Homo sapiens diseases - Blood and hematopoietic organs

HOMO SAPIENS DISEASES - BLOOD AND HEMATOPOIETIC ORGANS (HEMOPATHIES)
(see also physiology of blood

)
[where not otherwise specified all pictures refer to light microscopy images (1000x magnification) of peripheral blood slides after Wright's staining ]

Table of contents :

hematopoietic organs :

lymph nodes

thymus

blood

pancytopenias

myelodysplastic syndromes (MDS)

polycytosis

absolute

relative

alterations in platelets

alterations in RBCs

alterations in WBCs

neoplasms

infections
gas disorders
hyperviscosity syndrome
hyperosmolality
hypoosmolality
hypervolemia
hypovolemia

bibliography

web resources

extramedullary hematopoiesis (EMH) occurs in hemoglobinopathies, hemolytic anemias, leukemias, lymphomas, myelofibrosis, or skeletal metastases. The most common sites are liver, spleen, and paraspinal regions of thorax. Other unusual sites include thymus, heart, lungs, mediastinum, gastrointestinal tract, lymph nodes, and retroperitoneal spaces including kidneys. The perinephric space is a retroperitoneal space bounded anteriorly by Gerota fascia and posteriorly by Zuckerkandl fascia. It is divided into multiple compartments by lamellae and Kunin septa and contains kidneys, adrenals, proximal ureters, blood vessels, lymphatic vessels and perinephric fat. The adipose tissue is a novel extramedullary tissue possessing phenotypic and functional hematopoietic stem and progenitor cells. The role of splenectomy in accelerating the development of EMH in uncommon sites has become increasingly apparent. Perinephric involvement of EMH is very rare and may have two distinct patterns on computed tomography imaging—(1) soft tissue masses intermixed with fat and (2) a diffuse infiltrative process surrounding the kidneys. The differential diagnosis of macroscopic fat containing type is fatty neoplasms such as angiomylipoma, liposarcoma, or extraadrenal myelolipoma. The principal differential of diffuse infiltrative type is lymphoma. Thus, diagnosis is usually confirmed on histopathology examination, which in our case was EMH. The importance of knowing this entity lies in the fact that it is usually asymptomatic and does not require any treatment vis-à-vis lymphoma, which requires aggressive management.
alterations in all kinds of blood cells (i.e. impairment of HSC ) (cytohaematology)

quantitative alterations

pancytopenias : anemia + leukopenia (granulocytopenia (neutropenia + eosinopenia + basophilopenia ) + lymphopenia ) + thrombocytopenia

Aetiology

hypersplenism
bone marrow failure / medullary aplasia : failure of the hematopoietic function of the bone marrow
bone marrow suppression / myelophthisis / myelosuppression : suppression of bone marrow activity, resulting in reduction in the number of platelets, red cells, and white cells, such as in aplastic anemia

radiotherapy

aplastic anemias

chronic hypothermia ^{ref1,
ref2,
ref3,
ref4}
osteotabes : a disease, chiefly of infants, in which the cells of the bone marrow are destroyed and the marrow disappears
during of after viral infection from

Pathogenesis

virus-induced suppression of HSCs due to direct infection and lysis of the progenitor cells themselves, such as by B₁₉ virus , HHV-5 / CMV , and dengue virus
altered ability of bone marrow stromal cells to support progenitor cell development due to aberrant stromal cell cytokine expression
immunosuppressive immune cell cytokines that are released from virally activated cells. For example, TNF-a, TNF-b / LT-a, and IFN-g, induced during virus infection, can influence the development of bone marrow progenitor erythroid and myeloid-lineage cells in vitro.

