Introduction to Clinical

Hematology
Margaret Shepp, M.D.
2/26/2018
 What We Will Cover

• What every doctor needs to know

• Symptoms and findings in the most common

disorders of the blood and bone marrow (and a few
less common ones)

• Common bleeding disorders

Transfusion guidelines
are in your handout
Normal RBC smear
Name the white cells
The Complete Blood Count
• Automated, including the differential.
• Includes:
• Leukocyte count with differential
• Hemoglobin and hematocrit
• Erythrocyte (RBC) count
• RBC indices (MCV, MCHC, MCH)
• RDW (red cell distribution width): a measure of variation in cell size.
• Platelet count
• H&H and rbc count are ratios of cells to plasma. These measures rise as
plasma contracted (dehydration) and fall as plasma expands
(overhydration)
Anemias
 Evaluation of the Anemic
Patient
• Myriad possible causes

• A complete history and physical is often needed

• CBC with attention to wbc count, differential, and

platelets in addition to red cell measures.

• Morphologic assessment will frequently provide

clues to the underlying disease.
How does the anemic patient
present?
• Chronic: adaptation occurs as anemia develops slowly

• No symptoms in mild to moderate anemia - the chief “complaint” is often

an abnormal blood count

• Fatigue develops when anemia is moderately severe - a highly

nonspecific complaint

• Exertional dyspnea and exertional palpitation

• Angina or CHF if severe, especially if underlying cardiac disease

• Acute or subacute: (usually due to blood loss, rarely to hemolysis)

• Shortness of breath, palpitation, exercise intolerance. With acute blood

loss sometimes faintness and/or overt evidence of bleeding
 Physical Findings in Anemia
• Chronic:

• Pallor: usually present in significant anemia, but somewhat subjective.

• Pallor may be seen without anemia - vasoconstriction

• Look for splenomegaly, jaundice (uncommon, but would suggest

hemolysis)

• Fecal occult blood test often needed; may need to do rectal for this

• Tachycardia, functional murmur, and signs of CHF if severe

• Acute:

• Hypotension, tachycardia, pallor; sometimes gross evidence of bleeding

Why is My Patient Anemic?
• Anemias can be classified by mechanism

• Blood loss

• Hemolysis

• Failure of RBC production: Primary and secondary bone

marrow disorders

• Anemias can be further classified as to (MCV)

 Microcytic anemias
Differential Diagnosis

• Iron deficiency

• Lead poisoning

• Thalassemia

• Anemia of chronic disease (usually normocytic)

Case 1
 Case 1
• An 18 year old woman comes to see her physician for a
routine physical examination before entering college.
Her family history is unremarkable. Personal history
reveals her menstrual periods began at age 13 with
monthly abdominal cramping. Other than an occasional
cold she has remained healthy. She has no complaints.

• Physical exam reveals a well nourished woman with pale

mucous membranes. Her pulse is 90, blood pressure
110/78. A grade I/VI systolic ejection murmur is noted at
the LLSB.
 Case 1 Initial laboratory findings

• WBC = 9000

• Hgb = 9.2 (12-16)

• MCV = 72 (80-100)

• Platelet count = 460,000

• Retic. Count = 3.2 % (0.5-1.5)

Peripheral smear is on the next slide

Case 1 Peripheral Smear
 Case 1: Further History

• Menstrual periods about 27 days apart, reasonably

regular, duration 10 days, first 5 days heavy

• Follows a lactovovegetarian diet

• Takes no supplements, aspirin or NASAD’s

• No weight loss, diarrhea, steatorrhea, blood in stool

• No previous known heart murmur

What additional laboratory tests are needed?

 Case 1 Additional laboratory
Results
• Serum iron 29 (60-160)

• TIBC 480 (260-450)

• Saturation 6% (25-35%)

• Ferritin 4 (15-200)

Case 1 diagnosis: iron deficiency anemic

Case 1 Clinical Correlation
• Her need for iron is high because of her greater than
average menstrual blood loss

• Her diet is relatively deficient in iron for her needs

• Her cardiac output has increased to compensate for her

anemia - tachycardia and functional heart murmur

• Because she has been able to compensate for her

anemia she has no symptoms
 Iron Deficiency
• Always seek the cause of iron deficiency

• Babies (6-24 months) : growth of rbc’s may outstrip iron intake.

