Learn — Blood, immunity & lymphatics

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Plasma composition

Plasma is the straw-coloured fluid in which the blood cells are suspended — about 55% of blood volume and roughly 3 litres in an adult — and it is 91 to 92% water, about 7% protein and about 1% inorganic salts, nutrients, hormones, gases and waste. It is the compartment the nurse samples, transfuses and infuses into, so its protein and electrolyte values are the reference against which every laboratory report is read.

  • Blood is about 55% plasma and 45% formed elements; the packed cell volume (haematocrit) is 40 to 54% in men and 36 to 48% in women.
  • Total plasma protein is 6 to 8 g/dL — albumin 3.5 to 5.5 g/dL, globulins 2 to 3.5 g/dL and fibrinogen 200 to 400 mg/dL — giving a normal albumin to globulin ratio of about 1.7:1, which reverses in chronic liver disease and multiple myeloma.
  • Albumin is the smallest and most abundant plasma protein and supplies about 75 to 80% of the plasma colloid osmotic pressure of 25 to 28 mmHg; below about 2.5 g/dL fluid leaves the capillary and the patient becomes oedematous.
  • All the plasma proteins except the gamma globulins are made in the liver, and the gamma globulins come from plasma cells — so liver failure lowers albumin and the clotting factors while leaving the immunoglobulins intact.
  • Fibrinogen is clotting factor I: serum is plasma minus fibrinogen and the other consumed clotting factors, which is why a plain tube that has clotted gives serum and a citrate or EDTA tube gives plasma.
  • Principal plasma electrolytes: sodium 135 to 145 mEq/L, potassium 3.5 to 5.0 mEq/L, chloride 98 to 106 mEq/L, bicarbonate 22 to 26 mEq/L, calcium 8.5 to 10.5 mg/dL and magnesium 1.5 to 2.5 mg/dL, with an osmolality of 275 to 295 mOsm/kg and a pH of 7.35 to 7.45.
  • Plasma proteins do more than hold water: albumin transports bilirubin, calcium, free fatty acids and many drugs, transferrin carries iron, caeruloplasmin copper, and thyroxine- and cortisol-binding globulins their hormones, so a low albumin raises the free, active fraction of a protein-bound drug at the same dose.
  • Plasma volume is measured with Evans blue dye or radio-iodinated albumin; fresh frozen plasma is the product that replaces clotting factors and must be ABO-compatible, with group AB the universal plasma donor — the opposite of the rule for red cells.

Clotting factors

The clotting factors are the plasma proteins, numbered I to XIII with no factor VI, that act in sequence so that each activated factor turns on the next and a small trigger produces a large fibrin clot. They are grouped into an intrinsic (contact) pathway measured by the activated partial thromboplastin time, an extrinsic (tissue factor) pathway measured by the prothrombin time and INR, and a common pathway from factor X to fibrin, and a nurse uses that grouping every time she reads a coagulation report or gives an anticoagulant.

  • The named factors are I fibrinogen, II prothrombin, III tissue factor, IV calcium, V labile factor, VII stable factor, VIII antihaemophilic factor, IX Christmas factor, X Stuart-Prower factor, XI plasma thromboplastin antecedent, XII Hageman factor and XIII fibrin-stabilising factor; there is no factor VI because what was called VI turned out to be activated factor V.
  • All the factors are made in the liver except factor III (tissue factor, from subendothelial cells), factor IV (calcium, which is a mineral, not a protein) and von Willebrand factor with much of factor VIII, which come from vascular endothelium, so liver disease causes a bleeding tendency while factor VIII often stays normal or high.
  • Intrinsic pathway: XII to XI to IX, and factor IXa with VIIIa, calcium and platelet phospholipid forms the tenase complex that activates X; it is the longer pathway and it is monitored by the aPTT, normally about 25 to 35 seconds.
  • Extrinsic pathway: tissue factor released by injured tissue activates factor VII directly to activate X; it is the short, fast pathway and it is monitored by the prothrombin time, normally about 11 to 13.5 seconds, reported as the INR.
  • Common pathway: Xa with Va, calcium and phospholipid forms prothrombinase, which converts prothrombin (II) to thrombin (IIa); thrombin converts fibrinogen (I) to fibrin monomer and also activates factor XIII, which cross-links the mesh into a stable clot.
  • The vitamin K dependent factors are II, VII, IX and X plus the natural anticoagulants protein C and protein S; factor VII has the shortest half-life of the group, which is why the PT and INR are the first tests to become abnormal in liver failure and on starting warfarin.
  • Deficiency patterns to recognise: haemophilia A is factor VIII deficiency and haemophilia B (Christmas disease) is factor IX deficiency, both X-linked recessive with a long aPTT and a normal PT; factor XIII deficiency gives delayed bleeding with a normal PT and aPTT because the clot forms and then falls apart.
  • Heparin works through antithrombin III against thrombin and factor Xa and is followed by the aPTT (or anti-Xa) with protamine sulphate as its antidote; warfarin blocks vitamin K epoxide reductase and is followed by the INR, usually targeted at 2 to 3, with vitamin K and prothrombin complex concentrate or fresh frozen plasma as its reversal.

