Hematology

Iron-deficiency anemia
Etiology
• Blood loss from the gastrointestinal (GI) tract is the most common cause of iron-deficiency anemia in adult
men and postmenopausal women
• Blood loss due to menorrhagia is the most common cause of iron deficiency in premenopausal women
• In tropical countries, infestation of the gut may cause iron- deficiency anemia, especially with hookworm and
schistosomiasis
• Common causes of blood loss include:
Anemia of chronic disease
- Non-steroidal anti-inflammatory drug (NSAID) use e.g. Naproxen
- Decreased iron
- Colonic carcinoma - Decreased TIBC
- Gastric carcinoma - Raised ferritin
- Gastric or duodenal ulceration
• Dietary inadequacy
• Failure of iron absorption: Malabsorption conditions such as coeliac disease
• Excessive requirements for iron: Pregnancy
Features
• Angular stomatitis (can be seen in vit B12 deficiency as well)
• Koilonychia (spoon nails)
• PICA
Laboratory tests Hairy leukoplakia
• Low Hemoglobin • Irregular white patches on the side of the tongue
and occasionally anywhere on the tongue or in the
• Low Mean cell volume (MCV)
mouth
• Low Mean cell hemoglobin concentration (MCHC)
• Occurs primarily in HIV-positive individuals or in
• High Red cell distribution width (RDW) immunosuppression
• Low serum ferritin • Cannot be scraped off, benign and doesn’t require
• High Total iron-binding capacity (TIBC) treatment
Management
• Oral iron ⟶ Ferrous sulphate, ferrous gluconate (SE: black stool)
• Blood transfusion when:
- Hb <80 g/L
- Hb <90 g/L + known cardiovascular disease

A patient with RA on NSAIDs and methotrexate

• Low hg + low MCV ⟶ IDA due to GI bleeding from NSAIDs
• Low hg + high MCV ⟶ Folate deficiency from methotrexate
• Low hg + normal/low MCV ⟶ Anemia of chronic disease

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Vitamin B12 (Cobalamin) deficiency
➢ Found in meat, fish and dairy products but not in plants
• Folate ⟶ Fruits + Fegetables
➢ B12 binds to intrinsic factor in the stomach, and this complex is
• B12 ⟶ Beef + Bacon
absorbed in the terminal ileum
Causes Dude Is Just Feeling Ill Bro
• Pernicious anemia
➢ Dude Is ⟶ Duodenum, Iron
- Commonest cause ➢ Just Feeling ⟶ Jejunum, Folate
- Due to autoimmune gastric atrophy resulting in loss of intrinsic ➢ Ill Bro ⟶ Ileum, B12
factor production required for absorption if vitamin B12
- Usually associated with other autoimmune problems (e.g.
• Vitamin B1 (thiamine) deficiency in
vitiligo, hypothyroidism)
alcoholism → Werneck’s encephalopathy
• Chronic pancreatitis ⟶ inadequate absorption of Vit B12 • Folic acid is Vit B9
• Dietary (e.g. vegans)
• Following total gastrectomy, body stores of cobalamin only last a few years so depletion occurs after 1 to 2
years post-surgery
• Ileal disease ⟶ resection of the ileum, Crohn’s disease
• Malabsorption disorders ⟶ Celiac disease, tropical sprue
Features
• Symptoms of chronic anemia: fatigue, dyspnea on exertion
• Neurological symptoms (dementia, peripheral paresthesia and disturbances of position and vibration sense)
⟶ helps distinguish vit B12 deficiency from folate deficiency
• Can cause angular stomatitis, tongue is described as “beefy” or “fiery red and sore”
• If uncorrected ⟶ degeneration of the spinal cord and permanent ataxia

Hematological abnormalities
• Macrocytic anemia and the MCV is ⟶ seen in both B12 and folate deficiencies
• Hypersegmented neutrophils ⟶ seen in both B12 and folate deficiencies
• Homocysteine
- Deficiency of cobalamin results in elevation of plasma total homocysteine
- Not specific for cobalamin deficiency as it’s also elevated in folate deficiency
• Nucleated RBCs can be found in BM picture
Management
• Hydroxocobalamin IM
• Blood transfusion if:
- Symptoms of anemia + hemoglobin is <80 g/L
- Hemoglobin is <70 g/L in asymptomatic patient

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Folate Deficiency
Causes
• Dietary deficiency
- Malabsorption (e.g. coeliac disease, jejunal resection, inflammatory bowel disease).
- Poor intake
- Alcohol excess (also causes impaired utilization) • NSAIDs ⟶ IDA
• Antifolate drugs ⟶ Sulfasalazine, methotrexate • Methotrexate ⟶ Folate deficiency
Diagnosis •

