CHAPTER 9 Andrew Linklater Lakeshore Veterinary Specialists, Milwaukee, Wisconsin Coagulation is the ever‐present dynamic process of changing liquid blood into a semisolid mass (clot) within the vasculature. The coagulation process is accomplished by interactions of a combination of platelets, activated serine proteases, tissue factor (TF), TF‐bearing cells, cell membrane receptors, and natural anticoagulants; the end result is a platelet‐fibrin clot. The traditional cascade model of fibrin formation exhibited a sequential activation of the coagulation proteins initiated through extrinsic (outside the bloodstream) and intrinsic (within the bloodstream) pathways (Figure 9.1a). Figure 9.1(a) The cascade model of fibrin formation. This model divides the coagulation system into separate redundant pathways (extrinsic and intrinsic), either of which can result in generation of FXa. The common pathway results in generation of thrombin and subsequent cleavage of fibrinogen to fibrin. Many of the enzyme and enzymatic complexes require calcium (Ca2+) and binding to active membrane surfaces (PL) for full activity. For simplicity, feedback activation of pro‐co‐factors to co‐factors and the many inhibitors of the various enzymes have been omitted. Fb, fibrin: Fg, fibrinogen; HMWK, high molecular weight kininogen; K, kallikrein; PK, prekallikrein; PL, phospholipid membrane. Source: Reproduced with permission from Smith SA. J Vet Emerg Crit Care 2009;19(1):3–10. Research has shown that these two cascading pathways are intricately linked and that platelets and other cellular components of the blood are integral parts of the coagulation process. A cell‐based model of coagulation has evolved (Figure 9.1b) which incorporates three overlapping phases of coagulation: initiation, amplification, and propagation. This new model of understanding coagulation emphasizes the role of cells (particularly TF‐bearing cells and platelets) along with coagulation factors to accomplish coagulation and has gained prominence. Natural endogenous anticoagulant mechanisms are also present and important in regulating clot formation and fibrinolysis; the anticoagulants are found in blood and on endothelial cells, the endothelial glycocalyx, and platelets. Figure 9.1(b) The cell‐based model of fibrin formation. This model incorporates the contribution of various cell surfaces to fibrin formation. In this model, thrombin generation occurs in overlapping phases. (1) Initiation phase. This phase occurs on the TF‐bearing cell. It is initiated when injury exposes the TF‐bearing cell to the flowing blood. It results in the generation of a small amount of FIXa and thrombin that diffuse away from the surface of the TF‐bearing cell to the platelet. (2) Amplification phase. In the second phase, the small amount of thrombin generated on the TF‐bearing cell activates platelets, releases vWF and leads to generation of activated forms of FV, FVIII, and FXI. (3) Propagation phase. In the third phase the various enzymes generated in earlier phases assemble on the procoagulant membrane surface of the activated platelet to form intrinsic tenase, resulting in FXa generation on the platelet surface. Prothrombinase complex forms and results in a burst of thrombin generation directly on the platelet. AT, antithrombin; TF, tissue factor; TFPI, tissue factor pathway inhibitor; vWF, von Willebrand factor. Source: Reproduced with permission from Smith SA. J Vet Emerg Crit Care 2009;19(1):3–10. Evidence indicates that one of the key initiators of coagulation in vivo is TF [1]. In normal conditions, cells expressing TF are primarily localized outside the vasculature. Some circulating cells (such as monocytes) and circulating microparticles can express inactive or encrypted TF on their membrane surfaces. Microparticles arise from the plasma membrane of endothelial cells, platelets, and monocytes during normal cell activation, programmed cell death or exposure to shear stress [1]. Alterations in coagulation and anticoagulation can occur in critically ill animals as part of the presenting illness or can develop as a complication of the underlying disease process. When disease causes cells to be activated or injured, a calcium‐mediated reaction occurs which brings procoagulant receptors to the cell surface. This process can markedly increase the speed of some coagulation reactions. Cytokines, thrombin, shear stress, and hypoxia can stimulate the formation of additional microparticles from granulocytes and erythrocytes that can stimulate coagulation. The resultant clot formation and eventual fibrinolysis can occur at local sites of injury or at distant sites unrelated to the initial injury in these patients. Thrombosis or a consumptive coagulopathy are potentially life‐threatening consequences that can cause organ ischemia or uncontrolled hemorrhage, respectively. Hemorrhage can also occur as a result of insufficient production of coagulation proteins or alterations in platelet numbers due to peripheral destruction, consumption, or lack of production with bone marrow disease. While less common, hereditary coagulation factor deficiencies or a disruption in the