(Med-Ho) 02 Aplastic Anemia, Aiha, PV

MEDICINE 2 – [HEMA-ONCO]: BGD
AY 20-21
18 SEPT 20
MED 2 Hema-Onco Consultants
TABLE OF CONTENTS C. CLINICAL MANIFESTATIONS ........................................ 20
D. DIAGNOSIS ..................................................................... 20
I. APLASTIC ANEMIA..................................................................1
E. COMPLICATIONS ........................................................... 20
A. DEFINITION .......................................................................1
F. TREATMENT ................................................................... 20
B. EPIDEMIOLOGY ................................................................1
ESSENTIAL THROMBOCYTOSIS .................................................. 20
C. ETIOLOGY .........................................................................2
A. DEFINITION AND EPIDEMIOLOGY ............................... 20
D. PATHOPHYSIOLOGY .......................................................3
B. CLINICAL MANIFESTATIONS ........................................ 20
E. CLINICAL FEATURES .......................................................3
C. DIAGNOSIS ..................................................................... 20
F. LABORATORY STUDIES ..................................................4
D. COMPLICATIONS ........................................................... 21
G. DIAGNOSIS ........................................................................4
E. TREATMENT ................................................................... 21
H. COMPLICATIONS..............................................................5
IV. APPENDIX .............................................................................. 22
I. PROGNOSIS ......................................................................5
J. TREATMENT......................................................................5 MUST KNOW BOOK PREVIOUS TRANS
K. OTHER INFORMATION ....................................................6
PURE RED CELL APLASIA ...............................................................6
  
A. INTRODUCTION ................................................................6 Red is based on BGD Subgroup 2 report. Blue is based on BGD Subgroup 1
B. DEFINITION AND DIFFERENTIAL DIAGNOSIS .............6 report
C. CLINICAL FEATURES AND ETIOLOGY ..........................7 I. APLASTIC ANEMIA
D. TREATMENT......................................................................7
MYELODYSPLASTIC SYNDROME ..................................................7 A. DEFINITION
A. DEFINITION .......................................................................7
B. EPIDEMIOLOGY ................................................................7
● Pancytopenia with bone marrow HYPOCELLULARITY | 
C. ETIOLOGY AND PATHOLOGY ........................................7 ● Blood count depression: moderate or incomplete
D. CLINICAL FEATURES .......................................................8 → Results in anemia, leukopenia, thrombocytopenia, or
E. LABORATORY STUDIES ..................................................8 combination
F. PROGNOSIS ......................................................................9 ● Related to Paroxysmal Nocturnal Hemoglobinuria and
G. TREATMENT......................................................................9 Myelodysplastic Syndromes
MYELOPHTHISIC ANEMIA ...............................................................9 Acquired
A. DEFINITION .......................................................................9
B. PATHOLOGY AND ETIOLOGY ........................................9 ● Abrupt onset of low blood counts in a previously well young
C. SECONDARY MYELOFIBROSIS .....................................9 adult
II. AUTOIMMUNE HEMOLYTIC ANEMIA..................................10 ● Seronegative hepatitis or a course of incriminated medical drug
A. DEFINITION .....................................................................10 may precede onset
B. EPIDEMIOLOGY ..............................................................10 ● Acute history
C. ETIOLOGY .......................................................................10 ● Chemical exposure – benzene
D. PATHOPHYSIOLOGY .....................................................10 ● Radiation exposure (chemoradiotherapy)
E. CLINICAL FEATURES .....................................................10 ● Infectious processes – viruses
F. LABORATORY STUDIES ................................................10 → Parvovirus B19 (pure red cell aplasia)
G. COMPLICATIONS AND PROGNOSIS ...........................11 → Hepatitis (non-A, non-B, non-C hepatitis)
H. TREATMENT....................................................................11 → HIV-1 (AIDS)
I. OTHER INFORMATION ..................................................12 → EBV (Infectious mononucleosis)
HEMOLYTIC ANEMIA ......................................................................12 → CMV
A. INTRODUCTION ..............................................................12 ● Iatrogenic: Marrow hypocellularity after intensive cytotoxic
B. DEFINITION .....................................................................12
chemotherapy
C. CLINICAL FEATURES .....................................................12
D. PATHOPHYSIOLOGY .....................................................12 Constitutional/Inherited
INHERITED HEMOLYTIC ANEMIA .................................................12 ● Usually present in early childhood and have typical physical
A. HEMOLYTIC ANEMIA DUE TO ABNORMALITIES OF anomalies
MEMBRANE-CYTOSKELETON COMPLEX ..............................12 ● Fanconi anemia
B. DISORDERS OF CATION TRANSPORT .......................13 ● Dyskeratosis congenita
C. ENZYME ABNORMALITIES ............................................13 ● Telomere diseases
ACQUIRED HEMOLYTIC ANEMIA .................................................14
● Gene mutations (GATA2, RUNX1, MPL)
ACUTE BLOOD LOSS .....................................................................15
III. POLYCYTHEMIA VERA.........................................................16 B. EPIDEMIOLOGY
A. APPROACH TO POLYCYTHEMIA .................................16 ● Europe and Israel – 2:1,000,000 annually
B. DEFINITION .....................................................................17
● Thailand and China – 5-7:1,000,000
C. EPIDEMIOLOGY ..............................................................17
D. ETIOLOGY .......................................................................17
● Men and women affected equally
E. PATHOPHYSIOLOGY AND CLINICAL FEATURES ......18 ● Biphasic age distribution – peak in teens/20’s and older adults
F. LABORATORY STUDIES ................................................18
G. DIAGNOSIS ......................................................................18
H. COMPLICATIONS............................................................18
I. PROGNOSIS ....................................................................18
J. TREATMENT....................................................................19
PRIMARY MYELOFIBROSIS ...........................................................19
A. DEFINITION AND EPIDEMIOLOGY ...............................19
B. ETIOLOGY .......................................................................20
MUNAR, MARIANO | LETRAN, MANGALI, MENDOZA, NG, NUCUP, OBCEMEA, ONGCHINKE, PADOLINA, PAZON, PELIGRO, PUA PHEE, Page 1 of 23
QUILANG
MED 2-HO 1.02 – Aplastic Anemia, Autoimmune Hemolytic Anemia, Polycythemia Vera (18 SEPTEMBER 2020) Page 2 of 23
C. ETIOLOGY ● Most cases are idiopathic

● Little other than history separates these cases from those with a
Table 1. Differential Diagnosis of Pancytopenia
presumed etiology
Pancytopenia with Hypocellular Bone Marrow
Acquired aplastic anemia Radiation
Constitutional aplastic anemia (Fanconi anemia, dyskeratosis ● Marrow aplasia – major acute sequelae of radiation | 
congenita, and others) ● Damages DNA – tissues dependent on active mitosis are
Hypocellular myelodysplastic syndrome susceptible
Rare aleukemic leukemia ● Nuclear accidents
Some acute lymphoid leukemia → Power plant workers, employees of hospitals, laboratories,
Rare lymphomas of bone marrow industry, and innocents
Copper deficiency
● Dose - approximated from rate and degree of decline in blood
Pancytopenia with Cellular Bone Marrow
counts
Primary bone marrow diseases Secondary to systemic diseases
● Dosimetry
Myelodysplastic syndromes Systemic lupus
→ Reconstruction of exposure
Paroxysmal nocturnal erythematosus
hemoglobinuria (PNH) Hypersplenism → Estimate prognosis
B12, folate deficiency → Protect medical personnel from contact with radioactive
Myelofibrosis Copper deficiency tissue/excreta
Aleukemic leukemia Alcohol ● MDS and Leukemia (not aplastic anemia) – late effects
Myelophthisis HIV infection Chemicals
Brucellosis
● Benzene – notorious cause
Bone marrow lymphoma Sarcoidosis
Hairy cell leukemia Tuberculosis
→ Aplastic anemia
Leishmaniasis → Acute Leukemia
Sepsis → Blood and marrow abnormalities
Hypocellular Bone Marrow ± Pancytopenia ● Leukemia – cumulative exposure and susceptibility
Q fever (causative agent: Coxiella burnetii) → Employment history is important!
Legionnaires’ disease ● No longer used as a household solvent
Anorexia nervosa, starvation ● Exposure to its metabolites occur in normal diet and
Mycobacterium environment
Table 2. Classification of Aplastic Anemia and Single Cytopenias
● It is important to ask how long the exposure is
ACQUIRED INHERITED/CONSTITUTIONAL Drugs
Aplastic Anemia ● Many chemotherapeutic drugs have marrow suppression as
Secondary Fanconi anemia major toxicity in which effects are dose dependent
Radiation Dyskeratosis congenita/ → Agents that regularly produce marrow depression in
Drugs and chemicals telomere disease commonly used doses or normal exposures
Regular effects Shwachman-Diamond
■ Cytotoxic drugs used in chemotherapy: alkylating agents,
Idiosyncratic reactions syndrome
antimetabolites, antimitotic
Viruses Familial aplastic anemia/
Epstein-Barr virus leukemia predisposition
■ Some antibiotics
(infectious syndromes: GATA2, RUNX1, → Agents that frequently but not inevitably produce
mononucleosis) CTLA4, and others marrow aplasia
Hepatitis (non-A, non-B, ■ Benzene
non-C hepatitis) → Agents associated with aplastic anemia but with a
HIV-1 (AIDS) Nonhematologic syndromes relatively low probability
Immune diseases (Down, Dubowitz, Seckel) ■ Chloramphenicol
Eosinophilic fasciitis ■ Insecticides
Hypoimmunoglobulinemia ■ Antiprotozoals (quinacrine)
Large granular ■ NSAIDS (phenylbutazone)
lymphocytosis (LGL) ■ Anticonvulsants (hydantoins, carbamazepine)
Thymoma/thymic ■ Heavy metals (gold)
carcinoma ■ Sulfonamides
Graft-versus-host disease ■ Antihistamines (cimetidine)
in immunodeficiency ■ D-penicillamine
Paroxysmal nocturnal
■ Estrogens
hemoglobinuria (PNH)
Pregnancy
→ Agents whose association with aplastic anemia is more
Idiopathic tenuous
Cytopenias ■ Other antibiotics
PRCA Congenital PRCA (Diamond- ■ Sedatives and tranquilizers
Blackfan anemia) ■ Allopurinol
Neutropenia/ agranulocytosis ■ Methyldopa
Idiopathic Kostmann syndrome ■ Quinidine
Drugs, toxins Shwachman-Diamond ■ Lithium
LGL syndrome ■ Guanidine
Pure white cell aplasia (+/-) Reticular dysgenesis ■ Potassium perchlorate
thymoma) ■ Thiocyanate
Thrombocytopenia Amegakaryocytic ■ Carbimazole
Drugs, toxins thrombocytopenia
Acquired amegakaryocytic Thrombocytopenia with absent Infections
thrombocytopenia radii ● Post Hepatitis marrow failure accounts for ~5%, which is
Other rare germline mutations seronegative (non-A, non-B, non-C)
● Infectious mononucleosis is rarely followed by aplastic anemia
● Parvovirus B19 does not usually cause generalized bone Shwachman-Diamond Syndrome
marrow failure ● Presentation is early in life with neutropenia with pancreatic
● Transient, mild blood count depression is frequent in the course insufficiency and malabsorption
of many viral and bacterial infections ● Most patients have compound heterozygous mutations in SBDS
Immunologic Diseases that may affect both ribosomal biogenesis and marrow stroma
● Aplasia is a major consequence and inevitable cause of death function
in TA-GVHD that can occur after infusion of non-irradiated blood D. PATHOPHYSIOLOGY
products to an immunodeficient recipient ● Results from severe damage to the hematopoietic cell
● Strongly associated with the rare collagen syndrome compartment
eosinophilic fasciitis – painful induration of subcutaneous ● In morphology of the biopsy specimen & MRI of spine
tissues replacement of the bone marrow → fat
● Occasional associations with thymoma and ● Cells with CD34 antigen (marker of early hematopoietic cells)
hypogammaglobulinemia → Greatly diminished
● Pancytopenia with marrow hypoplasia can also occur in SLE ● Committed and primitive progenitor cells
Pregnancy → virtually absent
● Very rarely may occur and recur during pregnancy; resolves ● In in vitro assays (in severe cases)
with delivery or with spontaneous or induced abortion → stem cell pool is reduced to ≤1%
● In constitutional aplastic anemias: intrinsic stem cell defect
Paroxysmal Nocturnal Hemoglobinuria
● In Fanconi anemia: chromosome damage and death on
● Acquired mutation in PIG-A gene. exposure to certain chemical agents
● Patients with an initial clinical diagnosis of PNH, especially ● Shorten telomeres due to
younger individuals, may later develop frank marrow aplasia → heterozygous mutations in genes of the telomere repair
and pancytopenia complex
● Patients with an initial diagnosis of aplastic anemia may suffer → replicative demands on a limited stem cell pool
later from hemolytic PNH years after recovery of blood counts
Chemical and Drug Injury
Constitutional Disorders
● Due to high doses of radiation and toxic chemicals
● Genetic mutations are also risk factors for bone marrow failure ● Idiosyncratic reaction
● Mutations in TERT and TERC have subtle effects on → Due to altered drug metabolism
hematopoietic function ● Drugs which are polar and have limited water solubility
● Typical presentations include not only severe but also moderate → Involve enzymatic degradation to highly reactive electrophilic
aplastic anemia, which can be chronic and not progressive, and compounds
isolated macrocytic anemia or thrombocytopenia → Intermediates are toxic because of their propensity to bind to
● Physical anomalies are usually not found in the patient, cellular macromolecules
although early hair graying is a clue to the diagnosis. ● Example: derivative hydroquinones and quinolones
● A careful family history may disclose pulmonary fibrosis and → Responsible for benzene-induced tissue injury
hepatic cirrhosis. ● Excessive generation of toxic intermediates or failure to detoxify
● Variable penetrance means that TERT and TERC mutations the intermediates
represent risk factors for marrow failure, as family members with → May be genetically determined
the same mutations may have normal or only slight hematologic → Apparent only on specific drug challenge
abnormalities but more subtle evidence of (compensated)
hematopoietic insufficiency Immune-Mediated Injury
● Blood and bone marrow cells of patients
Fanconi Anemia
→ Can suppress normal hematopoietic progenitor cell growth
● Autosomal recessive disorder ● Removal of T cells from aplastic anemia bone marrow improves
● Manifests as congenital developmental anomalies, progressive colony formation in vitro
pancytopenia, and an increased risk of malignancy ● In aplastic anemia
● Chromosomes in Fanconi anemia are peculiarly susceptible to → Increased numbers of activated cytotoxic T cell clones
DNA cross-linking agents, the basis for a diagnostic assay → Type 1 cytokines are implicated
● Typically have short stature, café au lait spots, and anomalies → Interferon γ (IFN-γ) induces Fas expression on CD34
involving the thumb, radius, and genitourinary tract cells | 
● At least 16 different genetic defects have been defined; the ● Leading to apoptotic cell death
most common, type A Fanconi anemia, is due to a mutation in ● Oligoclonal T cell response implies antigenic stimulus
FANCA ● May be genetically determined
● Form a protein complex that activates FANCD2 by → Can convert a normal physiologic response into a sustained
monoubiquitination to play a role in the cellular response to abnormal autoimmune process
DNA damage and especially interstrand cross-linking → Including polymorphisms in histocompatibility antigens,
Dyskeratosis Congenita cytokine genes, and genes that regulate T cell polarization
● Triad of mucous membrane leukoplakia, dystrophic nails, and effector function
reticular hyperpigmentation and with the development of E. CLINICAL FEATURES
aplastic anemia in childhood
● Striking features of Aplastic Anemia
● Due to mutations in genes of the telomere repair complex,
→ Restriction of symptoms to the hematologic system
which acts to maintain telomere length in replicating cells
→ Patient feels and looks remarkably well despite drastic
● X-linked variety is due to mutations in the DKC1 (dyskerin) gene
reduction in blood counts
● More unusual autosomal dominant type is due to mutation in
TERC, which encodes an RNA template and TERT, which History
encodes the catalytic reverse transcriptase, telomerase ● May appear abruptly or insidiously
● Mutations in TNF2, a component of the shelterin complex, ● Bleeding: most common early symptom | 
proteins that bind the telomere DNA, also occur ● Thrombocytopenia:
→ Easy bruising (days to weeks)
→ Oozing from gums
→ Nose bleeds → Except for mildly megaloblastic erythropoiesis:

