When Thrombosis Gets Complicated

A thrombus is a blood clot that forms inside an intact vessel, which is an inappropriate response. Learn from Erika Loftin, DVM, DACVECC about thrombosis complications.

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Coagulation is a protective mechanism to prevent excessive hemorrhage following trauma. However, regulatory mechanisms are normally in place to control the timing and extent of the clotting process. For example, the procoagulant endothelial surface is not exposed to platelets and clotting factors in blood unless vascular injury occurs, and there are endogenous anticoagulant molecules usually in balance with the procoagulant clotting factors. When the system does not function properly, bleeding or clotting disorders can result. A thrombus is a blood clot that forms inside an intact vessel, which is an inappropriate response. An embolus is a blood clot that travels through the bloodstream and causes a vascular obstruction. Both can occur in dogs and cats, leading to a variety of consequences depending on the location.

Virchow’s triad is the concept commonly used to define the risk for thrombosis. The three components include endothelial injury or dysfunction (due to trauma or systemic inflammation), altered blood flow (turbulence or stasis), and hypercoagulability (an imbalance in procoagulant and anticoagulant factors). In addition, there is significant interplay between the processes of inflammation and coagulation, such that any inflammatory process can predispose to thrombosis. In most patients that develop thrombotic complications, the process is multi-factorial. In human patients, there is a relatively protocolized approach to identifying and treating thromboembolic events, including aggressive thrombolysis (pharmacologic clot dissolution) in some cases.

 

Pathophysiology and Underlying Causes

Documenting hypercoagulable states in veterinary practice can be challenging, and the index of suspicion for a thromboembolic event is often based on the presence of a compatible underlying disease. In feline patients, the most common underlying cause for thrombosis is heart disease, in which an enlarged left atrium leads to blood stasis and formation of an arterial clot. Neoplasia, pancreatitis, infectious disease, hepatic disease, systemic inflammatory response syndrome (SIRS) and sepsis have also been shown to predispose to thrombosis in cats.

In canine patients, common predisposing disease processes include systemic inflammation (pancreatitis, SIRS/sepsis), trauma, immune-mediated hemolytic anemia (IMHA), protein losing nephropathy (PLN) or protein losing enteropathy (PLE), heartworm infection, neoplasia, and administration of certain medications including exogenous corticosteroids or human intravenous immunoglobulin (IVIG).

Necropsy studies have documented relatively high rates of thromboemboli in these patient populations, including approximately 80 percent of dogs with IMHA (Carr, 2002) and 67 percent of dogs with a variety of critical illnesses (Thawley, 2016). Hypercoagulability was documented in nine dogs with naturally occurring parvovirus, almost half of which had clinical evidence of thrombosis or catheter-associated phlebitis (Otto, 2000). Known or suspected thromboembolic complications accounted for approximately 30 percent of deaths in a paper looking at risk factors for perioperative death in dogs undergoing splenectomy for splenic masses (Wendelburg, 2014). Trauma is a very common cause of thrombosis in human patients, and acute mesenteric ischemia secondary to vehicular trauma (which subsequently required an abdominal surgery with intestinal resection and anastomosis) has been reported in a dog (Hamilton, 2010). For trauma patients, intense intestinal vasoconstriction is thought to be the inciting event for the thrombosis, with subsequent activation of endothelial cells, leukocytes and platelets. Although hyperadrenocorticism has been traditionally thought to result in a prothrombotic state, a recent paper could not actually demonstrate any specific evidence of hypercoagulability in a group of 16 dogs with this condition (Klose, 2011).

 

Classification of Thrombosis

Location

Clinical signs of thrombi or thromboemboli (TE) are generally related to the location – hind limb weakness/paralysis and pain for aortic TE, neurologic signs (which can include changes in mentation, seizures, cranial nerve dysfunction, vestibular signs or coma) for central nervous system TE, profound gastrointestinal signs and abdominal pain for mesenteric or portal venous TE, acute renal failure with renal TE, and acute dyspnea of variable severity with PTE. Myocardial infarction, though commonly seen in people, is thought to be quite rare in veterinary patients.

