PHYSIOLOGY OF ADULT HOMO SAPIENS - BLOOD (HAEMATOLOGY : PLASMA, BLOOD CELLS, AND COAGULATION) AND LYMPH
(see also circulation, diseases affecting blood and hematopoietic organs and cardiovascular diseases)

Table of contents :


  • blood
  • lymph


  • hematopoietic system : the tissues concerned in production of the blood, including the bone marrow, liver, lymph nodes, spleen, and thymus

    Blood / haema / hema / sanguis : the fluid that circulates through the heart, arteries, capillaries, and veins, carrying nutriment and oxygen to the body cells. It consists of the plasma, a pale yellow liquid containing the microscopically visible formed elements of the blood: the erythrocytes, or red blood corpuscles; the leukocytes, or white blood corpuscles; and the platelets, or thrombocytes. Its amount in a normal adult is ~ 5 L (~ 7% of body volume or 8.5-9.0% of body mass) :

    Organogenesis :
  • Blood cells / blood corpuscles / hemacytes / hematocytes / hemocytes (cytohaematology)

  • Web resources : Long-term bone marrow culture (LTBMC) at COPE
    CD200 / MOX2 (widely expressed) -- CD200R / MOX2R (restricted to the surfaces of myeloid lineage cells) : both the receptor and substrate are cell surface glycoproteins containing 2 immunoglobulin-like domains. The receptor-substrate interaction may function as a myeloid downregulatory signal
    [a viral homologue of  CD200 encoded by the K14 ORF of HHV8 interacts with the CD200R with the same kinetics and low affinity as the host protein, although it has only 40% sequence identity. Cells expressing CD200 or K14 inhibits the secretion of pro-inflammatory cytokines by activated macrophages, indicating that infected cells might deliver downmodulatory signals to host myeloid cells through the CD200 receptor to evade eliminationref]


    Using hESC differentiation in coculture with OP9 stromal cells, we demonstrated that early progenitors committed to hematopoietic development could be identified by surface expression of leukosialin (CD43). CD43 was detected on all types of emerging clonogenic progenitors before expression of CD45, persisted on differentiating hematopoietic cells, and reliably separated hematopoietic CD34+ population from CD31+34+43-KDR+ endothelial and CD31-34+43-KDR mesenchymal cells. Furthermore, we demonstrated that the first-appearing CD34+41a+/-43-45-235a+ cells represent pre-committed erythro-megakaryocytic progenitors. Multipotent lymphohematopoietic progenitors were generated later as CD34+41a-43+45-235a- cells. These cells were negative for lineage-specific markers (Lin-), expressed KDR, VE-cadherin, and CD105 endothelial proteins, and GATA-2, GATA-3, RUNX1, c-myb transcription factors that typify initial stages of definitive hematopoiesis originating from endothelial-like precursors. Acquisition of CD45 expression by CD34+43+45-Lin- cells was associated with progressive myeloid commitment and a decrease of B-lymphoid potential. CD34+43+45+Lin- cells were largely devoid of VE-cadherin and KDR expression, and had a distinct Flt-3highGATA-3lowRUNX1lowPU1highMPOhighIL7Rhigh gene expression profileref.

    Ape1 is required in normal embryonic hematopoiesis and that the redox, but not the repair endonuclease function of Ape1 is critical in normal embryonic hematopoietic developmentref. Promoter polymorphisms between C57BL/6 (B6) and DBA/2 (D2) mice alleles may affect latexin (Lxn) gene expression and consequently influence the population size of hematopoietic stem cellsref.

    early progenitors with lymphoid and myeloid potential (EPLM) CD19B220+CD117lowCD135 / Flt+. Treatment of mice with the corresponding ligand, Flt3L, showed a 50-fold increase in EPLM. In addition to the expected increase in DC numbers, Flt3L treatment had a reversible inhibitory effect on B lymphopoiesis. Limiting dilution analysis of sorted EPLM from Flt3L-treated mice showed that B-lymphocyte progenitor activity was reduced 20-fold, but that myeloid and T-cell progenitor activity was largely preserved. EPLM from treated mice transiently reconstituted the thymus and bone marrow of recipient mice, generating cohorts of functional T and B cells in peripheral lymphoid organs. Thus, Flt3L treatment results in a dramatic increase in a novel bone marrow cell with lymphoid and myeloid progenitor activityref.
     