→ Heavy menstrual flow megakaryocytes are reduced/absent
→ Petechiae ● Granulomas may indicate infectious etiology of BM failure
→ Small amounts of bleeding in the CNS can result to
intracranial or retinal hemorrhage (fatal)
● Anemia
→ Lassitude
→ Weakness
→ Shortness of breath
→ Pounding ear sensation
● Infection is an unusual first symptom
● Family history pointing to a telomeropathy:
→ Hematologic diseases or blood abnormalities
→ Pulmonary or liver fibrosis
→ Early hair graying
● Prior drug use, chemical exposure and preceding viral illnesses
● Systemic complaints and weight loss points to other etiologies
of pancytopenia
Physical Examination
Figure 1. Aplastic Anemia (Marrow Smear) Source: Harrison’s Principle of
● Typical signs: Petechiae, Ecchymoses Internal Medicine, 20th ed.
● Hepatomegaly and Splenomegaly is unlikely – presence would
make one doubt the diagnosis of aplastic anemia
● Retinal hemorrhages may be present
● Pelvic and DRE should be done with gentleness to avoid
trauma; but often deferred
● Pallor of the skin and mucous membranes
→ except in the most acute cases or in transfused cases
● Lymphadenopathy and splenomegaly are highly atypical
→ Do not suspect aplastic anemia if these are present
● Other features:
→ Cafe au lait spots & short stature: Fanconi anemia
→ Peculiar nails and leukoplakia: Dyskeratosis Congenita
→ Early graying: Telomerase defect
F. LABORATORY STUDIES
Table 3. Diagnostic Criteria for Aplastic Anemia placed in the Appendix, p.22
Blood Figure 2. Aplastic Anemia (Marrow Biopsy) Source: Harrison’s Principle of
● CBC Internal Medicine, 20th ed.
→ ↑ MCV Ancillary Studies
→ Absent/few reticulocytes ● Chromosome breakage studies - exclude Fanconi anemia
→ N/↓ lymphocytes → Uses diepoxybutane or mitomycin C
● Smear: ● Family studies and nucleotide sequencing:
→ Normal to large erythrocytes (slight macrocytosis) → Very short telomere length - strongly suggests telomerase or
■ Due to stress erythropoiesis wherein body struggles to shelterin mutation
produce RBCs leading to release of immature forms (Left ● Chromosome studies of bone marrow cells:
shift), thus, a high %fetal Hgb → macrocytosis → (+) in MDS; (-) in typical aplastic anemia
→ Paucity of platelets and granulocytes ● Flow cytometry - sensitive diagnostic test for PNH
● (+) Immature myeloid forms suggests Leukemia or ● Serology - (+) viral infection (i.e., EBV, HIV)
Myelodysplastic syndrome (MDS) → Post Hepatitis aplastic anemia - seronegative
● (+) Nucleated RBCs suggest marrow fibrosis or tumor invasion ● CT Scan/US - determine spleen size if abdominal PE is
● (+) Abnormal platelets suggest peripheral destruction or MDS unsatisfactory
Bone Marrow ● MRI - may be helpful to assess fat content of vertebrae
● Cells may be aspirated from the iliac crest (If inadequate, → Distinguish aplasia from MDS
aspirate from sternum) G. DIAGNOSIS
● Still done to help in ruling out other diseases ● Straightforward: Pancytopenia + Fatty bone marrow | 
● BM is readily aspirated but dilute on smear; and the fatty biopsy
● Disease of the young
specimen may be grossly pale on withdrawal
→ Leading diagnosis in the pancytopenic adolescent or young
→ “Dry tap” suggests fibrosis or Myelophthisic adult
● In severe aplasia: ● Secondary pancytopenia - primary diagnosis is usually obvious
→ Smear shows only red cells, residual lymphocytes, and
from the Hx/PE
stromal cells
→ Massive spleen (alcoholic cirrhosis)
● Biopsy is superior for determining cellularity and shows mainly → History of metastatic cancer
fat under microscope |  → SLE
→ Hematopoietic cells occupy <25% |  → Miliary TB on CXR
→ May be all fat in serious cases ● May be difficult to distinguish from the hypocellular variety of
→ Note: marrow cellularity may decline physiologically with MDS:
aging → MDS if there are morphologic abnormalities (i.e.,
● By blood counts, empty iliac crest biopsies in moderate disease; megakaryocytes and myeloid precursor cells), and typical
“hot spots” of hematopoiesis in severe cases cytogenetic abnormalities
● Residual hematopoietic cells should have normal morphology
H. COMPLICATIONS gamma-interferons, which are responsible for inhibiting

● Infection hematopoiesis
→ Due to neutropenia ● Standard regimen: Antithymocyte Globulin (ATG) +
● Hemolytic/Thrombotic Cyclosporine | 
● Cardiovascular Problems → Induces hematologic recovery
→ Tachycardia, Hypotension, Cardiac Failure, and Death (in → Children do especially well
severe cases) → Older adult patients can suffer complications due to
comorbidities (70% would respond)
I. PROGNOSIS → Use of Eltrombopag is reserved for 30% of patients that fail
● Natural history of severe aplastic anemia is rapid deterioration to respond to immunosuppression
and death → But if patient is a good candidate and you have a donor,
● Major prognostic determinant: blood count prepare for transplantation:
● Prognosis will help in the management of the patient. ■ Combination: Eltrombopag + Immunosuppressive
● Severe disease: |  agents
→ ANC <500/uL ● Early robust hematologic response correlates with long-term
→ Platelet count <20,000/uL survival
→ Corrected Reticulocyte Count <1% (or ARC <60,000/uL) ● Improvement in granulocyte number is apparent within 2
● Predictors of treatment response and long-term outcome of months of treatment
immunosuppressive therapy ● Most recovered patients continue to have some degree of blood
→ ARC >25,000/uL count depression
→ ALC >1000/uL → MCV remains elevated
→ Bone marrow cellularity returns toward normal very slowly if
J. TREATMENT at all
● Can be cured by replacement of the absent hematopoietic cells ● Relapse (recurrent pancytopenia) is frequent with
by stem cell transplant discontinuation of cyclosporine
● Can be ameliorated by suppression of the immune system ● Complications
● Glucocorticoids are not of value as primary therapy → Development of MDS, with typical marrow morphologic or
Figure 3. Treatment Algorithm for Aplastic Anemia cytogenetic abnormalities
placed in the Appendix, p.22 → Return of pancytopenia
Hematopoietic Stem Cell Transplantation → Some develop leukemia
● Flow cytometry to diagnose PNH
● Best therapy for the younger patient with a fully
● Horse ATG
histocompatible sibling donor | 
→ Administered as intravenous infusions over 4 days
● Human leukocyte antigen (HLA) typing
● Rabbit ATG
→ Should be ordered as soon as the diagnosis of aplastic
→ Less effective
anemia is established
→ Reduces T-regulatory cell numbers in patients
→ In a child or young adult
● Serum sickness
● In transplant candidates
→ Flu-like illness with a characteristic cutaneous eruption and
→ Transfusion of blood from family members should be avoided
arthralgia
to prevent sensitization to histocompatibility antigens
→ Often develops 10 days after initiating treatment
● For allogeneic transplant from fully matched siblings
● Methylprednisolone
→ Long-term survival rates for children are ∼90%
→ Administered with ATG
● Transplant morbidity and mortality are increased among adults
→ To ameliorate the immune consequences of heterologous
due to
protein infusion
→ Higher risk of chronic GVHD
● Cyclosporine
→ Serious infections
→ Administered orally at an initial high dose, with subsequent
● Far more available are other alternative donors, either unrelated
adjustment according to blood levels
but histocompatible volunteers or closely but not perfectly
→ Side effects: nephrotoxicity, hypertension, and seizure
matched family members
● Immunosuppression - treatment of choice as most patients
→ High-resolution matching at HLA and more affective
with aplastic anemia lack a suitable marrow donor | 
conditioning regimens and GVHD prophylaxis have led to
improved survival rates
● Overall survival is equivalent with transplantation and
→ Survival is equivalent between matched unrelated and
immunosuppression
conventional sibling donors
→ Successful transplant cures marrow failure
■ Complication rates (mainly graft-versus-host disease and
→ But after immunosuppression there remains at risk of relapse
infection) are higher using unrelated donors
and malignant evolution
● Cord blood can be a source of stem cells especially for children
● Allogeneic transplant
● Transplantation from an HLA haploidentical family donor is
→ Should be performed if available suitable sibling donor
increasingly popular
→ Excellent results in children and younger adults
→ Donor is almost always quickly available
● Factors in weighing decision between transplant and
→ Post-transplant cyclophosphamide appears to be effective in
immunosuppression in adults who have a matched family donor
preventing graft-versus-host disease
→ Increasing age
● Transplant protocols for marrow failure now usually do not
● Older patients do better with ATG and cyclosporine
include radiation in order to avoid late occurrence of cancer
→ Severity of neutropenia
Immunosuppression ● Transplant is preferred if neutropenia is profound
● Why give immunosuppressive agents in a patient no longer Eltrombopag
producing enough RBC, WBC, platelets? Will patients not be
● Already approved for Severe Aplastic Anemia
more prone to infection with this?
● Hematopoietic growth factors (HGFs) such as Erythropoietin
→ Rationale: To eradicate the CTLs in order to allow
(EPO) and Granulocyte colony-stimulating factors (G-CSF) are
hematopoiesis to take place
not effective in aplastic anemia
■ There are cytotoxic T-lymphocytes (CTLs) present in the
→ Endogenous blood levels are extremely high
marrow, and they produce inhibitory cytokines, TNF,
→ Circulating thrombopoietin is also elevated ● Aspirin and other NSAIDS must be avoided in the presence of
● Eltrombopag is approved for patients with refractory thrombocytopenia
aplastic anemia |  ● RBCs should be transfused so as to allow patient a normal level
● Eltrombopag added to first-line immunosuppression with horse of activity
ATG markedly increased overall and complete response rates → Usually at hemoglobin value of 70 g/L
● Outcomes following both stem cell transplant and → 90 g/L is there is underlying cardiac or pulmonary disease
immunosuppression that have improved with time has ● A regimen of 2 units every 2 weeks will replace normal losses
complicated development of consensus algorithms in a patient without a functioning bone marrow
→ Children with histocompatible siblings should be offered ● In chronic anemia, the iron chelators (Deferoxamine and
transplant Deferasirox) should be added at approximately the 50th
→ Some advocate upfront transplants from well-matched transfusion to avoid secondary hemochromatosis
unrelated donors
K. OTHER INFORMATION
● Transplant has been advocated to older patients, including from
unrelated matched donors and haploidentical donors Not included in the BGD but is part of the Reading Assignments
● Immunosuppression combined with stem cell stimulation may PURE RED CELL APLASIA
lead to responses within a few months in almost all patients and
can be instituted at diagnosis A. INTRODUCTION
Androgens ● Agranulocytosis
● Effectiveness has not been verified in controlled trials → Most frequent | 
● Sex hormones upregulate telomerase gene activity in vitro → Usually a complication of medical drug use:
→ May also be their mechanism of action in improving marrow ■ By a mechanism of direct chemical toxicity
function ■ By immune destruction
● 3- to 4-month trial may improve all blood counts of patient with → More on older adults and in women
moderate disease, especially if a telomere gene defect is → Should resolve with discontinuation of exposure
present ● Both pure white cell aplasia (agranulocytosis without
incriminating drug exposure) and amegakaryocytic
Supportive Care thrombocytopenia
● Infection in the presence of severe neutropenia must be → Exceedingly rare
aggressively treated by prompt institution of parenteral → Due to destructive antibodies or lymphocytes (like PRCA)
broad-spectrum antibiotics → Can respond to immunosuppressive therapies
→ Empirical, must not await culture
→ Specific foci of infections should be sought on physical B. DEFINITION AND DIFFERENTIAL DIAGNOSIS
examination and with radiographic studies such as: ● Characterized by:
■ Oropharyngeal or anorectal abscesses → Anemia
■ Pneumonia → Reticulocytopenia
■ Sinusitis → Absent or rare erythroid precursor cells in the bone marrow
■ Typhlitis (necrotizing colitis) ● In adults
● When indwelling plastic catheters become contaminated, → PRCA is required
Vancomycin should be added ● In birth or in early childhood
● Persistent or recrudescent fever implies Fungal disease: → Diamond-Blackfan Anemia or Congenital PRCA | 
Candida and Aspergillus are common especially after several → Often responds to glucocorticoid treatment
courses of antibacterial antibiotics → Mutations in ribosome protein genes are etiologic
→ A major reason for the improved prognosis in aplastic ● Temporary red cell failure
anemia has been the development of better antifungal drugs → Occurs in transient aplastic crisis of hemolytic anemias
and timely institution of such therapy when infection is ■ Due to acute parvovirus infection
suspected → Occurs in transient erythroblastopenia of childhood
● Granulocyte transfusions using G-CSF-mobilized peripheral ■ In normal children
blood can be effective when infections are overwhelming or Table 4. Classification of PRCA
refractory Classification of Pure Red Cell Aplasia
● Handwashing is the single best method of preventing spread of Important associations with immune system diseases
infection Self-limited
→ Remains a neglected practice Transient erythroblastopenia of childhood
● Platelet and Erythrocyte numbers can be maintained by Transient aplastic crisis of hemolysis (Acute B19 parvovirus
transfusion infection)
● Alloimmunization historically limited the usefulness of platelet Fetal red blood cell aplasia
transfusions and is now minimized by several strategies: Nonimmune hydrops fetalis (in utero B19 parvovirus infection)
→ Use of single donors to reduce exposure Hereditary pure red cell aplasia
→ Physical and chemical methods to diminish leukocytes in the Congenital pure red cell aplasia (Diamond-Blackfan Anemia)
product Acquired pure red cell aplasia
→ HLA-matched platelets are usually effective in patients who Cancer
Thymoma
are refractory to random donor products
Lymphoid malignancies (and more rarely other
● Inhibitors of fibrinolysis (e.g., aminocaproic acid) have not been
hematologic diseases)
shown to relieve mucosal oozing Paraneoplastic to solid tumors
● Use of low-dose glucocorticoids to induce vascular stability is Connective tissue disorders with immunologic abnormalities
unproven and not recommended Systemic lupus erythematosus, juvenile rheumatoid arthritis,
● Goal of prophylactic platelet transfusions is to maintain the rheumatoid arthritis
platelet count >10,000/uL Multiple endocrine gland insufficiency
→ Oozing from the gut increases precipitously at counts Viruses
<500/uL Persistent B19 parvovirus, hepatitis, adult T cell leukemia virus,
● Menstruation should be suppressed either by oral estrogens or Epstein- Barr virus
nasal follicle-stimulating hormone (FSH) / luteinizing hormone Pregnancy
antagonists (LH) Drugs
Especially phenytoin, azathioprine, chloramphenicol, ● Idiopathic PRCA – responds favorably to immunosuppression

