1. Coagulopathies
Hayley Morse
May 29, 2008

2. Normal Hemostasis
First, injury to a blood vessel leads to immediate vasoconstriction, as well as activating the coagulation cascade.
Platelet adhesion: results from exposure of blood to subendothelial collagen
Adhesive proteins (von Willebrand factor and fibrinogen) mediate the adhesion of platelets to the subendothelium
Primary hemostatic plug is formed after platelets aggregate.
Platelet plug is unstable and short-lived, but serves as a framework for secondary hemostasis.

3. Normal Hemostasis
Activation of intrinsic pathway (contact phase) results in fibrin formation
This process occurs almost simultaneously with platelet adhesion and aggregation

4. Intrinsic Pathway
Factor XII is activated by contact with subendothelial collagen and the platelet plug
Prekallikrein and high molecular weight kininogen are important cofactors for factor XII activation
Fibrin (secondary hemostatic plug) is the result (through the Common Pathway)
The secondary hemostatic plug is stable and long-lasting.

5. Extrinsic Pathway
Tissue factor (factor III) is released whenever there is tissue trauma, and this activates the extrinsic pathway
End result is also fibrin formation through the Common Pathway

6. Coagulation Cascade

7. Nomenclature of clotting factors
I – fibrinogen
II – Prothrombin
III – Tissue thromboplastin/tissue factor
IV – Calcium
V – Proacelerin
VII – Proconvertin
VIII – Hemophilia A (antihemophilic factor)
IX – Hemophilia B (Christmas factor)
X – Stuart-Prower factor
XI – Plasma thromboplastin antecedent (PTA)
XII – Hageman factor
XIII – Fibrin stabilizing factor
Prekallikrein/Fletcher factor
High molecular weight kininogen (HMWK)/Fitzgerald factor

8. Fibrinolysis Fibrinolysis prevents excessive thrombus (clot) formation
It is activated by stimuli that activate the Intrinsic pathway (exposure to subendothelial collagen and the platelet plug)
Plasminogen is activated and becomes Plasmin, which is responsible for lysis of a clot; as well as inhibition of platelet aggregation and activation of clotting factors in the affected area

9. Natural anticoagulants
Other natural anticoagulants are activated by initiation of coagulation cascade (Antithrombin and proteins C and S).
Antithrombin is a protein synthesized by hepatocytes, and inhibits the activation of factors IX, X, and thrombin
Acts as a cofactor for heparin
Proteins C and S are also produced by hepatocytes, and are Vitamin K-dependent

10. Important questions to ask owners when animal presents with spontaneous or excessive bleeding:
Is this the first bleeding episode?
Has the pet had any surgeries before this, and if so, did the pet bleed excessively?
Do any littermates have similar clinical signs? Was there increased perinatal mortality in the litter?
Has the pet recently been vaccinated (especially with modified-live vaccines)?
Is the pet receiving any medications?
Does the pet have access to rodenticides or does it roam freely?

11. Clinical signs association with disorder of primary hemostasis
Petechiae, ecchymoses common on mucous membranes and skin
Bleeding from mucosal surfaces (epistaxis, gingival bleeding, hematuria, melena, hematochezia, hyphema)
Prolonged bleeding after venipuncture

12. Clinical Signs associated with disorder of secondary hemostasis
Hematomas are common
Bleeding into muscles, joints, and body cavities (i.e. hemoabdomen, hemothorax)
Delayed bleeding after venipunture

13. Coagulation tests Evaluation of blood smear
Platelet number
Platelet morphology
Look for platelet clumps and estimate platelet number
General rule: # platelets/oil x 15,000 = estimated platelet count (plts/ul)
Schizocytes (fragmented rbcs) suggest microangiopathic hemolysis (DIC)

14. Coagulation Tests
Buccal mucosa bleeding time (BMBT): time in minutes for bleeding to cease from a standardized incision (laceration in upper lip)
Evaluates formation of platelet plug and depends upon:
Adequate number of platelets
Adequate function of platelets
Normal blood vessel wall structure

15. Coagulation Tests
Activated partial thromboplastin time (APTT): time in seconds for clot formation in citrated plasma after addition of contact activator, phospholipid, and calcium
Platelets have no effect on this test since phospholipid is added
Evaluates intrinsic and common pathways
Detects 30% or less factor activity in these pathways

16. Coagulation tests
One-stage prothrombin test (OSPT or PT): time in seconds for clot formation in citrated plasma after addition or thromboplastin and calcium
Platelets have no effect on test since adding tissue thromboplastin (factor III)
Factor VII has the shortest half-life
Evaluates Extrinsic and Common Pathways
Detects 30% or less factor activity

17. Coagulation tests
Thrombin clotting time (TCT): time in seconds for clot formation in citrated plasma after addition of thrombin and calcium
Most sensitive measure of fibrinogen concentration
Prolonged TCT with:
Hypofibrinogenemia (DIC)
Increased FDPs, D-dimers
Heparin treatment
Uremia

18. Coagulation tests
Fibrin degradation products (FDPs): formed when plasmin dissolves the fibrin clot
Ultimately are removed by the liver (half-life 9-12 hours).

19. Coagulation tests
D-dimers: unique FDPs that are formed when cross-linked fibrin is lysed by plasmin
Specific for active coagulation and fibrinolysis
D-dimer is a sensitive test for DIC and likely is superior to traditional FDP assays for this purpose

20. Disorders of Primary Hemostasis
In theory, spontaneous bleeding as a result of primary hemostatic defect could be due to one of three mechanisms
Thrombocytopenia (decrease platelet number)
Thrombopathia (platelet dysfunction)
Vascular defect
Thrombocytopenia is most common cause; others are rare.