• The hematological features are similar to B12 deficiency (macrocytic, megaloblastic anemia). Distinction is on
basis of demonstration of reduced red cell and serum folate. Vitamin B12 levels should be assessed at the
same time due to the close relationship in metabolism.
Management
• Folic acid 5 mg/d PO for 4 months

Note: It is important in a patient who is also deficient in both vitamin B12 and folic acid to treat the B12 deficiency
first to avoid precipitating subacute combined degeneration of the cord. Once the vitamin B12 levels are normal,
then start oral folic acid. [Treat B Before F]

Vitamin B12 Folate deficiency

• Neurological findings • No neurological findings
• Raised Methylmalonic acid • Normal Methylmalonic acid

Aplastic anemia
➢ Aplastic anemia is a rare, potentially life-threatening failure of hemopoiesis characterized by pancytopenia and
hypoplastic marrow (the marrow stops making cells), usually found in adolescents
Causes
• Most cases are autoimmune, triggered by drugs, viruses (e.g. parvovirus, hepatitis) or irradiation
Presentation
• Aplastic anemia can present abruptly or insidiously over, weeks to months
• Clinical manifestations are proportional to the peripheral-blood cytopenia and include:
- Symptoms of anemia (pallor, headache, palpitations, dyspnea, fatigue, or ankle edema) Note: Anemic
symptoms are usually less severe due to the chronic onset
- Symptoms of thrombocytopenia (skin or mucosal hemorrhage, visual disturbance due to retinal
hemorrhage, petechial rashes)
- Infection (a less common presentation) particularly upper and lower respiratory tracts, skin, mouth, and
peri-anal
- There is NO lymphadenopathy or hepatosplenomegaly (in the absence of infection)
Diagnostic tests
• Bone marrow is diagnostic ⟶ gross reduction in all hemopoietic tissue that’s replaced by fat tissue
• Blood film morphology is unremarkable ⟶ differentiates it from other types of leukemia
• At least TWO of the following must be present:
- Hemoglobin <10 g/dL • CML = Pancytopenia + Splenomegaly
9
- Platelet count < 50 x 10 /L • Aplastic anemia = Pancytopenia + Hypoplastic BM
with NO splenomegaly
- Neutrophil count <1.5 x 109/L

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Autoimmune hemolytic anemia
➢ A disease in which the red blood cells are destroyed prematurely. When hemoglobin within red blood cells is
broken down, heme is converted into bilirubin ⟶ jaundice
Types
• Warm antibody ⟶ IgG [Global Warming]
- Idiopathic
- Secondary to other autoimmune diseases e.g. SLE or lymphoproliferative diseases e.g. Lymphoma, CLL
• Cold antibody ⟶ IgM [it’s Cold in Moscow]
- Idiopathic
- MyCoplasma pneumoniae
- Infectious mononuCleosis

Warm antibody induced hemolysis

➢ Most cases are idiopathic with no underlying pathology
➢ Affects predominantly individuals >50 years of age
Clinical features
• Highly variable symptoms, asymptomatic or severely anemic
• Mild jaundice
• Splenomegaly
Diagnosis
• Anemia
• Spherocytes on peripheral blood film
• Increased reticulocytes
• Detect on direct Coombs test

Thalassemia
• α thalassemia major → is usually lethal in utero. It should be considered with hydrops fetalis (abnormal
accumulation of fluid in two or more fetal compartments, including ascites, pleural effusion, pericardial
effusion, and skin edema. It may also be associated with polyhydramnios and placental edema)
• β thalassemia major → Presents in infancy often includes FTT, vomiting feeds, sleepiness, stunted growth
and irritability. In severe, untreated cases there may be:
- Hepatosplenomegaly
- Bony deformities (frontal bossing). The extra medullary hemopoiesis occurs in response to anemia
- Marked pallor and slight to moderate jaundice
- Iron overload → endocrinopathy with diabetes, thyroid, adrenal and pituitary disorders

β-thalassemia carrier status is often confused with iron deficiency due to reduced MCV and MCH. But note that in
iron deficiency, serum ferritin and iron are low while in thalassemia they are usually high
Investigation
• Most confirmatory → Hb electrophoresis • Alpha thalassemia trait has mild anemia but
usually clinically asymptomatic
• Serum studies → increased serum iron
Management
• Lifelong blood transfusions are needed to maintain a hemoglobin level >9.5 g/dL (or >9.0 g/dL)
• Iron chelation to prevent overload syndrome (Oral deferiprone + deferoxamine SC twice weekly)
• A histocompatible marrow transplant can offer the chance of a cure

