS

10:00-12:00
TTh
Pediatrics
LDT 408 Lita Fe Paclibar, M.D.

OUTLINE Mechanism for Hemostasis

I. Relevant Components of Hemostasis 1. Vascular constriction (vascular phase)

II. Hemophilia 2. Formation of platelet plug (primary hemostatic
III. Von Willebrand Disease mechanism: platelet phase)
IV. Thrombotic Disease
3. Formation of a blood clot
V. Disorders of RBC Synthesis
VI. Sources 4. Dissolution of the clot in order for blood flow to
resume
RELEVANT COMPONENTS OF HEMOSTASIS

Endothelial Cells

 Secrete substances that repel platelets (PGI2, ADP,

nitric oxide)
 Initiate coagulation (collagen, fibronectin)
 Promote platelet adhesion (vWF)
 Catalyze inhibition of thrombin (heparin)
 Inhibit fibrin dissolution (tissue plasminogen
activator inhibitor)
Vascular Constriction
 Limits blood flow to the area
Platelets
 Adheres to areas of vascular injury provides surface
for assembly of coagulation factors
 Mediates by contraction by releasing serotonin

Plasma coagulation factor

 Produced in the liver

 Elements in the blood vessel that promote its

constriction or elasticity
 Collagen
 This is a normal blood vessel  Actin
 It has to have an intact endothelium  Myosin
 Cut in the blood vessel  break in the endothelium
 Hemostasis (if no homeostasis, you will lose a lot Vasoconstriction is promoted by:
of blood)  Local myogenic spasm
 Local autacoid factors from traumatized tissues and
blood platelets
 Nervous reflexes

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 Platelets

 Platelets come from megakaryocyte (biggest cell in

the bone marrow)
 Fibrin Plug Formation
 Endomitosis
 Endpoint of coagulation system
 Process wherein megakaryocyte enlarges
 More stable plug to close blood vessel
 nucleus divides but cytoplasm does not

Clotting is prevented in Normal Vessels

 Injuries  break in the endothelium  exposure of
1. Coagulation proteins circulate in inactive forms
collagen  activation of platelets  platelet
 Something has to activate them
adhesion
2. Endothelium is devoid of thrombogenic tissue factor
and collagen
 Platelets stick to the endothelium: platelet adhesion
3. Brisk blood flow remove any activated proteins
 Platelets stick to each other: platelet aggregation

 Extrinsic Pathway: more important pathway

NV OF PLATELETS: 150, 000 – 450, 000
Half life- 8 to 12 days

Platelet Plug
 Platelets bind to collagen on damaged blood vessels
 It is temporary, thus need to be stabilized

 Intrinsic pathway
 Factor 13: aka Contact Factor, Fritsgerald,
Fletcher, Hageman Factor
o High molecular weight kininogen and
Coagulation Cascade Prekallikrein couples with factor 12
 Fibrin stabilizes the platelet plug  Factor 11: activated by Factor 12a
 Factor 9
 Extrinsic Pathway
 Factor 3 (Tissue Factor)
 Factor 7
 Common Pathway:
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  Factor 10  In cases of DIC, there is increased Fibrin degradation
o Activates factor 2 (Prothrombin) to products
Thrombin
o Thrombin activates Factor 1 (Fibrinogen) Characteristics of disorders of plasma phase of coagulation
to Fibrin 1. Hemorrhage resulting from deficient coagulation
2. Thrombosis resulting from excessive coagulation

Clinical Manifestations of Defect in Coagulation

1. Ecchymoses
2. Hematomas
3. Spontaneous or traumatic hemorrhage into deep
tissues esp muscles and joints
4. Delayed bleeding uncontrolled by local measures
 If you handle Hemophiliac patients in the ER
with a history of trauma, you will never go
wrong when you give plasma or factor
concentrate
 Fibrin is stabilized by Factor 13 = more stable clot  In hemophiliacs, vascular and platelet phase are
 Labile Factors/ Cofactors supposed to be intact. Once platelet plug
 Factor 8: cofactor of F9 dissolves and there is no activation of
 Factor 5: Cofactor of F10 coagulation system, that’s when the bleeding
 Those with yellow are Vitamin K dependent factors starts
and requires Calcium or Factor 4  Never send home a hemophiliac patient with a
 Factors 2, 7, 9, 10 history of trauma without giving plasma
products or factor concentrate because they
might go back with severe anemia and
hypotension due to bleeding

Genetics, Prevalence, Symptoms of Inherited Coagulation

Factor Deficiency
Factor Deficiency Genetics Est. Prev. Bleeding
FIBRINOLYSIS
Remove a clot once its usefulness is over Afibrinogenemia AR 1:1 M ++

Dysfibrinogenemia AR +/-
Plasminogen----------------------------------------Plasmin
II AR 1:2 M ++

V (Parahemophilia) AR 1:1 M ++
Tissue plasminogen activator, urokinase

VII AR 1:500,000 +
Plasmin cuts covalently linked fibrin polymers at outer
portion of alpha chains VIII (Hemophiliaa) XLR 1:10,000 +++

vWD 1:1000
Fibrin degradation products or Fibrin split products type 1 AD +

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 type 2 AD ++ Nice to Know: Queen Victoria, Prince Leopold have
hemophilia
type 3 AR ++