myelodysplastic syndromes (MDS) / preukemia
GR agonists

polycytosis

Aetiology

^ref

⁺

^ref

^ref1,
ref2

^ref

alterations in platelets
alterations in RBCs
alterations in WBCs

qualitative alterations
quantitative alterations

neoplasms

Laboratory examinations

minimal residual disease (MRD)

flow cytometric immunophenotyping
PCR analysis of antigen receptor genes
RT-PCR analysis of well-defined chromosomal aberrations with fusion gene transcripts :

t(1;19) with E2A / TCF3-PBX1
t(4;11) with MLL-AF4
t(8;21) with AML1-ETO
t(9;22) with BCR -c-Abl p190 and BCR-ABL p210
t(12;21) with TEL / ETV6-AML1
t(15;17) with PML-RARa
inv (16) with CBFB-MYH11
microdeletion 1p32 with SCL interrupting locus (SIL)-TAL1/SCL

single PCR

nested PCR

'shifted' PCR

^-2

^-4

^ref

Laboratory examinations

endothelioid cells (large protoplasmic cells frequently seen in disease of the blood-making organs and believed by some to be derived from the endothelial lining of the blood vessels and lymph vessels)
abnormal chromatin clumping (ACC) is a sign of severe dysplasia described in the abnormal chromatin clumping syndrome (ACCS), a distinct entity that has both proliferative and trilineal or bilineal dysplastic features^ref1,
ref2, but it is also present in myelodysplastic syndromes (MDS), reactive dyshemopoiesis^ref, chronic myelogenous leukemia both Ph' positive^ref and negative, and acute myeloid leukemias. Furthermore it has been described in the erythroid and megakaryocyte series, in eosinophils and basophils^ref, in neutrophils as far as the myelocyte stage^ref, in lymphocytes^ref, and in blast cells^ref.

Infections

viremia : transient or persistent presence of viruses in blood
bacteraemias : transient or persistent presence of bacteria in blood

nosocomial bacteraemias

Staphylococcus epidermidis (32%)
Staphylococcus aureus (18.7%)
Enterococcus (9.8%)
Escherichia coli (6.9%)
Klebsiella pneumoniae (5.2%)
others (21.6%)

fungemia / mycethemia : transient or persistent presence of fungi in blood

algaemia : transient or persistent presence of algae in blood

Prototheca wickerhamii

parasitemia : transient or persistent presence of protozoa or helminths in blood

Laboratory examination

hemoculture

Gas disorders

cyanosis : a bluish discoloration, especially of the skin and mucous membranes due to excessive concentration of deoxyhemoglobin (reduced hemoglobin) in the blood. P_{O2, artery} < 50 mmHg. Cyanosis becomes evident when reduced hemoglobin levels are > 5 g/dl of capillary blood (Lundsgaard C, Van Slyke D. Cyanosis. Medicine (Baltimore) 1923;2:1-76), a value roughly equivalent to 3 g of deoxyhemoglobin/dl of arterial blood^ref. The latter value has been verified by other investigators and has high interrater reliability^ref.

peripheral cyanosis

Aetiology

decreased cardiac output (CO)
cold exposure
hemometakinesia
arterial stenosis
venous stenosis

central cyanosis due to failure in pulmonary circulation

Aetiology

reduced P_{O2, artery}

decreased P_{O2, atmosphere} (high altitutides)
poor oxygenation of the blood in the lungs (pulmonary cyanosis)

alveolar hypoventilation
alterated V/Q rate (perfusion of hypoventilated alveola)
altered O₂ diffusion

shunt cyanosis : central cyanosis caused by mixing of unoxygenated blood with the arterial blood in the heart or great vessels.

cyanotic congenital cardiopathies with right=>left shunt (cardiac cyanosis)

tardive cyanosis : cyanosis in congenital heart disease that appears only after cardiac failure has developed.

pulmonary arterovenous fistulae
multiple small intrapulmonary shunts

hemoglobin with low affinity for O₂ :

hemoglobin Kansas

false cyanosis : cyanosis due to the presence of a pigment such as methemoglobin and not to deficient oxygenation of the blood.

methemoglobinemia : the presence of excessive methemoglobin in the blood

Aetiology

congenital or hereditary methemoglobinemia (hereditary methemoglobinemic cyanosis) : any of several rare types caused by inherited conditions

methemoglobin reductase deficiency
cytochrome B₅ reductase deficiency is an autosomal recessive condition that may be either confined to the erythrocytes and relatively symptom-free or generalized to the leukocytes and sometimes the brain, muscle, and fibroblasts, in which case the individual may be mentally retarded
abnormalities of hemoglobin M are autosomal dominant conditions that cause cyanosis in infancy but usually few other symptoms.

