Iron Deficiency and Microcytic Anemias

Iron is an essential element for oxygen transport within hemoglobin. Oddly enough it is the element that is missed the most in regards to adequate intake and proper nutrition. Over 1.62 billion people in the world are effected by anemia, which is most commonly caused by iron deficiency. Iron deficiency can be caused by chronic blood loss, and is most common in women and teenagers from loss of blood due to menses. Iron loss leads to increased fatigue and depression, pallor, and dry and splitting hair. It can also lead to confusion cognitive effects. Hemoglobin is made of four polypeptide chains, two of which are alpha, and two are beta that come together to form a tetramer heme group with iron located in the middle. Ferrous iron within each heme molecule reversibly binds to one oxygen molecule. With iron deficiency, there becomes a hemoglobin deficiency. A decreased hemoglobin lowers oxygen-carrying capacity leading to anemia. Anemia by definition is a reduced oxygen-carrying ability. Tissue hypoxia can wreak havoc on almost every cell of the body, and can shift the oxygen dissociation curve in an unfavorable direction. The structure of hemoglobin and its function and key elements can be reviewed here.

To understand iron deficiency its important to recognize important aspects of iron metabolism and transportation in cells. Review the Iron Absorption and Metabolism article here for that information. There are also laboratory values that give a good picture of the iron status within the body that one should pay attention to. Transferrin; which is measured as the total iron binding capacity (TIBC) indicates how much or how little iron is being transported throughout the body. Serum iron is an important indicator of the tissue iron supply, and finally serum ferritin gives a picture of iron storage status within the bone marrow and cells.

Iron Deficiency Anemia

There are three stages within iron deficiency. Each comes with their own classic picture of laboratory results and worsen from stage to stage. In the first stage, there is storage iron depletion. This is mild and the patient may not even feel a difference physically. The patients hemoglobin is normal, normal serum iron, and TIBC. There is however decreased ferritin which indicates that there is decreased storage of iron. The second stage of iron deficiency is characterized by transport iron depletion. The hemoglobin may or may not be abnormal, but there is increased TIBC, and decreased serum iron. An increased TIBC, means that there are more substrate (iron) binding spots within the transferrin molecule. This implies that less iron is binding, which when coupled with a decreased serum iron makes sense. The patient may experience mild anemia which comes with increased fatigue and pallor. A peripheral blood smear will most often start to exhibit anisocytosis and poikilocytosis. These reference indicators represent abnormal sized red cells and abnormal shaped red blood cells respectively. A good indicator is an increased RDW, an increased RDW indicates some degree of anisocytosis. This is accurate because the red blood cell is realizing the loss of this oxygen-carrying capacity so its trying to release red blood cells as fast it can from the bone marrow to compensate for the loss, and as a result these red blood cells will appear smaller in diameter and hypochromic. Hypochromasia indicates that there is less hemoglobin within the cell and there is more of a central pallor. The thought is that even though there is less hemoglobin within each cell, if the bone marrow can produce more of these red blood cells than normal then that equals out. This leads to a microcytic anemia, micro meaning small. Stage three of iron deficiency is often referred to as functional iron deficiency. Within this stage there is an unmistakable decrease in hemoglobin, serum iron, and ferritin. There is also a large increase in TIBC.

The overall effect of iron deficiency anemia on the body and on the bone marrow is ineffective erythropoiesis. The red cell production within the bone marrow is compromised. As a result, the bone marrow becomes hypercellular with red cell precursors reducing the M:E (Myeloid:Erythroid) ratio.


This picture depicts how a peripheral blood smear would illustrate iron deficiency anemia. The red cells are smaller and there is more of a central pallor to them, indicating a loss of hemoglobin. This is also called hypochromia.


This picture depicts a normal peripheral blood smear. The red blood cells are larger in size and they have more color to them.