IX (Hemophilia B) XLR 1:60, 000 +++

X AR 1:1 M ++

XI (Hemophilia C) AR 1:1 M +

XII AD -

XIII AR 1:1 M +

Prekallikrein AD -
 Hemophilia: x-linked
HMW kininogen AR -  Carrier Mother, Hemophiliac Father
Passovoy AD +/-  Every male offspring, there is a 50% chance of
being hemophiliac and 50% will be normal
Passovoy: discovered in a family in US with bleeding but all  Every female child 50% chance of being
factor assays were normal, PT and aPTT were abnormal, and hemophiliac and 50% will be carrier
they could not identify what clotting factor was deficient  Carrier mother and normal father
 50% male hemophiliac, 50% normal
Conceptualization of Commonly Used Screening Tests of  50% female normal, 50% carrier
Coagulation and the Coagulation Parameters they measure  Normal Mother, Hemophiliac father
 None of the sons will be affected
 All daughters will be carrier

Hemophilia may result from:

 reduction in amount of clotting factor
 production of dysfunctional protein
 no protein produced
 It could be a qualitative or quantitative defect

 aPTT: measures intrinsic and common

 PT: measures extrinsic and common
 Thrombin Time: measures formation of fibrinogen to
fibrin
 We usually use PT and TT

HEMOPHILIA
HEMOPHILIA A & B
“fondness for bleeding”

 Hemophilia A: more common (80%)

 Hemophilia B: 20%, one of the most painful
 If you have an injury  vasoconstriction occurs 
especially when there is bleeding in the joint
platelet plug formation  fibrin clot formation