fibrinolytic process may negatively impact the critically ill patient as well. While all ICU patients deserve to be monitored for a coagulation disorder, a high priority is set for patients that have experienced a potential trigger for systemic coagulation, such as prolonged capillary stasis, severe hypoxia or hypotension, massive tissue damage, and systemic inflammatory response syndrome (SIRS). A list of disease processes known to be associated with coagulopathies is presented in Box 9.1. In addition to the underlying disease process, fluid infusion and a variety of drugs administered as part of the treatment plan can interfere with normal coagulation. It is important to recognize the potential for a coagulation disorder in the ICU patient and to be prepared to intervene. Evaluation of the ICU patient for coagulation disorders begins by reviewing the patient history and assessing the physical examination findings. Early diagnosis of coagulation abnormalities depends in part on identifying changes with regular physical examinations and point of care (POC) testing; monitoring trends of change over time (rather than any single value) on POC testing and correlating those diagnostics with physical exam findings is vital. A definitive diagnosis may require additional clinicopathological testing that is not immediately available. Therapeutic intervention may be necessary while test results are pending. Monitoring the patient’s response to treatment is important and contributes to the diagnostic evaluation. The end goal is to avoid an unexpected hemorrhagic or thrombotic crisis. The signalment (age, sex, and breed) is important to assess for potential predilections to coagulopathies. Past medical problems, preventative care, transfusion history, postoperative bleeding, and current medications are all important. The environment is investigated relating to exposure to ticks, toxins, and infectious diseases. Any illness in other animals in the household or related pets may help detect toxic or inherited disorders. Specific physical examination findings that can reflect an alteration in coagulation status are listed in Table 9.1. Studies in animals have found that hemorrhage identified at more than one site is indicative of a hypocoagulable state [2]. Extremes in body temperature may alter coagulation; hyperthermia (>106 °F, >41 °C) permanently alters coagulation factors and prolonged hypothermia (<94 °F, <34 °C) prolongs clotting time. Table 9.1 Physical examination findings associated with coagulation disorders. These physical exam alterations can serve as a trigger to evaluate coagulation, an indication of ongoing hypocoagulation (bleeding) or hypercoagulation (thrombosis). Poor perfusion may be a cause of coagulation abnormalities or occur as a consequence of thrombosis or significant hemorrhage. The findings of a heart murmur, arrhythmia, gallop sounds or muffled heart sounds can be a consequence of volume loss, anemia, pericardial effusion or other cardiac disease. Intrapulmonary thrombosis or hemorrhage can cause tachypnea, labored breathing, altered lung sounds, and hypoxemia. Oropharyngeal hematomas and tracheal mucosal hemorrhage can manifest as stertorous breathing. Intraabdominal hemorrhage may distend the abdominal cavity and results in a fluid wave on abdominal palpation when blood loss is >40 mL/kg [3]. Red blood found on rectal examination suggests lower gastrointestinal (GI) bleeding while melena is typically due to upper GI bleeding. The eyes (anterior chamber, retina, and sclera), mouth, and nasal cavity may reveal signs of occult bleeding in the form of hyphema, gingival bleeding or epistaxis, respectively. The integument and mucous membranes (oral and genital) are carefully examined for ecchymosis (Figure 9.2) and petechiae (Figure 9.3). Skin bruising should be outlined with nontoxic permanent marker to monitor progression or resolution. Figure 9.2 Ecchymotic hemorrhage on the ventral abdomen of a dog with a coagulopathy. Figure 9.3 Buccal petechiae of a dog with a platelet disorder. Clinical signs of a hypercoagulable state, causing central or peripheral thrombosis, will vary depending on the location and degree of obstruction to blood flow. Cats presenting with feline aortic thromboembolism (FATE) will demonstrate paresis or paralysis of one or more limbs. The right forelimb or both hindlimbs are most commonly affected. There will be decreased or absent pulses, often a lowered rectal temperature and discoloration of the paw pads on the affected limb (Figures 9.4 and 9.5) and significant pain. Figure 9.4 A cat with aortic thromboembolism (FATE) secondary to heart disease. Note the pale color of the hindlimb pads (bottom) compared to the forelimb pads (top). Figure 9.5 A cat with unilateral (right) hindlimb venous thrombosis secondary to neoplasia. Note the cyanotic discoloration to the pads and the swelling of the foot. Problems resulting from thrombosis of blood vessels supplying major internal organs can cause clinical signs compatible with gastrointestinal dysfunction, acute renal failure, severe abdominal pain, and poor perfusion (shock). Altered mentation, seizures, stupor, coma, and