Minerals required for clotting (Ca, vit K)

Two non-protein requirements sit inside the coagulation cascade: calcium, which is factor IV, and vitamin K, which is not a factor at all but the vitamin without which four of the factors are made in a useless form. Calcium is needed at almost every step to bind the factors to phospholipid membranes, and vitamin K is the cofactor for the liver enzyme that adds the calcium-binding carboxyl groups in the first place, so a deficiency of either stops clotting even when every factor is present.

  • Calcium is factor IV; it bridges the gamma-carboxyglutamate residues of factors II, VII, IX and X to the phospholipid surface of activated platelets, which is how the tenase and prothrombinase complexes assemble, so no step from the tenase complex onwards proceeds without it.
  • Vitamin K is a fat-soluble vitamin and is the cofactor of gamma-glutamyl carboxylase, which carboxylates glutamate residues on factors II, VII, IX and X and on proteins C, S and Z; without it the liver still makes the proteins but they cannot bind calcium and are inactive.
  • Vitamin K1 (phylloquinone) comes from green leafy vegetables and vitamin K2 (menaquinone) is made by colonic bacteria; deficiency therefore follows fat malabsorption (obstructive jaundice, coeliac disease, cystic fibrosis), prolonged broad-spectrum antibiotics and prolonged parenteral nutrition without supplementation.
  • The newborn is naturally vitamin K deficient because placental transfer is poor, the gut is sterile at birth and breast milk is low in vitamin K, which is why vitamin K deficiency bleeding occurs and why a single intramuscular dose of vitamin K, 1 mg for a term baby, is given after birth as prophylaxis.
  • Warfarin does not touch calcium; it blocks vitamin K epoxide reductase so vitamin K cannot be recycled, which is why its effect takes days to appear, why the antidote is vitamin K, and why a sudden change in a patient's green-vegetable intake shifts the INR.
  • Citrate is the anticoagulant in blood bags and in the blue-top coagulation tube precisely because it chelates calcium; the laboratory adds calcium back to run the test, and the blood bank relies on the recipient's liver to clear the citrate after transfusion.
  • EDTA in the lavender-top tube also chelates calcium and is used for the full blood count, so a coagulation sample must never be sent in it; the citrate tube must also be filled to the mark, because the ratio of nine parts blood to one part citrate is what makes the result valid.
  • Massive or rapid transfusion delivers citrate faster than the liver can clear it, and the resulting fall in ionised calcium shows as perioral tingling, muscle twitching, a positive Chvostek or Trousseau sign, a prolonged QT interval and, in the extreme, tetany and poor cardiac contraction.

Normal blood parameters

The normal blood parameters are the reference ranges of the full blood count and the basic haematology indices against which every patient's report is read. They are examined relentlessly because they are the numbers a staff nurse must recognise as normal, borderline or critical before the doctor sees the chart, and because several of them differ by sex, by age and in pregnancy.