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  Hemophilia: only platelet plug occurs, so once it seldom
dissolves, they will bleed (oozing type of bleed) spontaneous
hemorrhage
Pathophysiology
Bleeds 4-6x/year
 Factors VIII and IX participate in a complex required
for the activation of factor X. Together with Mild 5-25 Severe
phospholipid and calcium, they form the “tenase,”
hemorrhage only
or factor X–activating, complex. In vivo, the complex
of factor VIIa and tissue factor activates factor IX to ff mod-severe
initiate clotting. trauma or surgery
 After injury, the initial hemostatic event is formation
of the platelet plug, together with the generation of High risk carrier variable Gyne and OB he
the fibrin clot that prevents further hemorrhage. females common, other
 In hemophilia A or B, clot formation is delayed and is symptoms depend
not robust. Inadequate thrombin generation leads to on plasma factor
failure to form a tightly crosslinked fibrin clot to level
support the platelet plug. Patients with hemophilia
slowly form a soft, friable clot. When untreated
bleeding occurs in a closed space, such as a joint,  You do not need to have 100% factor activity in
cessation of bleeding may be the result of order to be hemostatically stable
tamponade. With open wounds, in which
tamponade cannot occur, profuse bleeding may
result in significant blood loss. The clot that is Sample patient Factor VIII assay: Patient = -.83 u/L ( severe
formed may be friable, and rebleeding occurs during hemophiliac)
the physiologic lysis of clots or with minimal new Clinical Manifestations
trauma.  30% of male infants- bleed with circumcision
 1-2% of NB- experience intracranial hemorrhage
1 Unit of Factor- amount found in 1 ml of normal plasma
(expressed in percent) Musculoskeletal Bleeding
 Hallmark of hemophilia- deep bleeding into joints
Relationship of Factor levels to severity of clinical and muscles (hemarthrosis)
manifestations of hemophilia A and B  Bleeding into the joints may be induced by minor
 The severity will depend upon the amount of factor trauma; many hemarthroses are spontaneous.
that you have  Earliest joint hemorrhage appears most commonly in
the ankle.
Type %F VIII/IX Type of  In older child and adolescent, knees and elbows are
Hemorrhage also common.
Severe <1 Spontaneous;  Disorder of platelets: usually no bleeding into joints
hemarthroses and and muscles; only petechiae
deep soft tissue  joint hemorrhage usually begin when the child
hemorrhage reaches toddler age
- toddler: ankle most common site of hemorrhage
Bleeds 2-4 ff by knee
x/month - older child- knees and elbow
 hemorrhage usually preceeded by “aura”- tingling or
Moderate 1-5 Gross bleeding ff
warmth ff by increasing pain and decreased ROM of
mild- mod trauma;
joint
some
hemarthroses;  PE: pain, limitation of ROM of joint warmth,
swelling, tenderness
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  Tx: replacement therapy
- Aspiration of hip hemarthrosis
- Splinting and ice pack
Iliopsoas bleed- troublesome form of IM bleed
 You can’t see the bleed, patient will just have some
pain
 Severe type of bleed
 Diagnosis is made clinically from the inability to
extend the hip but must be confirmed with
ultrasonography or CT
 Vague lower abdomen or upper thigh discomfort
 Hip flexed and inwardly rotated
 PE: unable to extend hip but internal and external
rotation of hip joint is normal
 Potentially life threatening because large volumes of
blood can be lost into retroperitoneal space
 Tx: aggressive infusion
- Maintain for atleast 10-14 days or longer ff by
several months of prophylactic tx until clinical
and radiographic evidence demonstrated
resolution
Life-threatening Hemorrhage
1. Bleeding of CNS
2. Bleeding into and around airways
 can suffocate the patient
3. Exsanguinating hemorrhage
 Like in trauma cases
 Tx: factor conc- bring factor level to normal (achieve
factor level of 100% for FVIII, 80% for F IX)
- Maintain adequate hemostatic levels (>50-60%
for minimum of 14 days)
- Prophylactic tx for 1-2 weeks or longer
 Hemophilia is Aka “Royal Disease” because
concentrates are expensive
Surgery
 Hx & PE
 Measure inhibitor titer
 Inhibitor: just an antibody
 So, if you keep on giving factor VIII or factor IX to
your patients, they will form antibody against
that factor because they don’t have it.
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 You usually measure the inhibitor because you
have to adjust the amount of factor VIII and
Factor IX you give if they have the inhibitor and
your patient will undergo surgery
 Factor conc infusion to achieve level of 80% for F IX,
100% for F VIII pre-op
 You give the infusion before, during, and
after surgery
 so if you have hemophiliac patients,
never let them undergo any form of
surgery, be it minor or major, without
giving your factor concentrates because
severe bleeding can occur
 Maintain levels at >50%-60% for 7-10 days post-op
then >20-30% for 1-2 weeks or until healing has
occurred
Miscellaneous Hemorrhage
 Oral bleeding- fr torn frenulum, tooth extraction
 Tx: replacement tx- 30-40%
Antifibronolytic agents (EACA, tranexamic acid)
- Used to stabilize clot until wound healing
 You have to have bleeding only in the oral
mucosa
 Because in Kidney bleeds or Genitourinary
bleeds when clots are formed and pass out, it’s
really painful
 Hematuria- 40-50% ff by bed rest, steroids
 Summary of usual type of bleeds
Long term complications
 Chronic arthropathy
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 - Natural History: cycle of recurrent hemorrhage 1 “u” FVIII/kg raises F VIII by 2%
into a target joint leading to synovial thickening
or friability ff by additional hges into the joint Ex: 20 kg child, desired level 60%
 Target joint: if you bleed into that joint, it 60 x 20 x 0.5 = 600 “u” F VIII
becomes quite friable, so there will be synovial ½ life of F VIII- 10 to 12 hrs ( at least twice a day)
thickening, and bleeding can further destroy the Given every 8-12 hours ( if bleeding is more severe)
joint
 The synovium thickens and develops frondlike F VIII Treatment Products
projections into the joint that are susceptible to  Recombinant F VIII concentrates- use cloned F VIII
being pinched and may induce further gene
hemorrhage
 Plasma derived F VIII concentrate
- Common in knees, ankles, elbows
 Cryoprecipitate- contains 100 “u” F VIII
- Need prophylactic tx program to prevent
 Cryoprecipitate: from thawed FFP
spontaneous, severe joint bleeding
 If your patient does not have the means to buy you F
- Synovectomy
VIII concentrates, you can give cryoprecipitate
Desmopressin: treat mild- mod Hemo A & VWD
Symptomatic Carriers
Antifibrinolytic therapy: mucosal bleeding
1. Secondary to skewed lionization of a carrier female-
some carriers have high percentage of inactivated
Calculations of Dose (Hemophilia B)
normal X chromosome
2. Testicular feminization of a genotypic male, Turner’s
Dose F IX (units) = % desired rise x BW (kg)
syndrome (XO)
3. Daughter of maternal carrier & father with
1 “u” F IX/kg raises F IX by 1%
hemophilia A

Ex: 20 kg child, desired level 40%

Laboratory
20 x 40 = 800 “u” F IX
 Markedly prolonged PTT
½ life of F IX- 18 TO 24 hrs
 Absence of F VIII or IX
Given OD ( as needed)
 1:1 mixing- detect inhibitors
 Genetic testing- performed on propositus and
Gene Therapy
potential carriers

Complications of Transfusion Therapy

Management
Desired Factor Levels
Joint or simple hematoma
Simple dental extraction
Major soft tissue bleeds
Head Injury
Major surg (dental, ortho etc)
 Transfusion-transmitted infectious diseases: avoided
or minimized by using recombinant F VIII and IX and
50%
newer methods of viral attenuation
50%
 Because Factor VIII are plasma derived and they do
80-100%
not have thorough investigations into whether or
100%
not the donors are HIV carriers
100%

VON WILLEBRAND DISEASE

Calculation of Dose (Hemophilia A)

Von Willebrand Disease (VWD)

Dise of F VIII (units) = % desired rise in plasma F VII x Bw (kg)
 Most common inherited bleeding disorder, with an
x 0.4
estimated prevalence cited at 1 : 100 to 1 : 10,000
depending on the criteria used for diagnosis.