Acute vs. chronic

As expected, patients with a sudden onset of severe signs are likely experiencing an acute thrombotic event, and those with vague or nonspecific signs are more likely to have a chronic thrombotic event. In some cases, a thrombus may actually be an incidental finding at the time of detection. Determining the time course of the thrombosis may influence the aggressiveness and duration of the treatment plan, as well as the expectation of resolution. Detection of the underlying cause is essential to guide therapy to reduce the risk of future thrombotic events.

Venous vs. arterial

Venous thrombi tend to develop in low-flow areas and are primarily composed of fibrin. In contrast, arterial thrombi develop under high shear forces and are primarily composed of platelets. Peripheral arterial and venous thrombi have very different clinical signs – venous thrombi (commonly referred to as deep vein thromboses, or DVT, in humans) lead to a warm, swollen limb, while arterial thrombi lead to a white, cold, painful limb. The origin of the thrombus is important both in facilitating recognition of the event, and potentially in determining the most effective strategy for prevention of future events.

 

Diagnostic Investigation

While there are readily available tests to document hypocoagulability (including platelet count, buccal mucosal bleeding time (BMBT), prothrombin time (PT) and partial thromboplastin time (PTT), tests that accurately predict hypercoagulability are less readily available and interpretable. In clinical practice, the development of a thromboembolic event is often the first indication that a patient is even at risk. Table 1 provides information regarding supportive testing for hypercoagulability and/or thrombosis.

Table 1: Diagnostics to support hypercoagulability or diagnose thrombosis

Test

Findings and Interpretation

D-Dimers

  • D-Dimer >2000 ng/ml is 98% specific, 35% sensitive for thromboembolism
  • D-Dimer <103 ng/ml is 100% sensitive for ruling out pulmonary thromboembolism

Thromboelastography (TEG)

TEG parameters that may support hypercoagulability include:

  • Increased Maximum Amplitude (MA)
  • MA can be used to calculate a G value that is increase in hypercoagulability
  • Elevation of the calculated value coagulation index (CI)
  • Increased alpha angle
  • Shortened R time or K time

Fibrinogen

Elevated fibrinogen may support hypercoagulability

Thoracic Radiographs

  • Often normal in pulmonary thromboembolism (PTE)
  • Can see hyperlucent lung due to decreased regional blood flow
  • Can observe attenuated pulmonary vasculature

UItrasound

Can visualize the presence of aortic or hepatic venous, caval, splenic or mesenteric thrombi

CT angiography

Able to visualize intraluminal thrombi with contrast angiography

Echocardiography

  • Presence of spontaneous echocardiographic contrast (SEC) supports increased risk for thrombosis
  • Can see evidence for acute pulmonary hypertension with PTE
  • Can sometimes observe a clot in the proximal pulmonary artery

 

Because there are few highly reliable and readily available tests to diagnose thrombosis, veterinarians should be aware of subtle signs in patients with known or suspected risk factors. These indicators may include a drop in the platelet count, abdominal effusion with no other explanation, weak or absent femoral pulses, or a sudden onset of respiratory or neurologic signs with no identifiable cause. Clinical intuition should not be disregarded in the evaluation of high risk patients if adequate reason for suspicion exists.

 

Treatment Strategies

Thromboprophylaxis

While protocols in human medicine for both prevention and treatment of thrombosis are relatively well established, there is little evidence available in veterinary medicine to guide treatment strategies, which are primarily based on clinical experience and relatively small retrospective studies. Thromboprophylaxis is a term used to denote a strategy of clot prevention in patients considered to be at high risk. The potential benefit of thromboprophylaxis should be considered in each individual patient and always carefully weighed against the risk of hemorrhage. See Table 2 for medications used in thromboprophylaxis. In most cases, antithrombotic medications in veterinary patients are discontinued once the risk factors are gone, but there is a potential for rebound hypercoagulability.