acquired or toxic methemoglobinemia : that caused by exposure to a toxic chemical or drug :

nitrate and nitrite compounds

enterogenous cyanosis / Stokvis-Talma syndrome / van den Bergh's disease / autotoxic cyanosis : a syndrome due to absorption of nitrites and sulfides from the intestine, principally marked by methemoglobinemia and/or sulfhemoglobinemia associated with cyanosis. It is accompanied by severe enteritis , abdominal pain , constipation or diarrhea , headache , dyspnea , dizziness , syncope , anemia, and, occasionally, digital clubbing and indicanuria

centrimide (cetyltrimethylammonium bromide) 0.1% used to treat parasitic splenic cysts
sulfonamides
aniline dyes

Symptoms & signs

headache

dyspnea

nausea and vomiting

Therapy

sulfhemoglobinemia : the presence of sulfmethemoglobin / sulfhemoglobin (hemoglobin with a sulfur atom on one of its porphyrin rings, so that it is ineffective for transporting oxygen and has a green color) in the blood

Aetiology

Symptoms & signs

cyanosis

carboxyhemoglobinemia (false cyanosis) : the presence of carboxyhemoglobin (HbCO) (hemoglobin in which the sites usually bound to oxygen are bound to carbon monoxide , which has an affinity for hemoglobin over 200 times that of oxygen) in the blood

Aetiology

differential cyanosis : only in lower limbs, due to persistence of Botallo's duct .

Symptoms & signs

papilledema

hypertrophic osteoarthropathy (HOA) / acropachy / Marie's disease

Laboratory examinations

hyperviscosity syndrome (HS) : any of various syndromes associated with increased viscosity of the blood

Aetiology

leukostasis : increased blood viscosity and hypercoagulability, seen in acute leukemia that is accompanied by hyperleukocytosis (> 100,000 cells/ml), leaading to to pulmonary or cerebral infarctions
serum hyperviscosity

Symptoms & signs : spontaneous bleeding with neurologic and ocular disorders

polycythemia

Symptoms & signs

conditions in which the deformability of erythrocytes is impaired :

sickle cell anemia

Pathogenesis

^ref

₃

Symptoms & signs

^ref

Therapy

leukapheresis

^{ref1,
ref2,
ref3}

^ref

plasma hyperosmolality

hemoconcentration : decrease of the fluid content of the blood, with resulting increase in its concentration

Aetiology

exemia : loss of fluid from the blood vessels
polycythemia

hyperproteinemia

Aetiology

hyperalbuminemia

relative reduction in serum water (e.g., dehydration)

hyper-a₁-globulinemia

Aetiology

malignancy and acute inflammation
pregnancy

hyper-a₂-globulinemia

Aetiology

malignancy and acute inflammation
adrenal insufficiency
adrenocorticosteroid therapy
advanced diabetes mellitus
nephrotic syndrome

hyper-b-globulinemia

Aetiology

hyperferritinemia (> 2000 ng/ml) :

Aetiology

hematological diseases (45.9%)

hemophagocytic syndrome

liver diseases (23%)
chronic renal failure (17.78%)
neoplastic diseases (10.4%)
systemic inflammatory diseases (7.4%) : highest values (> 10,000 ng/mL) in adult onset Still's disease (AOSD)
chronic transfusions (7.4%)
non-HIV systemic infections (5.9%)

hyper-g-globulinemia

Aetiology

polyclonal gammopathies

infections

viral infections, especially hepatitis, human immunodeficiency virus infection, mononucleosis, and varicella
focal or systemic bacterial infections, including endocarditis, osteomyelitis, and bacteremia
tuberculosis

connective tissue disorders

systemic lupus erythematosus
mixed connective tissue
temporal arteritis
rheumatoid arthritis
sarcoid

