Pharmacotherapy of

Hematological Disorders
by Hailu C.(Asst.Prof)
1
Anemia
Anemia is a symptom of many pathologic conditions
characterized by a decrease in either Hb or RBCs and/or
Hematocrit values
Resulting in a lower ability for the blood to carry oxygen to
body tissues.
Anemia defined as (Hb) <13 g/dL in men or <12 g/dL in
women, WHO

2
WHO,
4 to 5 billion people (66%–80% of the world’s population)-
iron deficient,

Two billion people (30% of the world’s population) are anemic.

During pregnancy, - increased risk for low birth weights,

preterm delivery, and prenatal mortality .

The highest prevalence- women, the elderly, poor children and

low-income persons, (Lozoff B,2006).

3
Pathophysiology

4
Continued…
Anemias can result from
 Inadequate RBC production,

 Increased RBC destruction, or

 Blood loss.

Can be a manifestation of a host of systemic disorders, such

as infection, chronic renal disease, or malignancy.

Rapid diagnosis of the cause is essential.

5
Classification

Anemias can be classified on the basis of

Morphology of the RBCs,
Etiology
Pathophysiology

6
Morphology of the RBCs,
Macrocytic anemias
e.g. Megaloblastic anemias, Vitamin B12 deficiency, Folic acid
deficiency anemia
Microcytic hypochromic anemias
e.g. Iron-deficiency anemia, Genetic anomaly, Sickle cell anemia,
Thalassemia, Other hemoglobinopathies (abnormal hemoglobins)
Normocytic anemias
e.g. Recent blood loss, Hemolysis, Bone marrow failure, Anemia of
chronic disease

7
On the basis of Etiology
Deficiency
• Iron
• Vitamin B12
• Folic acid
• Pyridoxine

Central, caused by impaired bone marrow function

• Anemia of chronic disease
• Anemia of the elderly
• Malignant bone marrow disorders

Peripheral
• Bleeding (hemorrhage)
• Hemolysis (hemolytic anemias)

8
On the basis of pathophysiology
Excessive blood loss
e.g. Recent hemorrhage, Trauma, Peptic ulcer, Gastritis, Hemorrhoids
Chronic hemorrhage
e.g. Vaginal bleeding, Peptic ulcer, Intestinal parasites, Aspirin and
other nonsteroidal anti-inflammatory agents
Excessive RBC destruction
 Extracorpuscular (outside the cell) factors - e.g. RBC antibodies,
Drugs, Physical trauma to RBC (artificial valves), Excessive
sequestration in the spleen
 Intracorpuscular factors- e.g. Heredity, Disorders of hemoglobin
synthesis
9
Continued……
Inadequate production of mature RBCs
 Deficiency of nutrients (B12, folic acid, iron, protein)

 Deficiency of erythroblasts e.g. Aplastic anemia, Isolated (often transient)

erythroblastopenia, Folic acid antagonists, Antibodies
 Conditions with infiltration of bone marrow e.g. Lymphoma, Leukemia,
Myelofibrosis, Carcinoma
 Endocrine abnormalities e.g. Hypothyroidism, Adrenal insufficiency, Pituitary
insufficiency
 Chronic renal disease
 Chronic inflammatory disease e.g. Granulomatous diseases, Collagen vascular
diseases
 Hepatic disease

10
Causes

11
12
 Diagnosis
1. General Presentation
History, physical examination and laboratory testing are used
in the evaluation of anemia.
Anemia of rapid onset -
 Cardio-respiratory symptoms are common.
 such as tachycardia, palpitations, angina, hypotension,
lightheadedness, and breathlessness due to decreased oxygen
delivery to tissues or hypovolemia in those with acute bleeding.
 Severity of symptoms does not always correlate with the
degree of anemia.

13
 Continued…

Chronic onset Anemia- presenting symptoms may

include
 fatigue, weakness, headache, symptoms of heart failure, vertigo,
faintness, sensitivity to cold, pallor, and loss of skin tone.

 Traditional signs of anemia, such as pallor, have limited

sensitivity and specificity and may be misinterpreted.

14
 Continued…
IDA manifestations-

Include glossal pain, smooth tongue, reduced salivary flow,

pica (compulsive eating of nonfood items), and pagophagia
(compulsive eating of ice).

These symptoms are not likely to appear until the Hb

concentration falls to a level of 9 g/dL or below.

15
Continued…
Vitamin B12 deficiency- may include pale and mildly icteric, and
gastric mucosal atrophy.

Neurologic findings- Early findings include

numbness and paresthesia,

then peripheral neuropathy, ataxia, diminished vibratory sense,

decreased proprioception, and imbalance.

Vision changes may result from optic nerve involvement.

16
Continued…
Psychiatric findings- include irritability, personality
changes, memory impairment, dementia, depression, and,
infrequently, psychosis.
Other reported symptoms- include glossitis, muscle
weakness, dysphagia, and anorexia.

Pernicious anemia is associated with increased risk of

gastric cancer.

17
Continued…
Folate deficiency –
symptoms are similar to vitamin B12 deficiency, with the
absence of neurologic symptoms.
The symptoms of vitamin B12 deficiency will improve with
folate replacement but,
The neurologic manifestations - not reversed with folic acid
replacement therapy
Progress or become irreversible if not treated.