  • Haemoglobin: adult male 13.5 to 17.5 g/dL and adult female 12 to 15.5 g/dL. WHO 2024 defines anaemia by age, sex and pregnancy status: below 13 g/dL in men aged 15 and over, below 12 g/dL in non-pregnant women aged 15 and over, below 11 g/dL in the first trimester and below 10.5 g/dL in the second and third, below 10.5 g/dL in children aged 6 to 23 months, below 11 g/dL at 24 to 59 months, below 11.5 g/dL at 5 to 11 years and below 12 g/dL at 12 to 14 years.
  • Anaemia in pregnancy is graded by the Indian programme as mild 10 to 10.9 g/dL, moderate 7 to 9.9 g/dL, severe below 7 g/dL and very severe below 4 g/dL, and the grade decides oral iron, parenteral iron or transfusion.
  • Red cell count is 4.5 to 5.9 million per microlitre in men and 4.1 to 5.1 million in women; haematocrit is 40 to 52 per cent in men and 36 to 46 per cent in women, and the haematocrit is roughly three times the haemoglobin.
  • Total leucocyte count is 4,000 to 11,000 per microlitre, with a differential of neutrophils 40 to 75 per cent, lymphocytes 20 to 40, monocytes 2 to 8, eosinophils 1 to 6 and basophils 0 to 1; the neutrophil is the commonest white cell in an adult and the lymphocyte the commonest in an infant.
  • Platelet count is 150,000 to 450,000 per microlitre; spontaneous bleeding becomes likely below about 20,000 and surgery generally needs above 50,000.
  • Red cell indices: MCV 80 to 100 fL (below 80 is microcytic, above 100 macrocytic), MCH 27 to 32 pg and MCHC 32 to 36 g/dL; the reticulocyte count is 0.5 to 2.5 per cent and tells you whether the marrow is responding.
  • The Westergren ESR is 0 to 15 mm in the first hour for men and 0 to 20 mm for women; blood pH is 7.35 to 7.45 and total blood volume is about 5 litres in an adult, roughly 70 mL per kg.
  • Cell life spans are worth memorising: red cell 120 days, platelet 7 to 10 days and circulating neutrophil only a matter of hours, which is why marrow suppression shows first as neutropenia, then thrombocytopenia, and anaemia last.

Haemopoiesis

Haemopoiesis is the continuous formation of all blood cells from a single pluripotent haematopoietic stem cell, which divides and differentiates along a myeloid line to red cells, platelets, granulocytes and monocytes, and a lymphoid line to T, B and natural killer cells. The site of production moves during life, from the yolk sac to the liver and spleen and finally to bone marrow, and by adulthood only the marrow of the axial skeleton and the ends of two long bones is still red.

  • The fetal sequence is mesoblastic (yolk sac, from about the third week to the eighth), hepatic (liver from about six weeks, the chief site through mid-pregnancy, with the spleen and lymph nodes contributing), and medullary (bone marrow from about the fifth month), which is the only significant site by birth.
  • From birth to about five years the marrow of every bone is red and active; red marrow is then progressively replaced by yellow fatty marrow from the periphery inwards, so that by about 20 to 25 years it survives in the vertebrae, sternum, ribs, skull, ilium and the proximal ends of the femur and humerus.
  • One pluripotent stem cell, identified by the CD34 marker, gives a common myeloid progenitor (red cells, megakaryocytes and platelets, neutrophils, eosinophils, basophils, monocytes) and a common lymphoid progenitor (T lymphocytes, B lymphocytes, natural killer cells).
  • The erythroid sequence is proerythroblast, early or basophilic normoblast, intermediate or polychromatic normoblast, late or orthochromatic normoblast, reticulocyte and mature erythrocyte; the nucleus is extruded as the late normoblast becomes a reticulocyte, and the reticulocyte finishes maturing in the circulation in one to two days.
  • Erythropoietin drives red cell production and is made mainly by interstitial cells of the renal cortex in response to tissue hypoxia, with a small hepatic contribution, which is why chronic kidney disease produces a normocytic normochromic anaemia that responds to erythropoiesis-stimulating agents rather than to iron alone.
  • Raw materials are iron, vitamin B12, folate, protein, vitamin C and copper; a shortage of iron gives a microcytic hypochromic picture and a shortage of B12 or folate gives a macrocytic megaloblastic picture with a low reticulocyte response.
  • Thrombopoietin, made chiefly in the liver, drives the megakaryocyte, and each megakaryocyte sheds thousands of platelets by fragmenting its cytoplasm; granulocyte colony-stimulating factor drives the neutrophil line and is given to shorten chemotherapy-induced neutropenia.
  • When the marrow cannot cope, the fetal sites can restart as extramedullary haemopoiesis, giving hepatosplenomegaly and expanded marrow spaces (the hair-on-end skull and frontal bossing of thalassaemia major) and the leucoerythroblastic film of myelofibrosis.

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