liver diseases

cirrhosis
ethanol abuse
autoimmune hepatitis
viral-induced hepatitis
primary biliary cirrhosis
primary sclerosing cholangitis

malignancies

solid tumors
ovarian tumors
lung cancer
hepatocellular cancer
renal tumors
gastric tumors
hematologic cancers (see below)

hematologic and lymphoproliferative disorders

lymphoma

Hodgkin's disease

leukemia

chronic lymphocytic leukemia

thalassemia
sickle cell anemia

other inflammatory conditions

gastrointestinal conditions, including ulcerative colitis and Crohn's disease
pulmonary disorders, including bronchiectasis, cystic fibrosis, chronic bronchitis, and pneumonitis
endocrine diseases, including Graves' disease and Hashimoto's thyroiditis

monoclonal gammopathies :

multiple myeloma (M protein appears as a narrow spike in the g, b, or a₂ regions. M-protein level is usually > 3 g/dL. Skeletal lesions (e.g., lytic lesions, diffuse osteopenia, vertebral compression fractures) are present in 80% of patients. Diagnosis requires 10 to 15% plasma cell involvement on bone marrow biopsy. Anemia, pancytopenia, hypercalcemia, and renal disease may be present)
monoclonal gammopathy of undetermined significance (M-protein level is < 3 g/dL. There is < 10% plasma cell involvement on bone marrow biopsy. Affected patients have no M protein in their urine, no lytic bone lesions, no anemia, no hypercalcemia, and no renal disease.
smoldering multiple myeloma : M-protein level is > 3 g/dL. There is > 10% plasma cell involvement on bone marrow biopsy. Affected patients have no lytic bone lesions, no anemia, no hypercalcemia, and no renal disease
plasma cell leukemia : peripheral blood contains > 20% plasma cells. M-protein levels are low. Affected patients have few bone lesions and few hematologic disturbances. This monoclonal gammopathy occurs in younger patients
solitary plasmacytoma : affected patients have only one tumor, with no other bone lesions and no urine or serum abnormalities
Waldenström's macroglobulinemia : IgM M protein is present. Affected patients have hyperviscosity and hypercellular bone marrow with extensive infiltration by lymphoplasma cells
heavy chain disease : the M protein has an incomplete heavy chain and no light chain

when osmolar gap = (measured plasma osmolality) - (predicted osmotic activity = 2 Na⁺ + Glc + BUN (mmol/L) = 2 Na⁺ (mmol/L) + Glc (mg/dL) / 18 + BUN (mg/dL) / 2.8) > 15-20 mmol/Kg H₂O

pseudohyponatremia
accumulation of osmolytes other than Na⁺, Glc, or urea.

mannitol
contrast enhancement media
isopropylic alcohol
PEG
ethanol
methanol
acetone

non-ketotic hyperosmolar hyperglycemia (NKHH) in patients with type 2 DM / NIDDM

Epidemiology

Aetiology

onset of type 2 diabetes mellitus
inappropriate therapy of type 2 diabetes mellitus (overtreatment with hyperosmolar solutions)
infections
acute myocardial infarction (AMI)
stroke
thromboembolism
drugs
excessive food intake
traumas

Pathogenesis

less severe hypoinsulinemia

increased liver glycogenolysis and gluconeogenesis

hyperosmolarity of extracellular fluid

dehydration of intracellular fluid

Symptoms & signs

hyperosmolar nonketotic coma

Laboratory examinations

^ref

glycemia > 600 (700-2,200) mg/dL (increased)
kalemia = 3-5 mEq/L (normal); potassium deficit = 4-6 mEq/kg
natremia = 130-155 mEq/L (normal); sodium deficit = 100-200 mEq/kg
pH > 7.30 (7.25-7.4) (normal)
bicarbonatemia > 15 mEq/l (normal)
ketonemia = small (0.5-2 mM/L = normal)
ketonuria = small
uremia = 30-80 mg/dL (normal or increased)
plasma osmolality = 2[measured Na (mEq/l)] + glucose (mg/dl)/18 > 320 (340-450) mOsm/kg (increased)
water deficit = 9 (6-12) L = 100-200 ml/kg
chloride deficit = 5-15 mEq/l
phosphate deficit = 3-7 mmol/kg
magnesium deficit = 1-2 mEq/kg
calcium deficit = 1-2 mEq/kg
anion gap = (Na⁺) - (Cl^- + HCO₃^-) (mEq/l) = variable