Impairment in cognitive development may occur if severe.

• Menstrual blood loss

• Chronic GI blood loss

• Diet deficient in iron, or relatively deficient for needs

• Malabsorption: syndromes, gastric bypass,

gastroduodenectomy
 Some less usual signs and
symptoms of iron deficiency anemia
• Pica – eating unusual things such as ice, clay, dirt,
paper.

• Restless legs

• Hair loss

• Pale mucous membranes, cheilitis, atrophic

glossitis

• Koilonychia – spoon shaped nails

Atrophic Glossitis
Koilonychia
 Evaluation of Suspected
Iron Deficiency
• History focused on sources of blood loss

• Confirmatory lab tests: Serum iron low, TIBC high, ferritin low

• Pitfall in laboratory interpretation: in chronic disease states the rise in

iron binding capacity may be blunted and ferritin may be in normal
range

• Bone marrow assessment of iron stores: bone marrow is rarely done

for this purpose alone

• Fecal occult blood tests mandatory in adult male or

postmenopausal female

• GI endoscopy if FOBT positive; consider even if FOBT negative as GI

lesions may bleed intermittently
Treatment of Iron Deficiency
• Oral iron (ferrous sulfate, ferrous gluconate) - side
effects: dyspepsia, nausea, constipation,
occasionally diarrhea

• IV iron infusion ( iron sucrose, iron dextran) when

oral not tolerated or when rapid replacement
needed. Caution: anaphylaxis is possible; $$

• Give iron long enough to correct anemia and then

continue treatment to replenish iron stores
Treatment of iron deficiency:
Beyond iron supplementation

• Find and treat the underlying cause:

• GI blood loss

• Menstrual blood loss

• Malabsorption
For Case 1:

• Consider hypothyroidism

• Consider Von Willbrand’s Disease or other bleeding

disorder

• Consider hormonal contraceptive to reduce

menstrual blood loss
What do you see? Significance?
Ringed Sideroblasts
 What are the clinical signs and
symptoms of lead intoxication?

• Mental retardation in young patients

• Abdominal pain – colicky in nature
• Peripheral neuropathy (wrist drop is classic)
• Skin lesions
• Gingival lead line
• X-ray studies – radiodensity in tibia
 Lead Toxicity
• Children more susceptible than adults
• Main source of lead in children is pre-1979 housing
(lead paint)
• CDC no longer recommends universal pediatric
screening
• At pediatric health maintenance visit inquire about
possible sources of lead in home, and advise
amelioration
• Test at risk children and those with developmental
delay, or other symptoms that might indicate lead
excess
• Treatment: chelating agents
 Thalassemias

• Thalassemias: genetic disorders of globin chain

production.
• Mediterranean or African genetic background
• α thalassemias result from defect in α chain
production
• β thalassemias result from defect in beta chain
production
Beta Thalassemia Major
• Homozygous and fortunately rare

• Severe anema, transfusion dependent

• Extramedullary hematopoiesis, bone deformities

• Complications of iron overload from chronic

transfusions

• Functional asplenia and consequent infections.

Beta Thalassemia minor
• Heterozygote, also called “thal trait”

• Fairly common

• Mild, lifelong, asymptomatic anemia

• Laboratory clue: mild anemia paired with severe

microcytosis

• Diagnosis by hemoglobin electrophoresis

ear in beta thalassemia trait. Target cells are characteristic but no
 Macrocytic anemias
Differential Diagnosis
• B12 deficiency. (Pancytopenia may be present).

• Folate deficiency. (Pancytopenia occasionally present).

• Myelodysplastic syndrome (clonal disorder with impaired rbc

maturation, often a preleukemic state). Common in elderly. Often
pancytopenia is present

• Drug induced: antifolates (e.g. methotrexate) and other

chemotherapy, anticonvulsants (e.g. diphenylhydantoin)

• Macrocytosis without anemia may occur with alcohol excess.