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  Disorder of vW factor, a protein that contributes to Difference between VWD and Hemophilia A
adherence of platelets to damaged endothelium and
serve as carrier protein for F VIII VWD HEMOPHILIA A
 vWF help platelets to adhere to blood vessel and to
Symptoms Bruising, Joint and muscle
aggregate and it is needed to form the platelet plug
espistaxis, bleed
 VWD- most common hereditary bleeding disorder
Mennorhagia
(present in 1-2& of population)
mucosal bleeding
 Quite difficult to diagnose
 In doc’s practice, hemophilias are more common Sexual dist Males = females Males
than vWD
 Patients with VWD typically present with mucosal Frequency 1:100 = 1:500 1:5000 males
bleeding Abnormal vWF F VIII
 Autosomal inheritance, affects males and females, protein
no racial predilection
 vWf- glycoprotein synthesized in megakaryocytes
and endothelial cells and stored in alpha granules Function
and Welbel Palade bodies platelet adhesion Clotting factor

Endothelial cell
 Pathophysiology Site of
VWF Functions megakaryocte
Synthesis
 To tether platelets to injured subendothelium via
binding sites for platelets and for collagen Chromosome Chromosome 12 X Chromosome
 Carrier protein for factor VIII (FVIII), protecting FVIII
Inhibitor Rare 14-25%
from degradation in plasma
 Stored in endothelial cells and in platelet Weibel- Lab test
Palade bodies and circulates as a large multimeric
glycoprotein
History Abnormal Abnormal
Clinical Manifestations
 mucocutaneous hemorrhage including excessive BT Often abnormal Usually Normal
bruising, epistaxis, menorrhagia, postop hemorrhage
PTT Normal or inc Prolonged
especially after mucosal surgery
 more of a platelet disorder F VIII Borderline or dec Decreased or
 normal number of platelets but they can’t stick absent
together
 hemarthrosis rare even in severe VWD
 PTT may be abnormal because vWF also stabilizes F
 stress increases levels of vWf  px undergoing
VIII, so if you have low vWF, FVIII will be easily
major surgery (ex. Appendectomy, childbirth) may
destroyed since it is one of the labile factors
not bleed but may bleed excessively with cosmetic
or mucosal surgery
 Hallmark of vWD: prolonged BT and PTT
 minor surgeries may have more bleeding as
 Hemophilia: abnormal PTT
compared to major surgery

Von Willebrand Variants

 Type 1- most common (85%); decreased vWf
 Type 2A- abnormal proteolysis of vWf, with only
smallest multimers present
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  Type 2B- mutations result in “hyperactive” vWf
 Type 2M- mutations that result in loss of platelet
binding function of vWf
 Type 2N- loss of F VIII binding by vWf (autosomal
hemophilia)
 Platelet type (pseudo) VWD- abnormal vWf
receptors on platelets
 Type 3- undecetable plasma levels of vWf and low
but measurable F VIII
 Type 1 and 3: quantitative defect
o Type 1: decreased
o Type 3: total absence
 Type 2: qualitative defect
 Type 1 & 2: autosomal dominant (even with 1 gene,
patient could already be symptomatic) 50% chance
of being affected
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 Type 3: autosomal recessive (2 genes to be
symptomatic); 25% chance of being affected
Treatment
Desmopressin- effective in type 1 but not in type 2 and 3
Intermediate purify F VIII concentrates containing vWf
1 “u”/kg raises plasma levels by 2%
½ life = 12 hrs
Factor XI Deficiency (Hemophilia C)
 Autosomal deficiency
 Frequent among Ashkenazi Jews
 Bleeding tendency not as great as F VIII or IX
 Bleeding not correlated with amount of FXI
 Dx: prolonged PTT, F XI assay
 Tx: FFP; no F XI conc
Minor surgery- local pressure
Dental extractions- tx if with he
Major Surgery- replacement tx
1 “u”/kg raises plasma levels by 2%
½ life 48 hours or longer
Deficiencies of Contact Factors Nonbleeding Disorders
 F XII, prekallikrein, HMWK- prolonged PTT but no
bleeding
 No treatment necessary
Factor VII Deficiency
 Rare disorder with bleeding only in homozygous
state
 Prolonged PT but normal PTT, decreased FVII on
assay
 Plasma ½ life 2-4 hr; tx: difficult
Factor X Deficiency
 Rare autosomal disorder
 Mucocutaneous and post traumatic bleed
 Prolonged PT, PTT
 ½ life hrs, 1 “u”/kg raises plasma levels by 1%
Fibrinogen Deficiency
 Rare, autosomal recessive
 May present in NB with GI hge or hematomas ff
vaginal delivery
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  Markedly prolonged PT, PTT, TT  Inhibits factors VIIIa and Va ( cofactors)
 ½ life 2-4 Days  Autosomal dominant
 Tx: FFP cryoprecipitate  2 types
Type I- quantitative deficiency
Factor V Deficiency Type II- functional deficiency
 Parahemophilia
 Autosomal recessive Tx: heparin, chronic oral coumarin
 Mucocutaneous bleeding and hematomas
 Prolonged PT, PTT Protein S
 Tx: FFP <2 mos old  Required for optimal expression of anticoagulant
Factor XIII Deficiency activity of activated protein C
 Mild bruising, delayed separation of umbilical  Autosomal domimant
stump >4 weeks, poor wound healing, recurrent  Tx: heparim, chronic oral coumarin
spontaneous abortions
HEMOSTATIC CLASS OF SPECIFIC DRIGS
THROMBOTIC DISEASE PROCESS DRUGS
AFFECTED
Inherited Deficiencies
Primary Antiplatelet Reversible: NSAID
 Antithrombin III
platelet plug drugs
 Protein C Irreversible: ASA
formation
 Protein S
inhibition
 Plasminogen
Coagulation IV Standard and
 These are the naturally occurring anticoagulants cascade anticoagulants LMW