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Coombs tests
1. The direct Coombs test (DCT, also known as direct antiglobulin test or DAT)
2. The indirect Coombs test (also known as indirect antiglobulin test or IAT)

Direct Coombs test

• Used to test for autoimmune hemolytic anemia
Common examples of alloimmune hemolysis
1. Hemolytic disease of the newborn (also known as HDN or erythroblastosis fetalis)
2. Rh D hemolytic disease of the newborn (also known as Rh disease)
3. ABO hemolytic disease of the newborn
4. Alloimmune hemolytic transfusion reactions
Common examples of autoimmune hemolysis
- Cold agglutinin disease: Infectious mononucleosis
Drug-induced immune-mediated hemolysis In blood transfusion, we should test
• Cells of a giver
- Penicillin, Cephalosporins
• Serum of a receiver

Indirect Coombs test

• Used in prenatal testing of pregnant women (IgG antibodies) and in testing blood prior to a blood
transfusion

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Glucose-6-phosphate dehydrogenase (G6PD) deficiency
➢ X-linked recessive and clinically important cause of oxidant hemolysis. It affects all races but is most common
in those of African, Asian or Mediterranean descent
➢ ↓ G6PD enzyme → ↓ glutathione → ↑ red cell susceptibility to oxidative stress
➢ Being X-linked → almost always male patient
➢ Most individuals with the G6PD defect are asymptomatic and unaware of their status
➢ Hemolysis occurs after exposure to oxidants or infection
➢ There are many drugs that can elicit hemolysis in patients with G6PD deficiency. One drug that you would
definitely need to look out for in the exam is → antimalarials (e.g. primaquine) and sulfa drugs
Presentation
• Most are asymptomatic
• May be a history of neonatal jaundice, severe enough to require exchange transfusion
• May have history of drug-induced hemolysis
• Gallstones are common
• Pallor from anemia
• During a crisis jaundice occurs
• Back or abdominal pain (usually occurs when >50% hemolysis occurs)
• Splenomegaly may occur
Diagnosis
• G6PD enzyme activity - is the definitive test
- Usually done 6 weeks after the episode as if done during hemolytic crisis could result in equivocal results
• Blood film
- In steady state (i.e. no hemolysis) the RBCs appear normal
- Heinz bodies is seen on blood film in drug-induced hemolysis
- Bite cells are also seen
Management
• Avoidance of precipitating drugs, and broad (fava) beans
• Blood transfusion in severe hemolysis

There are typically 4 ways the patient might present in PLAB. Below are the specifics:
Drug-induced hemolysis in G6PD deficiency
• Begins 1-3 days after ingestion of drug
• Anemia most severe 7-10 days after ingestion
• Associated with low back and abdominal pain
• Dark urine (black sometimes)
• Red cells develop Heinz body inclusions
• Hemolysis is typically self-limiting
Hemolysis due to infection and fever
• 1-2 days after onset of fever
• Mild anemia develops
• Commonly seen in pneumonic illnesses
Favism
• Hours/days after ingestion of fava beans (broad beans)
• Red/very dark urine
• Shock may develop and it may be fatal
Neonatal jaundice
• May develop kernicterus (possible permanent brain damage)
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IDIOPATHIC thrombocytopenic purpura (ITP)
➢ Children ⟶ preceded by URTI HUS → Hemolysis, Uremia, Stomach virus + thrombocytopenia
➢ Adults ⟶ no prior infection + insidious onset - Associated with E. coli → bloody diarrhea
Features - Microangiopathic hemolytic anemia (MAHA)
TTP → HUS + fever + neurological symptoms
• Purpura (non-raised, non-blanching)
- Usually in adults
• Mucosal bleeding → epistaxis & bleeding gums - Platelet count is much lower (around 35)
• Hemorrhage or menorrhagia - Inhibition of ADAMTS 13, which breaks down vWF
Investigation
• Isolated thrombocytopenia with otherwise normal blood count
Management
• Prednisone
• IVIG
• Emergency platelet transfusion ⟶ if life threatening hemorrhage (platelets <20x109/L)

Henoch-Schönlein purpura (HSP)

