Thrombocytosis (also called thrombocythemia) is a condition of high platelet levels in the blood. A normal platelet count is between 150,000-450,000 platelets per microliter of blood. High platelets do not always signal any particular worry. Even when platelets are over 450,000, aggressive testing and investigation for cause is not generally undertaken until counts get over 750,000. Some common causes of high platelet levels are chronic inflammation causing excessive activation of megakaryocyte development, malignancy, infections, spleen removal, and surgery/other types of trauma can cause feedback to the bone marrow to increase hematopoiesis, particularly of the megakaryocyte line. Symptoms of this condition are often mild and may not even be noticed. However, there is an increased risk of blood clots with high levels of platelets. If very high platelets are picked up on a routine blood test, it is important to find out the cause, as most cases of thrombocytosis are secondary to some other underlying condition.
Thrombocytopenia is when the platelet count in the body is less than 150,000 platelets/microliter of blood. This can be caused by leukemia because cancer cells take up so much energy in the bone marrow that thrombocyte production is diminished. It can also be due to radiation/chemotherapy. There are other complications that can cause decreased platelet levels like antiplatelet antibodies, DIC, splenic sequestration, and dilution of the blood. Splenic sequestration is characterized by an enlarged spleen that traps more formed elements, including platelets. Dilution may occur when someone receives IV fluid for massive blood loss.
The anatomic site for bleeding in an individual with thrombocytopenia are the post-capillary venules of the integumentary system. Blood leaks through the intercellular junctions in this area. Why this happens is complex, but is thought to be related to chemical signals that are shared between platelets and endothelial cells of the postcapillary venule. Thrombocytopenia disrupts this signaling and results in a loss of junctional integrity between endothelial cells. The clinical sign of this is petechiae and purpura. Common sites for bleeding due to platelet disorders include the skin and mucous membranes of the nasal cavity, oral cavity, and gastrointestinal tract.
Immune Thrombocytopenia Purpura (ITP)
Image by Becky T. BYU-I S20
Immune Thrombocytopenia Purpura (ITP) is an autoimmune disease characterized by autoantibodies against the GPIIb/IIIa fibrinogen receptor on platelets. Platelets tagged with this autoantibody are more likely to be destroyed by the reticuloendothelial system of the spleen and liver. Common manifestations of ITP include thrombocytopenia, purpura in the gums, GI tract bleeding (which leads to bloody stools called melena) and epistaxis (nose bleeds). One common treatment for ITP is a splenectomy, which removes the source of rapid thrombocyte destruction by macrophages consuming antibody opsonized platelets. The spleen can also sequester a lot of platelets, so its removal will preserve more platelets in circulation. Treatment may also include corticosteroids to decrease the activity of the immune cells.
Heparin Induced Thrombocytopenia (HIT) and Heparin Induced Thrombocytopenia and Thrombosis (HITT)
Progression of HIT/HITT Image by Becky T. BYUI S2020
If HIT or HITT occurs with heparin drug therapy, complications arise 5-14 days after exposure to the heparin drug. In some individuals, heparin binds platelet factor 4 (PF4) and actually acts as a hapten. HIT occurs when, for unknown reasons, the body begins making antibodies against a heparin/PF4 complex. PF4 is a chemical released from alpha granules of platelets. PF4 is known to have a high affinity for binding to heparin and heparin-like molecules. It is also known to be a chemokine that can attract leukocytes. As you may recall, our bodies make endogenous heparin that works against coagulation by activating antithrombin. It is believed that the ability of PF4 to bind heparin promotes coagulation processes because binding up heparin will reduce the activity of AT-III. Therefore, any place where there are a lot of platelets being activated, PF4 is causing a reduction of AT-III activity.
The heparin/PF4 complex triggers an immune response that results in the mass production of IgG antibodies that target heparin/PF4. The Fc portion of these antibodies attaches to receptors on platelets and induces activation. These antibody-activated platelets result in thrombocytopenia (HIT) because they have mass activation and are subsequently destroyed by phagocytes in the reticuloendothelial system. This excessive activation of platelets plus the binding of PF4 to heparin reducing AT-III activation causes a hypercoagulable state which may lead to unintended formation of clots (thrombi). We call this heparin induced thrombocytopenia and thrombosis (HITT).
