What is the evolution of the hematopoietic process during intrauterine development?

Hematopoiesis in the developing embryo begins at approximately 2 weeks postconception. It begins in the yolk sac, but as the gut develops, hematopoiesis is gradually taken over by the liver and spleen. This continues until the late second trimester, when the bone marrow develops and begins producing cells. By the mid third trimester, most hematopoietic activity is in the bone marrow, but stem cell rests may still be found in the liver and spleen. KEY POINTS: HEMATOPOIETIC DEVELOPMENT Production: yolk sac liver and spleen bone marrow. Hemoglobin: embryonic fetal adult. The oxygen dissociation curve of Hb F is shifted to the left to enhance oxygen uptake in utero. Maturation of cell lines goes from larger cells to smaller cells.

How do the different cell lines differentiate?

All cell lineages derive from the pluripotent stem cells. These are uncommitted and self-renewing. Under the influence of various cytokines, the pluripotent stem cells initially differentiate into colonyforming units (CFUs) that are capable of multiplication and maturation. There are three types: CFUGM (granulocytes and monocytes), CFU-mega (megakaryocytes and platelets), and CFU-e (erythrocytes). The latter change to burst-forming units-erythrocytes, then mature through the erythroblast; early, intermediate, and late normoblast; and finally reticulocyte stage, into mature red blood cells (RBCs). CFU-GM cells similarly differentiate to produce myeloid precursors (e.g., promyeloblasts, myelocytes, metamyelocytes, and bands), which mature into neutrophils, eosinophils, basophils; and platelet precursors (megakaryocytes), which mature to form platelets

What is the structure and function of hemoglobin?

Hemoglobin is a tetramer of globin chains, usually of two distinct types, bound to a heme moiety. For example, adult hemoglobin consists of two chains and two chains. The function of hemoglobin is to transport oxygen and carbon dioxide to and from the tissues, respectively. This is primarily a function of the heme portion of the molecule.

How do the red cells change during development?

As with all cell lines, RBCs become smaller as they mature. The "primitive" megaloblast-like cells in the yolk sac are very large (180 fl). By birth, however, the red cell size (mean corpuscular volume [MCV]) decreases to 110-120 fl. The hemoglobin content also changes from being predominantly fetal to a mixture of fetal and adult. The RBC life span in the fetal and neonatal period is 90 days, compared with 120 days in older children and adults. In addition, fetal RBCs express the i antigen (adult red cells express the I antigen).

KEY POINTS: ANEMIA Physiologic anemia reaches its nadir at about 6 weeks in premature infants and 8 weeks in term infants. The primary causes of hemolytic anemia are immune defects (ABO, Rh), membrane defects (spherocytosis), and enzyme deficiencies (G6PD). The most common causes of anemia in the neonatal intensive care unit are bleeding and iatrogenic causes. The basic work-up for anemia should include CBC, type and Coombs' tests, reticulocyte count, review of a blood smear, and serum bilirubin measurement. Treatment for anemia includes transfusion, administration of EPO, and minimizing blood drawing.
How does the site of blood sampling affect hemoglobin and hematocrit?

Capillary samples obtained by heel stick shortly after birth have hemoglobin levels that are on average 3.6 gm/dL higher than corresponding venous samples. The ratio of the capillary hematocrit to the venous hematocrit is 1.21 at 26-30 weeks' gestation and decreases to 1.12 in term infants and 1.02 at 5 days of age in healthy infants. It is particularly important to remember that the differences between capillary and venous hemoglobins are most pronounced in sick, premature infants in whom anemia is most likely to be a clinical problem. Thus, unexpected changes in the hemoglobin level in such infants should prompt consideration of the site of sampling.
What is physiologic anemia?

The phrase physiologic anemia of infancy is actually a misnomer that describes the normal, nonpathologic drop in hemoglobin and hematocrit experienced by term and preterm infants. Expansion of the lungs after birth improves oxygen availability and tissue oxygen delivery, resulting in near cessation of red cell production in both term and preterm infants. Serum erythropoietin (EPO) concentrations decrease to 0-10 mU/mL. Reticulocyte (retic) counts drop from 6% to 10% at birth to <1% by day 3-5. As a result, the hemoglobin gradually decreases to a nadir of approximately 10-11 gm/dL by 8-10 weeks of age in the term infant and 9-10 gm/dL by 4-8 weeks in the preterm infant. At this point, there is stimulation of erythropoiesis from an increase in EPO production, and the hemoglobin rises to infant levels.