  • 55-60 % is represented by ECF, termed plasma, and can still undergo coagulation. Plasma contains 5% of total body water (ie 3 L in an adult with body mass = 70 kg). Serum (i.e. plasma less factor I / fibrinogen and factor V, so not coagulable) is rapidly obtained after coagulation of whole blood and separation from the clot by centrifugation.
  • enzyme
    blood concentration
    multiple forms
    assay
    distribution
    increased in
  • increased production
  • decreased excretion (bile, urine, RES)
  • increased permeability or necrosis (for intracellular enzymes)
  • decreased in
    alkaline phosphatase (AlkP / ALP)
  • liver/bone/kidney (tissue non-specific) isozyme of ALP (ALPL)
  • 100-300 IU/L at 37°C (varies with age (peak at birth, fall at age 5, lesser peak at age 12 and fall at age 20) and temperature) slow hepatic AlkP (normal) substrates for spectrophotometry : 
    • b-glycerophosphate (Bodansky)
      • Bodansky unit : the quantity of alkaline phosphatase that liberates 1 mg of phosphate ion from glycerol 2-phosphate in 1 hour at 37°C and under other standardized conditions.
    • pyrophosphate (King-Armstrong)
      • King-Armstrong unit : the amount of phosphatase that liberates 1 mg of phenol from an excess of disodium phenylphosphate under defined conditions; alkaline phosphatase can be measured under alkaline conditions and acid phosphatase under acidic conditions
    • PNPP (Bessey-Lowry)
    + Mg2+ =pH 9.8=> 
    hepatocytes (also in bile) cirrhosis, obstructive jaundice, liver metastases, cholestasis, acute and chronic hepatitis, occupation syndromes, partial choledocholithiasis scurvy
    magnesium deficiency
    infantile hypothyroidism
    cachexia
    congental hypophosphatemia 
    Fanconi syndrome
    renal failure
    idiopathic acidosis 
    bone radiotherapy
    bone AlkP (bALP) (normal) (2-15 mg/L) osteoblasts => values related to total bone mass, higher in males tumours, rickets, Paget's disease, bone fractures, osteomalacia, barbiturates, hyperparathyroidism; not increased in osteoporosis or multiple myeloma
    intestinal AlkP (normal) : neuraminidase-insensitive thanks to internal Sia residue => constant pI enterocytes only in 0 or B blood group individuals => also in faeces after meals, IBDs, chronic diarrhea, intestinal tuberculosis, cirrhosis or hepatitis-related ascitis
    placental alkaline phosphatase (PLAP) / heat-stable alkaline phosphatase (HSAP) / secreted embryonic alkaline phosphatase (SEAP) (normal) : the only form not inhibited by EDTA and 100% stable at 56°C for 10' placenta since formation of placenta (pregnancy wk 14-16) to wk 1 after delivery; preeclampsia, multiple pregnancies
    fast hepatic or biliary AlkP (pathological) hepatocytes as for slow isozymes, plus increased synthesis in HCC and liver granulomata (sarcoidosis)
    Regan carcinoplacental AlkP (pathological) various carcinomas (pleura, lungs)
    renal AlkP  (pathological) proximal renal tubule (also in urine) renal transplant recipients
    g-glutamyl transferase (gGT) (heterodimer) 6-28 IU/L at 25°C 
    9-50 IU/L at 37°C