18
 Continued…
2. Laboratory Evaluation

The initial evaluation of anemia involves a

 CBC (including RBC indices),
 Reticulocyte index, and
 Examination of a stool sample for occult blood.
The results of the preliminary evaluation determine the need
for other studies, such as examination of a peripheral blood
smear.

19
Continued…
The red cell population is defined by
1.Quantitative parameters:
 Volume of packed cells i.e. the hematocrit
 Hemoglobin concentration
 Red cell concentration per unit volume.
2.Qualitative parameters (Red Blood Cell Indices):
 Mean corpuscular volume
 Mean corpuscular hemoglobin
 Mean corpuscular hemoglobin concentration.

20
Continued…
 Hematocrit ( Packed cell volume): It is the proportion of the volume of
blood sample that is occupied by RBCs.
 Men -42-52%
 Women -36-48%

 Hemoglobin Concentration: It is the amount of hemoglobin per unit

volume of blood.(Gms/Dl)
 Women - 12-16gms/dl
 Men - 14-17 gms/dl

 Red Cell Count: Total number of Red Cells per unit volume of blood
sample. [ No.of RBC/ cu.mm ]
 Men - 4.2-5.4*106//mm3
 Women- 3.6-5.0* 106/mm3
21
Continued…
 Mean Corpuscular Volume: It is the average volume a RBC. [ fL ]
 Normal 82-98(µm)3or 82-98fL

 Mean Corpuscular Hemoglobin: It is the average hemoglobin

content per RBC.
 Normal value is 27 to 31 pL

 Mean Corpuscular Hemoglobin Concentration: - the average

concentration of hemoglobin in a given Red Cell Volume. [Gms/
dL ]
 Normal 32-36 g/Dl
22
Continued…
Total Reticulocyte Count Vitamin B12
Red Blood Cell Distribution Schilling Test
Width(RDW) Homocysteine
Peripheral Blood Smear Methylmalonic Acid
Serum Iron Coombs Test
Total Iron-Binding Capacity
Erythropoietin Levels
Percentage Transferrin
Saturation
Serum Ferritin
Soluble Transferrin Receptor
Folic Acid
23
General algorithm for diagnosis of anemias.

24
Iron Deficiency Anemia

25
Introduction

Diminished red blood cell production due to low iron

stores in the body.

The most common nutritional disorder worldwide

Accounts for approximately one-half of anemia cases.

Result from inadequate iron intake, decreased iron

absorption, increased iron demand, and increased iron loss.

26
Etiology

Results from prolonged negative iron balance or failure to meet

increased physiologic iron need.

The risks are largely related to dietary factors- In less industrialized

nations.

Mal absorptive syndromes

Increased demand for iron –

 frequent blood donations, participation in endurance sports,
menstruation, pregnancy and lactation, infancy, and adolescence.

27
Continued…….

At diagnosis, the cause - blood loss until proven otherwise.

GI bleeding- More than 50% of adults with IDA

Blood loss may occur as a result of many disorders,

Occult blood loss from a single gastrointestinal lesion has been

shown to be a frequent cause of “idiopathic” IDA

28
Pathophysiology
 Iron is vital to the function of all cells.
A critical element in iron containing enzymes
 such as the mitochondrial cytochrome system.
Without iron, cells lose their capacity for electron transport
and energy metabolism.
IDA can be associated with--
 abnormal neurotransmitter function and
 altered immunologic and inflammatory defenses.

29
 Continued……
 IDA- occurs when the Hb falls to less than normal values.
Deficiency progresses to the classic hypochromia and
microcytosis of iron-deficient erythropoiesis.

Another classification of iron deficiency is in accordance with

clinical state:
Iron-store depletion,
Iron-deficient erythropoietin, or IDA.

30
Diagnosis
Requires laboratory-confirmed evidence of anemia, as well
as evidence of low iron stores.
CBC helpful to determine the mean corpuscular volume or
RBC size.
Iron deficiency should be considered in all cases of anemia
unless the MCV > 95 μm3 (95 fL)
A serum ferritin level should be obtained in patients with
anemia and a MCV < 95 μm3

31
 Continued…
• Abnormal laboratory findings - include low serum iron and
ferritin levels and high TIBC.
• The first apparent sign is the increased RDW, although the
finding is not specific to IDA.
In the early stages of IDA,
RBC size is not changed.
Low ferritin concentration is the earliest and most sensitive
indicator
However, ferritin may not correlate with iron stores in the
bone marrow
Hb, Hct, and RBC indices usually remain normal
32
 Continued….
In the later stages of IDA,
Hb and Hct fall below normal values, and a microcytic
hypochromic anemia develops.
Microcytosis may precede hypochromia,
Slightly abnormal Hb and Hct levels –Significant depletion
of iron stores
 In terms of RBC indices, MCV reduction occurs earlier
than does reduction in Hb concentration.

33
 Continued…
Transferrin saturation is useful for assessing IDA.
Low values likely indicate IDA,
low serum transferrin saturation values also may be present
in inflammatory disorders.
The TIBC usually helps to differentiate the diagnosis in these
patients:
 TIBC >400 mcg/dL suggests IDA,
 values <200 mcg/dL usually represent inflammatory disease.