Oral Heparin
 Antithrombin III: acts on all activated clotting factors
Anticoagulants
 Protein C and S: act on F VIII and V Warfarin

Antithrombin III Fibrinolysis Fibrinolytic Streptokinase

agents
 Inhibits thrombin and other activated coagulation Urokinase
factors
t-PA
 Autosomal dominant
 2 categories of deficiency
Type I (classic)- activity and antigen levels are ACQUIRED DISORDERS OF COAGULATION
reduced 50% or more
Type II (functional)- normal antigen levels but
reduced activity
Not all individuals with reduced ATIII have
thrombotic disease
 Recurring deep venous thrombosis with or without
pulmonary embolism
 Tx: mild deficiency: heparin
Severe deficiency- warfarin
Thrombotic episode (acute tx)- heparin +
plasma
Protein C
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  In order for the homeostasis to occur, there must be a
balance between coagulation and fibrinolysis. If there is
an imbalance, Disseminated Intravascular Coagulation
can occur
Disseminated Intravascular Coagulation (DIC)
 Intravascular consumption of platelets and plasma
clotting factors
 Caused by the presence of thromboplastic
substances in the bloodstream (substances that can
trip off the clotting cascade)
Clinical Manifestations
Tissue thromboplastin- responsible for most cases of DIC ACUTE DIC
1. Released from damaged cells
2. Cause blood to clot
Other thromboplastic materials
1. Endotoxin from gram negative bacteria
2. Antigen- antibody complexes ( e.g. Autoimmune
hemolytic anemia, SLE)
3. Shock and tissue acidosis
4. Obstetrical causes ( e.g.retained fetal elements) CHRONIC DIC
5. Injuries and burns
6. Snake venom
 When you have a lot of thromboplastic substances
bombarding your coagulation system, you have a
continuous process of plasminogen formation, fibrin
formation, plasminogen activation, ultimately you will
have a lot of fibrin split products
NET EFFECTS OF DIC
1. Loss of plasma fibrinogen as it is consumed by the
clotting process and by the activation of plasmin
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2. Loss of other clotting factors, notably V, VIII and XIII
as they are used up during the operation of the
clotting cascade.
3. Fall of the platelet count as the platelets aggregate
and leave the circulation
 If you have a lot of fibrin strands, your
platelet could get embedded in fibrin
strands
4. Appearance of fibrin split products as plasmin acts
on its substances
 Mass of thromboplastic material is introduced into
the bloodstream
 Episode is more explosive
- Bleeding
- Traumatic hemolytic anemia
- Bilateral necrosis of the renal cortex
 Because you don’t have good blood flow
into that area
 Thromboplastic material is delivered into the
bloodstream in a slow, steady trickle
- Thrombosis: more common
- Bleeding
 Examples of patients with DIC
 With necrosis of the extremities
 If you cannot reopen the circulation there, sometime
they can be amputated
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 & tissues, “shift to the right” of the
O2 dissociation curve
 Resultant “shift to the right” of the oxygen
dissociation curve reduces the affinity of
hemoglobin for oxygen and results in more
complete transfer of oxygen to the tissues
 Same shift in the oxygen dissociation curve can
also occur at high altitude.
o Few symptoms experienced if
anemia develops slowly

 Clinical features
 Pallor, sleepiness, irritability, and decreased
 RBC Fragmentation: you can see bite cells or
exercise tolerance
schistocytes on peripheral blood smear  Pallor
o involve the tongue, nail beds, palms, or
TREATMENT palmar creases
1. Treat underlying cause  Flow murmur is often present
2. Replacement therapy as indicated  Severe anemia
1. Platelet concentrate o Weakness, tachypnea, shortness of breath
on exertion, tachycardia, cardiac dilation,
2. Cryoprecipitate
and high-output heart failure
3. FFP
3. Intravenous heparinization
 To dissolve the clot

VITAMIN K Deficiency
 Hemorrhagic disease between the 2nd to 4th day of
life
 Usually presents as CNS bleed as
exhibited by bulging of fontanelles
 Manifests as GI bleed, hemorrhage from the
umbilicus or internal hemorrhage
 Responsive to parenteral vitamin K
 Affected factors: Factors II, VII, IX, X
 Rare nowadays, except in those who are home
delivered and not given vitamin K at birth
 Now, Vit K is mandatory
Indicators (WHO)
DISORDERS OF RBC SYNTHESIS Nonpregnant women >15 yo Hb <120 g/L

What is Anemia? Pregnant women any age Hb <110 g/L

Reduction of the red blood cell (RBC) volume or
hemoglobin concentration below the range of values Men >15 yo Hb <130 g/L
occurring in the healthy person
Children 6-60 mos Hb <110 g/L
 <7-8g/dL – pallor becomes evident
 Physiologic adjustments to anemia Children 5-11 yo Hb <115 g/L
 INCREASED Cardiac output,
2
AUGMENTED O extraction, Children 12-14 yo Hb <120 g/L
shunting of blood to the vital organs