How is DIC defined?

DIC is as an acquired pathologic process in which there is generalized activation of the coagulation system with widespread fibrin deposition and simultaneous activation of the fibrinolytic system. The entire process occurs within the vascular compartment.

Why are sick newborns particularly susceptible to developing DIC?

Newborns have an immature reticuloendothelial system and liver that, when compromised, may not be able to clear activated products appropriately. In addition, the tiny size of the blood vessels predisposes the infant to small vessel thrombosis.

What are the major causes of neonatal DIC?

As defined, DIC is always acquired and always pathologic. The triggers for the activation of the coagulation system include activation of the intrinsic pathway after injury to the vascular endothelium (e.g., sepsis, large hemangiomas, hypotension, hypothermia, hypoxemia, polycythemia, excessive instrumentation or the placement of catheters and tubes), activation of the extrinsic pathway after severe tissue injury (e.g., abruption, preeclampsia, brain injury, surgical procedures, neoplasms, NEC), massive red cell or platelet injury (e.g., intravascular hemolysis, antigen-antibody reactions), and reticuloendothelial system injury. KEY POINTS: DISSEMINATED INTRAVASCULAR COAGULATION DIC in the neonate always results from some underlying pathology. Clotting and fibrinolysis are the etiologic keys. Thrombocytopenia and elevated D-dimers are diagnostic for the disease. The problem will not resolve until the underlying disorder is treated. Supportive care includes platelet and FFP transfusions, and heparin if there is a significant thrombus.

What is the pathophysiology and clinical picture of DIC?

When triggered, the two arms of the coagulation cascade combine to generate increased amounts of thrombin; this gives rise to more fibrin generation, activation of the fibrinolytic system, and plasmin-mediated lysis of this fibrin. In addition, there is activation of platelets by a variety of factors, leading to aggregation and consumption. These processes lead to microvascular thrombosis and a resulting microangiopathic hemolytic anemia. Because of consumption of coagulation factors, there may be a bleeding diathesis as well. The clinical picture may include symptoms related to thrombosis (small or large vessel) or hemorrhage (mucocutaneous or internal) and a mild to moderate intravascular hemolytic process giving rise to anemia (hematuria/hemoglobinuria and hyperbilirubinemia).
What is the classic constellation of laboratory abnormalities seen in severe DIC?

Elevated prothrombin time (PT) and partial thromboplastin time (PTT), low platelet count, low fibrinogen, elevated D-dimers, mild to moderate anemia, hyperbilirubinemia, and low levels of all coagulation factors. The peripheral blood smear will show the presence of schistocytes and fewer platelets than normally seen. Schistocytes are thought to be formed when RBCs pass through small blood vessels that are partially occluded or distorted by excess fibrin deposited because of the DIC process.

What is the differential diagnosis of DIC?

The differential diagnosis includes hemorrhagic disease of the newborn, a hereditary coagulopathy, hepatic failure, and other causes of isolated thrombocytopenia.

What single test can help distinguish DIC from hepatic failure?

Factor VIII level. This factor is thought to be synthesized in vascular endothelial cells, not in the hepatocyte. It is decreased in a state of consumption of coagulation factors, such as DIC, but remains normal in hepatic failure. Note that some factor VIII may be synthesized "in the liver" in endothelial cells rather than in hepatocytes.

What are the principles of management of DIC?

dentify and treat the underlying disease process that is triggering the DIC. Closely monitor the laboratory parameters to guide replacement therapy. Support with blood products to replace the coagulation factors, platelets, and "natural" anticoagulants that are consumed in DIC. Platelet transfusions, FFP, and cryoprecipitate are typically given. In severe situations where volume is an issue, exchange transfusion with FFP reconstituted fresh red cells may be undertaken. Platelets must be given in addition. Maintain optimal oxygenation and perfusion. Consider heparin therapy to interrupt the consumptive process. The value of this therapy is controversial in the absence of major vessel thrombosis. Provide supplemental vitamin K.