    5 (pathological) 
    Molecular forms are not determinated usually
    spectrophotometry 
    N-g-glutamyl-p-nitroanilide 
    N-g-glutamyl-naphthylamide
    kidney, pancreas, liver, intestine, lungs, spleen, thyroid, myocardium, many other tissues other than skeletal muscles liver diseases (hepatitis, metastases), cholestasis (higher specificity thank AlkP, higher sensitivity than 5'-nucleotidase and Leu-AP) 
    other (pancreatitis, diabetes mellitus, pancreatic carcinoma, AMI, renal or cerebral neoplasia, inducer drugs (barbiturates, antiepileptic drugs), infectious mononucleosis,hyperthyroidism
    asymptomatic condition
    5'-nucleotidase 0-1.6 IU/L at 37°C AMP + H2O + Mg2+ + Mn2+ =pH 7.5=> Ado + Pi + NH4+MoO4 => violet compound red with spectrophotometry at 630-640 nm; repeat assay with inhibitors (Ni2+, Zn2+) => difference is activity of 5'-nucleotidase only liver, brain, muscle, kidney, lung, bone, thyroid, endothelium liver diseases (cholestasis, occupation syndromes, hepatitis)
    aspartate transaminase (AST) / serum glutamate-oxalate transaminase (SGOT) : cytosolic and mitochondrial (80%) 17-22 IU/L at 25°C 
    25-40 IU/L at 37°C
    Asp + aKG + PPi (not all molecules had it added) =AST=> Glu + OAA =+NADH=MDH=> malate + NAD+ myocardium, brain, liver, fatty tissue, gastric mucosa, skeletal muscle, kidney, and less pancreas, spleen, testes, RBCs AMI (after 8-12 hrs, peak after 36 hrs, normal in 4-7 dd), myocarditis (not in angina pectoris
    hepatitis and cirrhosis (1-4 wks before haundice, 100-fold peak after 7-10 days, normal after 4-5 wks) 
    pulmonary and renal infarction 
    myopathies
    alanine transminase (ALT) / serum glutamate-pyruvate transaminase (SGPT) 15-18 IU/L at 25°C Ala + aKG + PPi (not all molecules had it added) =ALT=> Glu + Pyr =+NADH=LDH=> lactate + NAD+
    • Karmen unit : the amount of transaminase that under specified conditions will cause a change of 0.001 in the absorbance of NADH when measured at 340 nm in a 1 cm light path.
    liver and less in kidney, myocardium, skeletal muscles, pancreas, spleen
  • hepatitis and cirrhosis (De Ritis' ratio = [AST]/[ALT] = 1, then < 1) mtAST/(mtAST + cAST) > 0.8 and [AST]/ALT] > 2 in AMI, pulmonary and renal infarction
  • [AST] > [AlkP] => hepatitis
  • [AST] < [AlkP] => ostructive jaundice
  • lactate dehydrogenase (LDH) separated with electrophoresis, nonsandwich IRMA precipitation, tetrazolium salts, or densitometry; it is heat-unstable and inhibited by guanidine thiocyanate 
  • LDH1 / LDHA (skeletal muscle)
  • LDHA-like
  • LDHA-like 1 (seminoma)
  • LDHA-like 2
  • LDHA-like 3
  • LDHA-like 4
  • LDHA-like 5
  • LDH2 / LDHB (including K6E fast isozyme; heart)
  • LDHB-like 1
  • < 120-240 IU/L at 25°C 
    < 450 IU/L at 37°C
    LDH1 / aKBDH = H4 (at 25°C it also catalyzes aKBut => a-hydroxybutyrate) myocardium, kidney, RBC (18-33%) AMI (> 82%; after 12-24 hrs, peak after 36 hrs; normal after 7-10 days), intravascular hemolysis, tumors 11 different mutationsref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8, ref9 (M. Kamada, K. Fujita, I. Sakurabayashi et al., A family with a case of deficiency of lactate dehydrogenase H-subunit. Seibutsu Butsuri Kagaku 36 (1992), pp. 161–164) : 3 base deletion (AAT) at codon 220 of exon 5, which caused a deletion of one asparagineref
    LDH2 / H3M1 myocardium, kidney, RBC, WBC (28-40%) AMI (> 82%; after 12-24 hrs, peak after 36 hrs; normal after 7-10 days; lesser increase than LDH1), intravascular hemolysis, pulmonary infarction, tumors
    LDH3 / H2M2 liver, muscles, WBC (18-30%) pulmonary infarction, tumors
    LDH4 / H1M3 liver, muscles, WBC (6-16%) hepatopathies, tumors
    LDH5 / M4 skeletal muscles, liver (2-13%) traumas, DMD > 11-24%, hepatopathies, tumors
    LDH6 / LDHx testes, hypoxic tissues renal ischemia and pyelonephritis (not in cystitis), germ cell tumors
    creatine phosphokinase (CPK / CK) : cytosolic and mitochondrial

