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Disorders of coagulation (Proceedings)

Article

The primary hemostatic system alone is not sufficient to provide hemostasis if a large vessel is injured, or if there is significant vascular wall injury. Fibrin needs to be generated in order to form a stable clot, and this occurs through secondary hemostasis, or the coagulation cascade.

The primary hemostatic system alone is not sufficient to provide hemostasis if a large vessel is injured, or if there is significant vascular wall injury. Fibrin needs to be generated in order to form a stable clot, and this occurs through secondary hemostasis, or the coagulation cascade.

The extrinsic coagulation cascade is triggered when tissue factor (TF) is exposed. TF activates factor VII to make FVIIa, which then activates factors VIII, IX, and X. A small amount of thrombin is generated through this process, and this in turn activates the intrinsic cascade by activating factors XI, IX, and VIII. Through this circular process enough thrombin is generated to make fibrin from fibrinogen and to stabilize the clot. This process is controlled by both anticoagulants and fibrinolytics, preventing vessel closure or uncontrolled coagulation from occurring.

Most of the coagulation proteins are created in the liver, and factors II, VII, IX, and X require carboxylation in order to function (a vitamin K-dependent process). Therefore, hepatic dysfunction, vitamin K deficits or antagonism, or congenital or acquired factor deficiencies can lead to compromise of the secondary hemostatic system.

Diagnosing Disorders of Secondary Hemostasis

Disorders of secondary hemostasis often result in hematomas or cavitary hemorrhage, however gastrointestinal, respiratory and other hemorrhage may occur. Common presentations include hemoarthrosis, hemomediastinum, hemoperitoneum, hemothorax, and/or hematomas. Early cases may go undetected, as spontaneous hemorrhage does not occur until approximately 70% of clotting factors are gone. The patient should be examined carefully for signs of underlying disease.

Diagnostic tests for hemostatic disorders should be well understood by the clinician. If the disorder is primarily of the secondary hemostatic system, platelet count and function tests, vWF analysis and buccal mucosal bleeding time would all be expected to be normal. Keep in mind that with significant hemorrhage secondary to a secondary hemostatic disorder, platelet count may be decreased secondary to consumption. It is important to distinguish thrombocytopenia secondary to hemorrhage from thrombocytopenia as the primary cause of hemorrhage. Generally, platelet count must drop below 40,000/µl before bleeding occurs, and it often must drop below 10-20,000/µl before there is significant hemorrhage. It is very rare for platelet count to drop this low secondary to consumption. Therefore, if the platelet count is greater than 30-40,000/µl in a hemorrhaging patient, it is likely a consumptive process and not the primary problem.

Specific tests for secondary hemostasis should be run to narrow down the area along the coagulation cascade that is affected. Many of these tests are now available in-house using citrated whole blood. The prothrombin time (PT) and the Protein Induced by Vitamin K Antagonism (PIVKA) are both used to evaluate the extrinsic and common pathway. There is very little difference in these tests, and the PIVKA is not specific for rodenticide poisoning, so the PT is sufficient and is the recommended test at this time to evaluate the extrinsic and common pathways.

The activated Partial Thromboplastin Time (aPTT) and Activated Clotting Time (ACT) both test the intrinsic and common pathways. The aPTT is more sensitive than the ACT, and its increasing availability as an in-house test makes the aPTT the test of choice when evaluating the intrinsic system. The ACT can also be prolonged with severe thrombocytopenia.

The Thrombin Time (TT) specifically assesses the conversion of fibrinogen to fibrin, so this test is prolonged in situations of fibrinogen deficiencies (hepatic disease, consumption, inherited).

To further narrow down the deficiency, specific factor analyses can be performed. There are also DNA tests available for specific mutations that have been identified for several inherited coagulopathies.

Therapy for Disorders of Secondary Hemostasis

Patients with coagulopathies should be handled gently, and all invasive procedures (surgery, percutaneous biopsies) should be avoided until coagulation times are normal. Careful local hemostasis should be used for external bleeding. Any triggers identified that may be causing the coagulopathy (rodenticide, warfarin, heparin) should be removed.

Specific therapy should be instituted when necessary. Vitamin K should be started for patients with anticoagulant rodenticide toxicity or vitamin K deficiency. Heparin overdoses should be reversed with protamine sulfate. Another specific therapy that is currently being studied in dogs is recombinant factor VIIa for dogs (Beagles) with a hereditary factor VII deficiency. This drug is extremely expensive, and safety and efficacy are still not established in dogs.