paresis or paralysis are signs compatible with thrombosis or hemorrhage within the central nervous system (see Chapter 12). Proper sample collection is mandatory for accurate results (Box 9.2). It is important to remember that in vitro coagulation testing may not accurately reflect the exact status of in vivo coagulation [4]. Any therapeutic decisions based on coagulation test results must also take into consideration the primary diagnosis, current health status, and anticipated procedures. Clinicopathologcal testing of hemostasis begins at the cage side (point of care testing). Point of care testing can provide a rapid impression of the quantity and function of the cells and proteins required for clotting. A list of POC tests to initially assess coagulation is provided in Table 9.2. Table 9.2 Point of care coagulation tests and normal values. *Individual laboratory normal values may be different. ACT, activated clotting time; aPTT, activated partial thromboplastin time; BMBT, buccal mucosal bleeding time; C, cat; D, dog; PCV, packed cell volume; PT, prothrombin time. The minimal database will include packed cell volume (PCV), total protein (TP), blood glucose, blood urea nitrogen (BUN), electrolytes, blood gas (venous or arterial), and blood lactate. A normal or even elevated PCV with a disproportionate decrease in TP may be a reflection of acute hemorrhage in the dog, as the PCV is preserved through splenic contraction. The PCV and TP will both eventually decline after hemorrhage, particularly with fluid resuscitation. Icteric serum warrants concern for hepatic disease or red cell hemolysis, both with potential to cause a coagulopathy. Blood in the gastrointestinal tract can elevate the BUN when there is normal renal function. A low BUN can direct diagnostics for liver dysfunction. Calcium is an important component of the coagulation process and hypocalcemia is a potential cause of prolonged clotting times and bleeding. The detrimental effects of acidosis on coagulation include depleted fibrinogen levels and platelet counts, prolonged clotting times, and increased bleeding times. Monitoring lactate levels can provide a measure of restoration of oxygenation to tissue beds affected by significant hemorrhage or thrombosis. A thin, even blood smear with a monolayer is part of the minimum database to evaluate red blood cell (RBC) and platelet morphology and to estimate the platelet count. The presence of spherocytes, schistocytes or dacrocytes suggests RBC destruction. Reticulocytes, polychromasia and nucleated RBCs (nRBCs) are compatible with regeneration; nRBCs are also seen with heatstroke and other critical illness. A manual platelet estimate should be performed (Box 9.3). The feathered edge of the blood smear is examined for platelet clumping and platelet morphology. Large platelets suggest young platelets while small platelets may be seen with immune‐mediated thrombocytopenia (ITP) [6]. A declining trend in platelet numbers may provide the earliest indication of a coagulation disorder involving both the primary (platelets) and secondary (serine proteases) hemostatic mechanisms. A moderate reduction in platelet count (50 000–150 000/uL) can occur associated with a variety of underlying diseases (Table 9.3) and commonly reflects increased platelet consumption, dilution or sequestration. Following a trend in the platelet count over time can help detect ongoing consumptive processes such as disseminated intravascular coagulation (DIC). Patients are typically at risk for spontaneous hemorrhage when platelet numbers are less than 30 000–50 000/uL. Table 9.3 Differential diagnoses for causes of platelet disorders. FeLV, feline leukemia virus; FIV, feline immundeficiency virus; GI, gastrointestinal; IMHA, immune‐mediated hemolytic anemia; ITP, immune‐mediated thrombocytopenia. Buccal mucosal bleeding time (BMBT) is a method of evaluating in vivo primary hemostasis. The test uses a cartridge to create a standard size incision on the buccal mucosal surface to determine the time required for cessation of capillary bleeding. It should not be run if the platelet count is low. The steps to perform BMBT are noted in Box 9.4. Prolonged BMBT (see Table 9.2) found with normal platelet count suggests von Willebrand’s disease or other abnormal platelet function. Factors such as operator error and extreme abnormalities in hematocrit can alter the bleeding time. The BMBT can also be used to monitor patients receiving antiplatelet drugs (such as aspirin or clopidogrel) to assess the effect of the drug on platelet function [7]. Unfortunately, BMBT is a poor predictor of surgical bleeding [8]. Determination of the prothrombin time (PT), activated partial thromboplastin time (aPTT), and activated clotting time (ACT) can be done through POC testing. Normal values for these tests are listed in Table 9.2. The PT reflects both the function and quantity of the coagulation factors in the extrinsic (factor VII) and common (factors I, II, V, and X) coagulation pathways (see Figure 9.1a). Potential causes of prolongation of PT are listed in Table 9.4. A substantial decrease ( >70%) of one or more of these