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  Blood values of pediatric patients vary o Generalized: malabsorption
according to age syndrome (folic acid, iron)
 Increased loss
o Acute: hemorrhage (iron)
o Chronic: gut bleeding (iron)

B. Bone marrow failure

 Failure of a single cell line
o Megakaryocytes
 Amegakaryocytic
thrombocytopenic purpura with
absent radii (TAR)
o Red cell precursors
 Congenital red cell aplasia
(Diamond Blackfan)
 Acquired red cell aplasia (Transient
erythroblastopenia of childhood)
o White cell precursors
 Congenital neutropenia
 Failure of all cell lines
o Constitutional
 Fanconi anemia
 Familial without anomalies
 Dyskeratosis congenita

What are Red Cell Indices?

Mean cell volume: measures the size of the RBC’s.
 They can be classified as microcytic,
normocytic, or macrocytic

Age Mean -2SD

(g/dL)

1-3 days 108 95

 If you have more loss/ destruction as compared 1 wk 107 88
to production like in cases of hemolysis, then you
can have anemia 2 wk 105 86
 The same amount of blood being destroyed but if
production is deficient because of bone marrow 1 mo 104 85
failure then you can have signs and symptoms of
2 mo 96 77
anemia
3-6 mo 91 74
Anemia
Impaired Red Cell Formation 0.5-2 yr 78 70

A. Deficiency 2-6 yr 81 75
 Decreased dietary intake Ex. Iron deficiency
6-12 yr 86 77
anemia, vegan-vit. B12 deficiency
o Increased demand Ex. Growth (iron), 12-18 yr 90 (F) 78 (F)
hemolysis (folic acid)
 Decreased absorption 88 (M) 78 (M)
o Specific: lack of intrinsic factor
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 Mean corpuscular hemoglobin: estimates the amount of  Mean Cell Hemoglobin Concentration: measures
hemoglobin in the average red cell. the amount of the hemoglobin relative to the size
of the RBC
Age Mean -2SD  MCHC is very important in spherocytosis
(Increased MCHC) because you have the same
(g/dL) amount of hemoglobin in a decreased size of RBC
1-3 days 34 31

1 wk 34 28

2 wk 34 28

1 mo 34 28

2 mo 30 26

3-6 mo 30 25
Normal M:E (Myeloid: Erythroid) = 4:1- 3:1
0.5-2 yr 27 23  In cases of blood loss, more blood cells are
produced
2-6 yr 27 24

6-12 yr 29 25

12-18 yr 30 (F) 25 (F)

30 (M) 25 (M)

Mean Cell Hemoglobin Concentration (MCHC) – estimates

the concentration of Hemoglobin in the average Red Blood
Cell.  More erythroids than Myeloids

Age Mean (g/dl) -2 Standard

Deviations

1-3 Days 33 29

1 Week 33 28

2 Weeks 33 28

1 Month 33 29

2 Months 33 29

3-6 Months 33 30

0.5-2 Years 33 30

2-6 Years 34 31

6-12 Years 34 31

12-18 Years 34 31  In cases of Defective bone marrow (Pure red

cell aplasia)
(Females)
 Even if patient is anemic, it cannot increase
12-18 Years 34 31 production of red cells
(Males)

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 Folic Acid Deficiency
 Abundant in green vegetables, fruits, animal
Reticulocytes organs (liver, kidney)
 Normal percentage in childhood – 1-1.5%  Absorbed throughout small intestine but body
 Absolute reticulocyte count of 25,000-75,000/mm3. stores are limited (megaloblastic anemia occurs
  - marrow able to respond to RBC loss or destruction after 2-3 months of folate-free diet)
  - bone marrow failure or ineffective erythropoiesis  Clin: peak incidence at 4-7 mo of age
 Will tell you a good functioning marrow o Anemia, irritability, failure to gain weight,
chronic diarrhea

Etiology
1. Inadequate folate intake – pregnancy, hemolysis
2. Decreased folate absorption – infectious enteritis,
anticonvulsant drugs
3. Congenital abnormalities in folate metabolism
4. Drug-induced abnormalities in folate metabolism –
methotrexate
Treatment: Folic acid 0.5-1 mg/day
Megaloblastic Anemias Vitamin B12 (Cobalamine) Deficiency
 RBCs larger than normal  Humans cannot synthesize vit B12
 Asynchrony between maturation of nucleus and  We can get it from diet
cytoplasm
 Hypersegmented neutrophils
 Ineffective erythropoiesis
 Resulting from impaired DNA synthesis and nuclear
development
 Peripheral blood smear in megaloblastic anemias
o contains large macroovalocytes, and the
neutrophils often show nuclear
hypersegmentation
 Major causes  Cobalamin is released in your stomach
o Folate deficiency, vitamin B12 deficiency,
and rare inborn errors of metabolism

 and together with R protein and Intrinsic

Factor, it will go down to your duodenum

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 Microcytic Anemia

Iron Deficiency Anemia

 Anemia resulting from lack of sufficient
iron for synthesis of hemoglobin
 Most common hematologic disease of
infancy and childhood