procainamide, isoniazid → Treatment: glucocorticoids
Antibodies to erythropoietin → Also effective are:
Idiopathic
■ Cyclosporine
C. CLINICAL FEATURES AND ETIOLOGY ■ ATG
● Important associations with immune system diseases ■ Azathioprine
● Cases may be associated with ■ Cyclophosphamide
→ Thymoma
MYELODYSPLASTIC SYNDROME
→ Large granular lymphocytosis
→ Chronic lymphocytic leukemia A. DEFINITION
→ Hypogammaglobulinemia
● The myelodysplastic syndromes (MDS)
→ Idiosyncratic drug reaction
→ heterogeneous group of hematologic disorders broadly
● Can be provoked with subcutaneous administration of
characterized by:
erythropoietin (EPO)
■ Cytopenias due to bone marrow failure
● May have immune mechanisms:
■ A high risk of development of acute myeloid leukemia
→ Antibodies to RBC precursors
(AML)
→ T cell inhibition (more common than the antibodies)
● Anemia, often with thrombocytopenia and neutropenia
→ Cytotoxic lymphocyte activity restricted by histocompatibility
● Bone marrow: dysmorphic (abnormal appearing) and
locus
→ Specific for human T cell leukemia/lymphoma virus infected cellular
cells and natural killer cell activity inhibitory of erythropoiesis → Evidence of ineffective blood cell production
● “Low risk MDS”
Persistent Parvovirus B19 Infection → Marrow failure dominates the clinical course
● An important, treatable cause of PRCA |  ● “High risk MDS”
● In children: benign exanthem (fifth disease) → Leukemic progression dominates
● In adults: a polyarthralgia/arthritis syndrome → Myeloblasts present at diagnosis
● Can cause a transient aplastic crisis → Chromosomes are abnormal
● Can cause an abrupt but temporary worsening of the anemia ● May be fatal due to the complications of:
due to failed erythropoiesis → Pancytopenia
● In normal individuals, acute infection is resolved by production
→ Incurability of leukemia
of neutralizing antibodies to the virus
● Elderly at higher risk because of comorbidities
● If with congenital, acquired, or iatrogenic immunodeficiency
● According to French-American-British Cooperative Group in
→ Persistent viral infection may occur
1983, there were 5 entities:
● The bone marrow shows
→ Red cell aplasia → Refractory anemia (RA)
→ Presence of giant pronormoblasts → Refractory anemia with ringed sideroblasts (RARS)
→ Cytopathic sign of B19 parvovirus infection → Refractory anemia with excess blasts (RAEB)
● Viral tropism for human erythroid progenitor cells → Refractory anemia with excess blasts in transformation
→ Due to its use of erythrocyte P antigen as a cellular (RAEB-t)
receptor for entry → Chronic myelomonocytic leukemia (CMML)
● Direct cytotoxicity of virus causes anemia if demands on ● The World Health Organization (WHO) classification (2002)
erythrocyte production are high → Recognized that the distinction between RAEB-t and AML is
● May not be apparent in normal individuals arbitrary and grouped them together as acute leukemia
● Skin and joint symptoms → CMML behaves as a myeloproliferative disease
→ Mediated by immune complex deposition → Separated refractory anemias with dysmorphic change
restricted to erythroid lineage from those with multilineage
D. TREATMENT changes
● To know underlying disease: ● In a 2008 revision, specific categories for unilineage dysplasias
→ History were added
→ Physical examination ● Difficult to diagnose:
→ Routine laboratory studies → Because subtle clinical and pathologic features must be
● Thymoma distinguished, and precise diagnostic categorization requires
→ Radiographic procedures a hematopathologist knowledgeable in the latest
● Tumor excision is indicated classification scheme
→ but anemia does not necessarily improve with surgery
● Parvovirus infection B. EPIDEMIOLOGY
→ Requires detection of viral DNA sequences in the blood ● Idiopathic MDS
→ IgG and IgM antibodies commonly absent → Disease of the elderly
→ Mean age at onset: > 70 years
→ Tx: intravenous immunoglobulin therapy (e.g., 0.4 g/kg
● Slight male preponderance
daily for 5 days)
● Rare in children, but monocytic leukemia can be seen
→ Relapse and retreatment may be expected, especially in
● Secondary or therapy-related MDS is not age related
patients with AIDS
● The presence of erythroid colonies C. ETIOLOGY AND PATHOLOGY
→ Predictive of response to immunosuppressive therapy in ● Associated with environmental exposures
idiopathic PRCA → Radiation
● Red cell aplasia → Benzene
→ Compatible, long-term survival with supportive care alone ● Secondary MDS
→ Combination of erythrocyte transfusions + iron chelation → Occurs as a late toxicity of cancer treatment
→ Usually a combination of radiation and the radiomimetic
alkylating agents
■ Busulfan, nitrosourea, or procarbazine (with a latent → Splenomegaly