clotting factors is needed for the PT to be prolonged. Prothrombin time is often the first coagulation test altered when there is a consumptive coagulopathy, inadequate production of coagulation proteins or rodenticide toxicity. This is because factor VII has the shortest half‐life, and formation of TF receptor complex, which activates factor VII, is stimulated by circulating cytokines (inflammatory proteins) commonly found in critically ill animals. The PT is used to monitor the effectiveness of anticoagulant drugs such as coumadin, with the therapeutic goal of prolonging the PT 1.5–2.5 times beyond the pretreatment value. A shortened time for the PT result is not significant and more likely represents a collection or lab error; it does not represent a hypercoagulable state. Table 9.4 Assessment of PT and aPTT in small animal ICU patients. aPTT, activated partial thromboplastin time; BMBT, buccal mucosal bleeding time; CBC, complete blood count; DIC, disseminated intravascular coagulation; FDP, fibrin degradation product; PT, prothrombin time; SIRS, systemic inflammatory response syndrome; TEG, thermoelastography. The aPTT reflects the function and quantity of coagulation factors in the intrinsic (factors VIII, IX, XI, XII) and common (factors I, II, V, X) coagulation pathways (see Figure 9.1a). Similar to PT, the aPTT becomes prolonged when there is a functional or quantitative decrease of >70% of one or more of these coagulation factors. A list of possible causes of prolonged aPTT is provided in Table 9.4. It is important to note that prolonged aPTT in dogs that have sustained trauma has been correlated with nonsurvival [9]. Patients receiving heparin therapy can be monitored using aPTT, with the goal of increasing the aPTT by 1.5–2 times the pretreatment value. A shortened aPTT is not significant and more likely to represent a collection or lab error; it does not represent a hypercoagulable state. PT and aPTT testing do require specialized equipment, but are widely available and affordable, making other clotting parameters less utilized [10]. The activated clotting time (ACT) tests the coagulation factors of the intrinsic and common pathways. While similar to the aPTT, it is less sensitive; a functional or quantitative decrease in coagulation factors of >90% is required to prolong the ACT. The ACT, however, can be tested with minimal equipment, making it an option for clinics that do not have PT and aPTT testing available. The ACT test only requires appropriate tubes with diatomaceous earth and a heating block or water bath kept at 98 °F (37 °C). An i‐STAT® cartridge (Abbott, Princeton, NJ) that runs a kaolin‐based ACT test is also available. The results of coagulation testing should always be interpreted with the clinical picture of the patient (signs of blood loss, PCV/TP, etc,). If an intervention is deemed necessary (transfusions, vitamin K, etc.), it is appropriate to recheck these values to ensure the therapeutic benefit has been achieved. The complete blood count (CBC), serum biochemistry, and urinalysis provide important information for detecting metabolic or physical problems that can cause or be caused by a coagulation disorder. A high white blood cell count with a left shift can be compatible with inflammation or infection and warrants further patient evaluation for a SIRS disease. Red blood cell hemolysis sets the stage for intravascular coagulation. Significant elevations in RBC count or serum proteins can have a negative effect on capillary rheology, contributing to capillary status and intravascular coagulation. Blood testing for Dirofilaria, hyperthyroidism, hyperadrenocorticism, and tick‐borne disease may be necessary in select patients. Radiographs or ultrasound of the chest, and possibly echocardiography, may be necessary to evaluate for neoplasia, abscesses, fluid in the pericardial or pleural space, heart size and function, pulmonary parenchymal fluid or hemorrhage, size and prominence of pulmonary vasculature and any evidence of heartworm disease. Radiographs and ultrasound of the abdomen can identify abdominal fluid, masses, organ enlargement or displacement, infiltrative disease, and gastrointestinal changes. Animals with a compatible history can be quickly evaluated for free abdominal and thoracic fluid with the focused assessment with sonography techniques [11]. The presence of free fluid warrants centesis for fluid evaluation. Advanced imaging techniques (Table 9.5) are required for detection of intravascular clots. Echocardiography can be used to demonstrate echogenic thrombi in the heart and large vessels. Ultrasound can demonstrate echogenic thrombi in abdominal and peripheral vasculature (Figure 9.6). Intravenous contrast angiography may be used with computed tomography (CT) or fluoroscopy to indirectly visualize thrombi. Contrast administration can be contraindicated in patients with renal injury. Ventilation/perfusion scans (scintigraphy) use radioisotopes to aid in the diagnosis of large pulmonary thromboemboli. Table 9.5 Advanced clinicopathological testing and imaging to define coagulation status. *Reference values and collection methods will vary