Anemia of Chronic Disease

Anemia of chronic disease is another form of microcytic anemia similar to iron deficiency anemia. It usually arises from a chronic infection or from chronic inflammation, but its also associated with some malignancies. A buildup in inflammatory cytokines alters iron metabolism. IL-6, which is an inflammatory cytokine inhibits erythrocyte production. It also increases hepcidin production. Hepcidin blocks iron release from the macrophages and the hepatocytes by down-regulating ferroportin. Without ferroportin there is no transportation of iron throughout the body and no production of hemoglobin or red blood cells. Laboratory findings will usually demonstrate low serum iron, low TIBC, low transferrin, and an increased to normal ferritin. The reticulocyte count is also normal, and sometimes increased. Reticulocytes are released from the bone marrow in times of red cell shortages to compensate.

This is just a brief overview of iron deficiency anemia and other microcytic anemias. This is just the beginning, follow and look forward to more in-depth reviews of each microcytic anemia. Key differences to look for is the TIBC value. In iron deficiency anemia the TIBC is increased and in anemia of chronic disease the TIBC is decreased. Ferritin is increased in anemia of chronic disease because the stored iron can’t be released from cells and the bone marrow due to the increased hepcidin production. Also the degree of anemia is mild compared to the more severe iron deficiency anemia.




Iron Absorption and Metabolism

Iron is an essential element for almost all forms of life, but most important as an oxygen transporter. When iron is in its ferrous state, oxygen binds to it within the hemoglobin molecule allowing erythrocytes to circulate and deliver oxygen to all the human bodies cells and tissues. The human body also requires iron in order to obtain ATP from cellular respiration (Oxidative phosphorylation). Although iron is an essential element to the body, like anything in nature, too much of it can be toxic. Its ability to donate and accept electrons readily means that it can spontaneously catalyze the conversion of hydrogen peroxide into free radicals. Free radicals cause a wide array of damage to cellular structures and tissues. To minimize the chances of toxicity, almost every iron atom is bound to protein structures, an example being hemoglobin. The iron is bound to the globin protein. To learn more about the structure of hemoglobin, review the previous article written. There is tight regulation of iron metabolism that allows the body to remain in homeostasis. Understanding iron metabolism is important for understanding multiple diseases of iron overload, and iron deficiency.

Iron Absorption

Most of the bodies iron comes from dietary uptake. There is continuous iron recycling occurring within the body from the sequela of hemoglobin metabolism by the spleen. The macrophages of the reticuloendothelial system store iron from the process of breaking down engulfed red blood cells. Its stored as hemosiderin. Hemosiderin is just a defined deposit of protein and iron that occurs as a result of iron overload, either systemically or locally. The metabolic functions of iron depend on the ability to change its valence state from reduced ferrous state (Fe2+) to the oxidized ferric state (Fe3+). Ferrous iron in the lumen of the duodenum is transported across the luminal side of the enterocyte by a protein called divalent metal transporter-1 (DMT1). Once iron has been absorbed across the cell membrane of the enterocyte, it can either be stored by binding to apoferritin or the cell can release the iron through the help of another transporter called ferroportin. Ferroportin is the only know protein that exports iron across cell membranes. One of the ways that the human body manages iron homeostasis is by the production of hepcidin. When iron stores are adequate, the liver will produce hepcidin, which competitively binds to ferroportin and inactivates it. When iron stores begin to drop, suppression of synthesis of hepcidin allows ferroportin to transport iron again. Before iron is taken by ferroportin across the membrane, it must be converted to its ferric form. Hephaestin, another protein on the enterocyte cell membrane oxidizes iron as it exits to its ferric form (Fe3+). Once oxidized and in its ferric state, the iron binds to apotransferrin (ApoTf). This iron:apotransferrin complex is known as transferrin (Tf). Its important to note that two molecules of ferric iron can bind to one molecule of apotransferrin.