period of 5–7 years) → Unusual skin lesions
■ DNA topoisomerase inhibitors (2-year latency) ● Including Sweet’s syndrome (febrile neutrophilic
● The following can evolve to MDS dermatosis)
→ Acquired aplastic anemia ● In the younger patient
→ Fanconi anemia → Stereotypical anomalies point to a constitutional syndrome
→ Other constitutional marrow failure diseases
→ Short stature, abnormal thumbs → Fanconi anemia
● A disease of aging
→ Early graying → telomeropathies
→ Random cumulative intrinsic and environmental damage to
marrow cells → Cutaneous warts → GATA2 deficiency
● A clonal hematopoietic stem cell disorder ● Fever and weight loss
● Characterized by disordered cell proliferation and impaired → Should point to a myeloproliferative process NOT
differentiation myelodysplastic
→ Resulting in cytopenias
E. LABORATORY STUDIES
→ Risk of progression to leukemia
● May be due to chromosomal and genetic instability Blood
● Cytogenetic abnormalities ● Anemia is present in most cases
→ Aneuploidy (chromosome loss or gain) → translocations ● Isolated neutropenia or thrombocytopenia unusual
→ Revealed by sensitive assays like comparative genomic
● Macrocytosis is common
hybridization and single nucleotide polymorphism arrays
● Accelerated telomere attrition ● Smear may be dimorphic with a distinctive population of large
→ May destabilize the genome in marrow failure red blood cells
→ Predispose to acquisition of chromosomal lesions ● Platelets large and lack granules
● Cytogenetic abnormalities (not random) ● May have bleeding symptoms despite seemingly adequate
→ Loss of all or part of 5, 7, and 20, trisomy of 8 numbers
→ May be related to etiology (11q23 following topoisomerase II ● Neutrophils
inhibitors) → Hypogranulated
● Mutations in genes of the RNA splicing machinery → Have hyposegmented, ringed, or abnormally segmented
→ Especially SF3B1 nuclei
→ Strongly associated with sideroblastic anemia → Contain Döhle bodies
● Some mutations correlate with prognosis ● May be functionally deficient circulating myeloblasts
→ Good prognosis: spliceosome defects
→ Correlate with marrow blast numbers
→ Poor prognosis: mutations in EZH2, TP53, RUNX1, and
→ Quantity is important for classification and prognosis
ASXL1
● Mutations and cytogenetic abnormalities are not independent ● Total white blood cell count (WBC) normal or low
→ TP53 mutations: complex cytogenetic abnormalities → Except in chronic myelomonocytic leukemia
→ TET2 mutations: normal cytogenetics Bone Marrow
● Manifestations result from the accumulation of multiple genetic ● Usually normal or hypercellular
lesions
● 20% are hypocellular to be confused with aplasia
→ Loss of tumor-suppressor genes
● No single characteristic feature of marrow morphology
→ Activating oncogene mutations
→ Epigenetic pathways that affect mRNA processing and distinguishes MDS
methylation status ● May observe:
→ Other harmful alterations → Dyserythropoietic changes (especially nuclear abnormalities)
● The 5q– deletion leads to: and ringed sideroblasts in the erythroid lineage
→ Heterozygous loss of a ribosomal protein gene → Hypogranulation and hyposegmentation in granulocytic
→ Diamond-Blackfan anemia precursors, with an increase in myeloblasts
■ Both are characterized by deficient erythropoiesis → Megakaryocytes showing reduced numbers of
● In trisomy 8 MDS disorganized nuclei
→ Immune pathophysiology may underlie ● Megaloblastic nuclei associated with defective
■ Improved blood counts after immunosuppressive therapy hemoglobinization in the erythroid
■ T cell activity directed to hematopoietic progenitors ● Prognosis
D. CLINICAL FEATURES → Strongly correlates with the proportion of marrow blasts
● Anemia ● Cytogenetic analysis and fluorescent in situ hybridization
→ Dominates the early course → Can identify chromosomal abnormalities
● Some asymptomatic and discovered incidentally ● Exclude
● Look out for history of previous chemotherapy or radiation → Deficiencies of vitamin B12 or folate by appropriate blood
exposure tests
● Gradual onset: → Vitamin B6 deficiency by a therapeutic trial of pyridoxine if
→ Fatigue and weakness the bone marrow shows ringed sideroblasts
→ Dyspnea ● Difficult to differentiate:
→ Pallor → Hypocellular MDS and aplasia
● In Childhood → Refractory anemia with excess blasts and early acute
→ Rare leukemia
→ Increases the likelihood of an underlying genetic disease ● To differentiate AML:
→ If with Down syndrome: susceptible to MDS → The WHO considers the presence of 20% blasts in the
→ Can be caused by inherited GATA2 mutations, as in the marrow
MonoMAC syndrome
● Physical examination
→ Remarkable for signs of anemia
F. PROGNOSIS ● For those with low serum EPO levels who have no or only a
● Median survival modest need for transfusions
→ Years for patients with 5q– or sideroblastic anemia 7. RBC transfusion support
→ Few months in refractory anemia with excess blasts or ● Should be accompanied by iron chelation
severe pancytopenia associated with monosomy 7 → To prevent secondary hemochromatosis
● International Prognostic Scoring System (IPSS)
→ Assists in making predictions MYELOPHTHISIC ANEMIA
● Even “low-risk” MDS A. DEFINITION
→ Has significant morbidity and mortality
● Fibrosis of the bone marrow
● Most patients die as a result of complications of pancytopenia
● Usually accompanied by a characteristic blood smear picture:
→ Not due to leukemic transformation
leukoerythroblastosis | 
● Poor prognostic indicators
● Can occur as a primary hematologic disease:
→ Precipitous worsening of pancytopenia
→ myelofibrosis or myeloid metaplasia
→ Acquisition of new chromosomal abnormalities on serial
● Can occur as a secondary process: myelophthisis
cytogenetic determination
● Can be a response to invading tumor cells
→ Increase in the number of blast
→ Usually an epithelial cancer of breast
→ Marrow fibrosis
→ Lung CA
● Therapy-related MDS may progress to refractory AML
→ Prostate CA
G. TREATMENT → Neuroblastoma
● Only hematopoietic stem cell transplantation offers cure of ● May occur with infection
MDS |  → Mycobacteria (both Mycobacterium tuberculosis and
● Treatment-related mortality and morbidity increase with Mycobacterium avium)
recipient age → Fungi
● More complicated in high-risk patients → HIV
● MDS refractory to cytotoxic chemotherapy regimens → Sarcoidosis
● In older adults: drug toxicity is frequent and often fatal ● Can be due to intracellular lipid deposition in Gaucher’s
disease
● Drugs available are epigenetic modulators: Azacitidine &
● Can be due to obliteration of the marrow space related to
Decitabine
absence of osteoclast remodeling in congenital osteopetrosis
→ Believed to act through a demethylating mechanism
● Secondary myelofibrosis
→ To alter gene regulation and allow differentiation
→ Late consequence of radiation therapy
→ To mature blood cells from the abnormal MDS stem cell
→ Treatment with radiomimetic drugs
→ Used in high-risk patient who is not a candidate for stem cell
● Can also be a feature of a variety of hematologic syndromes
transplant
→ Especially chronic myeloid leukemia
→ Major toxicity:
→ Multiple myeloma
■ Myelosuppression → worsened blood counts | 
→ Lymphoma
1. Azacitidine → Myeloma
● SC Daily for 7 days at 4-week intervals → Hairy cell leukemia
● At least four cycles before assessing for response ● Remarkable for pancytopenia
→ Despite very large numbers of circulating hematopoietic
2. Decitabine
progenitor cells
● More potent
● Administered by continuous IV infusion B. PATHOLOGY AND ETIOLOGY
● 3 to 10 days in repeating cycles ● Three distinct features
3. Lenalidomide → Proliferation of fibroblasts in the marrow space
(myelofibrosis)
● Thalidomide derivative
→ Extension of hematopoiesis into the long bones and into
● Administered orally extramedullary sites, usually the spleen, liver, and lymph
● More favorable toxicity profile nodes (myeloid metaplasia)
● Effective in reversing anemia in MDS patients → Ineffective erythropoiesis
with 5q– syndrome ● Etiology is unknown; but may be due to dysregulated production
● Improves within 3 months of initiating therapy of growth factors:
● Toxicities include: → Platelet-derived growth factor
→ Myelosuppression → Transforming growth factor β
→ Increased risk of deep vein thrombosis ● Abnormal regulation of other hematopoietins
→ Pulmonary embolism → Would lead to localization of blood-producing cells in
nonhematopoietic tissues and uncoupling
4. ATG, Cyclosporine, and Alemtuzumab
● Effective in younger MDS patients (<60 years old) C. SECONDARY MYELOFIBROSIS
● With more favorable IPSS scores ● Characteristics:
● Who bear the histocompatibility antigen HLADR15 → Anemia: normocytic and normochromic characteristic
leukoerythroblastic smear
5. HGFs
→ Erythrocyte morphology highly abnormal
● Can improve blood counts ■ with circulating nucleated RBCs, teardrops, and shape
● Most beneficial to patients with the least severe pancytopenia distortions
6. EPO alone or in combination with G-CSF → WBC numbers are often elevated
→ May mimic a leukemoid reaction
● Can improve hemoglobin levels
→ With circulating myelocytes, promyelocytes, and myeloblasts
→ Platelets may be abundant and are often of giant size C. ETIOLOGY

→ Inability to aspirate the bone marrow: the characteristic dry ● Primary:
tap → Etiology: Unknown
● Course: ● Secondary:
→ Determined by its etiology → Autoimmune diseases
→ Usually a metastatic tumor or an advanced hematologic → Chronic lymphocytic leukemia
malignancy → Non-Hodgkin’s lymphoma
→ Treatable causes must be excluded → Epstein-Barr virus
■ Especially tuberculosis and fungus → Cytomegalovirus
● Transfusion support can relieve symptoms → Mycoplasma pneumonia
II. AUTOIMMUNE HEMOLYTIC ANEMIA → Hepatitis
→ HIV
A. DEFINITION D. PATHOPHYSIOLOGY
● Rare disorder characterized by premature destruction of RBC ● Once red cell is coated by autoantibody:
as well as anemia due to autoantibodies that bind to RBC → Macrophage has surface receptors for Fc region of IgG on
surface with or without complement activation red cell with preference for IgG 1 and 3 and surface
● Can be associated with autoimmune thrombocytopenia (Evan’s receptors for fragments of C3B and C4B
Syndrome) ■ This leads to erythrophagocytosis
● Mechanisms: − If partial – can lead to spherocyte formation because
→ Extravascular hemolysis part of RBC membrane is lost after binding and
■ RBC destruction wherever macrophages are abundant internalization of the lost part by the macrophage
(spleen, liver, bone marrow)
− Spherical RBCs are fragmented further by the spleen
→ Intravascular Hemolysis
since it is abnormal
■ IgM antibody on RBC can activate MAC complex directly
■ Antigen-Antibody complex activates complement and
to destroy the RBC
attack complex formed will cause intravascular hemolysis
● Determination of exact onset is difficult
→ If hemolysis was gradual and a small population of RBCs E. CLINICAL FEATURES
were destroyed, the patient may be asymptomatic ● 10% Mortality
→ But if not corrected, may progress to being symptomatic ● Abrupt and dramatic onset
■ Gradual – mild ● Triad that increases suspicion of AIHA | 
■ Abrupt – severe → Drop of hemoglobin to 4 g/dL in a matter of days
● Types of AIHA → Jaundice
→ Warm AIHA → Splenomegaly
■ More common type of AIHA (70% of cases) ● Hemoglobinuria means Intravascular hemolysis
■ Reacts best at 37°C
■ Antibodies are usually IgG | 
→ Cold Agglutinin Disease
■ 10-20% of all cases of AIHA
■ Reacts best at 4°C
■ Antibodies are usually IgM | 
− Usually has Anti-I specificity (I antigen present on red
cell of almost everybody)
− May have very high titer (1:100,000)
− Antibody is produced by an expanded clone of B
lymphocytes (can show as spike in plasma protein
erythropoiesis as a monoclonal gammopathy)
− Related to Waldenström’s macroglobulinemia
→ Paroxysmal Cold Hemoglobinuria
■ Rare form of AIHA occurring mostly in children (32-40% of
children with AIHA)
■ Triggered by viral infection | 
■ Usually self-limited
■ Characterized by involvement of Donath-Landsteiner
antibody | 
− Presence of this antibody will prove PCH
− Anti-P specificity
− Binds at low temperatures (optimally at 4°C)
− At 37°C, lysis of red cells occurs in presence of Figure 4. Aplastic Anemia (Marrow Smear) Source: BGD 2 report
complement F. LABORATORY STUDIES
■ Recovery of patient is expected
● CBC
B. EPIDEMIOLOGY → ↓ Hemoglobin
● Annual incidence: 1-3 per 100,000 individuals → ↓ Hematocrit
● US: Estimated increase of 2 per 10,000 per year → ↑ MCV
● Mortality: 5-10% → ↑ Reticulocyte count
→ Even with appropriate management ● Other blood tests (if CBC suggests anemia)
● Children: M > F → ↑ Indirect serum bilirubin
● Adults: F > M → ↑ Lactate dehydrogenase | 
● Median age: mid-50s; 60% are women ■ Suggestive of Hemolytic Anemia
● Idiopathic most of the time → ↓ Serum Haptoglobin
● 54% of AIHA cases are secondary to underlying causes ■ Decreased due to increased binding to free hemoglobin
● Smear: ■ Pulmonary emboli

→ Polychromasia ■ Infection
→ Spherocytes ■ Cardiovascular collapse
→ Nucleated RBCs ● Idiopathic Cold AIHA
→ Fragmented RBCs → Benign course (Survive for many years)
→ Erythrophagocytosis → Causes of death:
● Direct Antiglobulin Test (Coombs test) |  ■ Infection
→ Possible for about 5-10% of the population ■ Severe anemia
→ Perform Polybrene test ■ Lymphoproliferative process
→ Distinguishes immune from non-immune causes
H. TREATMENT
→ Determines whether RBCs are coated with antibodies or
complement in vivo Warm AIHA
■ (+) Result: Agglutination (when there are antibodies ● Non-life threatening AIHA
bound to RBCs) → Blood transfusion should be withheld (compatibility problems
− Confirms diagnosis of AIHA |  may occur)
→ First line: Immediate Prednisone (1mg/kg/day)
→ Second line: Rituximab (anti-CD20)
● Severe Acute AIHA
→ can be a medical emergency
→ Red cell transfusion
■ Important to identify patient’s ABO type to avoid hemolytic
transfusion reaction
■ 2 difficulties:
− Crossmatching
− Short half-life of transfused blood
■ Transfuse ABO matched but incompatible blood
− Patient needs transfusion but many blood units that are
crossmatched are usually incompatible
− Less dangerous to transfuse because it will destroy no
less but no more than the patient’s own RBCs and in
Figure 5. Direct Coombs Test / Direct Antiglobulin Test Source: BGD 2 report the meantime, the patients stay alive
● Indirect Antiglobulin Test (IAT) ○ However, you must watch or monitor patient
→ Detects unbound IgG autoantibodies against RBCs in a carefully and inform patient of risks as well as
patient’s serum and determines the specificity of an benefits
alloantibody ○ Need to transfuse slowly (so that interactions
→ E.g., Rh antibodies between antigen and antibody won’t happen so fast)
→ Warm AIHA: (+) IAT ● First-line treatment of Warm AIHA | 
● Serum haptoglobin → Rituximab (100mg/wk X 4) + Prednisone
→ Decreased in AIHA ■ Reduces rate of relapse
→ Can also be elevated in patients with AIHA ■ Very expensive (disadvantage)
■ Since it is an acute phase reactant it can still be normal or ● Second-line treatment of Warm AIHA
elevated despite significant hemolysis in conditions such → Splenectomy
as an infection ■ If refractory to first-line treatment
■ Benefit: Removing major site of hemolysis
G. COMPLICATIONS AND PROGNOSIS − But can’t cure AIHA
● If secondary to SLE, CLL, or another complication ■ Risk: Sepsis and Thrombosis
→ AIHA is already a complication ■ Postoperative prophylactic antibiotics, long-term follow up
● Association to Evans Syndrome ■ “Don’t forget to give prophylactic vaccines for
→ Very rare autoimmune disorder encapsulated organisms”
→ RBCs, WBCs and platelets are mistakenly destroyed − Patient counselled on infection risk and vaccinated at
→ Unresponsive to treatment → progression of life-threatening least 2 weeks before
complications ● Other second/third-line treatment of Warm AIHA
■ Sepsis, severe bleeding or hemorrhage → Immunosuppressive drugs
● Splenomegaly ■ Azathioprine, 6-Mercaptopurine, Cyclosporine,
→ Extravascular hemolysis Cyclophosphamide
● Death is rare → IV Immunoglobulin
● Children who recovers at 1 st hemolytic episode ● Very rare severe refractory cases
→ Good prognosis → Myelo-immuno-ablative chemotherapy followed by
→ Unlikely to relapse autologous/allogeneic hematopoietic stem cell
● Higher mortality rate transplantation (rescue)
→ Chronic/persisting AIHA
→ Evans Syndrome Cold Agglutinin Disease
● Even with proper treatment ● Mild CAD
→ AIHA can still be a very serious condition → Keep patient warm
● Idiopathic Warm AIHA → Avoid exposure to cold
→ May resolve spontaneously ● Chronic CAD first-line treatment
→ Complications: Splenic Infarct, DVT (active during early → Rituximab (375 mg/m2 per week for 4 weeks)
phase of disease) ■ Up to 60% of patients respond
→ Relapses and remissions ■ More durable with rituximab-fludarabine combination
→ Actuarial survival at 10 years: 73% → Effective and well-tolerated
→ Causes of death:
I. OTHER INFORMATION D. PATHOPHYSIOLOGY