34
Continued….
In microcytic anemias due to all other causes, iron stores
are detectable.

Serum transferrin receptor can be used to diagnose

 iron store depletion and

 defects in iron delivery to the marrow.

An elevated serum transferrin receptor level would be

expected in IDA and a normal level in ACD.
35
Goals of Therapy

To normalize the Hgb and Hct concentrations and

 To replete iron stores.
Up on treatment - reticulocyte count
begin to increase by the third to fourth day and
peak by the seventh to tenth day of therapy.
fall back to normal by the end of the second week
The Hgb response is a convenient index to monitor in
outpatients.
Hematologic response seen in 2 to 3 weeks with
a. 1to 2-g/dL increase in Hgb and
b. 6% increase in the hematocrit.
36
Dietary Supplementation and Therapeutic Iron Preparations
Treatment of IDA
dietary supplementation and
administration of therapeutic iron preparations.
Dietary recommendation-
 Meat, fish, and poultry – Best absorbed
 Veg’, grains, dairy, and eggs- Poorly absorbed
 Ascorbic acid–rich foods should be included with
meals
 Milk and tea in moderation between meals

37
Therapeutic Iron Preparations
Oral administration of iron therapy with soluble Fe2+ iron
salts is appropriate.

All are absorbed similarly (Fe2+ sulfate, succinate, lactate, fumarate,

glycine sulfate, glutamate, and gluconate )

The carbonyl iron -- lower risk for death in accidental overdose

The dose depends on - the patient’s ability to tolerate the

administered iron.
38
 Continued….

Tolerance of iron salts improves

 with a small initial dose and gradual escalation to the full dose.
 General recommendation of elemental iron daily, two or three
divided doses
 If not tolerable,
 smaller amounts of elemental iron (e.g., single 325-mg tablet
of Fe2+ sulfate)

39
Continued….
Administered at least 1 hour before meals

Many patients may experience nausea and diarrhea when

iron is administered on an empty stomach.

40
Continued…..
Adverse reactions
Primarily gastrointestinal in nature and may consist of a
dark discoloration of feces, constipation or diarrhea, nausea,
and vomiting.
Usually are dose-related
Are similar among iron salts when equivalent amounts of
elemental iron are administered.
H2 blockers or PPIs may impair iron absorption.

41
Continued…..
• If side effects become intolerable,

 the total daily dose can be decreased to 110 to 120

mg of elemental iron, or

 the dose can be taken with meals

• However, iron with meals reduces iron absorption by more

than half.

42
 Continued…
causes of treatment failure –
Poor patient adherence, inability to absorb iron, incorrect diagnosis,
continued bleeding, or a concurrent condition that impairs full
reticulocyte response.

Rarely a patient is not able to absorb iron, most often due

to previous gastrectomy or celiac disease.
Mal absorption can be ruled out by the iron test--
treatment should continue for 3 to 6 months after the
anemia is resolved
43
 Parenteral Iron Therapy
Recommended with the evidence of
 iron mal absorption
 intolerance to orally administered iron or
 suspected long-term nonadherence,
 Significant blood loss who refuse transfusions and
 cannot take oral iron therapy
 Does not lead to a quicker hematologic response than that of
oral iron

44
Continued..
Are safe, efficacious, and convenient and would maintain
consistent patient outcomes.
 Iron dextran, sodium ferric gluconate, and iron Sucrose
They differ in their molecular size, degradation kinetics,
bioavailability, and side-effect profiles.
Dextran parenteral preparations have been associated with
death due to anaphylactic reactions.
Studies suggest that Fe3+ gluconate and iron sucrose are
safer than iron dextran.

45
Continued….
The concern with parenteral iron is that
 Iron released too quickly and overload the ability of transferrin to
bind it,

 Leading to free iron reactions that can interfere with neutrophil

function.

Iron dextran contains 50 mg of iron per milliliter and

can be given via the intramuscular or intravenous route.

46
Iron dextran
IM Iron Dextran

Absorption of IM dose of iron dextran occurs in two phases.

Approximately 60% of IM dose is absorbed after 3 days, and

up to 90% is absorbed within 3 weeks.

The remainder is absorbed slowly over several months or

longer.

47
 Continued…
Iron dextran IV,
Small-to- intermediate intravenous doses can be cleared
from the plasma within 3 days of administration.
In contrast, larger intravenous doses of iron dextran are
processed by the mononuclear phagocytic system at a
constant rate of 10 to 20 mg/h and
result in high plasma concentrations of iron dextran for as
long as 3 weeks.

48
Continued…

The iron dextran carries a black box warning regarding the risk of
anaphylaxis and
A test dose is required before administration of the repletion dose.
Methods of intravenous administration include
multiple slow injections of undiluted iron dextran solution or
an infusion of a diluted preparation (total dose infusion)

49
Continued…
Multiple IM injections often are required.

Daily IM doses should not exceed

25 mg in patients weighing < 5 kg, 50 mg in patients weighing <

10 kg, and 100 mg in all other patients.

Problems with IM, - patient discomfort, unpredictable delivery, sterile

abscesses, tissue necrosis, and atrophy.

IV is the preferred parenteral route of administration

 As 30% of an IM administered dose remains physiologically unavailable.