Mechanism unknown. Useful clue.
Case 2
 Case 2
• A 56 year old woman consults her physician because
of weakness, fatigue and dyspnea over the past four
months. She acknowledges a problem with walking -
unsteady on her feet, falling occasionally.
• Physical exam reveals a tall, slender woman with
“lemon-yellow” skin and a smooth, red tongue. Liver
and spleen are not palpable. Vibratory sense in her
lower extremities is markedly decreased to above the
ankles. Pin prick sensation is intact. Romberg is
positive.
• Family history was unremarkable and she is currently
on no medications.
Case 2 Initial laboratory findings

• WBC = 3,200 (4k-10k)

• RBC = 2.2 (4.2-5.9)
• Hgb = 8.2 (12-16)
• MCV = 122 (80-100)
• MCHC = 38 (33-36)
• Platelets = 90,000 (150-450K)

Peripheral smear is on next slide

Peripheral Smear
Case 2 Laboratory results
• B12 100 (200-800)

• Folate 10 (2.5-20

• MMA 450 (150-370)

• Antiparietal cell antibody positive

Diagnosis: pernicious anemia

 Case 2: Clinical Correlations
• The classic lemon yellow skin results from
anemic pallor plus mild jaundice (mild
hyperbilirubinemia from ineffective
erythropoeisis and intramedullary hemolysis
of malformed cells)
• Degeneration of dorsal columns and lateral
corticospinal tracts lead to impairment of
vibration and position sense, and spastic
paraparesis.
• Gait impairment results
 B12 deficiency
• Virtually never on the basis of diet only in USA

• Most common cause: autoimmune (antiparietal cell

antibodies)

• Gastric resection, gastric bypass, terminal ileal disease or

resection

• May cause neurologic symptoms: impaired cognition,

dysequilibrium, impairment of position and vibration sense

• Neurologic symptoms may precede anemia

 Folate Deficiency

• Folate poor diet - tea and cookies diet; and

alcoholics

• Intestinal malabsorption syndromes

 Macrocytic Anemias
Evaluation: History
• The most common presentation is asymptomatic laboratory
abnormality

• B12 deficiency may present with impaired cognition or gait

disturbance, and these symptoms may precede anemia

• Ask about anemia symptoms and neurologic symptoms

• Ask about diet, alcohol intake, hx of GI disease or surgery,

presence of autoimmune conditions
 Macrocytic Anemias
Evaluation: Laboratory
• B 12 and folate blood levels

• Anti parietal cell antibody to confirm or rule out autoimmune

pernicious anemia (Schilling test outmoded)

• MMA (methylmalonic acid) rises early in B12 deficiency. Useful if

B 12 level borderline low or if macrocytosis is present without
anemia.

• Homocysteine is elevated in both B12 and folate deficiencies,

therefore will not discriminate between these.

• Consider bone marrow aspiration if macrocytic anemia remains

unexplained - to look for features of myelodysplastic syndrome
 Dietary Sources of
Vitamin B12

• Meat
• Fish
• Dairy products
• Eggs
• Nutritional yeast (not baker’s yeast)
• It is rare but possible for vegans to become
B12 deficient due to dietary lack alone
Treatment of B12 and Folate
deficiencies
• For folate deficiency - oral folic acid
• For B 12 deficiency
• Parenteral B12 initially: various high dose regimens
available
• Maintain indefinitely with parenteral cobalamin 1000 μcg
monthly. Patients learn to self administer B12 injections
• Or maintain indefinitely with high dose oral vitamin B12,
which can overcome the barriers to absorption in
sufficient doses.
 Normocytic anemias
Differential Diagnosis
• Blood loss without iron deficiency

• Anemia of chronic disease (ACD), including renal failure

• Most primary and secondary bone marrow disorders (these

often affect all 3 blood cell lines)

• Combined iron and B12 or folate deficiency may be

normocytic

• Most hemolytic anemias

• Drug-induced - aplastic, hemolytic

 Normocytic Anemias
Evaluation
• Anemias may be multifactorial. ACD is a diagnosis of exclusion.

• Check creatinine and eGFR, and look for chronic disease as

suggested by clinical symptoms and findings.