Etiology
1. Low birth weight
 And there it is absorbed together with Intrinsic 2. Perinatal hemorrhage
Factor in the distal ileum 3. Diet
4. Blood loss caused by lesions of GIT,
parasitism, pulmonary hemosiderosis

Clinical
 Pallor, pagophagia, irritability, anorexia,
tachycardia, cardiomegaly, hemic murmur
 Affects attention span, alertness, learning

Lab
 Absent marrow stores
 Carried by transcobalamin to the liver and bone  Low serum ferritin
marrow for the synthesis of RBCs o Provides a relatively accurate
estimate of body iron stores
Etiology  Ferritin: storage form of iron
1. Inadequate vit. B12 intake  Increased in infection (acute phase reactant)
2. Lack of intrinsic factor  Do not get ferritin when there is still infection
3. Impaired vit. B12 absorption  Low serum iron
4. Absence of vit. B12 transport protein  High total iron binding capacity
 Low transferrin saturation
Clinical  Hypochromic, microcytic red cells
 Pallor, glossitis, vomiting, diarrhea, icterus  Low reticulocyte count
 Neurologic symptoms
o parasthesias, sensory deficits, hypotonia,
seizures, developmental delay,
neuropsychiatric changes

Dx: Schilling test

Tx: vit. B12 1-5 ug/day

 In IDA, there is a large central pallor with

 Usually seen in elderlies who have poor diet
decreased RBC size
 Microcytosis

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 Tx: 4-6 mg/kg elemental iron daily in 3 divided doses Acquired Pure Red Blood Cell Anemias
 Do Fecalysis first, make sure that they don’t have  Causes:
parasitism (deworm) o Infection – parvovirus B19
 Urinalysis: look for microcytic hematuria  Causes erythema infectiosum (fifth disease)
 Cytotoxic to marrow erythroid progenitor cells
Responses to Iron Therapy  Binding to the red cell P antigen
Time after Response o Drugs – Chloramphenicol
o Tumor – thymoma
Administration o Autoantibodies vs. EPO
 Treatment
12-24 hours Subjective improvement
o Steroids, IVIG, ATG
36-48 hours BM: erythroid hyperplasia
Transient Erythroblastopenia of Childhood (TEC)
48-72 hours Reticulocytosis, peak at 5-7 days  Most common acquired red cell aplasia occurring in
children
4-30 hours Increase hgb  Previously healthy child, 6mo – 3yrs
1-3 mo Repletion of iron stores  Severe, transient hypoplastic anemia
 Cause : probably viral
(human herpesvirus 6?)
Congenital Hypoplastic Anemia (Diamond-Blackfan   reticulocytes & BM erythroid
Syndrome) precursors
 Rare, congenital bone marrow failure syndrome that o Normal MCV
usually becomes symptomatic in early infancy o Normal HbF, ADA
 Normochromic and macrocytic, reticulocytopenia, and  Recover in 1-2 mos, rare recurrence
insufficient or absent of red blood cell  Suppression of erythropoiesis has been linked to
 Mutations were initially identified in RPS19 immunoglobulin (Ig) G, IgM, and cel lmediated
 15% - recessive or dominant, 25% - mutation in chr mechanisms
19q13
 Profound anemia by 2-6 months of age Anemia of Chronic Disorders and Renal Disease
 No organomegaly initially  Anemia of chronic disease (ACD), also referred to as
 1/3 have congenital anomalies anemia of inflammation
o Craniofacial deformities  Anemia of Renal disease
 Hypertelorism, snub nose, and high arched o common in children with chronic kidney
palate disease (CKD)
o Defects of upper extremities o normocytic, and the absolute reticulocyte
 Thumb abnormalities, including flattening of count is normal or low
the thenar eminence and triphalangeal thumb o hemoglobin has been reported to decline
 Lab: macrocytic RBC’s with increased folic acid & vit. below a GFR threshold of 40-60
B12 mL/min/1.73 m2
o Reticulocytopenia even when anemia is severe  Kidneys are important because they release
o Markedly reduced RBC precursors in BM, other Erythropoietin which is produced in the
elements normal juxtaglomerular apparatus
1. Chronic pyogenic infections
Treatment 2. Chronic inflammatory processes – SLE
 Prednisone – 2mg/kg/day 3. Malignancies
o 1-3 wks – RBC precursors in BM 4. Advanced renal disease – production of EPO
o 4-6 wks – hemoglobin reach normal level  RBC lifespan + marrow hypoactivity + EPO
 Deferoxamine – iron chelator  Defective iron release from tissues to plasma
o Other therapies: androgens, cyclosporine,  Clin: mild to moderate anemia
cyclophosphamide, ATG, IVIG,  Lab: normocytic, normochromic anemia
methyprednisone o Normal or low retic,  WBC,  FEP
 BM Transplantation o  serum iron, /N TIBC

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 o  serum ferritin, normal serum ferritin
receptor
o BM – normocellular, low-normal RBC
precursors, /N marrow hemosiderin
 Treatment & Prognosis: control underlying disease;
hematinics & transfusions not indicated unless
there is underlying deficiency or anemia is severe
o EPO – cancer & ESRD