Iron Uptake into Cells

Individual cells regulate the amount of iron they absorb to avoid adverse toxicity. Cells possess a receptor for transferrin (Tf), called transferrin receptor-1 (TfR1). The physiological pH of the plasma and extracellular fluid allow for a strong affinity to transferrin for TfR1. Through receptor mediated endocytosis transferrin saturates the TfR1 and once a critical mass has accumulated, endocytosis begins. The iron is passed into the cell into an endosome vesicle. Hydrogen ions are then pumped into the endosome and as a result the pH drops causing dissociation of the iron from the transferrin. Almost simultaneously the affinity for TfR1 to apotransferrin increases so it remains bound to the receptor while the iron remains free. The iron is then exported from the endosome vesicle into the cytoplasm by divalent metal transporter 1 (DMT1). The molecules of iron are then either stored, or transported into the mitochondria where they are incorporated into cytochromes or heme for the production of hemoglobin. While the iron is transported in the cytoplasm, the endosome fuses again with the cell membrane and in the extracellular space pH, TfR1 has a low affinity for apotransferrin so it dissociates and begins circulating again in the plasma for free transferrin. Again transferrin being a diiron:apotransferrin complex. Cells are able to store iron so they have a reserve if needed. Ferric iron (Fe3+) is stored in a protein called apoferritin. When iron binds to it it known as ferritin. Ferritin can be used at anytime during iron depletion by lysosomal degradation of the protein.



Just like hepcidin, there are other ways that the body maintains iron homeostasis. Transcription of TfR1 on the surface of the cells can either decrease or increase depending on iron stores within the cell. When iron stores are sufficient, production of TFR1 decreases, and vice versa. This is also useful in diagnosis of iron deficiency. Turns out there is a truncated form of TfR1 that circulates in serum as soluble transferrin receptors (sTfR). These sTfRs reflect the amount of tFR1 in the body. So in iron depletion there will be more circulating sTfRs indicating more production of TfR1 on the cells surface. A useful tool in the diagnosis of iron deficiency anemia.

Iron Recycling

When cells die, they are sequestered by the spleen and liver in which mechanisms salvage iron. These mechanisms are often referred to as the haptoglobin-hemopexin-methemalbumin system. Free hemoglobin in the plasma is quickly complexed with haptoglobin. By binding haptoglobin, the hemoglobin, and consequently, the iron avoid filtration by the glomerulus in the kidneys. This complex is taken up by macrophages, primarily those in the liver, spleen, bone marrow and even in the lungs. These macrophages express CD163, which is the haptoglobin scavenger receptor. The entire complex is internalized into the macrophage within a lysosome. Inside this lysosome, the iron is salvaged, the globin is catabolized as any protein would be, and the protoporphyrin is converted to unconjugated bilirubin. To learn more about the process of bilirubin metabolism, review the previous article. The haptoglobin is also degraded by the lysosome. The iron in free hemoglobin becomes oxidized to its ferric state (Fe3+), and as a result, forms methemoglobin. The heme (metheme) molecule of the free hemoglobin binds to hemopexin, preventing oxidative injury to the cells and tissues, as well as prevents loss of iron through glomerulus filtration. Albumin acts as a carrier for many proteins, including metheme. So albumin acts as a carrier for metheme to find hemopexin, which has a much higher affinity for the metheme itself. This allows for more rapid degradation of the toxic metheme.

There was a lot to learn in this article. Read carefully and go back and refer. I will try to highlight certain areas that I think are more important to the bigger picture. The next step is what happens in certain physiological disease states that leads to either iron overload or iron deficiency.

Polycythemia Vera

Polycythemia vera is an uncommon neoplasm or blood cancer where the bone marrow produces too many erythrocytes, megakaryocytes, and granulocytes, resulting in panmyelosis. The cancer is caused by a mutation in the JAK2 gene. Janus Kinase 2 (JAK2) is a non-receptor tyrosine kinase that plays a role in signaling in the type II cytokine receptor family. Members of that family include interferon receptors, GM-CSF receptor family, gp130 receptors, and the single chain receptors (EPO-R, etc). The function of those receptors are not important. The most important receptor for this article is the EPO-R receptor. The erythropoietin receptor (EPO-R) is a protein encoded by the EPOR gene that pre-exists in a dimerized state. When the ligand erythropoietin binds to the EPO-R receptor it induces a conformational change that results in the autophosphorylation of the JAK2 kinases. This establishes the function of EPO-R which is to promote proliferation and the rescue of erythroid progenitors from apoptosis. EPO-R induces JAK2-STAT5 signaling and with help from the transcription factor GATA-1 induces the transcription of the protein BCL-XL which is anti-apoptotic and promotes red cell survival.