In patients who have lost a large quantity of blood, therapy should be instituted for hypovolemia and anemia. If volume is needed, crystalloids may be preferred over colloids, as colloids may adversely affect hemostasis further. The anemia can be corrected using packed red blood cells or whole blood transfusions. Fresh frozen plasma is a good choice for any of the coagulopathies and should be dosed at 10ml/kg with repeat transfusions as needed until clotting times are corrected and bleeding has ceased. For cases of vitamin K deficiency or antagonism, cryo-poor plasma or frozen plasma may be used as well and is often a cheaper option. In cases of hemophilia A and von Willebrand disease cryoprecipitate is the best product. When blood components are not available, fresh whole blood can be transfused, but larger volumes must be given to correct the coagulation deficit, so it is important to watch for fluid overload.

Specific Disorders of Secondary Hemostasis

• Acquired Disorders

        o Disseminated Intravascular Coagulation

• Vitamin K deficiency or antagonism (anticoagulant rodenticide toxicity, malabsorptive diseases)

        o Drug Toxicity (heparin, warfarin)

        o Dilutional Coagulopathy

        o Liver failure

• Inherited Disorders

        o Hemophilia A (Factor XIII deficiency, dogs)

        o Hemophilia B (Factor IX deficiency, dogs)

        o Factor I (fibrinogen deficiency) deficiency (dogs)

        o Factor II (prothrombin) deficiency (rare, dogs)

        o Factor VII deficiency (dogs and DSH cats)

        o Factor X deficiency (rare, dogs and DSH cats)

        o Factor XI deficiency (common in cattle, rare in dogs)

• Factor XII (Hageman Factor) deficiency (common in cats, does not result in bleeding disorder)

        o Multiple Factor Deficiency (very rare, Devon Rex)

Anticoagulant Rodenticide Toxicity

This is one of the most common toxicities of dogs, due the easy availability and widespread use of this toxin as well as its appealing taste. Cats rarely directly eat the toxin, but they can become ill by eating a rat or mouse that has ingested rodenticide. These patients can either present directly after owner-witnessed ingestion of the toxin, or they may present days later with symptoms of toxicity.

Anticoagulant rodenticides work by antagonizing the effects of vitamin K, thereby interfering with the carboxylation of factors II, VII, IX, and X, rendering them inactive. There are multiple generations of these rodenticides, differing in that each successive generation has longer lasting effects. Warfarin has only a 1-week anticoagulant effect. Second generation rodenticides (diphacinone, pindone, bromadiolone, and brodifacoum) often last at least a month. If the type is unknown, always assume it is a long acting variety and treat and monitor closely for at least a month.

Diagnosis

It is common for owners to either witness the ingestion or notice the chewed up bag of rodenticide. If the incident is unwitnessed, owners should be questioned carefully about access to rodenticide or unsupervised time where an animal may have hunted rodents or wandered into a neighbor's yard and found the toxin. A young, healthy animal that presents with signs of a coagulopathy and no underlying condition or history of previous bleeding problems or familial bleeding disorders should be assumed rodenticide toxicities and treated as such until proven otherwise.

The toxin generally takes a few days to a week to prolong PT and PTT enough to be detectible, so witnessed ingestion patients will often have normal clotting times. It is not a bad idea to still run these tests in order to have baseline numbers and assure that there isn't an underlying coagulation disorder or ingestion that took place earlier than the witnessed event. Samples should be drawn prior to beginning vitamin K therapy.

Treatment

In witnessed cases, if the ingestion occurred within 3 hours of presentation, or if the ingestion time is unknown, emesis should be induced and activated charcoal administered. A recent study showed that decontamination alone prevented clinical signs in most untreated dogs with witnessed ingestion. The owners can be given a choice at this point to go ahead and institute vitamin K therapy or to return in 2-3 days to have the PT repeated. Of the factors affected by vitamin K antagonism, factor VII has the shortest 1/2-life and is first to be inhibited. Therefore, the PT alone should be sufficient to get a diagnosis. If the PT is prolonged at that time, vitamin K therapy should be instituted. Some owners will choose to start prophylactic vitamin K therapy instead of returning in a few days.