➢ IgA mediated vasculitis of childhood
➢ Usually preceded by URTI
Presentation → [PAAN]
1. Purpura (raised, non-blanching) over buttocks and extensor surfaces
2. Arthralgia (especially in the knees and ankles)
3. Abdominal pain • Complications → Intussusception
4. Nephropathy → microscopic hematuria
Diagnosis
• Mainly a clinical diagnosis
• Look for elevated ESR, IgA
• Raised creatinine; labs consistent with nephropathy
Treatment
• Self-limiting; conservative management
• NSAIDs for arthralgia → beware of choosing this option if patient has impaired renal involvement
• Corticosteroids → arthralgia + GI dysfunction

Von Willebrand disease

➢ Mucosal bleeding ⟶ Epistaxis, menorrhagia
➢ Autosomal dominant (type 3 is recessive but rare)
➢ Role of vWF:
- Facilitate platelet adhesion to endothelial cells
- Carrier
Investigation • Bleeding due to dental extraction is considered mucosal bleeding

• 2 words ⟶ 2 abnormalities
- Prolonged bleeding time
- Prolonged aPTT
• Factor 8 is reduced, Defective platelet aggregation with ristocetin
Management
• Tranexamic acid ⟶ for bleeding
• Desmopressin ⟶ raises vWF
• Factor 8 concentrate
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Hemophilia A and B
➢ Congenital bleeding disorders with low levels of factor 8 (hemophilia A, classical hemophilia) or factor 9
(hemophilia B, Christmas disease)
➢ Hemophilia A is more common (90%)
➢ X-linked inheritance → Males are typically affected
➢ Female carriers are rarely symptomatic
Clinical presentation
• Hemophilia A and B are clinically indistinguishable
• Symptoms depend on the factor level
• History of spontaneous deep bleeding into joints, especially the knees, ankles and elbows, without a history
of significant trauma. Spontaneous hemarthrosis are virtually pathognomonic
• Intramuscular hemorrhage may also occur. Spontaneous bleeding into arms, legs, or any site. The bleeding
may lead to nerve compression, or compartment syndrome
Investigations
• Activated partial thromboplastin time (APTT) is usually prolonged but can be normal in mild disease
• Factor VIII/IX assay → to diagnose

Hemophilia A-specific treatment

• Desmopressin → raises factor VIII levels, and may be sufficient to treat Hemophilia type A
• Major bleeds (e.g. hemarthrosis) → recombinant factor VIII
• Do not give IM injections when factor is low

Hemophilia B-specific treatment

• Recombinant factor IX is the treatment of choice
Note: Desmopressin has NO value in treatment of hemophilia B

Avoid NSAIDS and IM injections

- Questions may arise with this topic. In PLAB, in whichever scenario, avoid NSAIDS and IM injection as the
answer in Hemophilia. NSAIDs must not be used for the fear of gastrointestinal hemorrhage. If needed, give
opiates for pain relief and if given → IV or SC but NOT IM → will produce a large and painful hematoma

Disseminated intravascular coagulation (DIC)

➢ In DIC, the increased clotting activity uses up the platelets and clotting factors in the blood. As a result,
serious bleeding can occur. DIC can cause internal and external bleeding
Features
• Ecchymoses or spontaneous bleeding at venipuncture or at trauma site
• Bleeding from ears, nose, throat and GIT
• Petechiae, purpura
Diagnosis
• All are elevated except platelets and fibrinogen
Treatment
• Treat the cause
• FFP in severe bleeding

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• 2 words 2 abnormalities
• 1 word 1 abnormality
• 3 words 3 abnormalities

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Hereditary Spherocytosis
➢ Hereditary Spherocytosis is the most common inherited RBC membrane defect
➢ Characterized by hemolysis, spherocytic RBCs with increased osmotic fragility
➢ 75% are autosomal dominant
Clinical features
• Hemolytic anemia, jaundice (either from hemolysis or gallstones) and splenomegaly
• 20-30% are mild with an increased red cell turnover compensated with adequate replacement. They are
neither symptomatic nor anemic, but may have mild splenomegaly, slight reticulocytosis and minimal
spherocytes visible
• 60-70% of patients have moderate disease and half of these present in childhood with anemia
• Neonates with severe hereditary disease do not always present at birth with anemia, but hemoglobin may
fall dramatically over the first few weeks of life and may be severe enough to require exchange transfusion
• Occasional aplastic crises occur, e.g. with parvovirus B19 infection
Diagnosis
1. Blood film → spherocytes and increased reticulocytes
2. MCHC → elevated • Spherocytes can be found also in autoimmune hemolytic
3. Osmotic fragility test (diagnostic) → spherocytes anemias. To distinguish the two → a direct Coombs test
- Hereditary spherocytosis → negative
- This is not reliable until six months of age
- Autoimmune hemolytic anemias → positive
Management
• When you see parvovirus B19 in the exam, immediately
• Steroid therapy
think of sickle cell anemia or hereditary spherocytosis
- In patients with moderate disease with the diagnosis of aplastic crisis at hand
• Folate supplementation
• Splenectomy
- Eliminates anemia and hyperbilirubinemia and lowers the high reticulocyte number to nearly normal
levels
- Splenectomy is curative in most patients but increased recognition of the long-term risks of splenectomy
has led to re-evaluation of the role of splenectomy
- Mild cases do not usually require folate supplements or splenectomy
Complications
• Rapid hemolysis can be triggered by viral infections and produce jaundice, anemia and occasionally
abdominal pain and tender splenomegaly. Supportive treatment is usually all that is needed
• Aplastic crises (aplastic anemia). They are most commonly caused by infection with parvovirus B19 and
usually last 10-14 days. This can be life-threatening