50
Continued…

Test dose should be given

If an anaphylaxis-like reaction occurs - intravenous

epinephrine, diphenhydramine, and corticosteroids.

If the test dose is tolerated, infuse the remaining during the
next 2 to 6 hours.

51
 Continued…

Total replacement doses of IV iron dextran have been given as

a single dose,

The ability to give a total dose infusion is a benefit of iron

dextran over the other parenteral iron products.

Iron dextran is best utilized when smaller frequent doses of

sodium ferric gluconate or iron sucrose are impractical, as with
peritoneal dialysis

52
Continued…..
Total dose infusions - higher risk for adverse reactions,

Patients most likely to experience adverse effects with iron

dextran include
 Individuals with a history of allergies,

Asthma, or inflammatory diseases.

Patients with preexisting immune-mediated diseases

53
Continued…..
Sodium ferric gluconate
FDA-indicated for iron supplementation in hemodialysis patients.

It appears to produce fewer anaphylactic reactions than does iron

dextran

Most hemodialysis patients require a minimum total of 1 g of elemental

iron over eight dialysis sessions to replete their stores.

Side effects - cramps, nausea, vomiting, flushing, hypotension, intense upper gastric pain, rash,
and pruritus.

54
Iron sucrose

For adults undergoing hemodialysis,

administered as an iv dose of 100 mg one to three times per

week to a total dose of 1,000 mg in 10 doses.

can be given directly into the dialysis line by

 slow intravenous injection (20 mg iron [1 mL] per
minute) or

 via infusion without the requirement for a test dose.

55
Iron sucrose
Iron sucrose injection should not be administered
concomitantly with oral iron preparations.

Adverse effects - leg cramps and hypotension.

Well tolerated but has less-than-expected efficacy at

maintaining Hb >11 g/dL and

transferrin saturation >25%.

56
Iron sucrose

• Iron overload (serum ferritin levels >1,100 ng/mL) occurs in

50% of patients studied.

• Oversaturation of transferrin and release of free iron result in

Reduced hematologic response and

Development of high serum ferritin levels

• Overall, iron sucrose has been shown to be safe and efficacious.

57
Evaluation of Therapeutic Outcomes

oral iron therapy - reticulocytosis in 5 to 7 days,

Increase Hb , 2 to 4 g/dL every 3 weeks until Hb is normalized.

Further evaluation- if a Hb response of <2 g/dL over a 3-week

period.

Iron therapy till sufficient for complete restoration of iron

stores.(Serum ferritin concentrations in normal range)

The time interval - at least 3 to 6 months of therapy

58
Evaluation of Therapeutic Outcomes
Therapy for 1 month- negative iron balances caused by bleeding
Long-term t/t (30 to 60 mg of elemental iron daily)-- recurrent
negative balances
Closely monitor when large amounts of parenteral iron are
administered (by total dose infusion or multiple IM/IV doses)
Intolerant of iron dextran - ferric gluconate and iron sucrose
The choice of parenteral iron products depend on
 Cost, number of infusions, impact on need to transfuse, and concurrent EPO
supplementation

59
Evaluation of Therapeutic Outcomes
Regular IV iron - monitored for iron toxicity or overload.
Iron overload- abnormal LFT, serum ferritin >800 ng/mL, or
transferrin saturation >50%.
Serum ferritin and transferrin saturation should be
measured
In the first week after doses of 100 to 200 mg and
2 weeks after larger intravenous iron doses.
Hb and Hct - measured weekly, and
Serum iron and ferritin levels - at least monthly.
Serum iron values - obtained reliably 48 hours after IV
dosing.
60
 Iron supplementation in patients with CKD
Untreated iron deficiency is an important cause of hypo
responsiveness to ESA treatment.

In the absence of menstrual bleeding, it usually results from

blood loss from the GIT.

Additional considerations in CKD patients i.e

 Hemo Dialysis patients are subject to repeated blood loss due to
retention of blood in the dialyzer and. blood lines.

61
Iron supplementation in patients with CKD
 Iron supplementation is widely used in CKD patients to
 treat iron deficiency,
 prevent its development in ESA- treated patients,
 raise Hb levels in the presence or absence of ESA treatment, and
 reduce ESA doses in patients receiving ESA treatment.

 Iron administration is appropriate - when bone marrow iron stores

are depleted or in patients who are likely to have a clinically meaningful
erythropoietic response.
 Avoid iron therapy in patients
 In whom it is unlikely to provide meaningful clinical benifit, i.e., avoid transfusion
and reduce anemia-related symptoms, and
 In whom potential benefit is outweighed by risks of treatment.

62
Megaloblastic Anemias

63
Megaloblastic Anemias

Macrocytic anemias
Megaloblastic
Non megaloblastic

Macrocytosis
caused by abnormal DNA metabolism resulting from
vitamin B12 or folate deficiency.
Other causes - drugs, such as hydroxyurea, zidovudine, cytosine arabinoside,
methotrexate, azathioprine, 6-mercaptopurine

64
Vitamin B12 Deficiency Anemia
Epidemiology

Prevalence of pernicious anemia in the US - 151 per 100,000.

Older adults in the US (up to 15%) have elevated Methyl

Melonic Acid levels and associated low vitamin B12 levels
due to atrophic gastritis and malabsorption of vitamin B12.

