Canine and Feline Coagulopathies

Michelle Fulks, DVM, Virginia Sinnott, DVM, DACVECC

William B. Henry, Jr. DVM, DACVS

Canine and Feline Coagulopathies
Bleeding disorders are considered a potential life-threatening emergency in small animal practice.  It is crucial to recognize the potential for a coagulation disorder through history and physical exam findings, pursue appropriate diagnostic tests and then treat appropriately in order to prevent massive bleeding in these patients.

Three areas of the hemostatic system may be affected to cause coagulopathies:

1.    Disorders of Primary Hemostasis
2.    Disorders of Secondary Hemostasis
3.    Disorders of Fibrinolysis 

Primary hemostasis is the formation of the initial platelet plug.  Decreases in platelet number, platelet function, or reduced von Willebrand factor (VWF) can all cause disorders of primary hemostasis and lead to mucosal bleeding or bruising.  Secondary hemostasis is the formation of a stable fibrin clot via cascade of enzymes that ultimately convert fibrinogen to fibrin.  Defects in coagulation factors can lead to severe bleeding diatheses.  Fibrinolysis is the breakdown of the fibrin clot by plasmin.  Excessive clot breakdown results in prolonged bleeding or delayed rebleeding.

Disorders of PRIMARY HEMOSTASIS

Thrombocytopenia is caused by decreased production, increased destruction or consumption and sequestration (Table 1).  Platelet count must fall below approximately 50,000/mcL for spontaneous bleeding to occur.

Table 1:  Causes of Thrombocytopenia

Decreased Production
Primary	Neoplasia, immune-mediated, fibrosis, andmyelophthisis
Drug-induced	Chloramphenicol, estrogen, bleomycin, lomustine, cytosine arabinoside, melphalan, methotrexate, platinum, doxorubicin, and actinomycin D
Secondary	FeLV, ehrlichiosis, and hypothyroidism
Consumption and Sequestration	Significant hemorrhage, splenomegaly, sepsis,vasculitis, and disseminated intravascular coagulation
Destruction
Drug-induced	Furosemide, H2 receptor antagonists, cephalosporins,penicillins, trimethoprim-sulfamethoxazole, quinines,phenylbutazone, many cardiac medications
Primary	Inflammation and neoplasia
Secondary	Antibodies directed against normal platelet antigens
Infectious	Distemper, herpesvirus, parvovirus, adenovirus, FeLV, panleukopenia, FIV, FIP, ehrlichiosis, babesiosis, haemobartonellosis, rickettsiosis, leishmaniasis, cytauxzoonosis, borreliosis, dirofilariasis, histoplasmosis, candidiasis, leptospirosis, and septicemia.

 

Thrombocytopathias occur when platelet function is abnormal.  The most common of these is von Willebrand disease, which may be inherited or acquired.  VWD should be considered with unexplained bleeding in young dogs with or without trauma.  It should also be considered when there is excessive bleeding following a planned trauma, such as a spay or neuter procedure.  Although Dobermans and VWD is the most well recognized, certain other breeds may also be prone to inherited thrombocytopathias.

 

 Disorders of Secondary Hemostasis

• Anticoagulant rodenticide toxicity inhibits vitamin K1 epoxide reductase resulting in dysfunction of factors II, VII, IX, X, protein C and protein S.  Brodifacoum is the most common anticoagulant rodenticide used, and therefore ingested by our patients.
• Hepatic disease causes decreased or abnormal coagulation factor synthesis.  This generally does not cause spontaneous bleeding.
• Cholestatic disease causes decreased absorption of vitamin K, which can cause dysfunctional forms of factors II, VII, IX and X.
• Inherited factor deficiencies.  Factor VIII deficiency (ie, hemophilia) is most common, although other factor deficiencies may also occur.

Disorders of Fibrinolysis

Post-operative bleeding in greyhounds has been the most well described fibrinolytic disorder, but should be considered in other breeds with post-operative bleeding if VWD is not diagnosed.

Disseminated intravascular coagulation (DIC) is a disorder affecting all aspects of coagulation.  The early stage is characterized by thrombosis, which results in excessive consumption of endogenous platelets and clotting factors.  This consumption results in hemorrhage in the late stages.  DIC is always secondary to an underlying issue such as severe trauma, neoplasia, sepsis, or overwhelming inflammation.