Not included in the BGD but is part of the Reading Assignments ● If the rate of red cell destruction exceeds the capacity of
the bone marrow to produce more red cells, the hemolytic
HEMOLYTIC ANEMIA
disorder will manifest as HA. Thus, the essential
A. INTRODUCTION pathophysiologic process common to all HAs is an increased
red cell turnover
Classification of Anemia ● The gold standard for proving that the life span of red cells is
● Due to: reduced (compared to the normal value of about 120 days) is a
→ Decreased production of red cells red cell survival study (although rarely necessary)
→ Increased destruction of red cells, and ● If hemolysis is recurrent or persistent, the increased bilirubin
→ Acute blood loss production favors the formation of gallstones.
● All patients who are anemic because of either increased ● Hypersplenism may develop, with consequent neutropenia
destruction of red cells or acute blood loss have one and/or thrombocytopenia
important element in common: ● With chronic intravascular hemolysis, the persistent
→ the anemia results from overconsumption of red cells hemoglobinuria will cause considerable iron loss, needing
from the peripheral blood, whereas the supply of cells replacement
from the bone marrow is normal ● With chronic extravascular hemolysis, the opposite problem,
● On the other hand, these two groups differ in that physical loss iron overload, is more common, especially if the patient needs
of red cells from the bloodstream or from the body itself, as in frequent blood transfusions. Chronic iron overload will cause
hemolytic anemias secondary hemochromatosis; this will cause damage
B. DEFINITION particularly to the liver, eventually leading to cirrhosis, and
to the heart muscle, eventually causing heart failure
● Increased RBC destruction within the body
● Diagnosis of Hemolytic Anemia is not difficult thanks to this INHERITED HEMOLYTIC ANEMIA
triad: |  ● Three essential components in the RBC: Hemoglobin,
→ Normomacrocytic anemia Membrane-cytoskeleton complex, Metabolic machinery
→ Reticulocytosis which keeps the first two working
→ Hyperbilirubinemia
A. HEMOLYTIC ANEMIA DUE TO ABNORMALITIES OF
Table 5. Classification of Hemolytic Anemias
a MEMBRANE-CYTOSKELETON COMPLEX
Classification of Hemolytic Anemias
INTRACORPUSCULAR EXTRACORPUSCULAR ● Includes Hereditary Spherocytosis and Hereditary
DEFECTS FACTORS Elliptocytosis | 
Inherited Hemoglobinopathies Familial (atypical) ● Glycophorins and band 3 are the most abundant red cell
Enzymopathies hemolytic-uremic membrane proteins
Membrane-cytoskeletal syndrome ● Spectrin – main cytoskeletal protein, its basic unit is a dimer
defects of α-spectrin and β-spectrin
Acquired Paroxysmal nocturnal Mechanical destruction ● Ankyrin, band 4.1 and band 4.2 attaches membrane to
hemoglobinuria (PNH) (microangiopathic) cytoskeleton
Toxic agents
● Abnormalities of almost and of the complex’s components leads
Drugs
to structural failure ultimately leading to hemolysis (mostly due
Infectious
Autoimmune to mutations)
aHereditary causes correlate with intracorpuscular defects because these 1. Hereditary Spherocytosis (HS)
defects are due to inherited mutations; the one exception is PNH because the
defect is due to an acquired somatic mutation. Similarly, acquired cases correlate ● RBCs are susceptible to lysis in hypotonic media
with extracorpuscular factors because mostly these factors are exogenous; the ● Osmotic Fragility Test – main diagnostic test for HS | 
one exception is familial hemolytic-uremic syndrome (HUS; often referred to as ● Severe cases may present in infancy
atypical HUS) because here an inherited abnormality allows complement ● Mild cases may present in young adults or later in life
activation to be excessive, with bouts of production of membrane attack complex
capable of destroying normal red cells, interestingly, in both PNH and aHUS
● Main findings: jaundice, splenomegaly, gallstones
hemolysis is complement-mediated. ● Variations in clinical manifestations are due to different
underlying molecular lesion
C. CLINICAL FEATURES ● Hemolysis is compensated and may become decompensated
● A patient with autoimmune HA or with favism may be a medical due to intercurrent conditions
emergency, whereas a patient with mild hereditary ● Normocytic anemia with spherical shaped RBCs
spherocytosis or with cold agglutinin disease may be diagnosed ● Increased MCHC (HS is almost the only condition in w/c
after years. increased MCHC occurs)
● At the clinical level, the main sign is jaundice; in addition, the ● Spleen plays a role in HS as a major site of RBC destruction
patient may report discoloration of the urine and as a means to make defective red cells more spherocytic,
● Enlarged spleen → preferential site of hemolysis accelerating RBC demise
● Hepatomegaly ● Family history can be used to diagnose but is not necessarily
● In all severe congenital forms of HA, there may also be important
skeletal changes due to overactivity of the bone marrow ● Definitive diagnosis is sometimes obtained only by molecular
(although they are never as severe as they are in thalassemia). studies demonstrating gene mutation
● Increase in unconjugated bilirubin and aspartate Treatment of HS
aminotransferase (AST) in the serum; urobilinogen will be ● Mild Cases: AVOID splenectomy
increased in both urine and stool ● Moderate Cases: Delay splenectomy until puberty
● If hemolysis is mainly intravascular, the telltale sign is ● Severe Cases: Delay splenectomy until 4-6 y/o
hemoglobinuria, (if extravascular, splenomegaly is most ● Anti-pneumococcal vaccination prior to splenectomy is
common because spleen [which is extravascular] becomes imperative
hyperactive in destroying ugly RBCs e.g. spherocytes) ● Cholecystectomy should only be carried out when clinically
→ The main sign of the erythropoietic response by the bone indicated
marrow is an increase in reticulocytes.
2. Hereditary Elliptocytosis (HE) ● In severe disease, splenectomy may be beneficial, as the