65
Etiology

Inadequate intake
strict vegans and only breast-fed infants, chronic alcoholics, and elderly
patients
Malabsorption syndromes
Pernicious anemia
Inadequate utilization
subtotal gastrectomy, atrophic gastritis resulting in decreased acid pepsin
production, and prolonged use of acid suppression therapy

66
Pathophysiology
Result from

Decreased supply (reduced intake, absorption, transport, or utilization) or

Increased requirement (high metabolic consm’n, destruction, and exc’n).

Vitamin B12 works closely with folate in the synthesis of building blocks for DNA
and RNA

In the liver, vitamin B12 is converted to coenzyme B12, which is essential for

Hematopoiesis,

Maintenance of myelin throughout the entire nervous system, and

Production of epithelial cells.

67
Pathophysiology (2)

Total body stores of vitamin B12 range from 2,000 to 5,000mcg

(50% to 90% of which is stored in the liver.)

Because body stores are extensive, 3 to 4 years are required

before symptoms of vitamin B12 deficiency develop.

The neurologic symptoms are associated with a defect in myelin

synthesis and
described as stocking-glove peripheral neuropathy or non
specific complaints (e.g., tinnitus, neuritis, vertigo, headaches).

68
Laboratory Evaluation

MCV usually is elevated to 110 to 140 fL

Mild leucopenia and thrombocytopenia are often present

A peripheral blood smear demonstrates macrocytosis

Accompanied by hyper segmented polymorphonuclear

leukocytes, oval macrocytes anisocytosis, and poikilocytosis.

Other laboratory findings include a low reticulocyte count, low

serum vitamin B12 level (<150 pg/mL), and low Hct.

69
Laboratory Evaluation (2)

As signs and symptoms may not be evident, and serum levels of
vitamin B12 may be within normal limits in the early stages

Measurement of MMA and Homocysteine is useful

Elevations in MMA are more specific for vitamin B12 deficiency,

whereas elevated homocysteine can be indicative of either vitamin

B12 or folic acid deficiency

70
Laboratory Evaluation (3)

Suggestive of B12 deficiency – if Vitamin B12 values <150 pg/mL in

patients with
 macrocytosis, hypersegmented polymorphonuclear leukocytes, peripheral
neuropathy, or dementia

Macrocytosis may be absent if pernicious anemia

complicated by iron deficiency, thalassemia, or a predominant neurologic
involvement.

71
Treatment – Vit. B12 Deficiency
The goals of treatment
reversal of hematologic manifestations,
replacement of body stores, and
prevention or resolution of neurologic manifestations.
Early treatment is of paramount importance because
neurologic damage may be irreversible
Permanent disabilities may range from mild paresthesias and
numbness to memory loss and outright psychosis.

72
 Treatment (2)
In the rare cases of nutritional deficiency, oral or parenteral
vitamin B12 is beneficial.
Counseling patients on the types of foods high in vitamin B12
Daily oral doses (1–2 mg) of vitamin B12 is as effective as IM
administration, In achieving hematologic and neurologic
responses.
If vitamin B12 are low and either MMA or both MMA and
homocysteine levels are elevated,
 1 mg of oral vitamin B12 daily should be considered 73
Treatment (3)
Daily injections of 1,000 mcg of cyanocobalamin for 1 week
To saturate vitamin B12 stores in the body and

Resolve clinical manifestations of the deficiency.

Thereafter, it can be given weekly for 1 month and

Monthly thereafter for maintenance

Vitamin B12 also can be effectively administered

parenterally in 2- to 3-month increments.

74
Treatment (4)

Hydroxocobalamin is a less popular formulation of

parenteral vitamin B12.

1 mg of oral cobalamin daily can be initiated on the due

date of the next injection (from parenteral to the oral form)

75
 .

Adverse effects rare

Uncommon side effects include

hyperuricemia and hypokalemia
Rebound thrombocytosis may precipitate thrombotic events.
Fluid retention [secondary to the sudden increase in production
of RBCs]
Rare cases of anaphylaxis with parenteral administration of
cobalamin

76
 Evaluation of Therapeutic Outcomes
Most patients respond rapidly to vitamin B12 therapy.

Normoblastic Bone marrow - after 24 hours

Reticulocytosis is evident in 2 to 5 days and peaks around day 7.

Hb begins to rise after the first week

Leukocyte and platelet counts normalize after 7 days.

Hyper segmented neutrophils persist for approximately 2 weeks.

77
Evaluation of Therapeutic Outcomes

A CBC count and serum cobalamin level usually are drawn

1 to 2 months after initiation of therapy and 3 to 6 months
thereafter

Homocysteine and MMA levels should be repeated 2 to 3

months after initiation of replacement therapy

Neuropsychiatric signs and symptoms can be reversible if

treated early.

78
Evaluation of Therapeutic Outcomes

If permanent neurologic damage has resulted, progression

should cease with replacement therapy.

Slow response to therapy/failure to observe normalization

of laboratory results may suggest:
 The presence of an additional abnormality such as iron deficiency,
thalassemia trait, infection, malignancy, or misdiagnosis.

