Coagulopathic disorders quiz

To clot or not to clot? Coagulopathic disorders

By Kenichiro Yagi, BS, RVT, VTS (ECC, SAIM)

To clot, or not to clot? That is the question. The hemostatic system is a complex protective mechanism sealing off avenues of blood loss through the vascular system upon damage. While cessation of blood loss is vital in preventing subsequent anemia and eventual death, coagulation of the blood is normally controlled to maintain normal blood flow and minimize chances of thrombotic complications. This delicate balance and interaction of procoagulant and anticoagulant mechanisms is essential in the proper function of the hemostatic system. In emergency and critical care, dysfunctions of the hemostatic system lead to life-threatening situations through a variety of mechanisms.


Balance of forces

The hemostatic system consists of four intertwined forces in balance with each other: thrombosis, antithrombosis, fibrinolysis, and antifibrinolysis. Thrombosis is the process of clot formation through normal coagulation mechanisms. Platelets and coagulation factors (CF) leading to a hemostatic plug temporarily seal the site of vascular injury, and are fortified by a fibrin to form a platelet-fibrin meshwork known as a clot. Sealing of the injury prevents further blood loss, and allows healing mechanisms to permanently repair the injury. The coagulation process is initiated through exposure of tissue factor (TF) serving as a signal for initiation, leading to production of a small amount of thrombin. The thrombin generated causes activation of several CFs (V, VIII, and XI) and platelets leading to amplification of the signal. Factors and platelets activated in the amplification phase facilitate further propagation of coagulation through activation of a large amount of thrombin, which in turn is responsible for activating fibrin from fibrinogen allowing clot formation. Thrombosis requires local control, as uncontrolled clotting alters blood viscosity and flow and can cause microvascular or macrovascular thromboembolism. Antithrombosis is maintained through tissue factor inhibitors, platelet inhibitors, and antithrombin (inhibiting thrombin activity), limiting coagulation to locations requiring clot formation.

Once vascular injury is repaired, the clot is no longer needed. A clot that has formed typically protrudes into the lumen of a blood vessel, narrowing the diameter. The reduced diameter impairs blood flow, and clot removal is required for recanalization of vessels and restoration of normal flow. Fibrinolysis is provided by the enzyme plasmin, which cleaves fibrin and dissolves the clot. Plasminogen activators are responsible for the activation of plasminogen into plasmin. Fibrinolysis also requires local control, since uncontrolled fibrinolysis would dissolve clots as formation is attempted. Antifibrinolysis is locally provided through inhibition of plasmin activity or reduction of plasminogen activation, to allow the vessel sufficient time to heal while the clot is in place. Through an intricate balance by complicated mechanisms of regulation, the procoagulant forces of thrombosis and antifibrinolysis, and the anticoagulant forces of antithrombosis and fibrinolysis, govern hemostasis.


A patient can develop a pathologic inability to achieve hemostasis. Depending on the cause and severity, signs can be as subtle as petechiation (pin point bruising) and ecchymosis (larger bruising) on the mucous membrane or skin, or as severe as bleeding into third spaces (abdomen, pleural space, lungs, gastrointestinal tract, and cerebrospinal space). Clinical signs may be related to anemia (weakness, increased breathing effort, tachycardia, pale mucous membranes, and altered mentation). Organ systems affected secondarily to hemorrhaging will result in clinical signs related to the organ. Pulmonary or pleural space hemorrhaging will result in signs of respiratory compromise, while upper airway hemorrhaging (larynx, thymus, and soft tissues surrounding the airway) will result in signs of acute upper airway obstruction. Cerebral or intracranial hemorrhage can cause seizures, comas, and other central neurologic signs while epidural or subdural bleeding may lead to paresis or paralysis. Gastrointestinal hemorrhaging will result in melena or hematochezia. Abnormal platelet count or buccal mucosal bleeding time will be seen in platelet depletion (thrombocytopenia) or dysfunction (thrombopathia). Prolonged prothrombin time or partial thromboplastin time will be seen in coagulopathies related to CF depletion.

Anticoagulant rodenticide ingestion and toxicity is a commonly seen coagulopathy. Active forms of CFs II, VII, IX, and X are vitamin K1 (VitK1) dependent, since VitK1 provides these CFs the ability to use calcium as a co-factor in coagulation. In this process, VitK1 is oxidized to VitK1-epoxide. VitK1-epoxide is normally reduced back to active VitK1 by an enzyme, VitK-epoxide reductase, but the anticoagulant contained in rodenticides (warfarin, coumarin) inhibit the activity of this enzyme and lead to the depletion of active VitK1. Without VitK1, active forms of CFs are unable to be produced and eventually are exhausted, leading to a coagulopathy. The process of depletion of VitK1, and subsequent CF deficiency takes 3 to 5 days from ingestion. The treatment of bleeding due to this “vitamin K antagonism” is to administer VitK1 and CFs through plasma transfusions if bleeding is present, as achieving hemostatic levels of CFs takes 6-12 hours following VitK1 administration.

Many procoagulants, CFs, and anticoagulant proteins are synthesized by the liver (factors II, V, VII, IX, X, XI, XII, XIII, protein S, and protein C). Production of these proteins is affected in a variable manner in hepatic failure, leading to decreased level of both procoagulants and anticoagulants. However, hepatic failure typically results in clinical manifestation of hemorrhaging from depleted CFs. CFs with the shortest plasma half-lives will be depleted first. In some cases, hepatic dysfunction may cause production of dysfunctional proteins, as seen in defective fibrin formation from production of dysfunctional fibrinogen. Treatment is directed at the cause of hepatic disease and supplementation of CFs through plasma transfusions.

In cases of high volume fluid resuscitation or massive transfusions, a dilutional coagulopathy results from diluted concentration of procoagulants as the intravascular volume is replaced with fluid without CFs. Dilution results from fluid shift from the intracellular and interstitial space into the intravascular space in response to change in hydrostatic pressure during hypovolemia, and additional intravenous administration of crystalloids, synthetic colloids, or red blood cell products. With severe vascular injury (e.g. trauma), activation of coagulation and consumption of CFs and platelets contribute to a reduction in available procoagulants. If blood products are used, citrate-induced hypocalcemia and hypothermia can lead to further exacerbation. Simultaneous administration of fresh frozen plasma and platelets along with red blood cells in massive transfusions have been observed to increase survival in humans, presumably due to replacement of CFs and platelets leading to a less severe dilutional effect.

There are many more acquired coagulopathies aside from those highlighted above. The increase in circulating inflammatory mediators triggers coagulation within vessels without vascular injury. This creates a significant demand on CFs in disseminated intravascular coagulation, leading to a consumptive coagulopathy. Snake envenomation can cause CF depletion and defibrination through proteases contained within the venom activating clotting factors or directly degrading available fibrinogen. Neoplasia can cause fibrinolysis to become hyperactive, preventing normal clot formation. Overdosing of anticoagulants like heparin and hirudin aid antithrombin function, inhibiting thrombosis. Various causes of platelet depletion and dysfunction will lead to surface bleeding disorders.

Hemostasis is a complex system involving proper coagulation, anticoagulation, fibrinolysis, and antifibrinolysis occurring in a fine balance. Disruption of these forces will result in hemorrhagic coagulopathies or thromboembolic consequences. As veterinary technicians, having thorough knowledge of risk factors and the progression of hemostatic disorders will allow us to minimize negative consequences. With potential clinical manifestations in mind, the improved ability to recognize consequences of hemostatic dysfunction will allow swift and appropriate action.

This article is based on Mr. Yagi’s presentation at the IVECCS Conference in San Diego, CA.CVT