Table 2: Drugs used for thromboprophylaxis in dogs and cats

(F)= Feline (C)=Canine

Drug

Mechanism of Action

Dose

Comments

Aspirin

Antiplatelet drug via irreversible cyclooxygenase and thromboxane A2 inhibition

20 mg/CAT PO q72hr (F)

5 mg/CAT PO q48-72hr (F)

0.5-2 mg/kg PO q24hr (C)

  • Blocks only one pathway for platelet activation and other pathways may activate platelets while on aspirin therapy
  • A true anti-platelet dose is not determined accounting for the variable dose recommendations

Clopidogrel (Plavix™)

Antiplatelet via platelet ADP receptor inhibitor

18.75 mg/CAT PO SID (F)

2-3 mg/kg PO SID +/- 10 mg/kg PO loading dose (C)

 

  • New recommendation for 75 mg loading dose in cats with clinical ATE of cardiac origin
  • Data suggests it may be a more effective platelet inhibitor compared to aspirin

Warfarin (Coumadin)

Inhibits Vit K dependent clotting factors II, VII, IX, X

0.05-0.2 mg/kg PO SID (F)(C)

  • Monitor effectiveness by international normalized ratio (INR) of two to three (rarely done in vet species)
  • Risk of hemorrhagic complications

Unfractionated Heparin (UFH)

Enhances function of antithrombin. Inactivates thrombin and Factor Xa

75-300 U/kg SQ q6-8hr after 100 U/kg IV loading dose (F)(C)

  • Can monitor with a target PTT of 1.5-2 times baseline
  • Can monitor with Anti Xa assay but this is not available as point of care test for quick dose changes
  • Risk of hemorrhagic complications

Low Molecular Weight Heparin (LMWH)

Blocks action of Factor Xa

Dalteparin: 100-150 U/kg SQ q8-12hr (F)(C)

Enoxaparin 0.8-1 mg/kg SQ q6-8hr (F)(C)

  • Can monitor with Anti Xa assay, but this is not available as point of care test for quick dose changes
  • The risk of hemorrhagic complications is thought to be lower than with UFH

Rivaroxaban

(Xarelto ™)

Thrombin Inhibitor

0.5 mg/kg PO SID titrated up to 1 mg/kg PO SID (F)(C)

  • Expensive
  • Risk of hemorrhagic complications

Fibrinolytic agents

These medications cause rapid breakdown of existing blood clots and carry a relatively high risk of complications, including reperfusion injury and hemorrhage. Some evidence suggests that catheter-directed thrombolytic therapy may be associated with improved outcomes and fewer complications than seen with systemic administration. The medications that have been used in veterinary patients include tissue plasminogen activator (t-PA) and streptokinase, which work by activating plasminogen to plasmin. Plasmin then breaks down fibrin clots to reestablish vessel patency. Based on human recommendations, thrombolysis should really only be considered in the first three to six hours following a thromboembolic event, and the infusion should be given over a relatively short period of time as these strategies may reduce the risk of reperfusion injury.

Thrombus removal

Rheolytic thrombectomy describes a procedure during which a directed jet of saline is used to break down a thrombus with subsequent suctioning for removal of clot fragments. This technique has been investigated in six cats with aortic thromboembolism, with documented thrombus resolution in five of the six patients and 50 percent survival to discharge (Reimer, 2006). However, it is quite invasive and not widely available, and a convincing benefit over conventional therapy has not been demonstrated. Likewise, surgical thrombectomy is only rarely indicated, such as in cases of adrenal tumor-associated thrombi of the vena cava.

 

References

Carr AP, Panciera DL, Kidd L. Prognostic factors for mortality and thromboembolism in canine immune-mediated hemolytic anemia: A retrospective study of 72 dogs. J Vet Intern Med 2002;16:504-509.

Hamilton TR, Thacher  CW, Forsee KM, Nakamura RK. Trauma-associated acute mesenteric ischemia in a dog. J Vet Emerg Crit Care 2010;20(6):595-600.

