Aspirin as a blood thinner?

Most people who have had previous cardiac issues, those who have even had a minor heart attack or survived a major infarction have often been prescribed to take an aspirin daily. To tackle this issue, its important to understand what a heart attack or an infarction actually is. Usually blood travels to the lungs, it gets oxygenated, and then travels through the coronary arteries to oxygenate the heart muscle itself. People over time can develop plagues that thin the artery lumen, or opening, eventually to the point where only a small amount of oxygenated blood can actually pass through. As a result, the heart can’t keep itself oxygenated. Without oxygen, tissues become hypoxic and die. When they die they release toxic cytokines and chemicals that damage tissue further, which coincidently we can objectively measure to determine whether an individual has experienced a heart attack. Heart attacks can come from a deep vein thrombosis, or an emboli as well. In that scenario, the clot actually happens somewhere else in the body and a piece of it breaks off and circulates until it gets to the heart and blocks the blood flow in the heart, causing an infarct.

Aspirin works as a blood thinner. It impairs the bodies ability to form a clot. What is a clot formed out of? Platelets. So aspirin directly targets a precursor to thromboxane A2, which activates downstream signaling to aggregate platelets and form a clot in primary hemostasis.

Synthesis of TXA2


The synthesis of thromboxane A2 is through the Arachidonic Acid, Cyclooxygenase (COX) pathway. Phospholipids are converted to Arachidonic Acid catalyzed by phospholipase C or phospholipase A2. Arachidonic acid can at that point go to two pathways; the Lipooxygenase pathway, or the Cyclooxygenase pathway. There are two Cyclooxygenase peroxidase; COX-1 and COX-2. COX-1 mediates the pathway through which thromboxane A2 is going to be synthesized, and COX-2 mediates another pathway that works to synthesize prostaglandins which directly counteract the function of thromboxane A2. Its the bodies way of keeping homeostasis. For every action, there has to be an equal reaction. In the next step in the pathway, Arachidonic Acid is converted to Prostaglandin H2 (PGH2) by PGH2 synthase and COX-1/COX-2 working synergistically. Prostaglandin H2 is then converted to thromboxane A2 (TXA2) by thromboxane synthase. TXA2 is a vasoconstrictor and potent hypertensive agent.

So, how does aspirin come into play at all? Good thing you asked. Aspirin as it turns out irreversibly binds to COX-1. This antagonist effect stops the pathway and does not allow for the synthesis of thromboxane A2. Without TXA2, there will be no platelet aggregation, and no clot. Without primary hemostasis being established, coagulation, or secondary hemostasis, can’t take over to stabilize the clot with fibrin.



Blood Components 101

This will serve as a guide for the specific indications, storage requirements and stability of the different blood components.


Whole Blood, Packed Red Blood Cells: 1-6 degrees Celsius.

Plasma, Cyroprecipitated AHF: -18 degrees Celsius.

Platelets: 20-24 degrees Celsius with continuous gentle agitation.

Granulocytes: 20-24 degrees Celsius without agitation.


Whole Blood: When refrigerated a unit of whole blood has a shelf life between 21-35 days depending on the additive that is used. Must be transfused within 4 hours when at room temperature.

Packed Red Cells: Packed red cells are stable for up to 42 days refrigerated, but they can also be frozen with glycerol as a cyroprotectant for up to 10 years. They must be deglycerolized by washing and thawed prior to transfusion and must be transfused within 24 hours once thawed.

Platelets: Platelets have a shelf live of only 5 days. Some hospitals and clinics are extending the shelf life out to 7 days with continuous bacterial testing to ensure there is no contamination.

Plasma: Plasma products must be processed and frozen within 8 hours of collection and are stable for 12 months. Once thawed they must be transfused within 24 hours.

Thawed Plasma: Has an expiration of 5 days.

Cryo: Cyro AHF once pooled and frozen has a stability of up to 12 months.

Granulocytes: Granulocytes must be transfused within 24 hours after donation.



Whole Blood: Used to replace the loss of both RBC mass and plasma volume. The product is 550-600 mL of whole blood, with a hematocrit of about 40%.

Packed Red cells: Usually the red cell product of choice. 330 mL of red cells, hematocrit of about 55-65% with an additive solution.



Platelets: Platelets derived from whole blood must contain at least 5.5×10^10 platelets in 40-70 mL of plasma in at least 90% of the units tested. Platelets donated through apheresis must contain at least 3×10^11/L platelets in 100-500 mL of plasma. One apheresis platelet collection is equivalent to six pooled random donor platelet concentrates.