• If creatinine is elevated or eGFR is low, the diagnosis seems

obvious, but rule out coexisting iron or vitamin deficiency or GI
blood loss

• Consider reticulocyte count, and haptoglobin in appropriate

clinical circumstance (more about this in PM lecture)

• Bone marrow exam may needed

Case 3
 Case # 3

• A 39 year old Scottish woman is seen

because of an acute attack of right upper
quadrant abdominal pain.
• Physical examination reveals scleral
icterus, jaundice, RUQ tenderness, and
prominent splenomegaly. Radiographic
studies show numerous gallstones.
 Case 3: Initial Labs
• WBC = 18,000 (high)
• Hgb = 7.9 (low)
• HCT = 22.6 (low)
• MCHC = high
• MCV = top normal
• Total bilirubin =2.5 (H), direct 0.3 (nml)
• LDH (lactate dehydrogenase) = elevated

• Hemolytic anemia is suspected

What are the next steps in laboratory testing?

 Case 3: Follow up Labs
• Reticulocytes 9% (Normal 0.5-2%)
• Corrected reticulocyte count 4.8%
• Retic % x (patient crit/normal crit)
• Haptoglobin undetectable. Haptoglobin is a plasma
carrier protein for free hemoglobin. The hemoglobin-
haptoglobin complex is excreted really. When
haptoglobin is consumed, hemolysis can be inferred.

Hemolytic anemia confirmed

What is the differential diagnosis of hemolytic
anemia?
 Hemolytic Anemia DDx (partial ist)
• Hereditary speherocytosis
• Autoimmune hemolytic anemia (AHA)
• G6PD deficiency
• Toxins and drugs
• Mechanical rbc damage
• Defective heart valves
• DIC, HUS, TTP
• March hemoglobinuria

Next slide shows the peripheral smear for case 3

Case 3: peripheral blood smear
 Diagnosis?

What additional tests would

confirm this diagnosis?
 Confirmatory blood tests
• Osmotic fragility test - positive

• Coomb’s test (used in blood banking to

detect antibodies on the surface of red
cells, and in clinical practice to rule in or
out AHA) - negative
 Hereditary Spherocytosis
• Usually autosomal dominant ; European ancestry
• Mutation in erythrocyte membrane proteins causing
reduced membrane stability and loss of membrane
integrity (cytoskeleton defect: spectrin, ankyrin, band 3,
protein 4.2)
• Produces osmotically fragile spherocytes
• The cells become spheroidal, cannot deform to pass
through the splenic sinusoids resulting in splenic
sequestration and rbc destruction
 Case 3: Clinical Correlation
• Classic triad:
• Anemia
• Splenomegaly
• Jaundice
• Biulirubin gallstones due to chronic
hyperbilirubinemia
• Patients usually feel well, as they can compensate
physiologically for the anemia.
• Parvovirus B-19 infection may transiently suppress
bone marrow, leading to acute anemia (“aplastic
crisis”)
 Treatment of Case 3
• Splenectomy (also needs
cholecystectomy)
• Blood transfusions may be indicated
preoperatively - or not
• Vaccinations for encapsulated organisms
ideally 2 weeks before splenectomy
• Folate supplementation- increased
requirement in hemolysis
Bleeding Disorders
Taking a Bleeding History
• Bruises

• Unprovoked? Or provoked, but out of proportion to trauma?

• Petechiae “little red dots” on hands or feet or elsewhere

• Bleeding

• Unprovoked? Or provoked, but prolonged?

• Ask about specific bleeding sites: nasal, gingival, wounds, soft

tissues, rectal, urinary, menses

• Past history of bleeding after surgery, dental extraction,

childbirth
 Bleeding Disorders
Physical Exam
• Lymph nodes, liver and spleen

• Bruising - note size, location, associated hematoma

• Look first at frequently traumatized areas - arms, legs, obese

abdomen (furniture finders)

• If there are bruises on face, neck, torso - consider abuse

• Is the extent of bruising consistent with trauma described?