    macro-CPK

  • I : 
    • BB + IgA 
    • BB + IgG
  • II : aggregates of mtCPK)
  • at 25°C : 
  • males : 10-70 mIU/L
  • females : 10-60 IU/L

  • at 37°C : 
  • males : 24-195 IU/L
  • females : 24-170 IU/L
  • CPK1 = BB (oncofetal) Oxidation of thiols, which reduces activity by 50% in 4-6 hrs at RT can be prevented by glutathione. Spectrophotometric assay with adenylate kinase inhibitors (Mg2+, AMP, diadenosine monophosphate, N-acetyl-cystein). Isozymes can be dosed with sandwich ELISA  brain, smooth muscle (< 1%) cerebral ischemia, encephalitis, various neoplasms, epilepsy, psychosis
    CPK2
    • MB1 (1 lysine residue)
    • MB2
    myocardium (< 3%) AMI (after 4 hrs, 8-fold peak in 24 hrs, normal after 2 dd; [MB2]/[MB1] increases after 90'); newborns, reject of heart transplant, after muscular damage or disease
    CPK3
    • MM1 (2 lysine residues)
    • MM2 (1 lysine residue)
    • MM3
    myocardium and skeletal muscles (97%) physical exercise, intramuscular injections, neuroleptic malignant syndrome,  trauma and muscle dystrophies (expecially DMD, before onset of symptoms, decreases during time due to replacement with fibroadipous tissue), myositis, dermatomyositis, AMI ([MM3]/MM4] increases after 3 hrs), hypothyroidism (increased membrane permeability) (not in nephropathies, hepatopathies, hemopathies, pulmonary infarction; decreased in hyperthyroidism)
    aldolase 0.5-3.1 IU/L at 25°C

    C
    Fru-1,6-bisP => GA3P + DHAP =+NADH=> NAD + glyceraol-3-phosphate skeletal muscle, myocardium, liver and brain AMI, viral hepatitis, myoglobinuria (not in myasthenia gravis and obstructive jaundice)
    a-amylase (ALS) / diastase 120-360 IU/L at 37°C pancreatic amylase
    • P1 (deglycosylated)
    • P2
    • P3 (-AsnGln)
    Somogyi saccharometric method : maltopentose => maltotriose + maltose => 5 Glc =hexokinase => 5 Glc-6-P + 5 NADP+ => 5 6-phosphogluconolactone + 5 NADPH (l = 340 nm) 
  • Somogyi unit : that amount of amylase that will liberate reducing equivalents equal to 1 mg of glucose per 30 minutes under defined conditions.