depending on species, methodology, and laboratory used. aPTT, activated partial thromboplastin time; BMBT, buccal mucosal bleeding time; C, cat; CBC, complete blood count; D, dog; DIC, disseminated intravascular coagulation; ELISA, enzyme‐linked immunosorbent assay; FAST, focused assessment with sonography for trauma; FDP, fibrin degradation products; GI, gastrointestinal; IFA, immunofluorescence assay; INR, international normalized ratio; ITP, immune‐mediated thrombocytopenia; LMWH, low molecular weight heparin; PIVKA, protein induced in vitamin K absence/antagonism; PT, prothrombin time; SIRS, systemic inflammatory response syndrome; TEG, thromboelastography; TFAST, thoracic FAST; UH, unfractionated heparin; vWD, von Willebrand. Figure 9.6 Ultrasound image showing an echogenic thrombus in a large vessel, outlined by measurement points. Information from these tests is used to further direct diagnostic and monitoring procedures. Patients with concern for pulmonary thrombosis should have their ability to oxygenate monitored via pulse oximetry, co‐oximetry or arterial blood gas. Indirect evidence of reperfusion injury (history, hyperkalemia, hyperphosphatemia) can warrant monitoring for cardiac arrhythmias or renal failure. Cats with evidence of thrombosis warrant echocardiographic evaluation of the heart, systemic blood pressure measurement, thoracic radiographs, and thyroid function testing. Advanced coagulation testing may be necessary to better define the presence of a coagulopathy, determine the inciting cause, and direct therapy that is specific for the patient. While POC evaluation of a patient with a coagulopathy remains necessary in the emergency setting, additional diagnostics may be necessary in the critically ill for further assessment, definitive diagnosis, and even specific intervention. Many of the tests discussed are not available at many emergency hospitals, require specialized or expensive equipment or do not have established points of intervention. Advanced techniques for assessing platelet function and factors, coagulation protein quantity and function, clot formation, clot dissolution, and natural anticoagulant components are gaining momentum and accessibility in veterinary medicine. Normal values and how to interpret abnormalities revealed through advanced coagulation testing are provided in Table 9.5. Platelets are identified as having three functions with respect to coagulation: control of thrombin generation, support of fibrin formation, and regulation of fibrin clot retraction. Platelet function analyzers evaluate the ability of the platelet to aggregate and form a platelet plug. There is less operator variability with these tests compared to BMBT. The PFA‐100® (Siemens, Malvern, PA) (see Table 9.5) monitors blood flow through an aperture, which stimulates platelet function, as it is coated with epinephrine or collagen. The “closure time” is the length of time for cessation of blood flow through the aperture due to platelet plug formation. The VerifyNow® (Accriva Diagnostics, San Diego, CA) measures light transmittance through a fibrinogen‐coated bead bed that initiates platelet aggregation. This instrument is more commonly used to assess the therapeutic response to platelet inhibitory drugs rather than for diagnosis of a clinical thrombocytopathy. Platelet flow cytometry and ELISAs (i.e. platelet antibody test; see Table 9.5) are available to detect platelet‐bound IgG. These tests aid in the diagnosis of idiopathic thrombocytopenia purpura and immune thrombocytopenia [12]. The results do not differentiate primary from secondary immune‐mediated disease. Other specific platelet function tests include light aggregometry and current impedance and flow cytometry. However, the significance of the results from these test procedures in small animals is unknown at this time. Von Willebrand factor (vWF) is a protein required for platelet adhesion. Deficiency is commonly hereditary but can be acquired as a result of disease or medications. vWF is measured in comparison to a species normal and is reported as a percentage of normal (see Table 9.5). Platelet function testing is abnormal in von Willebrand’s disease, while the platelet count, PT, and aPTT are typically normal. This is most commonly diagnosed in young animals that experience excessive bleeding during routine surgical procedures. Bone marrow aspiration or biopsy is used to evaluate the cause of thrombocytopenia. Recent evidence suggests that bone marrow evaluation for thrombocytopenia without concurrent pancytopenia (low white blood cell and RBC counts) may not provide significant diagnostic information [13]. Bone marrow aspirate is generally considered to be safe in patients with only thrombocytopenia. Concurrent submission of a complete blood count for pathologist review and/or bone marrow biopsy may be warranted. Fibrinogen (factor I) is cleaved by thrombin to produce the fibrin strands that form the stable blood clot. Low fibrinogen levels have been shown to provide an indication of risk for spontaneous hemorrhage (when <5%) or surgical bleeding (when <20%) [14,15]. However, the significance of fibrinogen levels