79
 Folic Acid Deficiency Anemia
associated with alcoholism, rapid cell turnover, and dietary
deficiency.

also can occur with chronic hemodialysis, diseases that impair

absorption from the small intestine, extensive jejunal
resections, and drugs that alter folate metabolism

Few patients have inborn errors of folate metabolism

80
 Etiology

 Inadequate intake, decreased absorption, hyper utilization

 Folic acid deficiency is associated with poor eating habits,
 it is common in elderly patients, teenagers whose diets consist
of “junk food,” alcoholics, the poverty stricken, and those who
are chronically ill or in demented states.

81
Etiology
 Hyper utilization of folic acid may occur when the
rate of cellular division is increased.
 pregnant women;
 patients with hemolytic anemia,
 malignancy,
 chronic inflammatory disorders
 patients undergoing long-term dialysis;
 burn patients; and
 In adolescents and infants during their growth spurts.

82
Etiology

Some drugs directly inhibit DNA synthesis.

e.g., azathioprine, 6-mercaptopurine, 5-fluorouracil, hydroxyurea, and
zidovudine

Other drugs are folate antagonists;

 the most toxic is methotrexate (other examples include pentamidine,
trimethoprim, triamterene

A number of drugs antagonize folate via poorly understood mechanisms

 e.g., phenytoin, phenobarbital and primidone

83
 Pathophysiology
The earliest signs of deficiency - seen in rapidly proliferating
cells as folate is required for DNA synthesis,
such as those of the bone marrow and gastrointestinal tract.

Severe folate deficiency - cause pancytopenia and megaloblastic

anaemia.

Folic acid is necessary for the production of nucleic acids,

proteins, amino acids, purines, and thymine, and hence DNA
and RNA.
84
Pathophysiology (2)

There is strong evidence of a causal association between

low maternal folate intake/lower folate status and increased risk
of neural tube defects (NTD)

Body stores approximately 5 to 10 mg of folate, primarily

in the liver,

Cessation of dietary folate intake can result in

megaloblastosis within 4 to 5 months.

85
Laboratory Findings

Rule out vitamin B12 deficiency when folate deficiency is

suspected.

Serum folate levels decrease to less than 3 ng/mL within a

few days of reduced dietary folate intake.

The RBC folate level (<150 ng/mL) also declines.

86
Laboratory Findings (2)

Patients with pernicious anemia (60%) have falsely low RBC folate
levels,
If serum or erythrocyte folate levels are borderline, serum homocysteine
usually is increased with a folic acid deficiency.
If serum MMA levels also are elevated, vitamin B12 deficiency must be
ruled out
As folate does not participate in MMA metabolism.

87
 Treatment
Goal of T/T:-

 To induce hematologic remission,

 Replace body stores, and

 Resolve signs and symptoms.

1 mg daily is sufficient to replace stores,1-5 mg daily- malabsorbtion

Parenteral folic acid rarely necessary.

Synthetic folic acid is almost completely absorbed by the GIT and is converted
to tetrahydrofolate without cobalamin.

88
 Treatment (2)

Therapy should continue for 4 months

Low-dose folate therapy (500 mcg daily) can be administered

when anticonvulsant drugs produce a megaloblastic anemia.

Folic acid is nontoxic at high doses and is rapidly excreted in

the urine.

89
Treatment (3)
During pregnancy - manifests as
 an underweight premature infant and
 suboptimal health of the mother.

Preconceptional folic acid supplementation is

recommended to decrease the occurrence and recurrence of
neural tube defects, specifically anencephaly and spina
bifida.

90
Treatment (4)

Supplementation at a dose of 400 mcg daily is recommended in

low risk women.

4 mg daily of folic acid for women

 who have previously given birth to offspring with neural tube defects
or

 those with a family history of neural tube defects should ingest.

It is essential that women in their childbearing years maintain

adequate folic acid intake.
91
Anemia Of Chronic Diseases

Occurs due to decreased RBC production

Normochromic, normocytic anemia

92
 Continued…..

Mechanism of Anemia of Chronic Disease ??

93
Treatment
Factors to address
Concomitant blood loss,
Iron deficiency, or
Deficiencies of vitamin B12 and/or folic acid.
Preferred initial form of therapy- treatment of the
underlying disease

Use of erythropoiesis-stimulating agents (ESAs) and blood

transfusion – when?

94
Hemoglobin target levels

What are the appropriate Hb target levels for the correction of

anemia during ESA therapy?

What if we use ESA therapy to achieve the higher target beyond

the upper normal level?

The FDA recommends that

Hb be measured twice per week for 2-6 weeks after a dose adjustment

Withholding the dose of the ESA if the Hb is >12 g/dL or increases by 1

g/dL over a 2-week period.

95
ESA therapy
FDA-approved uses
 patients with cancer receiving chemotherapy,

 patients with chronic kidney disease, and

 patients with HIV receiving myelosuppressive therapy.

Effective when the marrow has an adequate supply of iron, cobalamin, and
folic acid.

The dosage of epoetin alfa is 50 to 100 units/kg three times per week.