• Petechiae - appear first in areas of increased hydrostatic

pressure - feet, lower legs, hands if dependent, below bp cuff
 Bleeding Disorders
Basic Laboratory Evaluation
• CBC (includes platelet count)

• Prothrombin Time (PT)

• Partial Thromboplastin Time (PTT)

• {Bleeding time: infrequently used now}

• Special tests: Thrombin Time, Factor assays,

ristocetin cofactor assay, in vitro platelet function
tests such as PFA-100
Review of blood Coagulation
1. Primary hemostasis: Platelet activation and formation of
platelet plug

2. Secondary hemostasis: Thrombin, then fibrin formation via

the intrinsic and extrinsic pathways.

3. Amplification: Thrombin activates more platelets and feeds

back to activate Factors XII, XI and VIII, bringing intrinsic
pathway into play

4. Fibrin stabilization

5. Inhibition of inappropriate coagulation

 Source: thrombosiscanada.ca

http://thrombosiscanada.ca/wp-content/uploads/2013/08/Bloody_Easy_Coag_2013.pdf
 Laboratory
Evaluation of
coagulation
• To understand laboratory
evaluation, think:

• Intrinsic pathway

• Extrinsic pathway

• Common pathway

Source: thrombosiscanada.ca
 Prothrombin Time
“Protime” “PT”
• Indications: evaluation of bleeding disorders,
evaluation of liver disease severity, monitoring
of warfarin therapy

• A tissue factor equivalent (“thromboplastin”) is

added to an anticoagulated tube of blood

• Time is measured to formation of first visible

clot

• Lab has a choice of reagents, and

thromboplastins from different suppliers differ
functionally, so each lab will have a normal
range (in seconds) specific to the reagent used.

• Normal is somewhere from 9-12 seconds,

depending on lab.
Source: thrombosiscanada.ca
 International Normalized
Ratio (“INR”)
• Thromboplastins used in different laboratories provide different
ranges of norma, as measured in seconds to clot formation

• Each individual thromboplastin is compared to an international

standard and assigned a ratio

• This ratio is used to compare the patient’s results to the

international standard

• The patient’s result in seconds is converted to a value called the

international normalized ratio (INR)

• The INR provides standardization of PT’s, allowing the physician

to interpret results no matter what lab the patient uses.
 Activated Partial Thromboplastin Time
(“aPTT”) (PTT)
• Indications: evaluation of bleeding disorders,
monitoring of unfractionated heparin therapy
(no monitoring needed for low molecular
weight heparins)

• A contact activator plus phospholipid are

added to an anticoagulated tube of blood

• Time to formation of first clot is measured

• Normal usually 25-35 seconds

• Each lab will have its own normal range

depending on reagent used

• No lab-to-lab standardization exists

Source: thrombosiscanada.ca
 Platelet Disorders
Classification

• Disorders of platelet numbers

• Disorders of platelet function

• Disorders of both number and function

 Platelet Function Disorders
Causes
• Drug induced, by intent

• e.g. Aspirin or clopidogrel for MI or CVA prevention

• Drug induced, not by intent

• e.g. SSRI’s

• Congenital platelet function disorders

• A previously unsuspected platelet function disorder (or mild

thrombocytopenia) may be unmasked by aspirin or NSAID’s
 Thrombocytopenias
• May present with bruising, bleeding, petechiae, or asymptomatically (found
by the laboratory)

• Bleeding manifestations usually not seen with platelet counts above 30,000,
if platelets are functionally normal

• 70,000 functionally normal platelets will support major surgery

• Organize your thinking according to mechanism: (analagous to anemias)

• Destruction of platelets

• Consumption of platelets

• Failure to produce platelets

 Platelet Destruction
Causes
• Immune:

• Immune thrombocytopenic purpura (“ITP”)

• Part of SLE or related autoimmune disorder

• Drugs (quinidine, quinine, gold, and many others

rarely)

• Splenomegaly of any cause - liver cirrhosis, splenic

tumor
 Platelet Consumption
Causes
• Massive hemorrhage

• Heparin-induced thrombocytopenia - antibodies

activate platelets, causing thrombosis and
consumption

• DIC, TTP, HUS - but other features of these

syndromes need to be present , so these
diagnoses are not part of the differential diagnosis
of isolated thrombocytopenia
Lack of Platelet Production
Causes
• Primary or secondary bone marrow disorders