Asset 13b-Plasma resizeda

Plasma: Can be derived from whole blood or apheresis collection. Plasma contains albumin, coagulation factors, fibrinolytic proteins, and immunoglobulins. Fresh frozen plasma (FFP) derived from whole blood is usually 220-300 mL and units derived from apheresis usually contain 400-600 mL. The plasma must be frozen within 8 hours of collection.



Cryoprecipitated Antihemophilic Factor (AHF): AHF is prepared from FFP. It is slowly thawed, then refrozen within one hour of thawing. AHF typically contains 5-20 mL of plasma with 80-120 U/concentrate of Factor VIII, 150-250 mg/concentrate of fibrinogen, 40-70% of vWF, and 20-30% of Factor XIII that would normally be present in FFP. Making it the treatment of choice for Von Willebrands Disease and Hemophiliacs.


Red Cells

Red cell transfusions are used to treat hemorrhage and to improve oxygen delivery to tissues. The decision to transfuse red cells should be based on the patients clinical condition. Indications for red cell transfusion include acute sickle cell crisis, acute blood loss of greater than 30% of blood volume, or patients with symptomatic anemia that can’t function without red cell repleting. The threshold for transfusion of red cells should be a hemoglobin of 7 g/dL in adults and children. Maintenance can be at a level of >7-9 g/dL.  One unit of red cells should increase the hemoglobin by 1 g/dL and hematocrit by 3%.

Washed Red Cells

Washed red cells are washed with saline to remove any residual plasma proteins. These are used for patients with a history of allergic transfusion reactions. These patients have an IgA deficiency and have developed anti-IgA.

Leukocyte Reduced

Leukocyte reduced red cells decrease the incidence of febrile transfusion reactions. They are indicated for those at high risk of transfusion-associated GVHD or transfusion-related immune suppression. For a unit to be considered leukocyte reduced, there must be less than 5×10^6 leukocytes.

Irradiated Red Cells

Used for patients with a history of febrile transfusion reactions or patients that are immunocompromised immediately after an allogeneic bone marrow or stem cell transplant. Patients at risk for HLA-GVHD will receive irradiated red cells.


Plasma transfusion are recommended for patients with active bleeding and an international normalized ratio (INR) greater than 1.6. Its indicated for patients on anticoagulant therapy that are undergoing an invasive procedure. Plasma should not be administered for a high INR without active bleeding. Plasma is indicated for patients with inherited clotting factor deficiencies for which there is no safe recombinant factor available. Those factors are II, V, X, and XI. Plasma is used as an emergent reversal of warfarin (coumadin) toxicity to prevent intracranial hemorrhage. It is also used in acute disseminated intravascular coagulation (DIC) or other thrombotic microangiopathies such as thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS). Plasma is often times transfused with red cells during massive transfusions; with the definition of massive transfusion being greater than 5,000 mL in an adult of average weight (70 kg).


Platelet transfusions are indicated to prevent hemorrhage in patients with thrombocytopenia or those with functional platelet defects. Contradictions for platelet therapy are patients with TTP and heparin-induced thrombocytopenia (HIT) as transfusion in these clinical situations can result in exacerbation of thrombosis. Platelet transfusions can be used prophylactically in invasive surgeries with no active bleeding and commonly used in active bleeding situations along with transfusion of FFP and red cells. One unit of apheresis platelets should increase the platelet count in adults by 30-60×10^9/L.

Transfusion of neonates is complicated and should be based on upon clinical reasons with consideration to the platelet count. If the count is <20×10^3/mL, you should always transfuse if possible. When you reach 20-30×10^3/mL you should consider transfusion, but weigh all possibilities. In a case of active bleeding, transfusion is absolutely appropriate, but all factors should be considered. Transfusion is also indicated in there is signs of a coagulation disorder, intraventricular or intraparenchymal cerebral hemorrhage, an invasive procedure, or if there is alloimmune neonatal thrombocytopenia.

Cryoprecipitate AHF

Cryo contains high concentrations of factor VIII and fibrinogen and is used especially in cases of hypofibrinogenemia. Hypofibrinogenemia is typically seen in the setting of massive hemorrhage or in a consumptive coagulopathy such as DIC. Indications for cyroprecipitate AHF are factor VIII and factor XIII deficiency, congenital fibrinogen deficiency, and von Willebrand disease.



Granulocyte Pheresis

Indicated for patients with fever, neutropenia, septicemia or an antibiotic resistant bacterial infection.

















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.