Therapy

adults (> 20 years)

potassium :

if initial kalemia < 3.3 mEq/l, hold insulin and give 40 mEq K+ (2/3 as KCl and 1/3 KPO₄) until K⁺ > 3.3. mEq/l
if initial serum K+ > 3.3 but < 5.0 mEq/l, give 20-30 mEq K+ in each liter of IV fluid (2/3 as KCl and 1/3 KPO₄) tp keep serum K⁺ at 4-5 mEq/l
if initial serum K+ > 5.0 mEq/l, do not give K+ but check potassium every 2 h

regular insulin 0.15 U/kg as IV bolus => 0.1 U/kg/hr IV insulin infusion => check serum glucose hourly. If serum glucose does not fall by at least 50 mg/dl in the first hour, then double insulin dose hourly until glucose falls at a steady hourly rate of 50-70 mg/dl => check electrolytes, BUN, creatinine and glucose every 2-4 h until stable. After resolution of HHS, if the patient is NPO, continue IV insulin and supplement with SC regular insulin as needed. When the patient can eat, initiate SC insulin or previous treatment regimen and assess metabolic control. Continue to look for precipitating cause(s) => change to 5% dextrose with 0.45% NaCl and decrease insulin to 0.05-0.1 units/kg/hr to maintain serum glucose between 250-300 mg/dl until plasma osmolality is < 315 mOsm/kg and patient is mentally alert
IV fluids => determine hydration status =>

hypovolemic shock => administer 0.9% NaCl (1.0 L/h) and/or plasma expanders
mild hypotension => evaluate corrected natremia =>

hypernatremia or normonatremia => 0.45% NaCl (4-14 ml/kg/hr) depending on state of hydration => when serum glucose reaches 300 mg/dl => change to 5% dextrose with 0.45% NaCl and decrease insulin to 0.05-0.1 units/kg/hr to maintain serum glucose between 250-300 mg/dl until plasma osmolality is < 315 mOsm/kg and patient is mentally alert
hyponatremia => 0.9% NaCl (4-14 ml/kg/hr) depending on state of hydration => when serum glucose reaches 300 mg/dl => change to 5% dextrose with 0.45% NaCl and decrease insulin to 0.05-0.1 units/kg/hr to maintain serum glucose between 250-300 mg/dl until plasma osmolality is < 315 mOsm/kg and patient is mentally alert

pediatric patients (< 20 years) :

IV fluids => determine hydration status =>

hypovolemic shock => administer 0.9% NaCl (20 ml/kg/h) and/or plasma expanders until shock resolved
mild hypotension => administer 0.9% NaCl (10 ml/kg/h) for initial hour =>
replace fluid deficit evenly over 48 h with 0.45-0.9% NaCl => when serum glucose reaches 250 mg/dl => change to 5% dextrose with 0.45-0.75% NaCl, at a rate to complete rehydration in 48 h and to maintain glucose between 150-250 mg/dl (10% dextrose with electrolytes may be required) => check glucose and electrolytes every 2-4 h until stable. Look for precipitating causes. After resolution of DKA, initiate SC insulin (0.5-1.0 U/kg/d given as 2/3 in the a.m. [1/3 short-acting, 2/3 intermediate-acting], 1/3 in p.m. [1/2 short-acting, 1/2 intermediate-acting]) or as 0.1-0.25 U/kg regular every 6-8 hours during the first 24 hours for new patients to determine insulin requirements

insulin =>

IV route => IV insulin infusion : regular insulin 0.1 U/kg/h => continue until acidosis clears (pH > 7.3, HCO₃ > 15) => decrease to 0.05 U/kg/h until SC insulin replacement intiated
IM (if no IV access) : regular insulin 0.1 U/Kg IV bolus followed by 0.1 U/kg/hr SC or IM

potassium

K⁺ < 2.5 mEq/l => administer 1 mEq/kg of KCL in IV over 1 h. Withhold insulin until K⁺> 2.5
K⁺ 2.5-3.5 mEq/l => administer K⁺ 40-60 mEq/l in IV solution until K+ > 3.5. Monitor K⁺ hourly => check results of hourly K+ monitoring =>