• Rbc’s and wbc’s are usually affected, too

• Drugs and toxins:

• Pancytopenia or isolated thrombocytopenia

• Cytotoxic chemotherapy

• Thiazides

• Alcohol
 Thrombocytopenia
Evaluation
• Drug and toxin history

• Recent viral infection? (may trigger pediatric ITP but

not usually a trigger in adult ITP)

• Review WBC, Differential, H&H

• Evaluate lymph nodes, liver and spleen, skin

• Antiplatelet antibodies, platelet associated IgG

• Bone marrow exam

Case 4
 Case 4

• A 32 year old woman, gravida 3, para 2 is in her

36th week of gestation. She suddenly develops
an acute onset of abdominal pain and has
profuse vaginal bleeding.
• Physical exam reveals a BP of 90/50, lethargy,
tachycardia and mild fever. She also manifests
bleeding from a venipuncture sites.
 Case 4: Initial lab results

• WBC’s 16,300 (4000-10,000)

• Hemoglobin 9.5 (12-15)
• Hematocrit 28% (36-47)
• Platelets 25,000 (150,000-450,000)

Next slide shows the peripheral smear

 Case 4

• Given the clinical circumstances, what is

your diagnosis?

• What other tests would you order to support

our diagnosis?
 Case 4: Additional Testing
Results

• PT - elevated
• PTT- elevated
• Fibrinogen - low
• Fibrin degradation products (fibrin split
products) - high

These results confirm the impression of

disseminated intravascular coagulation (DIC)
 Pathophysiology of DIC

• Unchecked activation of coagulation system by a

trigger —> activation of fibrinolytic system
• Consumption of clotting factors
• High PT and PTT
• Low fibrinogen levels;
• Elevated d-dimer and fibrin degradation products
• Peripheral destruction of platelets
• Low platelet count
• Mechanical damage to red blood cells as they
squeeze by micro thrombi
• Microangiopathic hemolytic anemia
 Case 4: Clinical Correlation
• Abruptio placentae is suspected, triggers activation of
the coagulation system

• Patient presents with bleeding due to consumption of

clotting factors

• Hemolytic anemia occurs as red cells are literally

chewed up while passing through partially occluded
microvasculature

• Microthrombi in various organs lead to organ

dysfunction, typically kidney, liver, and CNS.
 Some Triggers of DIC
• Obstetrical catastrophes
• Retained dead fetus, placental abruption,
amniotic fluid embolism
• Trauma, burns
• Sepsis
• Hemolytic transfusion reaction
• Acute promyelocytic leukemia
• Mucin-secreting adenocarcinoma
 Von Willebrand’s Disease

• The most common inherited bleeding disorder

• Most kindreds have autosomal dominant inheritance.
• Many different mutations have been identified and no
single mutation is predominant.
 Physiology of Von
Willebrand Factor
• Von Willebrand Factor (VWF) is manufactured in endothelial
cells and megakaryocytes, and is stored in platelets and
blood vessel endothelium.

• VWF is released from storage upon endothelial injury. VWF

promotes platelet adhesion, participating in the initiation of
primary hemostasis.

• VWF also binds to and stabilizes Factor VIII. Instability of

factor VIII may (but does not always) lead to low levels of
factor VIII in VonWillebrand’s Disease.
Subtypes of VonWillebrand’s
Disease
• Type 1(classical) (66-75%) patients have a
deficiency in the quantity of VWF, but the VWF is
functionally normal.

• Type 2 patients (20-25%) usually have a normal

amount of VWF, but it is functionally defective.
There are subtypes of type 2

• Type 3 (rare, autosomal recessive or double

heterozygote) patients have absent VWF
 Von Willebrand’s Disease
Presentation
• May cause any bleeding or bruising symptom (but not
usually GI bleeding)

• Menorrhagia is common and is often the presenting

complaint

• Severe cases may present in neonates with

cephalohematoma, umbilical cord bleeding, post-
circumcision bleeding

• Milder cases may not present until adolescence or

adulthood, sometimes after aspirin or NSAID use, or surgical
challenge
 Von Willebrand’s Disease:
Testing
• Platelet count normal

• Bleeding Time - prolonged

• PT normal; PTT mildly prolonged in 50% (due to factor VIII instability),

normal in 50%

• Von Willebrand factor antigen assay measures amount of Von Willebrand

Factor antigen present. Since the measured antigen is not on the functional
portion of the molecule, this test tells you nothing about function.

