Blood factor deficiency

Recessively inherited coagulation disorders (RICDs) refer to relatively rare deficiencies in factor II, V, VII, and X-XIII resulting in either decreased clotting factor production or production of a dysfunctional molecule with reduced activity.19 The clinical severity of bleeding varies and generally is poorly correlated with the factor blood levels. Table 64-6 illustrates these clotting factor deficiencies and some of their characteristics. 

Cows and calves fed low-zinc diets of 25 mg Zn/kg ration showed a decrease in plasma zinc from 1.02 mg/L at start to 0.66 mg/L at day 90 cows fed 65 mg Zn/kg diet had a significantly elevated (1.5 mg Zn/L) plasma zinc level and increased blood urea and plasma proteins (Ram-achandra and Prasad 1989). Biomarkers used to identify zinc deficiency in bovines include zinc concentrations in plasma, unsaturated zinc-binding capacity, ratio of copper to zinc in plasma, and zinc concentrations in other blood factors indirect biomarkers include enzyme activities, red cell uptake, and metallothionein content in plasma and liver (Binnerts 1989). 

Studies on growth factors required by certain microorganisms, for example Streptococcus faecalis and Lactobacillus casei, and of their relevance in animal nutrition, led to the isolation and characterization of folic acid, pteroylglutamic acid (104), the structure of which was determined in 1946. It is an essential vitamin for man and together with vitamin B12 it is involved in the development of blood cells. Deficiency causes macrocytic anaemia. Many microorganisms do not use exogenous folic acid, but synthesize their own, and some... 

Blood factor VIII (FVIII) is a glycoprotein with 2351 amino acids and 330 kDa. Its deficiency causes hemophilia A. The first products based on recombinant factor VIII to reach the market were Recombinate and Kogenate, expressed in CHO and BHK cells, respectively. Over the last decade, other rFVIII products were approved, with modifications to the molecule (e.g. deletion of the B-domain), in the formulation or in the production processes. 

Toomey JR, Kratzer KE, Lasky NM et al. (1996) Targeted disruption of the murine tissue factor gene results in embryonic lethality. Blood 88 1583-1587 Toomey JR, Kratzer KE, Lasky NM, Broze GJ (1997) Effect of tissue factor deficiency on mouse and tumor development. Proc Natl Acad Sci USA 94 6922-6926... 

Coagulation disorders result from a decreased number of platelets, decreased function of platelets, coagulation factor deficiency, or enhanced fibrinolytic activity. A series of complex actions and reactions of procoagulant and anticoagulant events regulate blood flow. Maintenance of blood flow involves the interplay of four major components (1) the vessel wall, (2) platelets, (3) the coagulation system, and (4) the fibrinolytic system. 

Blood factor IX-based products are indicated for the control and prevention of bleeding episodes in patients with hemophilia B. Hemophilia B again is a hereditary disorder caused by a deficiency in circulating levels of coagulation factor IX, resulting in impaired blood clotting ability (see also Part III, Chapter 6). 

A second lipothrophic factor is betaine, which is effective because the transfer of at least one of its methyl groups to homocysteine is very efficient and can replenish methionine for choline formation. In the absence of sufficient lipotrophic factors, a fatty liver develops, and there is insufficient movement of fats either ingested or synthesized in the liver to the adipose tissue. As fats enter or are synthesized in the liver, they are repackaged or packaged as VLDLs to be moved out for transport from the blood to adipose tissue. The VLDLs contain protein, triacylglycerol, cholesterol, cholesterol esters, and phospholipids, especially phosphatidylcholine (lecithin). If one has either a protein deficiency or a lipotrophic factor deficiency, the movement of triacylglycerol s from the liver to adipose is ineffective and a fatty liver can develop. Choline can be present in the diet and need not be synthesized de novo. Phospholipid synthesis has been discussed previously (Chapter 15). 

B. Other Blood Cell Deficiencies Deficiency in the concentration of the various lineages of blood cells can be a manifestation of a disease or a side effect of radiation or cancer chemotherapy. Recombinant DNA-directed synthesis of hematopoietic growth factors now makes possible the treatment of more patients with deficiencies in erythrocytes, neutrophils, and platelets. Some of these growth factors also play an important role in stem cell transplantation. 

Figure 33-1. Drugs used in the treatment of anemias and blood cell deficiencies. G-CSF, granulocyte colony-stimulating factor GM-CSF, granulocyte-macrophage colony-stimulating factor IL-11, interleukin-11.

Almost a dozen glycoprotein hormones that regulate the differentiation and maturation of stem cells within the bone marrow have been discovered. Four growth factors, produced by recombinant DNA technology, have FDA approval for treatment of patients with blood cell deficiencies. 

V.B12 is also known as antipemicious anemia factor. Pernicious anemia is characterized by a severely reduced production of red blood cells, deficient gastric secretion and disturbances of the nervous system. It is not usually caused by dietary deficiency of V.B]2, but by the absence of intrirrsic factor, which is required for V.B[2 absorption. Intrinsic factor is a neuraminic acid-containing glycoprotein, normally present in the gastric mucosa, which forms a pepsin-resistant complex with V.B,2, and enables V.B,2 absorption in the lower part of the intestinal traet. 

In the tissues of animals, most thiamine is found as its phosphorylated esteis (4—6) and is piedominandy bound to enzymes as the pyrophosphate (5), the active coen2yme form. As expected for a factor involved in carbohydrate metaboHsm, the highest concentrations ate generally found in organs with high activity, such as the heart, kidney, Hver, and brain. In humans this typically amounts to 1—8 p.g/g of wet tissue, with lesser amounts in the skeletal muscles (35). A typical healthy human body may contain about 30 mg of thiamine in all forms, about 40—50% of this being in the muscles owing to their bulk. Almost no excess is stored. Normal human blood contains about 90 ng/mL, mostly in the ted cells and leukocytes. A value below 40 ng/mL is considered indicative of a possible deficiency. Amounts and proportions in the tissues of other animal species vary widely (31,35). 

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