can be difficult to interpret. As fibrinogen is also an acute‐phase protein, levels can be elevated in response to inflammation; in addition, normal removal of circulating fibrinogen by the liver may be impaired by liver disease. Individual coagulation protein factor assays can be quantitated from blood samples. Identification of specific factor deficiencies is necessary for the diagnosis of hemophilia A (factor VIII deficiency) or hemophilia B (factor IX deficiency), as well as Hageman factor (factor XII) deficiency in cats. Other individual clotting factor deficiencies (I, II, VII, X, XI, XII) occur but are much less common. Thromboelastography (TEG) and thromboelastometry (TEM) (also called rotational thromboelastography – ROTEM) are viscoelastic assays that determine the efficiency and speed of blood coagulation. They provide an evaluation of whole clot formation, platelet function, clot strength, kinetics of fibrin formation and cross‐linking and fibrinolysis; they are amongst the few tests that can be used to identify a hypercoagulable state. The results are displayed as a tracing that shows the development of the clot. Coagulation variables that are measured include reaction time (R), clotting time (K), speed of fibrin accumulation and cross‐linking (α angle), clot strength (maximum amplitude, MA), and fibrinolysis (LY60), as seen in Figure 9.7. Figure 9.7 Thromboelastogram. The thromboelastography tracing (thromboelastogram) provides a visual representation of hemostasis. The reaction time (R) represents the time of latency from test initiation until beginning of fibrin formation, measured as an increase in amplitude of 2 mm. The clotting time (K) is the time to clot formation, measured from the end of R until an amplitude of 20 mm is reached. The angle (α) represents the rapidity of fibrin accumulation and cross‐linking. Maximum amplitude (MA) represents clot stregth. LY60 reflects fibrinolysis, determined by the percentage decrease in amplitude 60 minutes following MA. Source: Reproduced with permission from Hackner SG, White CR. Bleeding and hemostasis. In: Tobais JM, Johnston SA, eds. Veterinary Small Animal Surgery, vol. 1. St Louis: Elsevier Saunders, 2012: pp 100. One of the advantages of these viscoelastic assays is the ability to identify a hypercoagulable state, which traditionally has been quite difficult. A group of veterinary specialists have attempted to identify known information and knowledge gaps that are present in TEG evaluations of veterinary patients [16–21]. Each site that runs these tests is encouraged to develop its own normal values [17,20]. As with many coagulation assays, specific and consistent collection and storage of blood samples are recommended; samples that are not run in a timely fashion may falsely demonstrate hypercoagulability [18]. Thromboelastography has been used to identify hypercoagulable states and predict thromboembolic events in human surgical patients [22]. TEG and ROTEM are also potential tools for diagnosing DIC in human sepsis [23]. Sequential measurements have been necessary to understand the TEG/ROTEM coagulation patterns seen during sepsis as well as during other underlying diseases. Fibrinogen levels and platelet counts are reported to have a major influence on TEG variables [24]. The TEG results of decreased α angle and decreased MA with a prolonged aPTT in dogs with severe trauma have shown significance in predicting the need for blood transfusion and an increase in mortality [9]. A positive correlation has been made between TEG results that indicate reduced clotting ability and bleeding tendencies in dogs. The importance of these findings and the use of the TEG results during various stages of disease and therapeutic intervention in small animals are under investigation. Fibrin degradation products (FDPs), also called fibrin split products, are the fragments of protein produced when fibrin is broken apart by plasmin during fibrinolysis. The FDPs produced have a short half‐life and are cleared by the liver. An elevation in FDPs suggests that active coagulation and fibrinolysis are occurring systemically. However, other disease states can have elevated FDPs, such as severe liver disease, renal disease, monoclonal gammopathy, and burns. Elevated FDPs have been reported in dogs with pulmonary thromboembolism (sensitivity 80%, specificity 30%). In this study, an absence of thrombosis was found when FDP levels were below 103 μg/mL (sensitivity 100%) [25]. D‐dimers are specific FDPs that occur after fibrinolysis of cross‐linked (by factor XIII) fibrin and contain two “D domains” of the original fibrin molecule. D‐dimers are only elevated when the coagulation and fibrinolytic systems have been activated. Because D‐dimers are more specific than FDPs for active fibrinolysis and have a short half‐life, the measurement of D‐dimers has gained favor for detecting thrombosis or DIC. However, D‐dimers can be elevated with many disease processes (see Table 9.5) so are not specific for DIC [26–29]. D‐dimers and antithrombin levels have been examined in cats with cardiac disease; further investigation may help us define if any of these factors are indicative of impending thromboembolic events [30]. The INR is essentially a PT test that is “standardized” across laboratories as a means of accounting for inequality in the clotting agent used in coagulation testing. The formula for INR is:
Coagulation
Introduction
Monitoring methods
History
Physical examination
Triggers to evaluate coagulopathy
Physical evidence of hypocoagulation
Physical evidence of thrombosis (hypercoagulation)
Severe pyrexia (>106 °F, > 41 °C)
Hypothermia (<94 °F, <34 °C)
Cardiac arrhythmias, murmurs (cat and dog) or gallop sounds (cat)
Peripheral edema or vasculitis
Prolonged seizures
Organomegaly
Acute abdominal pain
Evidence of tissue trauma
Severe systemic infection
Pale or yellow mucous membranes
Evidence of infection or systemic inflammation
Poor perfusion:
Petechiae
Ecchymosis
Bleeding/bruising
Sudden soft tissue swelling
Poor perfusion
Altered thoracic auscultation
Labored rapid breathing
Cyanosis
Muffled or quiet heart sounds
Depressed mentation or change in mentation/consciousness
Seizures or sudden cranial or peripheral nerve changes
Melena or frank blood in stool
Marked red/brown pigment of urine
Pale or white mucous membranes
Abdominal fluid wave
Epistaxis
Frank blood or digested blood (“coffee grounds”) in vomit
Retinal hemorrhage or hyphema
Gingival bleeding
Cool skin or limb
Discoloration (pale or cyanotic) of mucous membranes, foot pads or skin
Labored, rapid breathing
Cyanosis
Acute abdominal pain
Absent single pulse
Sudden change in mentation, consciousnessPeripheral or central nerve deficits
Sudden inability to use limb(s); swelling, painful limbs and over time a firmness to the tissues or vessels
Sudden‐onset organ dysfunction or failure
Acute‐onset seizures
Acute‐onset paresis/paralysis
Unexplained anxiety
Sudden onset of severe pain
Clinicopathological testing
Point of care testing
Test
Normal*
Collection tube
Notes
Microhematocrit tube
37–55 (D); 25–45 (C)
5.8–7.2 (D); 5.7–7.5 (C)
Micro hematocrit tube
Buffy coat should be examined as well as it may indicate alterations in WBC
Clear to light yellow
Platelet estimate
10–30 per 100 × field
Lavender top (EDTA) or capillary tube
(EDTA)
Smeared on glass slide, monolayer examined for count; feathered edge examined for platelet clumping
Platelet count
170 000–575 000/ul (D)
200 000–680 000/ul (C)
Lavender top (EDTA)
Within 5 hours room temperature or 24 hours (refrigerated)
BMBT
<4 min (D)
<2.5–3 min (C)
N/A
Site should not be disrupted while performing test
PT
13–18 sec (D)
14–22 sec (C)
Blue top (Na citrate)
Run within 1 hour of collection or kept in fridge/shipped with ice
aPTT
10–17 sec (D)
14–18 sec (C)
Blue top (Na citrate)
Run within 1 hour of collection or kept in fridge/shipped with ice
ACT
60–90 sec (D)
45–160 sec (C)
Gray top (diatomaceous earth)
Run immediately and at 37 °C (98 °F) in a heated block or water bath
Minimum database
Blood smear
Thrombocytopenia
Thrombocytopathy
Thrombocytosis
Destruction
Primary
Immune mediated
Systemic lupus
Secondary
Drugs
Vaccination
Neoplasia
FeLV/FIV
Drug related
Aspirin
Clopidogrel
Antibiotics
Cardiac drugs
Hydroxyethyl starch
Barbiturates
Heparin
Massive transfusion
Systemic illness
Neoplasia
GI disease
Endocrine disease
Immunological
Rebound from IMHA, ITP therapy, blood loss or trauma
Consumption/sequestration
Hemorrhage
Disseminated intravascular coagulation
Splenic torsion
Sepsis
Hepatic disease
Hypothermia
Severe uremia
Systemic illness
Uremia
Anemia
Acidemia
Severe hepatic disease
Hypothermia
Myeloproliferative disease
Ehrlichiosis and other tick‐borne disease
Snake envenomation
Drugs
Steroids
Chemotherapy (e.g. vincristine)
Decreased production
Post vaccination
Radiation
Tick‐borne infection
Bone marrow aplasia
Other
Vasculitis
Hyperadrenocorticism
Hypocalcemia
Von Willebrand’s
Congenital disorder
Other
Fractures
Post splenectomy
Buccal mucosal bleeding time
POC coagulation tests (PT, aPTT, ACT)
PT
aPTT
Differential
Additional testing
Normal
Normal
No coagulopathy or early stages or mild disease or lab error
Investigate other sources of disease, CBC (platelets count/function), BMBT
Prolonged
Normal
“Early” vitamin K deficiency (toxic or therapeutic anticoagulants), severe liver failure, DIC, FVII or other factor deficiency (rare)
Blood levels of anticoagulants, FVII testing, liver tests, CBC
Normal
Prolonged
FVIII deficiency (hemophilia A), FIX deficiency (hemophilia B), FXII deficiency (primarily seen in cats and not associated with bleeding), von Willebrand’s disease, other (rare) factor deficiencies
Liver tests, individual factor testing, CBC, von Willebrand’s quantification
Prolonged
Prolonged
Severe liver disease, “late” anticoagulant toxicity, DIC, common pathway deficiency (FI, II, V, X), severe malabsorptive disease (bowel disease, cholestatic disease), heparin therapy, acute traumatic coagulopathy/trauma‐induced coagulopathy, severe sepsis or other SIRS disease
Liver function tests, CBC, individual factor testing, anticoagulant rodenticide blood tests, TEG, FDP, D‐dimers, fibrinogen
Blood profiles, imaging, and other supportive diagnostics
Test
Normal value*
Interpretation/indication
Limitations/notes*
Fibrinogen (I)