In polycythemia vera (PV) there is a JAK2V617F mutation that causes independent continuous expression of the JAK2 kinase without erythropoietin (EPO) that acts on signaling pathways involving the EPO-R or hyperexpression in the presence of EPO. This causes increased gene expression for erythroid precursor cell proliferation and differentiation. It up regulates BCL-XL, which as mentioned above is an anti-apoptotic. This causes an abnormal accumulation of red cells in the peripheral blood. Its important to note that the accumulation of the red cells is due to lack of apoptosis, NOT because they are dividing quicker. Also there is a difference between primary PV and secondary PV. In primary PV there is a decreased expression of EPO, this is a compensation method for the body. As there is autophosphorylation of the EPO-Receptor, the body tries to reverse the process by down regulating the expression of erythropoietin (EPO). In secondary PV, there is normal to increased expression of EPO.



Diagnosis of PV according to the World Heath Organization (WHO) has to satisfy both major and minor criteria. The major criteria that has to be observed is a hemoglobin higher than 18.5 g/dL in men, and greater than 16.5 g/dL in women. There also has to be the presence of the JAK2 mutation. Minor criteria include presence of bone marrow hypercellularity demonstrating panmyelosis, serum EPO levels decreased, and a demonstration of endogenous erythroid colony growth in vitro. Meaning that there is presence of red cell growth in the laboratory using EPO from the patient, which assumes there is an issue with the downstream signaling of EPO, not EPO itself.

Laboratory results illustrate an increased hemoglobin, hematocrit, and MCV. There is an increased red cell count, platelet count, and white blood cell count. The leukocyte alkaline phosphatase is also increased. Its important to know that although the platelet count is increased, there is also an altered function of the platelets. The erythrocyte sedimentation rate will be decreased due to the decrease in the zeta potential. The zeta potential is the electrokinetic potential between the red cells that stops them from stacking or from sticking to one another. One classic characteristic of PV is erythromelalgia. This is a burning sensation in the pain and feet, with a reddish or bluish discoloration. This is caused by an increased platelet agglutination, from being dysfunctional that results in microvascular blood clots.


If untreated, PV can be fatal. Although the disease can’t be cured, it can be controlled and the life expectancy has risen with modern advances in medicine. Phlebotomy is recommended to reduce the hemoglobin and hematocrit levels, but can induce iron deficiency anemia if not monitored. Low dose aspirin is prescribed to reduce the risk of thrombotic events. The accumulation of the red cells increases the risk for the patient to develop thrombotic events because the blood is “thick”. Chemotherapy can be used, but is not normally indicated, unless therapeutic phlebotomy is unable to maintain a normal hemoglobin or hematocrit or when there is significant thrombocytosis. It is dangerous because of the risk for transformation to acute myeloid leukemia (AML).

To recap; its important to know the mutation in the JAK2 kinase that induces polycythemia vera. Although this mutation is demonstrated in 90% of cases, its possible that its absent. Panmyelosis and elevation of RBC indices is a diagnostic finding. Its important to know the major and minor criteria for the diagnosis of PV. Treatment is therapeutic phlebotomy and chemotherapy in rare cases, only when prior treatment has failed.

Transfusion Reactions


The blood bank of any laboratory deals with a huge responsibility. They play a role in the initial compatibility testing of blood donor products and the recipient or patient serum. The patients serum contains naturally occurring antibodies or in certain circumstances where the patient has had a previous transfusion, the serum can contain alloantibodies that have been synthesized from previous donor blood products. Research has progressed suggesting that whole blood donor products are not as effective at replacing volume as individual components are. When a donor comes in and donates a pint of blood there are techniques that are used to separate the plasma from the blood products. Platelets are collected via an apheresis machine. When the plasma is separated out it must be frozen at >-20 degrees C within 8 hours of collection. When a patient needs plasma, it takes about 18-20 minutes to thaw and release. Fresh frozen plasma (FFP) has an expiration off 12 months.  Red blood cells are usually stored in a refrigerator at 1-6 degrees C. RBC products have an expiration of 42 days once collected. They can be frozen for 10 years if needed.