With HIT, excessive bleeding eventually occurs because of the low platelets. When HITT occurs, thrombosis may result in a free floating embolism that can cut off blood supply to the brain, heart and limbs and lead to strokes, heart attacks, and gangrene. These syndromes may occur simultaneously in the same person. Patients with this condition should be treated with alternative anticoagulants other than heparin.
Thrombotic Thrombocytopenic Purpura (TTP)
Thrombotic thrombocytopenic purpura (TTP) is a rare condition and type of thrombotic microangiopathy (which is a pathology that causes thrombosis due to endothelial injury in capillaries and arterioles). In this disease, platelets are excessively activated and little platelet aggregations occur in small blood vessels throughout the body. Cells of the blood may be sheared, split and damaged beyond repair as they pass through these rather net-like platelet clusters. As platelets get used up in this process of platelet aggregation, thrombocytopenia results. As mentioned before, thrombocytopenia leads to petechiae and purpura. Based on this description, we can understand why this condition has thrombotic (due to platelet activation), thrombocytopenic (decreased levels of platelets), and purpura (symptom) in its name.
TTP is due to decreased activity of ADAMTS13. Also known as von Willebrand factor-cleaving protease, the ADAMTS13 enzyme is responsible for the breakdown of vWF. Remember that vWF has the ability to activate platelets, especially if it comes into contact with collagen. Autoantibodies against ADAMTS13 or acquired mutations in the gene that codes for ADAMTS13 can cause a deficiency in this enzyme and lead to excessive activation of platelets because of the inability to remove vWF. The inability to keep vWF levels in check in the blood creates a situation where the risk of inappropriate platelet activation is high. This increases the risk for clots due to excessive activation and bleeding due to decreased platelet levels.
Hemolytic Uremic Syndrome (HUS)
HUS is another thrombotic microangiopathy that results in hemolysis of blood cells and can lead to kidney damage. The symptoms of HUS can be quite similar to TTP, but its cause is different. HUS generally occurs after an E. coli infection. E. coli 0157:H7 produces shigella toxin (also called shiga toxin). Through mechanisms that we will explore more in module eight, shigella toxin can damage endothelial cells, particularly in the vasculature of the kidney. This toxin can also impair the function of ADAMTS13, leading to increased vWF levels. Shigella toxin is also capable of activating the complement system through the alternative pathway. This combination of effects leads to a rapid development of activated platelets. The platelet aggregation is particularly aggressive in the kidneys and results in them being at particular risk of damage.
Similar to TTP, the platelet clusters in HUS may cause fragmented blood cells as well as the symptoms of thrombocytopenia. The hemolytic anemia that can occur with both HUS and TTP does so via a mechanism known as microangiopathic hemolysis. As mentioned, thrombi lodged in smaller vessels tear apart blood cells as they squeeze by. If enough RBCs are damaged in the narrowed blood vessels, it causes anemia. Portions of the RBCs that are sheared off can be seen on a blood smear. These sheared red blood cells are called helmet cells or schistocytes.
Plasmapheresis, a method of removing blood plasma from the body without withdrawing blood cells, can be used as a treatment for HUS and TTP. The plasma removed from the body can be treated so that unwanted components are removed (such as certain types of antibodies causing damage) or the plasma can be exchanged with a donor plasma. In TTP, this helps to remove unwanted antibodies that might be damaging tissues and impairing ADAMTS13. In HUS, this helps to provide working ADAMTS13 and remove shigella bacteria and toxins.
Results of TTP and HUS Image by Becky T. BYU-I S20
Drug-Induced Platelet Dysfunction
Platelet function can be impaired by NSAIDs such as aspirin (ASA) because they inhibit platelet cyclooxygenase (COX) enzymes and thereby inhibit the formation of thromboxane A2. These drugs are useful in preventing strokes and myocardial infarctions because they prevent the formation of thrombi and emboli, but care of increased bleeding risk should be taken into account.