● The shape of the red cells gives the name of the condition, but anemia improves (paradoxically, reticulocytes increase
there is no direct correlation between the elliptocytic considerably)
morphology and clinical severity ● There is a single case report of curative treatment of PK
● Some mild or even asymptomatic cases may have nearly 100% deficiency by bone marrow transplantation (BMT) from an HLA-
elliptocytes, whereas in severe cases, all kinds of bizarre identical PK-normal sibling.
poikilocytes can predominate → This seems a viable option for severe cases when a sibling
donor is available. Prenatal diagnosis has been carried out in
Clinical Features and Management of HE a mother who had already had an affected child.
● Similar to those for HS 2. G6PD Deficiency
● The spleen may not have a specific role it has in HS, in severe
cases splenectomy may be beneficial ● Glucose 6-phosphate dehydrogenase deficiency
● An in-frame deletion of nine amino acids in the SLC4A1 gene ● G6PD is a house-keeping enzyme critical in the redox
encoding band 3, causing the so-called Southeast Asia metabolism of all aerobic cells.
ovalocytosis, has a frequency of up to 7% in certain ● In red cells – it is the only source of NADPH, which directly and
populations, presumably as a result of malaria selection via glutathione (GSH) defends these cells against oxidative
→ Asymptomatic in heterozygotes and probably lethal in stress.
homozygotes ● G6PD deficiency is a prime example of an HA due to interaction
between an intracorpuscular cause and an extracorpuscular
B. DISORDERS OF CATION TRANSPORT cause because in the majority of cases hemolysis is
● Rare conditions with autosomal dominant inheritance are triggered by an exogenous agent
characterized by increased intracellular sodium in red cells, with ● The G6PD gene is X-linked | 
concomitant loss of potassium ● Widely distributed in tropical and subtropical parts of the world
● They are sometimes discovered through incidental finding, in a (Africa, Southern Europe, the Middle East, Southeast Asia, and
blood test, of a high serum K+ (pseudohyperkalemia) Oceania) and wherever people from those areas have migrated.
● In patients from some families, the cation transport disturbance ● A conservative estimate is that at least 400 million people have
is associated with gain of water a G6PD deficiency gene.
→ As a result, the red cells are overhydrated (low MCHC), and ● G6PD is one of the best-characterized examples of genetic
on a blood smear, the normally round shaped central pallor is polymorphisms in the human species.
replaced by a linear-shaped central pallor, which has earned ● G6PD deficiency has been selected by Plasmodium
this disorder the name stomatocytosis falciparum malaria, by virtue of the fact that it confers a
● In patients from other families, instead, the red cells are relative resistance against this highly lethal infection | 
dehydrated (high MCHC), and their consequent rigidity has Clinical Manifestation of G6PD Deficiency
earned this disorder the name xerocytosis ● Majority remain clinically asymptomatic throughout their lifetime
→ In these disorders the primary defect may be in a cation ● NNJ related to G6PD deficiency
transporter; indeed, xerocytosis results from mutations in → Very rarely present at birth
PIEZO1 → The peak incidence of clinical onset is between day 2 and
● In other patients with stomatocytosis, mutations are found in day 3
other genes also related to solute transport, including SLC4A1 ● Acute hemolytic anemia (AHA) can develop as a result of three
(encoding band 3), the Rhesus gene RHAG, and the glucose types of triggers
transporter gene SLC2A1 responsible for a special form called → Fava beans
cryohydrocytosis → Infection
● From the practical point of view, it is important to know that in → Drugs
stomatocytosis, splenectomy is strongly contraindicated ● Typically, a hemolytic attack starts with
because it has been followed in a significant proportion of cases → Malaise
by severe thromboembolic complications → Weakness
→ Abdominal or lumbar pain
C. ENZYME ABNORMALITIES
● After 2–3 days, the patient develops jaundice and often dark
1. Pyruvate Kinase Deficiency (PKD) urine.
● Abnormalities of the glycolytic pathway are all inherited and all ● The onset can be extremely abrupt, especially with favism in
rare children
● Among them, deficiency of pyruvate kinase (PK) is the least ● Usually normocytic and normochromic
rare, with an estimated prevalence in most populations of the → Due partly to intravascular hemolysis
order of 1:10,000 ● LDH is high, and so is the unconjugated bilirubin
● The clinical picture of homozygous (or compound biallelic) PK → Indicating that there is also extravascular hemolysis
deficiency is that of an HA that often presents in the newborn ● The most typical feature of G6PD deficiency is the presence of:
with neonatal jaundice; the jaundice persists, and it is usually → Bizarre poikilocytes
associated with a very high reticulocytosis → Red cells that appear to have unevenly distributed
● The anemia is of variable severity; sometimes it is so severe as hemoglobin (“hemighosts”)
to require regular blood transfusion treatment, whereas → Red cells that appear to have had parts of them bitten away
(“bite cells” or “blister cells”)
sometimes it is mild, bordering on a nearly compensated
hemolytic disorder ● Supravital staining with methyl violet
→ Heinz bodies (consisting of precipitates of denatured
Treatment of PKD hemoglobin and hemichromes), which are regarded as a
● The management of PK deficiency is mainly supportive signature of oxidative damage to red cells (they are also
● The marked increase in red cell turnover, oral folic acid seen with unstable hemoglobins).
supplements should be given constantly ● Acute renal failure
● Blood transfusion should be used as necessary, and iron → The most serious threat from AHA in adults
chelation may be required even in some patients who, though → This is exceedingly rare in children
not receiving blood transfusion, may be developing iron
overload
● Once the threat of acute anemia is over and in the absence of → Antibody directed at a certain molecule and RBC may get
comorbidity, full recovery from AHA associated with G6PD caught in the reaction
deficiency is the rule. ● It may be idiopathic or part of a systemic autoimmune disease
● Primaquine (PQ) led to the discovery of G6PD deficiency, this (e.g., SLE)
drug has not been very prominent subsequently, because it is ● Antibodies differ in optimum reactivity temperatures and it is
not necessary for the treatment of life-threatening P. falciparum classified as “cold” and “warm”
malaria. Table 6. Classification of Acquired Immune Hemolytic Anemias
→ Today there is a revival of interest in PQ because it is the TYPE OF ANTIBODY
only effective agent for eliminating the gametocytes of P. COLD, Mostly IgM, HOT, Mostly IgG,
falciparum (thus preventing further transmission) and Clinical Optimal Temperature Optimal Temperature
eliminating the hypnozoites of Plasmodium vivax (thus Setting 4C-30C 37C; or Mixed
preventing endogenous relapse). Primary CAD AIHA (idiopathic)
→ The latest addition to the list of potentially hemolytic drugs is Secondary EBV HIV
rasboras to viral CMV Viral Vaccines
Treatment of G6PD Deficiency infection Other
Secondary Mycoplasma infection;
● Avoid triggering factors to prevent AHA to other paroxysmal cold
● Transfusion in severe anemia and dialysis in acute renal failure infection hemoglobinuria
● Folic acid and iron supplementation Secondary CAD in: AIHA in:
● Prevent favism by not eating fava beans to/ Waldenstrom’s SLE
3. Pyrimidine 5’ Nucleotidase (P5N) Deficiency associated disease CLL
with other Lymphoma Other malignancy
● Basophilic stippling – key characteristic disease Chronic inflammatory
● Lifelong anemia, of variable severity, splenectomy may be disorders (e.g., IBD)
beneficial After allogenic HSCT
4. Familial Hemolytic Uremic Syndrome After immune checkpoint
modulating drugs
● Affects mainly children
Secondary Small minority (e.g., Majority: currently most
● FAMILIAL HUS is atypical
to drugs: with lenalidomide) common culprit drugs are
→ Distinguished from typical HUS which is caused by shiga-
drug- cefotetan, ceftriaxone,
toxin-producing E. coli induced piperacillin)
→ TRIAD: immune Drug-dependent: antibody destroys red cells only
■ Microangiopathic HA with fragmented erythrocytes hemolytic when drug present (e.g., rarely penicillin)
■ low platelets anemia Drug-independent: antibody can destroy red cells
■ acute renal failure even when drug no longer present (e.g.,
● Inherited defects extrinsic to RBC: complement factor H (CFH), methyldopa)
CD46, complement factor I (CFI), complement component C3,
Hemolytic Anemia from Toxic Agents and Drugs
complement factor B (CFB), and thrombomodulin
→ In HUS, there is a deficiency in the complement regulators ● A number of chemicals with oxidative potential can cause
(which is why it is an extracorpuscular defect), hence the hemolysis even in people who are not G6PD-deficient
complements are “hyperactive”. So, one treatment is → Hyperbaric oxygen (or 100% oxygen), nitrates, chlorates,
Eculizumab, which is anti-c5 methylene blue, dapsone, cisplatin, numerous aromatic
● Treatment (cyclic) compounds
→ Traditional: plasma exchange to replace factors ● Other chemicals may be hemolytic through nonoxidative,
→ Replaced by anti-C5 complement inhibitor Eculizumab largely unknown mechanisms
■ Ameliorates microangiopathic features → Arsine, stibine, copper, lead
→ The HA caused by lead poisoning is characterized by
ACQUIRED HEMOLYTIC ANEMIA basophilic stippling
Mechanical Destruction of RBC ● Hemolysis appears to be mediated by direct chemical action on
red cells
● March Hemoglobinuria
● Drugs can also cause hemolysis through other mechanisms
→ Acute and self-inflicted
→ A drug can behave as a hapten and induce antibody
→ Develops in marathon runners, prolonged barefoot ritual
production (rarely with penicillin)
dancing, intense playing of bongo drums
→ A drug can trigger, perhaps through mimicry, the production
● Microangiopathic hemolytic anemia
of an antibody against a red cell antigen (methyldopa)
→ Chronic and iatrogenic
→ Develops in patients with prosthetic heart valves (e.g., ● Severe intravascular hemolysis can be caused by venom of
certain snakes and HA can also follow spider bites
paraprosthetic regurgitation)
Paroxysmal Nocturnal Hemoglobinuria
Infection
● Malaria in endemic areas ● Acquired chronic HA characterized by the TRIAD of: | 
● Shiga toxin-producing E. Coli O157:H7 → Persistent INTRAVASCULAR HEMOLYSIS with recurrent
→ Main etiologic agent of HUS exacerbations
→ Common in children → PANCYTOPENIA
● Clostridium perfringens sepsis → Tendency to VENOUS THROMBOSIS
→ Life threatening intravascular hemolysis ● Classical presentation
→ Due to a toxin with lecithinase activity → Suddenly “passed blood instead of urine“
→ Following an open wound, septic abortion, or accident due to ● Presents simply as a problem in the differential diagnosis of
contaminated blood unit ANEMIA
→ Sometimes assoc. from the outset with neutropenia,
Immune Hemolytic Anemia thrombocytopenia, or both → signals BM failure
● Two distinct mechanisms: ● Some patients present with recurrent attacks of severe
→ True antibody against RBC antigen abdominal pain → may be related to thrombosis or NO
depletion associated with intravascular hemolysis
● In the presence of acute hepatomegaly with ascites → (A) – Normal red cells are protected from complement
→ Thrombosis in hepatic vein activation and subsequent hemolysis by CD55 and CD59.
■ In full-fledged Budd-Chiari Syndrome These two proteins, being GPI-linked, are missing from the
→ In the absence of liver disease, raises suspicion of PNH surface of PNH red cells as a result of a somatic mutation of
● Natural History the X-linked PIG-A gene that encodes a protein required for
→ Extends over decades an early step of the GPI molecule biosynthesis.
→ Without treatment: survival is at 8-10 years → (B) – In the steady state, PNH erythrocytes suffer from
→ Common cause of death is venous thrombosis spontaneous (tick-over) complement activation, with
→ Followed by infection secondary to severe neutropenia and consequent intravascular hemolysis through formation of
hemorrhage secondary to severe thrombocytopenia the membrane attack complex (MAC); when extra
→ Rarely, PNH terminates as AML complement is activated through the classical pathway, an
→ Rarely, full spontaneous recovery exacerbation of hemolysis will result.
● Most consistent blood finding: anemia of variable severity, → (C) – On eculizumab, PNH erythrocytes are protected from
normo-macrocytic, with unremarkable red cell morphology hemolysis from the inhibition of C5 cleavage; however,
→ High MCV usually accounted for by reticulocytosis which upstream complement activation may lead to C3
may be quite marked opsonization and possible extravascular hemolysis.
→ Microcytic anemia may be seen if the patient is allowed to ● Treatment of PNH
become iron-deficient due to chronic iron loss through → PNH may be lifelong
hemoglobinuria → The only form of treatment that currently can provide a
→ Unconjugated bilirubin mildly or moderately elevated definitive cure for PNH is allogeneic BMT
→ LDH markedly elevated → Eculizumab (anti-c5)
→ Haptoglobin undetectable ■ Binds to the complement component C5 near the site of
→ Hemoglobinuria MAC formation
■ May be overt in random urine sample; if not, obtain serial ■ Blockage of C5 relieves patient of intravascular hemolysis,
urine samples and transfusions are significantly reduced or abolished
→ Bone marrow is cellular with marked to moderate ■ Since the problem here is RBCs are “hypersensitive” to
dyserythropoeitic features complements
■ May become hypocellular or frankly aplastic at some ■ Significantly improves the quality of life of PNH patients
stage of the disease → Expensive and not accessible to many patients
● Definitive diagnosis is based on the demonstration that a → Folic acid supplements (at least 3mg/d) are mandatory
substantial proportion of RBC have an increased susceptibility → Serum iron is checked periodically
to complement (C) ■ Iron supplements are administered as appropriate
→ Due to deficiency on surface proteins (CD59 and CD55)
■ These normally protect RBC from activated C ACUTE BLOOD LOSS
→ Sucrose hemolysis test is NOT reliable ● Blood loss causes anemia by two main mechanisms:
→ Acidified serum IS highly reliable → By the direct loss of red cells; and
→ Gold standard is FLOW CYTOMETRY, which can be carried → If the loss of blood is protracted, it will gradually deplete iron
out on granulocytes and RBC stores, eventually resulting in iron deficiency
● Pathophysiology of PNH → Direct loss of red cells causes post-hemorrhagic anemia
→ Hemolysis in PNH is mainly intravascular and is due to an ■ Follows acute blood loss
intrinsic abnormality of the red cell ■ Can be external (after trauma or obstetric hemorrhage) or
■ Which makes it exquisitely sensitive to activated C internal (from bleeding in the GI tract, rupture of spleen,
whether C is activated through the alternative or classical rupture of ectopic pregnancy, SAH)
pathway ● 3 clinical stages of blood loss
→ Hypersusceptibility to C is due to deficiency in the red cell → Hypovolemia
membrane of several protective proteins ■ Poses a threat particularly to organs that normally have a
■ CD59 – able to hinder insertion into the C9 polymer high blood supply (e.g., brain and the kidneys)
membrane ■ Loss of consciousness and acute renal failure are major
threats
■ Ordinary blood count will not show anemia because the
hemoglobin concentration is not affected
→ Anemia
■ Baroreceptors and stretch receptors will cause release of
vasopressin and other peptides
■ The body will shift fluid from the extravascular to the
intravascular compartment
■ Producing hemodilution
■ The hypovolemia gradually converts to anemia
■ The degree of anemia will reflect the amount of blood lost
→ Provided bleeding does not continue, the bone marrow
response will gradually ameliorate the anemia
■ The reticulocyte count and erythropoietin levels will be
elevated
Treatment of Acute Blood Loss
● In many cases, the blood lost needs to be replaced promptly
→ Unlike with many chronic anemias wherein finding and
correcting the cause of the anemia is the first priority and
blood transfusion may not be even necessary because the
body is adapted to the anemia
Figure 6. The Complement Cascade and the Fate of Red Cells. Source:
Harrison’s Principle of Internal Medicine, 20 th ed.
→ In acute blood loss, because the body is not adapted to the Clinical Manifestations
anemia, blood transfusion takes priority ● May be asymptomatic
● While the emergency is being confronted, it is imperative to ● May experience symptoms related to the ↑ red cell mass or the
stop the hemorrhage and to eliminate its source underlying disease process that leads to the ↑ red cell mass
→ In an acute hemorrhage situation, plasma may be preferred → Dominant symptoms of ↑ red cell mass are related to
to saline for volume expansion since dilution of clotting hyperviscosity & thrombosis (both venous and arterial)
factors with crystalloid may interfere with hemostasis. ■ Blood viscosity ↑ logarithmically at hematocrits >55%
● A Holy Grail of emergency medicine for a long time has been ● Manifestations range from digital ischemia to Budd-Chiari
the idea of a blood substitute that would be universally syndrome with hepatic vein thrombosis
available, suitable for all recipients, easy to store and to ● Abdominal vessel thromboses are particularly common
transport, safe, and as effective as blood itself.
● Neurologic symptoms may occur
● Two main paths have been pursued:
→ Vertigo
→ Fluorocarbon synthetic chemicals that bind oxygen
reversibly, → Tinnitus
→ Artificially modified hemoglobins, known as hemoglobin- → Headache
based oxygen carriers (HBOCs) → Visual disturbances
■ Although there are numerous anecdotal reports of the use ● Hypertension is often present
of both approaches in humans, and although HBOCs ● Polycythemia vera may have aquagenic pruritus and
have reached the stage of phase 2–3 clinical trials, no symptoms related to hepatosplenomegaly
“blood substitute” has yet become standard treatment. ● May have easy bruising, epistaxis, or bleeding from the GI tract
● Peptic ulcer disease is common
III. POLYCYTHEMIA VERA
● Patients with hypoxemia may develop
A. APPROACH TO POLYCYTHEMIA → Cyanosis on minimal exertion or have headache
● Polycythemia → Impaired mental acuity
→ Increase in the hemoglobin above normal → Fatigue
■ ↑ may be real or apparent because of a ↓plasma volume Physical Examination
(spurious or relative polycythemia)
● Usually reveals a ruddy complexion
● Erythrocytosis
● Splenomegaly
→ May be used interchangeably with polycythemia
→ Favors polycythemia vera as the diagnosis
→ Erythrocytosis: documentation of ↑ red cell mass
→ Polycythemia: any ↑ in red cells ● Presence of cyanosis or evidence of a R-to-L shunt suggests
● Often detected through incidental findings of ↑hgb or hct levels congenital heart disease presenting in the adult
● Concern that the hemoglobin level may be abnormally high is → Tetralogy of Fallot or Eisenmenger’s syndrome
usually triggered at: ● ↑ blood viscosity -> ↑ pulmonary artery pressure
→ Men: 170 g/L (17 g/dL) ● Hypoxemia -> ↑ pulmonary vascular resistance
→ Women: 150 g/L (15 g/dL) → Can produce cor pulmonale
● Hematocrit level may be abnormal
→ Men: >50%
→ Women: >45%
● Hematocrits that are almost invariably assoc. with ↑ red cell
mass
→ Men: >60%
→ Women: >55%
→ Machine quantitates red cell parameters measures
hemoglobin concentrations and calculates hematocrits
■ Hemoglobin levels may be a better index
● Features of the clinical history that are useful in the differential
diagnosis include:
→ Smoking history
→ Current living at high altitude
→ History of congenital heart disease, sleep apnea, or chronic
lung disease
● Polycythemia can be:
→ Spurious
■ Related to a decrease in plasma volume; Gaisbock’s
syndrome
→ Primary (inherited/acquired)
■ E.g., a rare familial form of polycythemia is assoc. with
normal EPO levels but hyperresponsive EPO receptors
due to mutations
→ Secondary
■ All are associated with ↑ in EPO levels either due to:
− Physiologically adapted appropriate elevation based on
tissue hypoxia (lung disease, high altitude, CO
poisoning, high affinity hemoglobinopathy)
− Abnormal overproduction (renal cysts, renal artery
stenosis, tumors with ectopic EPO production)
Figure 7. Approach to Diagnosing Patients with Polycythemia. Source:

Harrison’s Principle of Internal Medicine, 20 th ed.
Figure 8. Diagnostic Criteria for Polycythemia Vera Table 7. Summary of Possible Diagnoses for Patients Presenting with
placed in the Appendix, p.22 Polycythemia
Approach to the Patient with Polycythemia

● First step is to document the presence of an increased red cell
mass using the principle of isotope dilution
→ Administer 51Cr-labeled autologous red blood cells to the
px & sampling blood radioactivity over a 2h period
● If red cell mass is normal
→ Men: <36 mL/kg
→ Women: <32 mL/kg
→ Spurious or relative polycythemia
● If red cell mass is increased
→ Men: >36 mL/kg
→ Women: >32 mL/kg
→ Serum EPO levels should be measured
● If EPO levels are low or unmeasurable
→ Most likely polycythemia vera
→ 90-95% of patients with polycythemia vera has a mutation in
JAK2 (V617F)
■ Key member of cytokine intracellular signaling pathway
→ Many of those w/o JAK2 mutation have mutations in exon 12
→ Few centers assess red cell mass in the setting of an
increased hematocrit. The short workup is to:
■ Measure EPO levels
■ Check for JAK2 mutation
■ Perform an abdominal ultrasound to assess spleen size
→ Tests that support the diagnosis of polycythemia vera
■ ↑ white blood cell count
■ ↑ absolute basophil count
■ Thrombocytosis
● If serum EPO levels are elevated
→ Needs to distinguish whether the elevation is physiologic B. DEFINITION
response to hypoxia or autonomous EPO production ● Polycythemia Vera (PV)
● Patients with low arterial O2 saturation (<92%) → clonal hematopoietic stem cell disorder and a major
→ Should be further evaluated for the presence of heart or lung myeloproliferative neoplasm in which phenotypically normal
disease (if not living at high altitude) red cells, granulocytes, and platelets accumulate in the
● Patients with normal O2 saturation (smoker) absence of a recognizable physiologic stimulus
→ Have ↑ EPO levels because of CO displacement of O2
→ If ↑ carboxyhemoglobin (COHb) levels C. EPIDEMIOLOGY
■ Diagnosis: smoker’s polycythemia ● Most common among MPNs | 
■ Should be urged to stop smoking ● 2.5 per 100,000 persons
■ If cannot stop → Increases with age
− Require phlebotomy to control polycythemia ● Adults more affected
● Patients with normal O2 saturation (non-smoker) either have: ● M>F
→ Abnormal hemoglobin that does not deliver O2 to the tissues → Sporadic cases: F > M
■ Evaluated by finding ↑O2–hemoglobin affinity ● Infrequent familial transmission
→ A source of EPO production that is not responding to normal ● In a study conducted for Filipino clinical profile:
feedback inhibition. → No sex predominance
● Further workup is dictated by the differential diagnosis of EPO- → Mean age at diagnosis was 54 years old (range 17-76)
producing neoplasms → No mortality was noted in the study
→ Detectable w/ abdominopelvic CT scan
D. ETIOLOGY
■ Hepatoma
■ Uterine leiomyoma ● Unknown
■ Renal cancer or cysts ● Deletion 20q and deletion 13q or trisomy 9
→ Cerebellar hemangiomas → In 30% of PV patients
■ May produce EPO → No consistent cytogenetic abnormality (unlike CML)
■ But present w/ localizing neurologic signs and symptoms ● JAK2 V617F mutation | 
rather than polycythemia-related symptoms → Change of Amino Acid at 617 th position from Valine to
Phenylalanine (constitutive kinase activation)
→ > 95%
→ Function:
■ Cognate tyrosine kinase for the erythropoietin and
thrombopoietin receptors
■ Obligate chaperone in the Golgi apparatus
■ Responsible for cell-surface expression
→ Elevation of LAP score
→ Observed in patients with long-standing idiopathic
erythrocytosis
● Also associated with LNK and CARL mutations (not as much)
● Loss of heterozygosity on chromosome 9p
→ Most common cytogenetic abnormality
E. PATHOPHYSIOLOGY AND CLINICAL FEATURES ● Other labs:

→ Red cell count, mean corpuscular volume, and red cell
Figure 9. Pathophysiology of PV placed in the Appendix, p.23,
distribution width (RDW)
Source: BGD 2 Report
→ pulse oximetry, serum chemistries, urinalysis,
● Plethoric appearance abdominopelvic CT scan
● Initial presenting manifestations of PV ● Bone marrow exam provide no specific diagnostic information
→ Isolated thrombocytosis because these may be normal or indistinguishable from
→ Leukocytosis essential thrombocytosis or PMF
→ Splenomegaly
● However, most often the disorder is first recognized by: G. DIAGNOSIS
→ Incidental discovery of a HIGH hemoglobin or hematocrit ● Diagnosis is apparent
● NO symptoms distinguish PV from other causes of → PV presents with erythrocytosis in combination with
erythrocytosis (with the exception of aquagenic pruritus) leukocytosis, thrombocytosis, or splenomegaly
● Aquagenic Pruritus |  ● Diagnosis is more complex
→ Symptom that differentiates PV from other MPNs → Patients present with an elevated hemoglobin or hematocrit
→ Due to mast cell activation and increased basophil count alone
● Uncontrolled erythrocytosis ● Unless the hemoglobin level is ≥20 g/dL (hematocrit ≥60%)
→ Causes hyperviscosity |  → It is NOT possible to distinguish true erythrocytosis from
→ Leading to neurologic symptoms: |  disorders causing plasma volume contraction
■ Vertigo → Why? There is expansion of the plasma volume
■ Tinnitus ■ Unique in PV, in contrast to other causes of true
■ Headache erythrocytosis
■ Visual disturbances ■ Which can mask the elevated red cell mass
■ Transient ischemic attacks (TIAs) ● Red cell mass and plasma volume determination
● Systolic hypertension → To establish the presence of an absolute erythrocytosis
→ Feature of the red cell mass elevation ■ To distinguish this from relative erythrocytosis (known as
● In thrombosis as a presenting manifestation of PV, any vessel stress or spurious erythrocytosis or Gaisböck’s syndrome)
can be affected d/t a reduction in plasma volume alone
→ cerebral, cardiac, or mesenteric vessels → MOST commonly ● Assay for JAK2 mutations in the presence of a normal arterial
involved oxygen saturation
→ Can present with prominent conjunctival vessels → Provides an alternative diagnostic approach to erythrocytosis
● Intraabdominal venous thrombosis → red cell mass and plasma volume determinations NOT
→ Common in young women available
→ Catastrophic if a sudden and complete obstruction of the → TODAY, the assay for JAK2 V617F has superseded other
hepatic vein occurs! tests for establishing the diagnosis of PV!
● PV should be suspected in any patient who develops hepatic
H. COMPLICATIONS
vein thrombosis
→ Budd-Chiari syndrome ● Complications are directly related to hyperviscosity and
■ Common in young women; catastrophic if sudden and indirectly related to increased cell turnover
complete obstruction occurs ● Thrombosis
● May occur due to vascular stasis or thrombosis → Liver – Budd-Chiari Syndrome (Hepatic Vein Thrombosis)
→ Digital ischemia → Heart – AMI
→ Easy bruising → Lungs – Pulmonary Embolism
→ Epistaxis → Brain – Stroke
→ Acid-peptic disease → Eyes – Retinal Vein Thrombosis (may lead to visual
→ Gastrointestinal hemorrhage disturbances)
● Erythromelalgia ● Peptic Ulcer Disease - increased susceptibility to H. pylori
→ Symptom complex of erythema, burning, and pain in the ● Von Willebrand Disease – d/t absorption and proteolysis of
extremities VWD multimers by large platelet mass
→ Complications of the thrombocytosis of PV ● Erythromelalgia – d/t thrombocytosis
■ d/t increased platelet stickiness → Primarily involves lower extremities
● Other complications → Manifests with erythema, warmth, pain of affected
→ Hyperuricemia with secondary gout appendage, and occasionally digital infarction
■ d/t the large turnover of hematopoietic cells ■ d/t increased platelet stickiness and blockage of blood
→ Uric acid stones vessels that leads to hyperemia and inflammation
→ Symptoms d/t hypermetabolism → Ocular migraine (variant)
● Gout (increased uric acid) – d/t increase uric acid deposition
F. LABORATORY STUDIES secondary to increased cell turnover
● CBC ● Enlarged Spleen (Splenomegaly/Hypersplenism)
→ ↑ Hemoglobin and Hematocrit |  → Prone to thrombotic events
■ Absolute vs Relative Erythrocytosis ● Myelofibrosis (Spent Phase - pancytopenia)
■ Elevation of red cell mass with normal to increased → Usually 10 years after diagnosis
plasma volume vs Normal red cell mass with ● AML – low incidence
increased plasma volume
I. PROGNOSIS
→ ↑ WBC count
→ ↑ Platelet count ● Prognosis is favorable
● Serum EPO → Most patients with PV can live long lives without functional
→ Primary vs Secondary causes of PV impairment if their red cell mass is maintained within target
→ Low vs High values
● Assay for JAK2 mutation → Prognosis becomes poor if PV transforms into Myelofibrosis
or AML
● 15 months survival - half of PV patients without treatment → Cytoreductive therapy

→ Mean survival of untreated PV patients: 18 months → Prevents vascular complications in high risk patients
● 14 years survival - PV patients treated with phlebotomy only → Disadvantage:
(younger patients (below 60 y/o) have 24 years survival) ■ Leukemogenic (used for only a short time)
● Overall median survival: 10 - 20 years ■ Side effects
− low-grade fevers, night sweats, flu-type symptoms,
J. TREATMENT
long-term myelosuppression, hair loss, autoimmune
● Treatment option can be placed into 3 groups: diseases, and depression
→ Therapeutic Phlebotomy ■ Some patients are resistant or intolerant to hydroxyurea
→ Myelosuppressive Therapy ● Pegylated-Interferon alpha – for younger patients
→ Targeted Molecular Therapy → Can reduce symptomatic splenomegaly
● Busulfan – for older patients
Targeted Molecular Therapy
● Ruxolitinib
→ Non-specific JAK1/JAK2 kinase inhibitor
→ Can reduce spleen size (reduce need for splenectomy) and
alleviate symptoms such as fever, weight loss, fatigue, and
pruritus
→ Also used for those who are resistant or intolerant to
Hydroxyurea
→ It is expensive
Other Treatments
● Hyperuricemia
→ Allopurinol (for decreasing uric acid)
■ Febuxostat is more effective in reducing serum uric acid
levels with less side effects
→ Colchicine (for Acute Gouty Flares)
● Aquagenic Pruritus
→ Antihistamines
● Splenomegaly unresponsive to chemotherapy
→ Splenectomy
● Thrombocytosis after phlebotomy or thrombotic tendencies
→ Anagrelide (alternative to HU)
Figure 9. Treatment algorithm for Polycythemia Vera Source: Tefferi, A., → Provides less marrow toxicity and can prevent venous
Vannucchi, A.M., and Barbui, T. (2018). Polycythemia vera treatment algorithm thrombosis (unlike HU)
2018. Blood Cancer Journal, 8(1), pp. 3-9 ● Erythromelalgia
Therapeutic Phlebotomy → Salicylates or Reduction of platelet number
● Goal: Maintain Hct at less than 45% for men and 42% for ● Von Willebrand Disease
women (If Hgb, < 14g/dL for men and <12 g/dL for women) → ε-aminocaproic acid
→ To avoid complications especially thrombosis ● Myelofibrosis
● Restores normal blood flow and ameliorates associated → Ruxolitinib (for symptom palliation), bone marrow
symptoms such as headache, fatigue, pruritus transplant
● Once iron-deficient state has been achieved, phlebotomy is PRIMARY MYELOFIBROSIS
usually required in 3 months interval
→ Reduce viscosity and induce iron deficiency to inhibit A. DEFINITION AND EPIDEMIOLOGY
erythropoiesis and delay erythrocytosis ● Chronic PMF, idiopathic myelofibrosis, agnogenic myeloid
→ No rule when phlebotomy should be done (some patients: do metaplasia, or myelofibrosis with myeloid metaplasia
phlebotomy if patient has hematocrit levels that increased ● Clonic hematopoietic stem cell disorder associated with
within 2-3 months) mutations in JAK2, MPL, CALR
→ Monitor regularly because if blood count goes higher even if
● Characterized by marrow fibrosis, extramedullary
undergoing phlebotomy, maybe need more frequent
hematopoiesis, and splenomegaly
phlebotomies
→ Don't remove more than 1 unit of whole blood at a time ● Least common MPN
because there may be a risk of circulatory collapse if you ● Primarily affects men in their sixth decade or later
take out too much - need to replace blood fluid with NSS or Table 8. Disorders Causing Myelofibrosis
colloid to maintain circulating blood volume MALIGNANT NON-MALIGNANT
● Low dose aspirin can also be taken to minimize thrombosis ● Acute leukemia ● HIV infection
→ Indications: (Lymphocytic, myelogenous, ● Hyperparathyroidism
■ Insufficient control of microvascular symptoms after megakaryocytic) ● Renal osteodystrophy
obtaining the targeted hematocrit level ● CML ● SLE
■ Presence of other cardiovascular risk factors ● Hairy cell leukemia ● TB
→ Must balance with other risk factors ● Hodgkin’s disease ● Vit. D deficiency
● Anticoagulants can also be taken when thrombosis has ● Primary Myelofibrosis ● Thiorum dioxide exposure
occurred but difficult to monitor if red cell mass is elevated ● Lymphoma ● Gray platelet syndrome
● Multiple myeloma
Myelosuppressive Therapy
● Myelodysplasia
● Hydroxyurea considered as first line therapy ● Metastatic carcinoma
→ Selectively inhibits ribonucleoside diphosphate reductase ● Polycythemia vera
■ Prevents cells from leaving the G1/S phase of the cell ● Systemic mastocytosis
cycle
■ Stops DNA synthesis and proliferation
B. ETIOLOGY ESSENTIAL THROMBOCYTOSIS