For transfusion purposes compatibility needs to be done correctly and cautiously. Platelets do not need to be ABO or Rh compatible, but if ample supply is available, its best to ABO match donors with the patient. Red blood cells absolutely need to be ABO and Rh compatible. If a compatible unit is not available then the hospital should use an O negative unit. O negative units are used as the universal donor. Plasma should be ABO compatible. Contrary to RBCs units, an AB plasma donor is considered the universal donor where in RBC products an O negative donor is the universal donor as mentioned previously. Plasma products contain the donors antibodies. When the donor is AB, they do not have anti-A, or anti-B. It is because of this principle that AB plasma is considered as the universal donor.

Even when every precaution is taken to ensure proper testing took place and compatibility testing was as objectively accurate as possible transfusion reactions can still take place. There is no way to 100% prevent them. Acute hemolytic reactions are typically the most severe and occur when ABO-incompatible blood is given. With acute hemolytic reactions fever and chills develop quickly, back and flank/pain (Renal failure) can occur with hemoglobinuria/hemoglobinemia. Bleeding and DIC can commonly be seen. Treatment is to stop transfusion immediately and volume replacement. Diuretics may be given, most commonly furosemide. Febrile non-hemolytic reactions are typically caused by transfusion of leukocytes that attack the recipient. A fever that is characterized as greater than 1 degree Celsius increase. The infusion of the leukocytes cause cytokine release such as IL-6, and TNF. Transfusion of HLA antibodies can occur as well. Antipyretics can be given to resolve. It is also recommended to infuse leukocyte reduced units in the future.

Bacterial contamination can occur which can cause sepsis. Typically there will be a rapid high fever with symptoms of rigor, shock and gastro symptoms. Bacterial contamination usually is able to be cultured from the donor bag along with the collection site. Antibiotics should be administered with support as necessary. A way to get around this is to leukoreduce donor units.

Transfusion-related Acute Lung Injury (TRALI) is an acute lung injury <6 hours after transfusion that presents with hypoxemia and lung infiltrates. The anti-HLA antibodies activate the PMNs in the lung endothelial which causes physiological stress. TRALI is 20% fatal, but treatment should be aggressive supportive care with fluids.

Acute afebrile reactions include allergic, anaphylactic, and transfusion associated circulatory overload (TACO) reactions. A typical urticarial or allergic reaction presents with localized hives/redness which is caused by a IgE hypersensitivity. Typical treatment includes antihistamines. Anaphylactic reactions are caused by anti-IgA antibodies in the recipient. Usually signifying that the recipient is also IgA deficient. Presents with hypotension, GI symptoms and fever with anti-IgA. Treatment is immediate epinephrine or transfusion with washed RBCs or platelets. TACO usually occurs with a history of cardiopulmonary disease with too rapid of blood infusion. High risk groups include the elderly and adolescents. TACO presents with dyspnea, and hypoxia during and after transfusion. Elevated BNP, JVD and BP. Treatment is to slow the rate of infusion and diuretics.

Delayed febrile reactions typically present greater than one week post transfusion. There is a positive DAT along with hyperbilirubinemia and evidence of a new alloantibody. Delayed febrile reactions are caused by a anamnestic response to re-exposure to red cell antigens. Treatment is support therapy. Graft-vs-host-disease (GVHD) is caused by cellular immune response by transfused T-lymphocytes versus the host or recipient. Presentation includes fever, diarrhea, skin rash. Treatment includes immunosuppressive therapy with supportive care. GVHD can be 90% fatal.

Delayed afebrile reactions include post transfusion purpura and iron overload. PTP is caused by a recipient antibody versus the absent platelet antigen (HPA-1a). There is a decrease in platelets, and increased bleeding. Treatment includes IVIG and plasma exchange. Its important to avoid platelet transfusion. Iron overload typically occurs when >100 units have been transfused. Liver, pancreas, and cardiac dysfunction occurs. Iron chelation is standard treatment.

All reactions are serious and should be treated as such. Its important to check for clerical error in pre-transfusion compatibility testing as that is the number one cause of transfusion related reactions.