• Ristocetin cofactor assay - measures Von Willebrand Factor activity

(function), but tells you nothing about the amount of VonWillebrand Factor
present.

• Test for both: antigen and activity.

 Von Willebrand’s Disease
Treatment
• In type 1, treatment with DDAVP (desmopressin)
causes Von Willebrand Factor to be released from
endothelial storage sites.

• VWF levels are raised and because the VWF is

functionally intact, hemostasis can proceed.

• This strategy does not work in types 2 and 3.

Recombinant Von Willebrand Factor is available to
treat these subtypes.
 Hemophilias

• Congenital deficiencies of factor VIII (hemophilia A)

or Factor IX (hemophilia B)
• Gene is X linked. Patient’s mother is silent carrier,
but her father or brothers may be affected.
• Rarely may be acquired, due to acquisition of
autoantibodies against factor VIII
 Hemophilia
• Varies in severity from case to case, and therefore in age
at presentation. Mild cases may not present until
hemostatic challenge in adulthood

• Hemorrhage out of proportion to trauma; hemarthrosis of

weight-bearing joints characteristic, but may bleed
anywhere.

• Hemoglobin may be normal or low; prolonged PTT

• Evaluation: Factor VIII and IX assays and VonWillebrand

factor antigen and activity (Ddx includes Von Willebrand’s
Disease)
Case 5
 Case 5
• A 60 year old man flies from Maine to Florida. Shortly after leaving
his plane he collapses. He is brought to the an emergency room

• 10 years ago he had a total hip replacement. Postoperatively he

had a pulmonary embolus. He was anticoagulated with warfarin for
6 months.

• In the emergency room his bp is 96/60, pulse 120, and oxygen

saturation 84% on room air. Lungs show good breath sounds with
no rales, wheezes or rhonchi. An EKG shows sinus tachycardia
with no ischemic changes. Troponin is normal.

• What test would you order next?

 Case 5 results
• Chest X ray is normal

• Chest CT angiogram shows large bilateral proximal

pulmonary embolism (saddle embolism)

• In the X ray suite he is given catheter-directed

thrombolytic therapy, follow by unfractionated heparin.

• His vital signs improve; he is anticoagulated indefinitely

with warfarin.

• Would you order testing for congenital thrombophilias?

 Prothrombotic States
• Risk factors for venous thromboembolism (VTE):

• Immobilization (including prolonged travel)

• Major surgery, especially orthopedic

• Lower extremity fracture, especially femur

• Pregnancy; Exogenous estrogens: OCP’s, HRT, Tamoxifen

• Antophospholipid antibodies

• Heritable thrombophilas
Inherited thrombophilias
(Prothrombotic States)
• Deficiency or dysfunction of a natural anticoagulant

• Fairly common: Factor V Leiden (abnormal Factor V

variant)

• Rare: Protein C or protein S deficiency, prothrombin

gene mutation, antithrombin III deficiency

• Suspect a thrombophilia when VTE occurs without risk

factors, or recurs, or where there is a family history of
VTE
 Antiphospholipid antibody
syndromes
• Anticardiolipin antibodies or “Lupus anticoagulant” - so named
because it may be seen in SLE and tit causes a prolonged PTT in
vitro

• In vivo these acquired antibodies do not cause bleeding

• They cause an acquired prothrombotic state: arterial and venous

thrombosis, pulmonary emboli, and pregnancy loss (early
miscarriage and late fetal demise)

• Patients may or may not have SLE or related autoimmune disorder

• Tests for antiphospholipid antibodies may be ordered as part of the

workup of recurrent thromboses, or of pregnancy loss.
Case 6
 Case 6

• This 71 year old man complains of headaches,

dizziness and pruritus especially during hot shower,
vague epigastric pain and blurred vision.