Klose TC, Creevy KE, Brainard BM. Evaluation of coagulation status in dogs with naturally occurring canine hyperadrenocorticism. J Vet EmergCrit Care 2011;21(6):625-632.

Otto CM, Rieser TM, Brooks MB, Russell MW. Evidence of hypercoagulability in dogs with parvoviral enteritis. J Am Vet Med Assoc 2000;217:1500-1504.

Reimer SB, Kittleson MD, Kyles AE. Use of rheolytic thrombectomy in the treatment of feline distal aortic thromboembolism. J Vet Intern Med 2006;20:290-296.

Thawley VJ, Sanchez MD, Drobatz KJ, King LG. Retrospective comparison of thromboelastography results to postmortem evidence of thrombosis in critically ill dogs: 39 cases (2005-2010). J Vet Emerg Crit Care 2016;26(3):428-436.

Wendelburg KM, O’Toole TE, McCobb E, Price LL, Lyons JA, Berg J. Risk factors for perioperative death in dogs undergoing splenectomy for splenic masses: 539 cases (2001-2012). J Am Vet Med Assoc 2014;245:1392-1390.

 

Complete List of References and Suggested Reading

Borgeat K, Wright J, Garrod O, Payne JR, Fuentes VL. Arterial thromboembolism in 250 cats in general practice: 2004-2012. J Vet Intern Med 2014;28:102-108.

Carr AP, Panciera DL, Kidd L. Prognostic factors for mortality and thromboembolism in canine immune-mediated hemolytic anemia: A retrospective study of 72 dogs. J Vet Intern Med 2002;16:504-509.

Davidson BL, Rozanski EA, Tidwell AS, Hoffman AM. Pulmonary thromboembolism in a heartworm-positive cat. J Vet Intern Med 2006;20:1037-1041.

DePaula KM, deLaforcade AM, King RG, Hughs H, Boudrieau RJ. Arterial thrombosis after vehicular trauma and humeral fracture in a dog. J Am Vet Med Assoc 2013;243:394-398.

Dunn M. Thrombectomy and thrombolysis: the interventional radiology approach. J Vet Emerg Crit Care. 2011;21(2):144-150.

Epstein SE, Hopper K, Mellema MS, Johnson LR. Diagnostic utility of D-dimer concentrations in dogs with pulmonary embolism. J Vet Intern Med 2013;27:1646-1649.

Hamilton TR, Thacher  CW, Forsee KM, Nakamura RK. Trauma-associated acute mesenteric ischemia in a dog. J Vet EmergCrit Care 2010;20(6):595-600.

Helmond SE, Polzin DJ, Armstrong PJ, Finke M, Smith SA. Treatment of immune-mediated hemolytic anemia with individually adjusted heparin dosing in dogs. J Vet Intern Med 2010;24:597-605.

Hogan DF, Fox PR, Jacob K, Keene B, Laste NJ, Rosenthal S, Sederquist K, Weng H-Y. Secondary prevention of cardiogenic arterial thromboembolism in the cat: The double-blind, randomized, positive-controlled feline arterial thromboembolism; clopidogrel vs. aspirin trial (FAT CAT). J Vet Cardiol 2015;17 Suppl 1(0): S306-17.

Johnson LR, Lappin MR, Baker DC. Pulmonary thromboembolism in 29 dogs: 1985-1995. J Vet Intern Med 1999;13:338-345.

Kidd L, Mackman N. Prothrombotic mechanisms and anticoagulant therapy in dogs with immune-mediated hemolytic anemia. J Vet Emerg Crit Care. 2013;23(1):3-13.

Klainbart S, Kelmer E, Vidmayer B, Bdolah-Abram T, Segev G, Aroch I. Peripheral and central venous blood glucose concentrations in dogs and cats with acute arterial thromboembolism. J Vet Intern Med 2014;28:1513-1519.