K⁺ < 2.5 mEq/l => see above
K⁺ = 2.5-3.5 mEq/l => continue as above
K⁺ > 3.5 mEq/l => see below

K⁺ 3.5-5.5 mEq/l => administer K⁺ 30-50 mEq/l in IV solution to maintain serum K⁺ at 3.5-5.5 mEq/l

assess need for bicarbonate =>

pH < 7.0 => repeat pH after initial hydration bolus =>

pH < 7.0 => over 1 h, administer NaHCO₃ (2 mEq/kg) added to NaCl to produce a solution that does not exceed 155 mEq/l of Na over 1 hr
pH > 7.0 => see below

pH > 7.0 => no HCO₃ indicated

plasma hypoosmolality

Aetiology

hypotonic syndromes : a group of syndromes involving inadequate water excretion in comparison to the amount ingested, so that body fluids become hypotonic and hyponatremic; some are due to excessive water intake as in water intoxication, while others are caused by derangements of the excretory process such as the vasopressin excess in the syndrome of inappropriate diuretic hormone or complications of the nephrotic syndrome , congestive heart failure, or kidney failure.
hypoproteinemia

hypoalbuminemia

Aetiology

hormone therapy
pregnancy
burns
chronic cachectic or wasting diseases
chronic infections
hemorrhage, burns, or protein-losing enteropathy
liver failure resulting from decreased synthesis of albumin
malnutrition
proteinuria

hypo-a₁-globulinemia

Aetiology

a₁-antitrypsin deficiency
liver failure

hypo-a₂-globulinemia

Aetiology

hypo-b-globulinemia

Aetiology

protein malnutrition

hypo-g-globulinemia

Aetiology

agammaglobulinemia
hypogammaglobulinemia

Laboratory examinations

serum protein electrophoresis : indications

suspected multiple myeloma , Waldenström's macroglobulinemia , primary amyloidosis , or related disorder
unexplained peripheral neuropathy (not attributed to longstanding diabetes mellitus, toxin exposure, chemotherapy, etc.)
new-onset anemia associated with renal failure or insufficiency and bone pain
back pain in which multiple myeloma is suspected
hypercalcemia attributed to possible malignancy (e.g., associated weight loss, fatigue, bone pain, abnormal bleeding)
rouleaux formations noted on peripheral blood smear
renal insufficiency with associated serum protein elevation
unexplained pathologic fracture or lytic lesion identified on radiograph
Bence Jones proteinuria

immunofixation also should be performed because this technique may be more sensitive in identifying a small monoclonal (M) protein.5

hypervolemia

Aetiology

hypovolemia : decreased plasma volume (associated with hyponatremia , eunatremia, or hypernatremia )

Aetiology

decreased extracellular compartment volume

extrarenal sodium loss

gastrointestinal sodium loss : vomiting , nasogastric probe, diarrhea
sweat sodium loss : fever defervescence, prolonged heat exposure, physical exercise
respiratory airways sodium loss : hyperventilation in febrile patients with assisted ventilation
hemorrhages

renal sodium and water loss due to polyuria

diuretics
osmotic diuresis
transient, due to expansion of extracellular compartment due to oliguria

polyuria during acute tubular necrosis
removal of bilateral obstructive uropathy

hypoaldosteronism

renal water loss (less severe hypovolemia as 66% of water depletion occurs in intracellular volume)

diabetes insipidus

normal or increased volume of extracellular compartment

decreased cardiac output due to cardiopathies
redistribution

exit of fluid from capillaries into interstitium (edema )
exit of fluid from capillaries into "third space" (a compartment not in equilibrium with ECF nor ICF)