Congenital Dyserythropoietic Anemias

 Rare, inherited anemias displaying multinuclearity
and abnormal chromatin pattern in RBC precursors
 3 types
o Type I (15%)
 Causative gene (CDAN1) on
chromosome 15 between q15.1 and
q15.3 Physiologic Anemia of Infancy
 Binuclear erythroblasts, thin  Progressive decline in hemoglobin that begins
internuclear chromatin bridges bet. and persists for 6-8 wks
separate erythroblasts, megaloblastic  Factors:
morphology; defect in chr. o With respiration, more O2 is available
15q15.1–15.3; AR for binding to hbg & hgb-O2 saturation
 Associated with dysmorphic features increases from 50-95% or more
o Syndactyly, absence of nails, o Switch to adult hgb synthesis allows
supernumerary toes greater fraction of hgb-bound O2 to the
o Type II (>60%) tissues
 Chromosome 20p11.2 as the location o Increased blood and tissue O2 content
of the candidate CDAN2 gene that was downregulates EPO production, thus
later identified to be the SEC23B gene suppressing erythropoiesis
 HEMPAS (Hereditary Erythroblastic  Lifespan of Newborn RBCs: 90 days
Multinuclearity with Positive Acidified  In adults: 120 days
Serum lysis test); erythroblastic
multinuclearity and positive Ham’s test;
AR
 Characteristic findings
o anemia, jaundice, splenomegaly, or
hepatomegaly
o Posterior mediastinal or
paravertebral masses of
extramedullary hematopoietic
tissue
o Signs of iron overload
o Type III (<15%)
 Gene : KIF23
 Pronounced erythroid multinuclearity; AD
 Blood smear
Premature Infants
o Macrocytes, anisopoikilocytosis, and occasional
 Exaggerated;
basophilic stippling
 more extreme and more rapid decline
 Minimal Hgb 7-9 g/dL by 3-6 wks
 Factors:
o Blood loss through phlebotomy

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 o Suboptimal erythropoietic response to Constitutional Pancytopenias
anemia because of inadequate synthesis Feature Fanconi A. Dyskeratosis C.
of EPO in response to hypoxia
o Absence of 3rd trimester hematopoiesis Genetics AR X-L, AR, or AD
& iron transport
Physical Abn (%) 80 100
o Shorter RBC lifespan (7-9 d)
o Spontaneous resolution by 40 wk Hand/Arm 48 15
gestational age anomaly (%)
 Treatment
o No therapy Age at Dx (yr) 7.5 16
o Ensure infant’s diet contains essential
nutrients for normal hematopoiesis esp. Hema Pancytopenia Pancytopenia
folic acid & iron manifestation

Pancytopenias BM Aplastic Aplastic

 Loss of all marrow elements  anemia, Aplastic Anemia >95 50
neutropenia, thrombocytopenia
(%)
 Causes:
o Failure of production Leukemia (%) 12 0.4
o Increased destruction
o Replacement by tumor or fibrosis Chromosomes Breaks Bleomycin sensitive

Tx, responses BMT, androgens Androgens

Prognosis Poor Poor

Fanconi’s Anemia

In
Normal marrow

 Usually presents with aplastic anemia

 The shorter one has Fanconi’s anemia

 hypoplastic marrow, there are more fats

 Usually associated with epidermal problems

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 o Pregnancy
Feature Schwachman-D Amega. o PNH
o Prelukemia
Synd. Thrombo  Idiopathic
 Hallmark – peripheral pancytopenia with
Genetics AR X-L, AR
hypoplastic or aplastic marrow
Physical Abn 40 60  Severe aplastic anemia – ANC (Actual Neutrophil
Count) <500/mm3, plt <20.000/mm3, retic <1%,
(%) hypocellular BM
 ANC= WBC x Segmenters+ Bands x 1000
Hand/Arm <2 0
 Normal ANC= >1500/mm3
anomaly (%)
 Clin: anemia, leukopenia, thrombocytopenia 
Age at Dx (yr) 4 mo <1 wk fatigue, cardiac failure, infection, bleeding
 DDx: CA, collagen vascular disease, PNH, infections
Hema Neutropenia Thrombcytopenia  Tx: supportive; ATG, steroids, cyclosporine, BMT,
manifestation CSF
 Aplastic anemias are very difficult to treat
BM Hypocellular or Absent/small  Prognosis: poor if severe; spontaneous recovery rare

myeloid arrest mega

SOURCES
Aplastic 20 45  Dr. Paclibar’s ppt
Anemia (%)  Recording
 Nelson Textbook of Pediatrics
Leukemia (%) 5 5

Chromosomes Normal Normal

Tx, responses G-CSF, BMT BMT

Prognosis Fair Poor

Acquired Pancytopenias
 Causes
o Direct destruction of progenitors
o Disruption or destruction of
supporting marrow microenvironment & its
growth factors
o Direct/indirect immune-mediated
destruction of marrow elements

Acquired Aplastic Anemia

 Secondary
o Drugs & Chemicals
 Predictable: Cytotoxic
agents, benzene
 Idiosyncratic:
chloramphenicol, antiepileptics, etc.
o Viruses – EBV, Hep, Parvovirus, HIV
o Immune Diseases –
hypogammaglobulinema
o Thymoma
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