Max -150 units/kg/dose

96
Adverse effects of ESAs

Long-term treatment - systemic blood pressure and

occurrence of seizures

Blood pressure should always be closely monitored

Others

nausea, headache, fever, bone pain, and fatigue.

seizures, thrombotic events, and allergic reactions such as

rashes and local reactions at the injection site

97
ESA resistance
Is the requirement for greater than 150 units/kg of ESA at least
3 times per week or
The sudden response refractoriness to a previous stable
maintenance dose (hemoglobin levels fall below target levels)
The most common cause of ESA resistance??
Iron deficiency

chronic infection/inflammatory state (IL-1)

Hyperparathyroidism

Severe malnutrition

98
 Role of iron

Oral iron supplementation should be given if Transferrin

saturation drops below 20% or the serum ferritin level drops below
100 ng/mL.

Current guidelines recommend against use of iron products when

ferritin is 500 ng/mL or greater.

99
Coagulation Disorders

100
Blood Coagulation Pathways

101
Coagulation Disorders
1. Congenital Coagulation Disorders
 Hemophilia
 Von Willebrand Disease
2. Acquired Coagulation Disorders
 Disseminated Intravascular Coagulation
 Vitamin K Deficiency

102
 1. Congenital Coagulation Disorders
Hemophilia

A bleeding disorder that results from a congenital deficiency in a plasma

coagulation protein.

Two types

Hemophilia A (classic hemophilia)

hemophilia B (Christmas disease)

The incidence of hemophilia A is approximately 1 in 5,000 male births.

Hemophilia B occurs less commonly, with only one fourth the incidence of
hemophilia A.

103
 Clinical Presentation
 Hemarthrosis (especially knee, ankle, Potential life-threatening blood loss,
and elbow) especially with thigh bleeding

Joint pain Oral bleeding with dental extractions or

Joint swelling and erythema trauma

Decreased range of motion Hematuria

Muscle hemorrhage Intracranial hemorrhage (spontaneous or

following trauma)
Swelling
Excessive bleeding with surgery
Pain with motion of affected muscle

Signs of nerve compression

104
Laboratory Testing
Prolonged aPTT

Decreased factor VIII or factor IX level

Normal PT

Normal platelet count

Normal von Willebrand factor antigen and activity

Normal bleeding time

105
Treatment
may involve the following:
 Management of hemostasis

 Management of bleeding episodes

 Use of factor replacement products and medications

 Treatment of patients with factor inhibitors

 Treatment and rehabilitation of patients with hemophilia

synovitis

106
Hemophilia A
 For treatment of acute bleeds, target levels by hemorrhage
severity are as follows:
Mild hemorrhages: Maintain an FVIII level of 30%

Major hemorrhages : Maintain an FVIII level of at least 50%

Life-threatening bleeding episodes : Maintain an FVIII level of 80-100%

Units of factor VIII needed to correct the factor VIII activity
level
Units factor VIII = (weight in kg)(50 mL plasma/kg)(1 U factor
VIII/mL plasma)(desired factor VIII level minus the native factor
VIII level)

107
FVIII regimens are as follows:
The second dose should be administered 12 hours after the initial dose
and is one half the initial calculated dose

Minor hemorrhage requires 1-3 doses of FVIII

Major hemorrhage requires many doses and continued FVIII activity

monitoring with the goal of keeping the trough activity level at least
50%

Continuous infusions of FVIII may be considered for major

hemorrhage.

108
The following types of FVIII concentrates are available:

Plasma-based products
First-generation recombinant products: Produced in mammalian
cell lines, with a small amount of human serum albumin added
for stability
Second-generation recombinant products: Manufactured
without human albumin
Third-generation products: Have no exposure to animal
proteins

109
Desmopressin :
Considered the treatment of choice for mild and moderate
hemophilia A

Not effective in the treatment of severe hemophilia

Can be intravenously administered at a dose of 0.3 mcg/kg of

body weight in the inpatient setting

Peak effect is observed in 30-60 minutes

A concentrated DDAVP intranasal spray is available for

outpatient use
110
Antifibrinolytics for oral mucosal hemorrhage and
prophylaxis:

Epsilon aminocaproic acid (Amicar)

Tranexamic acid (Cyklokapron)

111
Treatments used in patients with inhibitors of FVIII

High doses of FVIII for low-titer inhibitors

Anti-inhibitor coagulant complex

Porcine FVIII, which has low cross-reactivity with human FVIII antibody

Activated prothrombin complex concentrate (PCC)

Activated FVII- by passing agent

Desensitization

Immune tolerance induction (ITI)

112
Hemophilia B

Factor IX is the treatment of choice for acute hemorrhage or

presumed acute hemorrhage in patients with hemophilia B.

Recombinant factor IX is the preferred source for

replacement therapy.

113
Medications used in the management of hemophilia B

Factor IX-containing products (eg, factor IX, recombinant

factor IX, factor IX complex)

Recombinant coagulation factor VIIa

Recombinant coagulation factor IX

Antifibrinolytics (eg, epsilon aminocaproic acid,

tranexamic acid)

114
 Continued...

Antihemophilic agents (eg, desmopressin, human antihemophilic

factor, recombinant human antihemophilic factor, plasma-derived

prothrombin complex concentrates/factor IX complex concentrates,

plasma-derived coagulation factor IX concentrate)

Monoclonal antibodies (eg, rituximab)

Analgesics (eg, narcotic agents, NSAIDS, acetaminophen with

codeine or synthetic codeine analogs)

115
Pain Management
can be challenging in patients with severe hemophilia

Nonsteroidal anti-inflammatory drugs may be used because

 their effects on platelet function are reversible and

 these drugs can be effective in managing acute and

chronic arthritic pain.