● Nonrandom chromosome abnormalities
A. DEFINITION AND EPIDEMIOLOGY
→ 9p, 20q-, 13q-, trisomy 8 or 9, or partial trisomy 1q are
common ● Clonal disorder of unknown etiology
● No cytogenetic abnormality specific to the disease ● Uncommon disorder
● 50%; JAK2 V617F mutation ● Female predominance
● 8%: MPL mutation (thrombopoietin receptor) ● Megakaryopoiesis and platelet production: TPO and its
● Most have CALR (calreticulin) gene mutation receptor, MPL
● Degree of myelofibrosis and extent of extramedullary ● Multipotent hematopoietic progenitor cell is involved
hematopoiesis are not related
B. CLINICAL MANIFESTATIONS
● Fibrosis – associated with overproduction of transforming
growth factor β and tissue inhibitors of metalloproteinases ● Often identified incidentally when platelet count is obtained
● Osteosclerosis – overproduction of osteoprotegerin, an ● No symptoms or signs specific for ET
osteoclast inhibitor → Hemorrhagic and thrombotic tendencies:
● Marrow angiogenesis – due to increased production of ■ Easy bruising
vascular endothelial growth factor ■ Erythromelalgia
● Fibroblasts are polyclonal and not part of the neoplastic clone ■ Ocular migraine
→ But can be induced by it to produce inflammatory cytokines ■ TIA
● PE: generally unremarkable
C. CLINICAL MANIFESTATIONS → Occasionally mild splenomegaly
● No PMF specific signs and symptoms ■ Splenomegaly: indicative of other MPN (PV, PMF, CML)
● Asymptomatic at presentation ● Anemia unusual
● Usually detected by splenic enlargement and/or abnormal blood ● Mild neutrophilic leukocytosis
counts during routine examination ● Blood smear
● Night sweats, fatigue, and weight loss are common → (+) remarkable number of platelets, some are very large
● Blood smear – characteristic features of extramedullary → May prevent accurate measurement of serum K+ due to
hematopoiesis release of platelet K upon blood blotting (Hyperkalemia- not
→ teardrop-shaped cells assoc. with electrocardiographic abnormality)
→ nucleated red cells ● Inaccurate arterial oxygen measurements
→ myelocytes and promyelocytes ● Normal PT, aPTT
→ myeloblasts may also be present ● Abnormal platelet function: prolonged Bleeding Time
● Mild anemia is common → No platelet dysfunction is characteristic of ET
● Leukocytes and platelet counts may be normal or increased, but → No platelet function test will predict thrombosis or bleeding
either can be depressed ● Bone Marrow Aspiration:
● Mild hepatomegaly may accompany splenomegaly but is → Megakaryocyte hypertrophy and hyperplasia
unusual in its absence → If marrow reticulin is elevated- consider other diagnosis
● Isolated lymphadenopathy suggests a different diagnosis ● Nonrandom cytogenetic abnormalities
● Serum LDH and ALP levels can be elevated → Can occur but uncommon
● Marrow is inaspirable due to myelofibrosis → No specific or consistent abnormality
● Bone x-rays may reveal osteosclerosis → Chromosomes 3 (gene for thrombopoietin) and 1 (receptor
● Extramedullary hematopoiesis MPL)
→ Ascites
→ Portal, pulmonary, or intracranial hypertension C. DIAGNOSIS
→ Intestinal or ureteral obstruction ● Thrombocytosis is seen in clinical disorders in which cytokines
→ Pericardial tamponade are also increased
→ Spinal cord compression Table 9. Causes of Thrombocytosis
→ Skin nodules Causes of Thrombocytosis
● Rapid splenic enlargement can cause splenic infarction with Tissue inflammation; collagen Hemorrhage
fever and pleuritic chest pain vascular disease, inflammatory
● Hyperuricemia and gout bowel disease
Malignancy Iron-deficiency anemia
D. DIAGNOSIS Infection Surgery
● Diagnosis of exclusion; clinical features overlap with PV or CML Myeloproliferative disorders: PV, Rebound: Correction of vitamin
● Intriguing feature: autoimmune abnormalities Primary myelofibrosis, essential B12 or folate deficiency, post-
thrombocytosis, chronic ethanol abuse
E. COMPLICATIONS myelogenous leukemia
● Shorter survival (if compared to PV or ET patients) Myelodysplastic disorders: 5q- Hemolysis
● Natural history: increasing marrow failure with transfusion- syndrome, idiopathic refractory
dependent anemia and increasing organomegaly due to sideroblastic anemia
extramedullary hematopoiesis Postsplenectomy or Familial: Thrombopoietin
● May evolve from a chronic phase to an accelerated phase with hyposplenism overproduction, JAK2 or MPL
constitutional symptoms and increasing marrow failure mutations
F. TREATMENT ● Absolute level of platelet count is NOT a useful diagnostic aid in

distinguishing between benign and clonal causes of
● No specific therapy
thrombocytosis
● Corticosteroids; low-dose thalidomide with prednisone
● JAK2 V617F mutation
● Allogeneic bone marrow transplantation = ONLY CURATIVE → Seen in 50% of ET patients
TREATMENT (considered in younger patients) → If absent, cytogenetic evaluation is mandatory to determine if
it is due to CML or myelodysplastic disorders such as 5q-
syndrome
● Fluorescence in situ hybridization (FISH) END OF TRANSCRIPT

→ Preferred analysis for bcr-abl for patients with thrombocytosis
with negative Ph chromosome REFERENCE
● CALR mutations Jameson J.L, Kasper, D.L., Longo, D.L., Fauci, A.S., Hauser, S.L., and Loscalzo,
→ Present in most patients without JAK2 mutations J. (2018). Harrison’s Principles of Internal Medicine. USA: McGraw-
Hill Education. (Chapter 59 p. 393; 96 pp. 708-723; 97 p. 723; 99 pp.
→ Diagnostic tools to detect this are not yet widespread 733-739)
● Anemia and ringed sideroblasts
Keohane, E.M., Otto, C.N., and Walenga, J.M. (2020). Rodak’s Hematology:
→ Not features of ET Clinical Principles and Applications. 6th edition. St. Louis, Mo.:
→ Features of idiopathic refractory sideroblastic anemia Elsevier Saunders
→ In some patients, thrombocytosis can occur in association Tefferi, A., Vannucchi, A.M., and Barbui, T. (2018). Polycythemia vera
with JAK2 V617F expression treatment algorithm 2018. Blood Cancer Journal, 8(1), pp. 3-9
● Splenomegaly Obnial, J.C., Ocampo, J.M., Oguan, J., Ong, E.Y., Ong, G.S.M, Ong, M.C.G,
→ Suggest presence of other MPN Ong, P.J., Ong, S.I., Ongchinke, J.D.P. (2020). APLASTIC ANEMIA,
→ In this setting, red cell mass determination should be AIHA, and PV [Powerpoint Presentation]. Manila, Philippines: Faculty
performed (splenomegaly can mask presence of of Medicine and Surgery, University of Santo Tomas, MED 2
erythrocytosis) Manansala, Manapat, Malanog, Malicse, Mallari, Manalo, Mariano, Maristela, and
● ET can evolve into PV or PMF after many years, revealing the Martinez (2018). Aplastic Anemia, Myelodysplasia & Related BM
true nature of underlying MPN Failure Syndromes. Manila, Philippines: Faculty of Medicine and
● JAK2 V617F neutrophil allele Surgery, University of Santo Tomas, MED 2
→ Cannot be used to distinguish between ET and PV Manansala, Mahangas, Manipon, Manuel, Manzano, Maramba, Maranan,
■ Only red cell Marcelo A, Marcelo C, Marfil. (2018). Hemolytic Anemia & Anemia
Due To Acute Blood Loss. Manila, Philippines: Faculty of Medicine
D. COMPLICATIONS and Surgery, University of Santo Tomas, MED 2
● Commonly believed that high platelet count causes Ortua, Naguiat, Nepomuceno, Ng, Ngoyahon, Ozaeta. (2018). Polycythemia
intravascular stasis and thrombosis Vera and Other Myeloproliferative Disorders
→ No study has ever established its association
→ Tobacco use – most important risk factor for thrombosis in
ET patients | 
● Hemorrhage – associated with very high platelet due to von
Willebrand’s disease
● Neurologic problems: migraine-related – may respond only
by lowering platelet count
● Erythromelalgia – may respond to platelet COX1 inhibitors
(Aspirin or Ibuprofen)
● Atherosclerotic vascular system – may be related to high
platelet count or not
● Can evolve into PMF
E. TREATMENT
● Elevated platelet count, asymptomatic, w/o cardiovascular risk
→ NO therapy required | 
● Cause of thrombocytosis must be identified before therapy
● Platelet count: 1 x 10⁶/μL
→ Substantial quantity of high-molecular-weight von Willebrand
multimers are removed from circulation
→ Results in acquired von Willebrand’s disease | 
→ Aspirin – can cause hemorrhage
→ EACA – used in bleeding; can be prophylactically used
before and after elective surgery
→ Plateletpheresis – a temporary and inefficient remedy,
rarely required
● ET patients with 32P or alkylating agents
→ At risk for developing acute leukemia without any proof of
benefit
→ Combining either therapy with hydroxyurea increases the risk
● Refractory salicylates alone, pegylated IFN-α, the quinazoline
derivative, anagrelide, or hydroxyurea
→ Can be used to reduce platelet count
→ None of these is uniformly effective
● Hydroxyurea and aspirin
→ More effective anagrelide and aspirin for prevention of TIAs
(due to NO donor)
→ But NOT more effective for the prevention of other types of
arterial thrombosis
→ LESS affective for venous thrombosis
● Normalizing the platelet count
● Does NOT prevent either arterial or venous thrombosis
● Gastrointestinal bleeding – risk is higher if aspirin + anagrelide
● ET appears more benign than previously thought
● Acute Leukemia – more likely to be consequence of therapy
than the disease itself
● In managing patients, first do NO harm
IV. APPENDIX
Table 3. Diagnostic Criteria for Aplastic Anemia
Figure 3. Treatment Algorithm for Aplastic Anemia (p. 5)
Figure 8. Diagnostic Criteria for Polycythemia Vera (p. 17) Source: World Health Organization (WHO) Diagnostic Criteria for Polycythemia Vera
Figure 9.1. Pathophysiology of PV Source: BGD 2 Report (p.18)
Figure 9.2 Pathophysiology of PV Source: BGD 2 Report (p.18)

(Med-Ho) 02 Aplastic Anemia, Aiha, PV

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MEDICINE 2 – [HEMA-ONCO]: BGD

C. ETIOLOGY ● Most cases are idiopathic

→ Nose bleeds → Except for mildly megaloblastic erythropoiesis:

H. COMPLICATIONS gamma-interferons, which are responsible for inhibiting

Especially phenytoin, azathioprine, chloramphenicol, ● Idiopathic PRCA – responds favorably to immunosuppression

■ Busulfan, nitrosourea, or procarbazine (with a latent → Splenomegaly

→ Platelets may be abundant and are often of giant size C. ETIOLOGY

● Smear: ■ Pulmonary emboli

I. OTHER INFORMATION D. PATHOPHYSIOLOGY

2. Hereditary Elliptocytosis (HE) ● In severe disease, splenectomy may be beneficial, as the

Figure 7. Approach to Diagnosing Patients with Polycythemia. Source:

Approach to the Patient with Polycythemia

E. PATHOPHYSIOLOGY AND CLINICAL FEATURES ● Other labs:

● 15 months survival - half of PV patients without treatment → Cytoreductive therapy

B. ETIOLOGY ESSENTIAL THROMBOCYTOSIS

F. TREATMENT ● Absolute level of platelet count is NOT a useful diagnostic aid in

● Fluorescence in situ hybridization (FISH) END OF TRANSCRIPT

Figure 3. Treatment Algorithm for Aplastic Anemia (p. 5)

Figure 9.1. Pathophysiology of PV Source: BGD 2 Report (p.18)

Figure 9.2 Pathophysiology of PV Source: BGD 2 Report (p.18)

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