Parvovirus and anemia

➢ Although most patients have a decrease of erythropoiesis (production of red blood cells) during parvovirus
infection, it is most dangerous in patients with sickle cell anemia or hereditary spherocytosis, as they are
heavily dependent on erythropoiesis due to the reduced lifespan of the red cells

Hereditary spherocytosis Autoimmune hemolytic anemia

- Spherocytes - Spherocytes
- +ve osmotic fragility test - +ve osmotic fragility test
- -ve direct comb test - +ve direct comb’s test

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Polycythemia rubra Vera (PRV)
➢ The most common form of primary polycythemia. It is a malignant proliferation of a clone derived from one
pluripotent marrow stem cell
- There is excess proliferation of RBCs, WBCs, and platelets, leading to hyperviscosity and thrombosis
- More commonly found in patients who are >60 years old
- A mutation in JAK2 is present in >90% → Diagnostic
Presentation
• It may be discovered accidently with no related symptoms or there may be nonspecific complaints of lethargy
and tiredness
• About a third present with features of thrombosis (stroke, myocardial infarction, deep vein thrombosis and
pulmonary embolism)
• Headaches, dizziness, sweating, and tinnitus
• Bleeding from gums or easy bruising is usually mild but gastrointestinal hemorrhage can be more severe. This
is secondary to abnormal platelet function
• Pruritus → worse after a hot shower or bath
• Splenomegaly → 75% of patients (OHCM says 60%) → left upper quadrant mass
• Hypertension is common → 30%
• Erythema, warmth, pain, and even sometimes infarction of the distal extremities. Burning sensation in
fingers and toes, are characteristic but not very common
• Facial plethora
• Gout from increased cell turnover
Investigation • There is usually an abnormally low serum erythropoietin
• Initial → EPO
- 1ry PRV → low erythropoietin, low ferritin (high demand)
- 2ry PRV → high erythropoietin → high RBCs count
• Definitive → JAK2 mutation screen
Management
• Venesection (phlebotomy), a surgical opening or puncture of a vein in order to withdraw blood
• Chemotherapy options include:
- <40 years of age → interferon
- >40 years of age → hydroxycarbamide (hydroxyurea)
• Low dose aspirin 75mg OD → To reduce thrombotic events

2ry polycythemia
• Chronic hypoxemia ⟶ increased production of erythropoietin by the kidneys ⟶ increased RBCs production
• Causes ⟶ living at high altitudes, smokers, patients with COPD
• Labs ⟶ High erythropoietin, normal WBCs and platelets
- The long-term hypoxia triggered an increased production of EP by the kidneys to stimulate the bone marrow to
produce more RBCs to transport O2 to the tissues
- If repeated hemoglobin is still high in 2 months, further investigations would be warranted

Red → PRV
Pale → CKD
Yellow → Liver failure

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Acute lymphoblastic leukemia (ALL)
Etiology
➢ Mostly unknown but there are several well-known associations with the development of acute leukemia that
are sometimes present. These include radiation exposure, chemotherapeutic agents, as well as some
retroviruses
➢ Commonest childhood leukemia. Peak age is 2-4 years old
➢ ALL and AML are indistinguishable clinically
Clinical Presentation
• Symptoms of pancytopenia even if the total white blood cell count is normal
- Low RBCs → Anemia, the most common presenting complaint
- Low platelets → Bleeding, petechiae, purpura or ecchymoses
- Low/ abnormal WBCs → Recurrent and severe infections (oral, throat, skin, perianal infections
commonly
- Splenomegaly (10-20%) → NOT a key feature
- ALL is more often associated with infiltration of other organs (liver, spleen, and lymph nodes and bone)
Diagnosis
• FBC [ALL are low] • When pancytopenia is in the options, it is
- Anemia → Hb may be below 5 g/L usually leukemia, or aplastic anemia
- WBCs → low, normal, or elevated • The Philadelphia chromosome occurs in
- Thrombocytopenia 15–30% (mostly adults) and is associated
with a poor prognosis
• Bone marrow biopsy → numerous blasts is diagnostic