History
A thorough history is essential and can help guide diagnostic tests.  Signalment may help make inherited coagulopathies more likely.  Breed predilection may also be seen, such as cocker spaniels, poodles and old English sheepdogs being over-represented in immune-mediated thrombocytopenia. Duration and progression of clinical signs as well as any recent trauma or surgery should be identified.  The owner should also be questioned about any previous bleeding events such as with elective surgeries, teething or vaccination.  Numerous repeated bleeding episodes in a young patient make inherited coagulopathies likely.  Environment and travel history is also important, as certain infectious diseases are endemic in different regions.  Medication history and any possibility of toxin exposure are other historical questions that should be addressed.   Any patient with bleeding that may ultimately have a transfusion should be specifically asked about any previous transfusion history.

Physical exam
Physical exam findings may be related to sites of bleeding and can help increase suspicion for either primary or secondary hemostatic disorders.  With primary hemostatic disorders capillary or small vessel hemorrhage is generally seen.  Therefore, physical exam findings may includepetechia (Figure 1), ecchymosis or mucosal hemorrhage such as epistaxis, hematuria, gingival bleeding, hematemesis, melena or hemoptysis.  Secondary hemostatic disorders tend to have subcutaneous or cavity bleeding and physical exam findings are generally based on the location of the bleeding.  Single or multiple hematomas may be seen with subcutaneous bleeding, dyspnea with pulmonary hemorrhage, dull lung or heart sounds with pleural hemorrhage, abdominal distension with hemoabdomens or lameness with hemorrhage into joints.  Systemic signs of blood loss may also be identified and include lethargy, inappetance, collapse, pale mucous membranes, tachycardia and bounding or weak pulses.

Figure 1: Petechiation in a 4-year-old boxer with immune-mediated thrombocytopenia.

  

 

• Complete blood count and blood smear evaluation should be performed to determine platelet count.  It should also be evaluated for the presence of anemia or leukopenia, intracellular organisms and RBC morphology.
• Serum biochemical profile allows evaluation of total protein concentration and liver function studies.
• Buccal mucosal bleeding time (BMBT) should be performed in patients suspected of primary hemostatic abnormalities that have normal platelet counts.  Prolonged BMBT indicates abnormal platelet function or vasculitis.
• Von Willebrand factor activity directly measures the amount of VWF and is used to diagnose and characterize type of VWD.  Patients with prolonged BMBT with normal platelet counts should have VWF activity measured.
• Prothrombin time (PT) evaluates extrinsic (factor VII and tissue factor) and common(factors II, V, and X) coagulation pathways.  Due to the half-life of factor VII, this is seen elevated first with anticoagulant rodenticide toxicities.
• Activated partial thromboplastin time (aPTT) evaluates intrinsic (factors VII, IX, XI, and XII) and common coagulation pathways.  Prolonged aPTT with normal PT suggests specific factor abnormalities.  PTT may also be mildly elevated with a normal PT with consumptive coagulopathies.
• Activated clotting time (ACT) also evaluates intrinsic and common pathways, but is less sensitive than aPTT.
• High-performance liquid chromatography (HPLC) is recommended if exposure to anticoagulant rodenticides is suspected but not confirmed, especially in cases where other differentials are likely (ie, hemagiosarcoma).
• Individual factor analysis should be performed to identify inherited factor deficiencies.
• Tests of fibrinolysis includes fibrinogen assays, thrombin time, fibrin degradation products and D-dimers.
• Infectious disease screening should be performed to screen cases with primary hemostatic defects, fever, and/or generalized illness for Ehrlichiacanis, Anaplasmaphagocytophilium, Anaplasma platys, Ricketsia ricketsii by measuring antibody titers or PCR as indicated by geographic location.
• Bone marrow aspiration or biopsy is indicated with thrombocytopenia if other cell lines (RBC or WBC) are unusually increased or decreased.
• Radiographs and abdominal ultrasonography are indicated for pulmonary (Figure 2),pleural, or abdominal hemorrhage.  They should also be performed to evaluate for primary disease processes in DIC (ie, masses and pneumonia).  

• Advanced imaging such as CT scan or MRI are indicated in cases of central nervous system hemorrhage.  **SEE THIS MONTHS DIAGNOSTIC BRAIN SCANS IN SIDEBAR LINK

Table 2: Coagulation testing results used to identify type of hemostatic defect.  