Klose TC, Creevy KE, Brainard BM. Evaluation of coagulation status in dogs with naturally occurring canine hyperadrenocorticism. J Vet Emerg Crit Care 2011;21(6):625-632.

Lake-Bakaar GA, Johnson EG, Griffiths LG. Aortic thrombosis in dogs: 31 cases (2000-2010). J Am Vet Med Assoc 2012;241:910-915.

Laurenson MP, Hopper K, Herrera MA, Johnson EG. Concurrent diseases and conditions in dogs with splenic vein thrombosis. J Vet Intern Med 2010;24:1298-1304.

Moore KE, Morris N, Dhupa N, Murtaugh RJ, Rush JE. Retrospective study of streptokinase administration in 46 cats with arterial thromboembolism. J Vet Emerg Crit Care 2000;10:245-257.

Nelson OL, Andreasen C. The utility of plasma D-dimer to identify thromboembolic disease in dogs. J Vet Intern Med 2003;17:830-834.

Otto CM, Rieser TM, Brooks MB, Russell MW. Evidence of hypercoagulability in dogs with parvoviral enteritis. J Am Vet Med Assoc 2000;217:1500-1504.

Panek CM, Nakamura RK, Bianco D. Use of enoxaparin in dogs with primary immune-mediated hemolytic anemia: 21 cases. J Vet Emerg Crit Care 2015:25(2):273-277.

Ralph AG, Saunders AB, Hariu CD, Nabity M. Spontaneous echocardiographic contrast in three dogs. J Vet Emerg Crit Care 2011;21(2):158-165.

Reimer SB, Kittleson MD, Kyles AE. Use of rheolytic thrombectomy in the treatment of feline distal aortic thromboembolism. J Vet Intern Med 2006;20:290-296.

Respess M, O’Toole TE, Taeymans O, Rogers CL, Johnston A, Webster CRL. Portal vein thrombosis in 33 dogs: 1998-2011. J Vet Intern Med 2012;26:230-237.

Rogers CL, O’Toole TE, Keating JH, Penninck DG, Webster CRL. Portal vein thrombosis in cats: 6 cases (2001-2006). J Vet Intern Med 2008;22:282-287.

Schermerhorn T, Pembleton-Corbett JR, Kornreich B. Pulmonary thromboembolism in cats. J Vet Intern Med 2004;18:533-35.

Scott KC, Hansen BD, DeFrancesco TC. Coagulation effects of low molecular weight heparin compared with heparin in dogs considered to be at risk for clinically significant venous thrombosis. J Vet Emerg Crit Care 2009;19(1):74-80.

Song J, Drobatz KJ, Silverstein DC. Retrospective evaluation of shortened prothrombin time or activated partial thromboplastin time for the diagnosis of hypercoagulability in dogs: 25 cases (2006-2011). J Vet Emerg Crit Care 2016;26(3):398-405.

Stokol T, Brooks, M, Rush JE, Rishniw M, Erb H, Rozanski E, Kraus MS, Gelzer AL. Hypercoagulability in cats with cardiomyopathy. J Vet Intern Med 2008;22:546-552.

Thawley VJ, Sanchez MD, Drobatz KJ, King LG. Retrospective comparison of thromboelastography results to postmortem evidence of thrombosis in critically ill dogs: 39 cases (2005-2010). J Vet Emerg Crit Care 2016;26(3):428-436.

Welch KM, Rozanski EA, Freeman LM, Rush JE. Prospective evaluation of tissue plasminogen activator in 11 cats with arterial thromboembolism. J Feline Med Surg 2010;12(2):122-128.

Wendelburg KM, O’Toole TE, McCobb E, Price LL, Lyons JA, Berg J. Risk factors for perioperative death in dogs undergoing splenectomy for splenic masses: 539 cases (2001-2012). J Am Vet Med Assoc 2014;245:1392-1390.

Yang VK, Cunningham SM, Rush JE, de Laforcade A. The use of rivaroxaban for the treatment of thrombotic complications in four dogs. J Vet Emerg Crit Care 2016;00(00):1-8.

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