Acute myeloid leukemia (AML)

➢ This neoplastic proliferation of blast cells is derived from marrow myeloid elements. It progresses rapidly
(death in about 2 months if untreated)
➢ Children or young adults may present with acute symptoms over a few days to a few weeks
➢ Most AML subtypes show >30% blasts of a myeloid lineage in the blood, bone marrow, or both
Presentation
• Anemia
• Thrombocytopenia → Bleeding. Thrombocytopenia often causes petechiae on the lower limbs. DIC may
aggravate the situation and cause larger lesions
• Low WBCs → Infection
• Gingivitis is common, with swollen, bleeding gums
• There can also be bone pain
• Hepatomegaly and splenomegaly (Left upper quadrant fullness and early satiety)
• Lymphadenopathy is less common
Investigations
• FBC
- High WBCs. However, it may also be normal or even low
- Depleted neutrophils and blast cells are seen in their place
• Bone marrow aspiration → >20% blasts in the peripheral blood is diagnostic
• Sudan black stain → Auer rods is diagnostic
• Flow cytometry (immunophenotyping) → to distinguish AML from ALL

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Chronic lymphocytic leukemia (CLL)
➢ CLL often presents as an asymptomatic elevation of white cells found on routine investigations for other
health problems
➢ These patients are exclusively older >50 years old
When patients do have signs and symptoms, they are usually non-specific:
• Fatigue
• Lethargy
• Cervical lymphadenopathy

When should you suspect CLL?

• When an older patient has marked elevation in WBCs (manifesting as recurrent infections) with marked
lymphocytic predominance
• The marrow is often infiltrated with mature lymphocytes → “Smudge cells” are seen on smear

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Chronic myeloid leukemia (CML)
➢ CML is a clonal bone marrow stem cell disorder in which a proliferation of mature granulocytes (neutrophils,
eosinophils and basophils) and their precursors is found
➢ Mnemonic: CML ⟶ Crazy Massive Large Spleen ⟶ approaches the right iliac fossa (DD: Malaria ⟶ travel Hx)

CML typically progresses through three phases:

• Chronic phase
- The immune system is competent and patients are asymptomatic for prolonged periods - (typically 4-5
years) More than 90% of patients are diagnosed in the initial chronic phase
• Accelerated phase
- In about two thirds of patients, the chronic phase transforms into an accelerated phase characterized by
a moderate increase in blast cells, increasing anemia or thrombocytopenia
• Blast crisis or blastic phase
- After a variable amount of time (usually months) the accelerated phase progresses to acute blastic
transformation. Features of blastic phase include bone marrow or peripheral blasts ≥30%, severe
constitutional symptoms due to tumor burden (weight loss, fever, night sweats, bone pain), infection
and bleeding
Clinical Presentation
• Usually presents at age 40 to 50 years old (middle-age)
• 85-90% of patients are diagnosed in the chronic phase and in recent years about 40% of patients have been
diagnosed before any symptoms developed, with incidental abnormalities spotted on a blood test.
- Fatigue (due to anemia)
- Weight loss
- Night sweats
- Abdominal discomfort → from massive enlargement of spleen (this is common)
- Splenomegaly → Most common reaches right iliac fossa (Seen in >75%)
- Hepatomegaly
• Enlarged lymph nodes are rare and infection are
- Enlarged lymph nodes (rare)
uncommon because these white cells retain the
- Low grade fever majority of their function
- Gout due to rapid cell turnover • The main feature of the disease is an elevated white
blood cell count consisting predominantly of
Investigations at presentation neutrophils. Blasts are either absent or low in count
• The Philadelphia chromosome is present in more
• FBC
than 90% of patients with CML
- Leukocytosis is common (often >100 x 109/L)
- Differential shows granulocytes at all stages of development (increased numbers of neutrophils,
myelocytes, basophils, eosinophils)
- Platelets may be elevated, decreased or normal levels
- A mild-to-moderate, usually normochromic and normocytic, anemia is common
• Peripheral blood smear
- All stages of maturation seen
• Biochemistry
- U&Es are usually normal at presentation, LDH is usually raised, serum urate may be raised
• Bone marrow aspiration and biopsy
- To quantify the percentage of blasts and basophils, to assess the degree of fibrosis and to obtain
material for cytogenetic-molecular analyses
• Cytogenetics → Ph chromosome is diagnostic, found in about 90% of cases. (OHCM says > 80%). This can be
found on cytogenetic analysis of blood or bone marrow
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Classic features of Lymphoma
• Drenching night sweats, fever, weight loss
• Enlarged but asymptomatic lymph nodes, typically in the lower neck or supraclavicular region
• Occasionally, hepatomegaly or splenomegaly