  • chromogenic method : PNP-maltohexose => 2-PNP-maltotriose + H2O =a-glucosidase, basic pH=> Glc + PNP (l = 405 nm) 
    starch => glucose or +I2 => amylose(I)n blue (l = 560-600 nm)
    pancreas >> lungs, testes, ovaries pancreatic disease :
    • pancreatitis
      • acute pancreatitis (rise after 2-12 hrs, peak after 24 hrs (urinary peak after 48 hrs), normal in 3-5 days)
      • chronic pancreatitis: ductal obstruction
      • complications of pancreatitis
        • pancreatic pseudocyst
        • pancreatogenous ascites
        • pancreatic abscess
        • pancreatic necrosis
    • pancreatic trauma
    • pancreatic carcinoma
    nonpancreatic disorders :  other abdominal disorders
    chronic pancreatitis with pancreatic failure
    salivary amylase or ptyaline (inhibited by lecithine) 
    • S1
    • S2 (deglycosylated)
    • S3 (-AsnGln)
    salivary glands parotitis, irradiation sialadenitis, maxillofacial surgery, sialolithiasis, renal failure, macroamylasemia (polymers + IgA => decreased clearance)
    lipases (LPS) 190 IU/L at 25°C 
    200 IU/L (0.05-1 conventional units) at 37°C
    pancreatic lipase (acts on sn-1 rather than on sn-2) activated by Ca2+
  • triolein =pH 8.8=> glycerol + FFAs => turbidimetry
  • olive oil =3 hrs at pH 8=> glycerol + 3 oleic acid titred with NaOH 0.5 N and thymolphtahalein (virates at pH ?
  • pancreas and pancreatic ducts acute pancreatitis, pancreatic carcinoma, tumor or calculus of Vater's ampulla
    lipoprotein lipase (activated by heparin)
    cholinesterase true cholinesterase / acetylcholinesterase (AChE) hydrolysis of thioesters (inhibted by [ACh] > 10-2 M) 
    acetylthioCh => acetate + ... 
    butirrylthioCh => butyrrate + ...
    ...thiocholine =+ 5,5'-dithiobis-(2-nitrobenzoate) (DTNB, Ellman reagent)=> 5-thio-2-nitrobenzoate (inhibited by citrate, fluoridde, morphine, quinine, alkaloids, organophosphates; spectrophotometry, l = 405-470 nm)
    RBCs, lungs, spleen, gray matter of brain (cholinergic synapses) multiple sclerosis, psychoses, schizophrenia (normal in viral hepatitis, chronic hepatitis, obstructive jaundice, AMIAMI, intestinal malabsorption) paroxysmal nocturnal hemoglobinuria, autoimmune and newborn hemolytic anemia
    3,000-9,000 IU/L at 25°C serum cholinesterase, benzoylcholinesterase, butrrylcholinesterase or pseudocholinesterase liver, pancreas, myocardium, white matter, serum organophosphate poisoning, liver cirrhosis, acute necrotizing hepatitis, HCC, carriers of atypical allozyme have decreased catabolysis of suxamethonium (succinyldicholine) => anaesthetic apnea (lower Kcat and less inhibited by dibucain)
    acid phosphatase (AcP / ACP) < 11 IU/L at 25°C very sensitive to L-tartrate (isoforms 2a, 2b and 4) keep at 4°C with acetate 3 mM (pH = 2) (otherwise decreased activity at 23°C : -30% in 3 hrs, -100% in 3 days). To produce color, the reaction of the ancillary enzyme should be practiced after rising pH with alkaline solution (which also stops reaction) : only then PNP is convertred to quinoid. P-ACP is also dosed with ELISA (as for AlkP) or with subtraction dosing respect to L-tartrate inhibition granulocytes, pancreas, prostate (but as it flows into seminal fluid, concentration in males and females are roughly the same metastatic prostatic carcinoma (100-fold increase) (prostatic or osteoclastic isozyme if bone metastases occur: ACPtotal and P-ACP are poorly sensitivity in initial stages, when PSA dosage is preferred), hemocytolysis, sphingolipidoses, Paget's disease, primary and secondary hyperparathyroidism
    moderately sensitive to L-tartrate (isoform 3) lysosomes (liver, spleen, muscles, stomach, platelets, WBCs)
    L-tartrate resistant acid phosphatase (TRAP) (5a and 5b isoforms) hairy cell leukemia, osteoclasts, RBCs
    lactate spectrophotometry 2-3 hrs of muscular immobility
    pyruvate spectrophotometry
    amino acids HPLC
  • global blood parameters : blood viscosity = 1.4-1.8 relative units
  • Simultaneous multiple analyzer computerized (SMAC) and sequential multi-analysis (SMA) includes the following measures : Web resources Lymph
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