Disseminated Intravascular Coagulation

Disseminated intravascular coagulation (DIC) is a generalized activation of homeostasis secondary to a systemic disease. There are multiple different diseases that can activate different homeostatic factors that can contribute to DIC. Conditions such as physical trauma and endothelial cell damage exposing tissue factor that finds its way into circulation; or being exposed to tissue factor through vasodilation from hypovolemic shock, malignant hypertension or even heat stroke. There is a long list of secondary conditions that can set off an array of events that can lead to DIC. DIC involves all aspects of homeostasis; the vascular intima, platelets, leukocytes, coagulation, coagulation regulation, and fibrinolysis. DIC is often called a consumptive coagulopathy as it is consuming platelets at a rapid rate that form fibrin microthrombin that partially occlude small vessels. These thrombi that form are small and ineffective so systemic hemorrhage occurs which is often the first sign of DIC or one of the first signs prevalent.

To understand the pathophysiology of DIC its important to have a handle on normal primary and secondary homeostasis in the body. Normal physiological coagulation initiation begins on tissue-bearing cells such as fibroblasts and the subendothelial cells. This is called the extrinsic tenase complex which is composed of tissue factor, factor VIIa, and calcium. When tissue factor that is released from damaged subendothelial cells comes into contact with coagulation factor VII it activates it and that complex produces factors Xa, and IX and miniscual amounts of thrombin. There is also a minute amount of factor VIIa that is circulating in the blood that is resistant to breakdown from tissue factor pathway inhibitor (TFPI) and can bind to tissue factor to start coagulation. The initiation phase and the small amount of thrombin produced starts the initial fibrin formation by splitting the fibrinogen peptides A and B from fibrinogen and activates platelets through cleavage of protease activated receptors PAR-1 and Par-4, cofactors, factor Va released from the platelet alpha granules, factor VIIIa to be released by vWF, and procoagulants such as factor IX to be used further in propagation.

Coagulation Cascade

Propagation is where more than 95% of the thrombin is generated and occurs on the surface of the platelets. Initiation attracts a copious amount of platelets to adhere to the site of the injury from both the low-level thrombin released and exposed collagen. These initial platelets are sometimes called COAT-platelets or platelets partially activated by collagen and thrombin. The COAT-platelets have a higher level of procoagulant activity than platelets activated by collagen alone. These platelets also provide a surface for the intrinsic and prothrombinase tenases to form. Factors Va and VIIIa that were activated by thrombin in initiation bind to platelet surfaces and become receptors for factors IXa and Xa. Factor IXa binds to VIIIa and forms in the intrinsic complex. The intrinsic complex then activates factor Xa, which binds to factor Va that forms the prothrombinase complex. The prothrombinase complex activates prothrombin which generates thrombin. Thrombin activates factor XIII to stabilize the fibrin clot by covalently cross-linking the fibrin polymers initiated by the extrinsic tenase, binds to its cofactor thrombomodulin to activate the protein C pathway and also activates thrombin activatable fibrinolysis inhibitor (TAFI) to inhibit fibrinolysis to protect the formation of the fibrin clot.

Platelets as mentioned above have an important role in homeostasis. Platelet activation occurs once the platelet binds to collagen or the vWF that is present on the surface of the damaged endothelial cells. Adhesion occurs through the integrin GP IX V platelet receptor. Upon binding they secrete their primary granules that secretes molecules such as ADP, epinephrine, serotonin, and calcium. Calcium and other molecules like ADP activate phospholipase A2 through GCPRs otherwise known as 7 transmembrane receptors. Thomboxane A2 (TXA2) is then synthesized by thromboxane synthase in multitude of events. TXA2 generates secondary messengers DAG and IP3. DAG helps mediate actin contraction for shape conformational changes and IP3 binds to the IP3 receptors in the dense tubular system that opens calcium channels to allow release of more calcium. The activation of DAG and IP3 induces a conformational change that activates the fibrinogen receptor GP IIb/IIIa which allows adjacent platelets to aggregate and form the initial platelet plug. Platelets are also important in that they allow a surface for propagation of coagulation to occur.