Lymphoma (Hodgkin’s) TB
• Painless LNs • Painful LNs
• No cough • Cough
• No travel history • Travel history to endemic areas OR congested
environment/close contact

➢ Extrapulmonary TB ⟶ not always accompanied by

cough

Non-Hodgkin lymphoma
➢ Lymphomas WITHOUT Reed-Sternberg cells HIV-related lymphomas
➢ Most are derived from B-cell lines; diffuse large B-cell lymphoma 1. NHL
(DLBCL) is commonest 2. Burkitt’s lymphoma (form of NHL)

➢ Known as AIDS-related lymphoma

Presentation
• Painless, slowly progressive peripheral lymphadenopathy ⟶ most common
• Primary extra-nodal involvement and systemic symptoms (fatigue, weakness, fever, night sweats, weight
loss) are not common at presentation but are common in patients with advanced or end- stage disease
• Bone marrow is frequently involved and may be associated with pancytopenia - anemia, infection, bleeding
(platelets).
• NHL → spread involvement (neck & spleen)
• Hepatosplenomegaly
• HL → neck and mediastinum
• Constitutional symptoms are less common in
Hodgkin’s & indicates disseminated disease
Hodgkin's lymphoma
➢ Hodgkin's lymphoma is a malignant tumor of the lymphatic system that is characterized histologically by the
presence of multinucleated giant cells (Reed-Sternberg cells)
➢ Bimodal age distribution, one peak around 20-29 years while the other peak at 60 years
Presentation
• Enlarged but asymptomatic lymph node, typically in the lower neck or supraclavicular region. They are
painless, non-tender, ‘rubbery’ superficial lymph nodes. They also can be axillary or inguinal nodes
• Mediastinal masses are frequent and are sometimes discovered on a routine CXR
• B symptoms
Superior mediastinum mass → 5Ts
• Pruritus and lethargy • Thymus
• Hepatomegaly, splenomegaly, and superior vena cava syndrome (due • Thyroid
to an obstruction from mediastinal lymph node involvement causing • Thoracic aorta
features of a mass effect) • Terrible lymphoma
Diagnosis • Teratoma & germ cell tumors

• Lymph node excision biopsy if possible

Hodgkin’s Vs leukemias → Hodgkin’s has normal CBC as the problem is outside the bone marrow

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Multiple Myeloma
➢ A cancer of plasma cells resulting in their overproduction replacing the bone marrow as well as the
production of large quantities of functionless immunoglobulins → recurrent infections
Clinical Presentation [CRAB + recurrent infections]
• Bone disease → Bone pain is the most common clinical manifestation. This is most commonly in the back
and the ribs, secondary to pathologic fractures
• Renal failure
• Anemia (normocytic, normochromic) → may present with weakness, fatigue, and pallor
• HyperCalcaemia → may present with polyuria, polydipsia, and altered mental status
• Rarely, symptoms of a hyperviscosity syndrome such as blurry vision, and confusion, may occur.
Diagnosis
• Serum protein electrophoresis → markedly elevated monoclonal immunoglobulin
• Urine protein electrophoresis → Bence Jones' protein
• X-ray of the skeletal system and skull → punched out lytic lesion caused by the overproduction of osteoclast
activating factor from the plasma cells
• Hypercalcaemia from the destruction of bone
Note that the hypercalcemia is associated with normal alkaline phosphatase
• Bone marrow biopsy → plasma cells (>10%) is diagnostic
• Blood film → Rouleaux formation

Tumor lysis syndrome

➢ Severe metabolic disturbance following the rapid lysis of malignant cells a short while after chemotherapy,
radiotherapy, surgery or ablation procedures
Key features
• History of leukemia or NHL (Burkitt’s lymphoma)
• Chemotherapy
• AKI
• Blood results [UK Pc]
- Hyperuricemia → Gout
- Hyperkalemia (earliest sign) → Paresthesia, muscle weakness, arrythmia
- Hyperphosphatemia → AKI
- Hypocalcemia → SPASMODIC
Management → IV fluids

Cold haemagglutinin disease (CHAD)