2–400 mg/dL (D)
50–300 mg/dL (C)
Low levels: consumption; DIC, thrombosis; lack of production: liver disease, malnutrition, congenital disorders, use of plasma expanders, snake envenomation
Elevated: systemic inflammation, liver dysfunction, tissue necrosis, ongoing coagulopathy
Na citrate tube or EDTA depending on methodology, refrigerate or freeze
Heparin, phenobarbital and fibrinolytic agents may decrease values
FDPs
<10 μg/mL (serum; D and C)
Increased: DIC, SIRS, liver and renal disease, protein‐losing disease, hemorrhage, trauma, gammopathies, burns, parvovirus, hyperadrenocorticism, pulmonary or other thromboembolic disease, regardless of cause
Na citrate or FDP tubes depending on laboratory method
Fibrinolytic agents will increase values
D‐dimer
<25 μg/mL (D and C)
Same as FDPs and heart disease
Collection method depends on lab,
fibrinolytic agents will increase values
Antithrombin
65–145% (D)
75–120% (C)
Decreased: consumption: DIC, thromboembolism; poor production: liver disease, heparin therapy or increased loss with protein‐losing enteropathy and nephropathy
Na citrate tube
INR
Target 2.0–3.0 baseline
2.5–3.5 for heart valve replacement
Monitoring patient on warfarin or coumarin
Several labs may run this test which is then compared to an in‐house normal to give a ratio
PIVKA
16–24 sec (D)
16–25 sec (C)
Anticoagulant rodenticide toxicity, severe liver, GI, pancreatic or biliary disease leading to fat malabsorption, disease that results in decreased vit K absorption; inherited factor deficiencies, DIC, neoplasia
Markedly prolonged with anticoagulant toxicosis
vWD
70–180% of control
Primary hemostatic disorder with normal platelet numbers and/or abnormal BMBT
Values <50% indicate vWF deficiency, <25% poses a risk of bleeding, <1% is diagnostic for severe (type III) vWF deficiency
TEG
Normals are laboratory dependent
See Figure 9.7
Helpful with hyper‐ and hypocoagulable states; points of intervention are not established
PFA‐100
<98 sec (ADP)
<300 sec (epinephrine)
Results are listed as closure time. Prolonged times indicate primary platelet dysfunction. Should only be run when platelet numbers are normal as thrombocytopenia will prolong results
Citrate tubes, must be run within 4 h of collection
Anti‐Xa activity
0.1–0.2 U/mL
These are suggested target goals for monitoring patients on UH or LMWH
There are no well‐established target goals
Bone marrow aspirate
Laboratory dependent
Of most diagnostic value when pancytopenia is present
Should be interpreted concurrently with a CBC and pathologist review
Anticoagulant levels
Anything above 0
Anticoagulant rodenticide toxicity suspected
Must be sent to reference laboratory; point of care detection is not useful
Protein C (APC)
75–135% (D)
65–120% (C)
Liver disease, DIC, sepsis, portosystemic shunts, vit K deficiency (rodenticide, coumarin therapy, cholestasis)
Na citrate. Protein C plays a role in coagulation (inactivates FV and FVIII) as well as inflammation
Individual clotting factors
Expressed as a percentage of normal with a range
Patients with suspected hemophilia or prolonged PT or aPTT
VIII, IX deficiencies are most common in dogs; VIII, IX and XII deficiencies in cats (XII deficiency rarely causes clinical hemorrhage)
Anti‐Xa
Suggested values: 0.35–0.7 U/mL (D)
Monitoring patients receiving heparin therapy
Studies determining target ranges for therapeutic monitoring are lacking
Platelet antibody
Negative
ITP, other autoimmune disorders
Flow cytometry is most commonly used, ELISA and IFA are alternative methods; does not differentiate primary from secondary disease
Angiography
Normal anatomy and flow
Cardiovascular disease and congential abnormalities (e.g. cardiac shunts, portovascular anomalies, valvular disease and stenosis, thromboembolic disease – venous or arterial)
Advanced procedure that should be performed and interpreted by someone with skill in the diagnostic arena. Selective and nonselective methods are possible
Nuclear medicine (scintigraphy)
Uniform distribution of radioactive isotope in lungs
Suspected pulmonary thrombosis or right to left cardiac shunts
Must be performed in a facility with appropriate equipment
Ultrasound
Normal anatomy and blood flow
Identification of underlying disease that may contribute to embolic complications (e.g. neoplasia or liver disease) or identification of hemorrhage (hypoechoic to mixed echogenic fluid); identification of echogenic thrombi
FAST and TFAST scans can easily be performed by most clinicians to identify cavitary effusions/hemorrhage; experience is often required to identify echogenic thrombi
Echocardiography
Normal anatomy and blood flow
Identification of underlying cardiac disease
Echocardiograms are often performed by individuals with experience in this field
Advanced clinicopathological testing
Monitoring platelet function and related factors
Platelet function
Von Willebrand factor
Bone marrow evaluation
Monitoring clot formation and fibrinolysis
Fibrinogen
Individual clotting factors
Viscoelastic coagulation assessment
Fibrin degradation products
D‐dimers
Anticoagulant therapy monitors
International normalized ratio (INR)
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