	Platelet count <50,000/mcL	PT	aPTT	Other
Thrombocytopenia	Yes	Normal	Normal
Thrombocytopathia	No	Normal	Normal	Increased BMBT
Rodenticide	No, unless hemorrhage is extreme	Prolonged	Prolonged
Hepatic Failure	No, unless hemorrhage is extreme	Prolonged	Prolonged	Abnormal liver values
DIC	Typically	Prolonged	Prolonged	Increased D-dimers
Hemophilia A+B	No, unless hemorrhage is extreme	Normal	Prolonged	Factor analysis

  

Treatment
The first goal in treatment in patients with life-threatening hemorrhage is to stabilize those in shock with IV fluid therapy.  Isotonic crystalloids (lactated Ringer solution or 0.9% saline solution) should be used in increments of 20-30 ml/kg until heart rate, blood pressure, mucous membrane color and mental status are normal. Hypertonic saline (7.2-7.5% NaCl) may also be used for rapid intravascular volume replacement in patients that are not already dehydrated or hypernatremic.  Hypertonic saline should be given at a dose of 4-6 ml/kg over no faster than 15 minutes followed by isotonic crystalloids. Packed red blood cells or fresh whole blood may also be indicated if the patient remains symptomatic after fluid resuscitation (ie tachycardia, abnormal pulses, hypotension, etc) or weak after IV fluid resuscitation.  A packed cell volume of <20% after an episode of acute bleeding warrants consideration of a transfusion.  A fresh whole blood transfusion would provide both red blood cells and clotting factors.
 
The second goal of treatment is to arrest bleeding, if possible.  This includes transfusing missing clotting factors with fresh frozen plasma or cryoprecipitate.  Fresh frozen plasma supplies clotting factors XII, XI, X, IX, VIII, VII, V, II, VWF and fibrinogen rapidly.  FFP is indicated for hemophilia, VWD and anticoagulant rodenticide ingestion with hemorrhage.  Frozen plasma may also be used to provide vitamin K dependent clotting factors for rodenticide toxicities and has a long shelf life.  Cryoprecipitate is another treatment option for VWD.  Desmopressinacetate stimulates release of VWF and is indicated in cases of VWD.  It may be used pre-operatively prior to surgical procedures in patients known to have VWD to limit surgical hemorrhage.  In thrombocytopenic patients, vincristine may be given to encourage platelet formation (as plasma provides very few platelets).  Management of local bleeding should also be pursued if possible, by wrapping distensible areas such as an abdomen or subcutaneous space.  Excising bleeding masses should also be pursued as soon as it is safe to do so.

The third goal of treatment for coagulopathies is to treat the underlying cause.  These treatments will be diagnosis-specific and may include immunosuppressive medication, vitamin K1, or antibiotics.  In patients with recent rodenticide ingestion (1 to 3 hours), immediate decontamination with apomorphine to induce vomiting and activated charcoal should be pursued.  In these patients with successful decontamination, vitamin K therapy is not immediately indicated.  A prothrombin time should be measured 48-72 hours after known exposure to anticoagulant rodenticides, and if results are within reference ranges administration of vitamin Ktherapy is not required.  However, if PT is prolonged at this time or in patients that did not have immediate decontamination or are actively bleeding, oral vitamin K therapy (3-5 mg/kg divided q 12 hr for 4 weeks) should be initiated.  The injectable form is poorly absorbed but necessary for cases when malabsorption of vitamin K is suspected such as cholestasis, liver failure (0.5-1 mg/kg SQ q12-24 hr) and shock.  Doxycycline at 5-10mg/kg PO BID is indicated in cases of thrombocytopenia while infectious disease testing is pending.   
 
Immunosuppressive medications (prednisone, azathioprine, cyclosporine, and leflunomide) are indicted to treat immune-mediated thrombocytopenia.  Antifibrinolytic agents such as aminocaproic acid have been shown effective in greyhounds to prevent postsurgical bleeding.
 
Prognosis
Prognosis varies based on the type of coagulopathy and underlying cause. In cases of thrombocytopenia, those with infectious causes have a good long-term prognosis.  However, the prognosis for immune-mediated thrombocytopenia is only fair and the risk of relapse is always present.  Patients with hereditary coagulopathies (such as VWD or factor deficiencies) can live normal life spans, although multiple transfusions may be required throughout the course of their lives.  Owners of these patients should be warned about clinical signs of bleeding and potential for multiple transfusions.  They should be educated to inform any future veterinary providers about prior transfusions and history of coagulopathy.  Patients with recent exposure to anticoagulant rodenticides that have immediate decontamination have an excellent prognosis.  With un-witnessed ingestion and bleeding 3-5 days post-exposure, prognosis is still good but treatment is more costly due to the possible need of multiple transfusions.  Patients with disseminated intravascular coagulation have a guarded prognosis, unless the underlying cause can be rapidly corrected.