➢ Describes syndrome associated with acrocyanosis in cold weather due to RBC agglutination in blood vessels
of skin. Caused by RBC antibody that reacts most strongly at temperatures below 32°C
➢ May be idiopathic or secondary to infection with Mycoplasma or EBV (infectious mononucleosis)
Clinical features
• Acrocyanosis (blue discoloration of extremities e.g. fingers, toes) in cold conditions
• Splenomegaly
Diagnosis
• Anemia
• Increased reticulocytes
• +ve direct Coombs test

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 Hematology
Warfarin and high INR management
• For major bleeds
1. Stop warfarin
• High INR → increased risk of bleeding
2. Administer IV or oral Vit K1 (phytomenadione)
3. Prothrombin complex concentration (factor 9 complex)
4. FFP
• INR >8 + minor/no bleeding → Stop warfarin, administer Vit K1
• INR (6-8) + minor/no bleeding → Stop warfarin, restart when INR <5
• INR (5-6) but more than 0.5 units above target range → Reduce the dose OR stop the warfarin, restart when
INR <5
• INR above target range but less than 5 → Reduce or omit one or two doses and measure INR in 2-3 days

Surgery and warfarin

➢ Warfarin should always be stopped temporarily 5 days before planned surgery in patients with intermediate
to high risk of thromboembolism
➢ Recent TIA or patients with mechanical cardiac valves, surgery can proceed once INR is <1.5
➢ Replace with Heparin “heparin bridging”
➢ Warfarin is usually resumed at the normal dose on the evening of surgery or the next day if hemostasis is
adequate

Superficial thrombophlebitis (superficial venous thrombosis)

➢ Thrombosis + inflammation of superficial veins most commonly in the great saphenous veins of the legs
➢ Most case DON’T require antibiotics as they are not infective
➢ US is needed (specifically with proximal long saphenous vein) → to exclude concurrent deep vein thrombus
Management
1. Symptoms reduction Cellulitis
- Pain → Oral/topical NSAIDs • Acute, painful, spreading infection of
- Swelling → Compression stockings + Leg elevation deeper dermis and SC tissue
• Starts with a break in the skin
2. Prevention of DVT and PE
(trauma or other infections) allowing
- With other risk factors of DVT → SC LMWH or Fondaparinux the bacteria to enter (Strept, Staph)
- NO other risk factors of DVT → LMWH

↑ effects of warfarin (↑INR) ⟶ [SICKFACES.COM] ↓ effects of warfarin (↓INR) → [CRPA GPs]

• Sodium valproate • Carbamazepine
• Isoniazid • Rifampin
• Clarithromycin, Cimetidine • Phenytoin
• Ketoconazole • Alcohol
• Fluconazole • Griseofulvin
• Alcohol (binge drinking) • Phenobarbital
• Chloramphenicol • Sulphonylurea
• Erythromycin
• Sulfonamides
• Ciprofloxacin
• Omeprazole
• Metronidazole

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Notes
• PT, aPTT, BT are normal ⟶ Thalassemia
• BT (mucosal bleeding), aPTT raised ⟶ VWD
• Only aPTT is prolonged ⟶ Hemophilia
• All elevated except for platelets and fibrinogen ⟶ DIC
• PT, platelets are low ⟶ ITP
• BT is prolonged ⟶ TTP
• Helmet cells ⟶ Schistocytes
• Blast cells ⟶ ALL, AML, CML (blastic crisis)
• Granulocytes without blast ⟶ CML (chronic phase)
• Smudge cells ⟶ CLL
• Plasma cells ⟶ MM
• Hypersegmented Neutropenia ⟶ B12 & Folate deficiency
• Target cells ⟶ IDA or Thalassemia
• Heinz bodies, Bite cells ⟶ G6PD
• Owl eyes or reed Sternberg ⟶ Hodgkin’s lymphoma
• Target INR for Thromboembolism/most cases ⟶ 2-3
• Target INR for patients with metallic valves ⟶ 3-4
• Low INR ⟶ Lesser bleeding, faster clotting
• High INR ⟶ More bleeding, slower clotting
• Bruising on the face or forearm ⟶ Non-accidental injuries
• Hip/shoulder joints ⟶ Accidental injuries
• HIV/autoimmune ⟶ NHL
• EBV ⟶ HL
• High LDH indicates → Tissue breakdown
• Severe anemia + low reticulocytes in sickle cell anemia → Parvovirus B19 is the culprit
• Severe anemia + high reticulocyte count in sickle cell anemia → Splenic sequestration crisis
• Vitamin K deficiency → prolonged aPPT + prolonged PT
• Von Willebrand disease→ prolonged aPPT + prolonged bleeding time

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