Vitamin K1 is the proper formulation to use for treatment. If treating parenterally it should be given subcutaneously, as intravenous administration may cause anaphylaxis. The parenteral dose is 2.2 - 5mg/kg. For long-term therapy, oral vitamin K1 should be instituted at 2.2mg/kg q 12 hours for up to 6 weeks. The dose can be tapered down slowly to 1mg/kg q 48 hours by week 6 to save money. Alternatively, the therapy can be instituted for 3-4 weeks, and then the PT rechecked two days after discontinuing the treatment. If it is still prolonged, therapy should be reinstituted for two more weeks. It is recommended to repeat the PT two days after finishing the vitamin K therapy.

If the patient is actively bleeding at presentation, vitamin K therapy should be started immediately, and the patient should be hospitalized for observation and possible transfusion therapy. Transfusion therapy is indicated if the patient has respiratory tract or CNS involvement, or if the bleeding is severe and the hematocrit dropping rapidly. Fresh frozen plasma, frozen plasma, or cryo-poor plasma (10ml/kg) will supply the needed clotting factors. These should be repeated along with vitamin K therapy, until the bleeding has stopped and bleeding times are normal. If the patient has lost a large quantity of blood, whole blood can be substituted to supply red blood cells as well as clotting factors.

Thoracocentesis to remove blood should not be performed on these patients who present with hemothorax unless absolutely necessary to aid breathing. If this is the case, vitamin K should be given parenterally and a plasma transfusion started immediately prior to thoracocentesis.

Prognosis is generally very good as long as the diagnosis is made and proper therapy instituted. It is very important that the clinician have a high index of suspicion for anticoagulant rodenticide in any unexplained spontaneously hemorrhaging patient so that early diagnosis and therapy can be instituted.

Disseminated Intravascular Coagulation

Disseminated Intravascular Coagulation (DIC) is actually a dysfunction of both primary and secondary hemostasis, but it will be covered under this lecture. DIC is a syndrome characterized by activation of systemic intravascular coagulation leading to the formation of microthrombi and eventually consumption of platelets and coagulation factors. Several diseases and clinical conditions have been associated with DIC, including sepsis, neoplasia (hemangiosarcoma), severe trauma, pancreatitis, immune-mediated hemolytic anemia, and gastric dilatation-volvulus.

The pathogenesis is based on an imbalance between the procoagulant and anticoagulant systems of the vasculature. Inflammation is closely tied in with coagulation, so systemic or severe localized inflammation can set off the coagulation system, leading to consumption of anticoagulants and production of microthrombi. These microthrombi can become emboli and lodge in small vessels, leading to ischemic damage to organs (kidneys, lungs). Eventually, the massive systemic coagulation leads to consumption of the body's available platelets and coagulation factors, and an anticoagulant bleeding diathesis can occur.

Clinical signs may be related to ischemic organ damage from microthrombi, including oliguria or dyspnea, or the first signs may be evidence of hemorrhage. This can occur as cutaneous bleeding, petechiae and ecchymoses, GI hemorrhage, bleeding from puncture sites and wounds, or bleeding into body cavities.

DIC should be suspected if there is an underlying disease or condition present that may lead to systemic inflammation. Screening coagulation tests may be normal or only mildly abnormal in the early phases, but as the disease progresses, platelet count will be low, BMBT, PT, ACT, and aPTT will be prolonged, and fibrin degradation products (FDP's) and D-dimer will be elevated.

Therapy should be aimed at treatment for the underlying disease in order to stop the pro-coagulant stimulation. Microcirculatory blood flow may be stimulated by intravenous fluid therapy for volume expansion to open narrowed or closed capillaries. Specific therapy usually involves replacing the consumed coagulation and anticoagulant components. Fresh frozen plasma contains coagulation proteins as well as Antithrombin III and other anti-coagulants that are consumed in the process. Fresh whole blood transfusions may be used instead if massive blood loss has occurred. Treatment with anticoagulants, such as heparin (150 IU/kg Sq TID), might be considered if the systemic process is still ongoing, however this is controversial.

Prognosis for DIC depends on timing of diagnosis and treatment, severity of underlying disease, and severity of organ ischemic injury. The clinician should maintain a high index of suspicion that DIC may occur when a patient presents with a predisposing condition. Close hemostatic monitoring and efforts to treat the underlying condition while maintaining normal blood volume and perfusion can help prevent the onset of DIC and improve outcome.

Conclusion

The clinician should have a good understanding of the pathophysiology of bleeding disorders, clinical signs, and diagnostic tests. Treatment should be aimed at the underlying cause as well as stopping any ongoing hemorrhage by replacing deficient clotting factors as needed.

References available by request

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