• Physical exam reveals a plethoric man with a blood

pressure of 180/90. Spleen is palpable 2 cm below the
left costal margin.
Case 6: Initial Laboratory Findings

• Hgb 18.9 (14-17)

• Hct 55% (41-51%)
• MCV 101 (80-100)
• WBC 21,000 (4000-10,000)
• Platelet count 600,000 (150,000-350,000)
• Basophils in peripheral smear 7 %
Case 6: Initial Laboratory Findings

• Hgb = 18.9 (H)

• RBC = 6.0 (H)
• MCV 101 (H)
• WBC = 21,000 (H)
• Platelet count – 600,000 (H)
• Basophils in peripheral smear –7 % (H)

How would you describe these findings?

Case 6: Initial Laboratory Findings

• Hgb = 18.9 (H)

• RBC = 6.0 (H)
• MCV 101 (H)
• WBC = 21,000 (H)
• Platelet count – 600,000 (H)
• Basophils in peripheral smear –7 % (H)

How would you describe these findings?

What is the differential diagnosis
of erythrocytosis?
• Normal red cell mass but plasma volume contraction:
• Dehydration, overdiuresis
• Gaisbock’s syndrome (“spurious polycythemia,” or
idiopathic chronic plasma volume contraction)
• Increased red cell mass, normal plasma volume:
• Polycythemia vera
• Chronic hypoxemia
• Ectopic erythropoeitin production
What is the differential diagnosis
of pancytosis?

• Polycythemia vera
• Essential thrombocytosis (may have
erythrocytosis or anemia)
 Differential Diagnosis of
Elevated Platelet Count
(Thrombocytosis)
• Secondary thrombocytosis - platelets usually 500,000-1,000,000

• Acute hemorrhage

• Iron deficiency (a useful clue if you know this fact)

• Inflammation, infection, cancer - mediated by inflammatory cytokines

• Post splenectomy

• Primary thrombocytosis - platelets usually > 800,000, often >1,000,000

• Myeloproliferative disorder: ET, P. vera - unregulated clonal

proliferation
 Myeloproliferative Disorders
• Disorders caused by clonal proliferation of a bone marrow elements

• Heterogeneous group of disorders, but with overlap in clinical

features

• Chronic myelogenous leukemia (CML)

• Polycythemia vera (P. vera)

• Essential thrombocythemia (ET)

• Myelofibrosis with myeloid metaplasia (MMM)

• Understanding of cancer genetics has led to advances in treatment

 Polycythemia Vera
• High red cell count

• High red cell mass - contrast high H&H due to contraction of

plasma volume

• EPO level is low. Red cells are proliferating autonomously

• JAK2 gene activating mutation. Lab test exists for this.

• Blood literally too thick - sludging in microcirculation. Cyanosis,

dizziness, headache, angina, claudication

• Leukocytosis and thrombocytosis are also usually present as all

3 bone marrow cell lines are involved
 Case 6 Clinical correlations

• Headaches are due to increased blood

viscosity, chronic cerebral hypoxemia
• Spleen is enlarged due to increased blood
volume, increased viscosity, and sludging
• Pruritus is due to histamine release from
increased basophils
 How would you treat this patient?

• Regular phlebotomy to decrease the hematocrit

to < 45%
• Low dose aspirin to decrease risk for venous and
arterial thrombosis
• Myelosuppressive therapy: hydroxyurea, busulfan
• Ruxolitinib (kinase inhibitor aimed at JAK
mutation)
• Note: 10% of PV cases will develop AML
 CML
• Anemia, thrombocytopenia, leukocytosis with immature forms in
peripheral blood, splenomegaly

• Chronic phase of 2-3 years duration followed by transformation to

an acute leukemia-like phase

• Acquired translocation between the long arms of chromosomes 9

and 22.

• The translocation occurs in such a place (termed BCR) as to

activate the oncogene ABL, which produces a tyrosine kinase - a
signaler that promotes cell division.

• This knowledge has led to the development of tyrosine kinase

inhibitors (imatinib and others) for treatment