Avoid aspirin because of its irreversible effect on platelet

function.

116
Von Willebrand Disease

A common, inherited, genetically and clinically

heterogeneous hemorrhagic disorder

Caused by a deficiency or dysfunction of the protein termed

von Willebrand factor (vWF).

Consequently, defective vWF interaction between platelets

and the vessel wall impairs primary hemostasis.

117
Continued…
vWD is divided into three major categories:

1. partial quantitative deficiency (type I),

2. qualitative deficiency (type II), and

3. total deficiency (type III)

vWD type II is further divided into four variants (IIA, IIB,
IIN, IIM), based on characteristics of dysfunctional vWF.

118
Clinical presentation

 Nose bleeds and hematomas – most common

Prolonged bleeding from trivial wounds, oral cavity

bleeding, and excessive menstrual bleeding -common.

Gastrointestinal bleeding rarely occurs

119
Treatment
The main treatment options are

Desmopressin (DDAVP),

Recombinant von Willebrand factor (rVWF)

von Willebrand factor/factor VIII (vWF/FVIII)

concentrates.

120
Type I von Willebrand disease
DDAVP is the treatment of choice
Typically, a maximal rise of vWF and FVIII is observed in 30-
60 minutes.
Dosing DDAVP at 24 hour intervals - reduce the risk of side
effects without significantly compromising vWF activity/FVII
Standard IV and SC DDAVP doses are 0.3 µg/kg, but
a fixed dose of 15 µg for patients over 50 kg,
Fluid retention and hyponatremia are common complications

121
Type II von Willebrand disease
Responses to DDAVP are variable in such patients
some respond while others should receive vWF
concentrates.
vWD type IIA have a response to DDAVP, with peak vWF
and FVIII levels at 30-60 minutes.
contraindicated in patients with type IIB,.
Not effective in patients with type IIM and
Rarely effective in patients with type IIN.

122
Type III von Willebrand disease
have a virtually complete deficiency of vWF

Thus, DDAVP has no effect in such patients

The treatment of choice for patients with vWD type III is

rVWF (with or without FVIII) or

virus-inactivated, vWF-containing FVIII concentrates

123
 2. Acquired Coagulation Disorders
Vitamin K Deficiency
It is a cofactor for activation of factors II, VII, IX, and X
Also necessary for the active forms of proteins C and S, which
inhibit factor Va and VIIIa.
Vitamin K1, phytonadione, is found in green vegetables.
Bacteria in the large intestine produce vitamin K2, the
menaquinones,
which require bile salts to be solubilized and absorbed

124
VK deficiency

Infants with VK deficiency are at risk for hemorrhagic

disease of newborn,

About 80-85% of VK is absorbed in the terminal ileum

into the lymphatic system;

 Bile salts and normal fat absorption, as well as normal

functioning villi of the ileum, are necessary

125
Etiology
In infants, the followings account for VK deficiency
The low transmission of vitamin K (VK) across the placenta,
Liver prematurity with prothrombin synthesis,
Lack of VK in breast milk, and
The sterile gut in neonates.

Neonatal diseases that cause cholestasis can result in VK

deficiency.

126
In adults, the causes of VK deficiency include
Chronic illness
Malnutrition
Alcoholism
Multiple abdominal surgeries
Malabsorption syndromes
Infectious diarrhea
Cholestatic disease
Parenchymal liver disease
Cystic fibrosis
Inflammatory bowel
disease
 Drugs
 Massive transfusion
 Parenchymal liver
diseases
 Chronic kidney
disease/hemodialysis
 Malabsorption syndrome
 Biliary diseases
 Dietary deficiency
127
 Treatment
The goals of therapy are to
correct the deficiency,

reduce morbidity, and

prevent complications.

Newborns - VK-1 im injections to prevent bleeding problems.

In adults, VK-1 - administered sc or im.

If the PT does not normalize, good evidence exists for the
presence of liver disease or Disseminated intravascular
Coagulation
128
Treatment
Phytonadione is used to treat vitamin K deficiency.

The dose, frequency, and duration of vitamin K depend on

 the severity of the deficiency and the patient’s response.

Severe hypoprothrombinemia - avoid the intramuscular route

IV administration- restricted to patients who are

 Thrombocytopenic

 unable to absorb the drug via the gastrointestinal tract

129
Treatment (2)
 After an oral vitamin K1, blood coagulation factors
increase within 6 to 12 hours.

 When vitamin K1 is administered parenterally, PT may

take 12 to 24 hours to normalize.

 Failure of vitamin K1 to correct PT after 48 hours ??

 Patients with life-threatening bleeding should receive

fresh frozen plasma
130
Treatment (2)
Patients with malabsorption or obstructive jaundice require
parenteral administration of vitamin K.

Phytonadione 10 mg weekly usually is sufficient in adults.

If a high risk for hematoma formation with im or sc VK

 Oral form of VK can be administered in 5- to 20-mg doses,
depending on the severity

131
Thanks !