With a basic background of primary and secondary homeostasis it will now be easier to understand what actually occurs during DIC. Triggering events may activate coagulation at any point in its pathway. Circulating thrombin that is released activates platelets, activates coagulation proteins that have positive feedback loops within the coagulation cascade and catalyzes fibrin formation. The fibrinolytic system enzymes such as plasminogen and TPA may become active subsequent to fibrin clot formation. Monocytes may also be induced to released tissue factor caused by inflammation in DIC. Normally thrombin cleaves fibrinogen creating fibrin monomers which spontaneously polymerize to from this insoluble gel which is strengthened through factor XIII. In DIC, a high percentage of the fibrin monomers fail to polymerize and just circulate in plasma as soluble monomers. These circulating monomers coat platelets and coagulation proteins which doesn’t allow any binding creating an anticoagulant effect. Plasmin, which is the activated form of plasminogen is a part of the fibrinolytic system. In normal homeostasis plasmin only cleaves the solid fibrin clot formed. Although in DIC, plasmin circulates in the plasma and degrades all forms of fibrin. It is because of this that fibrin degradation products, otherwise known as D-dimers become detectable in the plasma in concentrations commonly exceeding 20,000 ng/mL. The normal range for the D-dimer is 0-240 ng/mL. At the same time coagulation pathway control is lost as protein C, protein S, and anti-thrombin are consumed by the plasmin. Plasmin also digests factors V, VIII, IX, and XI. The platelets become enmeshed within the fibrin monomers and become exposed to thrombin which triggers platelet further platelet activation and consumption. Plasmin can also trigger complement which causes hemolysis and the kinin system which triggers inflammation and hypotension and as an end result shock.

It is important to diagnose DIC early and as a physician be aware of the early signs. A lot of times the symptoms of DIC are masked by the underlying disease and may be chronic or acute. The initial laboratory testing includes a platelet count, blood film examination, PT, aPTT, D-dimer and fibrinogen assay. The PT time is usually >14 seconds (Ref. 11-14) aPTT is usually >35 seconds (Ref. 25-35). These time intervals clue in that there is a coagulation issue as the PT tests the function of the extrinsic pathway and the aPTT tests the function of the intrinsic pathway. The platelet count is lower than 150,000 uL (Ref. 150,000-450,000 uL). The D-dimer as noted previously is significantly elevated. Although a D-dimer alone can’t diagnose DIC because a D-dimer is elevated in other conditions such as inflammation, pulmonary embolism and deep vein thrombosis. The fibrinogen levels may drop below 220 mg/dL (Ref. 220-498), but that provides little diagnostic information because in a lot of cases the fibrinogen level may not rise or may become elevated because of the level of inflammation occurring while the patient is in DIC. A peripheral blood smear confirms thrombocytopenia as well as the presence of schistocytes. Schistocytes are broken red blood cells because the microvessel walls are occluded they get shredded while passing through the blood vessels. Although not one test result can rule in DIC or rule it out, a panel of specialized tests can help in the diagnosis. It’s important to get the whole picture.


Treatment of chronic DIC is to diagnose and treat the underlying condition. This may include surgery, anti-inflammatory agents, or antibiotics to stabilize homeostasis. Supportive therapy to maintain fluid and electrolyte balance is important in the treatment of chronic DIC. In acute DIC where there is multi organ failure from microthrombi and hemorrhagic bleeding therapies are targeted at slowing the clotting process and to replace the consumed coagulation factors and proteins. Unfractionated heparin is commonly used for its anti-thrombotic properties. Normally the aPTT is used to monitor heparin therapy, but in the case of DIC other assays must be used so it’s important to pay close attention to the patient when administering heparin as it can aggravate bleeding tendencies. Physicians may also order fresh frozen plasma (FFP), platelets, and red cell transfusions as needed. FFP will replace the coagulation factors and proteins. The platelets will correct for the thrombocytopenia and the red cells are transfused because of the resulting anemia. Cryoprecipitate can also be administered to replace the low levels of fibrinogen. A physician may use an INR to figure out the best way to treat the DIC as well as monitor the therapy. The INR or international normalized ratio is a way of standardizing the PT results, regardless of test methods and where the testing occurred. A normal INR should be between 2-3. An INR too low puts the patient as risk for blood clots, on the contrary and INR too high puts the patient as too high of a risk for bleeding. As the underlying condition begins to stabilize the DIC will begin to subside and patient will slowly recover.

There will be more covered about DIC and how it relates to different leukemias and solid tumor cancers. This article provides an overview and how it affects normal homeostasis.