21. Thrombocytopenia Causes: Decreased platelet production
Increased platelet destruction
Increased platelet consumption
Increased platelet sequestration

22. Decreased platelet production
Most common cause for thrombocytopenia in cats
Usually caused by retrovirus-induced bone marrow disorders (FeLV)
Other causes: Drugs (estrogen, phenybutazone, some chemo agents); toxins; radiation; infectious (FIV); neoplastic process in bone marrow; specific platelet infectious agents (Ehrlichia platys); pure megakaryocytic hypoplasia (rare)
Diagnosis by bone marrow aspiration or biopsy

23. Increased platelet destruction
Most common cause of thrombocytopenia in dogs; extremely rare in cats
Immune-mediated:
Primary: Idiopathic, Evan syndrome, systemic lupus erythematosus
Secondary: Drugs, live-virus or modified-live virus vaccination, tick-borne disease, neoplasia, bacterial infection

24. Increased platelet consumption
Occurs most commonly in dogs and cats with DIC
Other causes: Acute Hemorrhage, Neoplasia, Microangiopathies, Sepsis, vasculitis, splenic torsion, hyperslenism, hepatic disease, hemolytic uremia syndrome

25. Increased platelet sequestration
Splenic congestion
Neoplasia (hemangiosarcoma, lymphoma)

26. Platelet dysfunction
Can be congenital (von Willebrand’s disease) or acquired – more common
Rarely result in spontaneous bleeding
Acquired causes - secondary to:
Drug therapy (esp. aspirin, cephalosporins, B-lactams, synthetic colloids)
Uremia
Neoplasia
DIC
Monoclonal gammopathies (multiple myeloma, plasma cell )
Ehrlichiosis
Retroviral infections
Snake venom

27. Von Willebrand’s disease
More common in dogs; rare in cats
Common in Doberman pinschers, GSD, Poodles, Golden retrievers, Shetland sheepdogs.
vWF is produced by megakaryocytes and endothelial cells, and it circulates in plasma complexed to factor VIII
It is important in the formation of the primary platelet plug (causes platelets to adhere to subendothelial cartilage)

28. vWD Usually see excessive bleeding during or after surgery
Excessive bleeding during teething and estrus can occur
Perinatal mortality or abortion/stillbirths are common in litters with vWD
BMBT is most cost effective screening test in at-risk breeds
Can also send out blood to quantify vWF:
<50% indicate vWF deficiency

29. Treatment of vWD
Fresh frozen plasma, whole fresh blood, or cryoprecipitate - causes the circulating vWF concentration to increase within minutes
Desmopressin acetate – causes massive release of vWF from endothelial cells
Can use topical hemostatic agents (fibrin, collagen, methacrylate) to control local bleeding

30. Disorders of secondary hemostasis: Congenital
Specific factor deficiencies
Clinical severity depends on magnitude of factor deficiency and the exposure of the animal to trauma that may cause bleeding.
Most animals develop bleeding in the first year of life.
Mildly affected animals may not bleed until later in life, especially if they do not undergo surgery or trauma.

31. Inherited Coagulopathies
Should be suspected in younger animals, esp taking breed into account
Should be suspected if there is a history of recurrent bleeding
If acquired causes have been ruled out
Diagnosis requires specific factor assays performed by specialized laboratories.

32. Inherited Coagulopathies
Treatment is aimed at controlling bleeding
If bleeding is severe, transfusion of plasma products is indicated to provide needed clotting factor(s).
For deficiencies of factors VIII and I, cryoprecipitate is the ideal plasma product.
For deficiencies of factors II, VII, IX, X, and XI, cryosupernatant is ideal.
Fresh frozen plasma is an acceptable alternative.

33. Disorders of Secondary Hemostasis: Acquired
Vitamin K deficiency and antagonism
Hepatic disease
DIC

34. Vitamin K deficiency
Synthesis of Vitamin K-dependent factors occurs in the liver
Factors II, VII, IX, X
Vitamin K is an essential cofactor (for carboxylation) to activate these factors
Anticoagulant rodenticides interfere with recycling of Vitamin K, resulting in rapid depletion
Proteins C and S are also vitamin K-dependent

35. Diagnosis
Factor VII has shortest half-life (4-6 hours), so will see prolongation in PT first
Clinical signs usually occur 2-3 days after ingestion
By the time hemorrhage is seen, PT and APTT will be prolonged
FDP, D-dimer, and fibrinogen concentrations are usually normal
Platelet count is usually normal, but can be decreased due to consumption

36. Treatment
Fresh frozen plasma or whole fresh blood to replenish clotting factors
Prbc transfusion if animal is anemic
Vitamin K1 – 5mg/kg SC in multiple sites, followed by oral Vitamin K1 2.5mg/kg BID 12 hrs later (give with fatty meal to enhance absorption)
May take 12 hours to shorten PT

37. Hepatic Disease
Severe damage to hepatocytes or obstruction of bile duct results in variable factor deficiencies and/or abnormalities in Vitamin K metabolism
Disorders of platelet number and function may occur
PT and PTT can be prolonged
FDP, D-dimer, and fibrinogen concentrations may be increased due to reduced clearance of plasminogen activators, as well as reduced synthesis of fibrinolytic inhibitors

38. Hepatic Disease
Based on results of coagulation tests, may be difficult to differentiate from DIC
Look to physical exam findings, chemistry profile changes, and liver function testing.
Treatment with fresh frozen plasma transfusion +/- Vitamin K1
Repeat coags in 12 hrs to assess if Vitamin K1 was beneficial

39. Disseminated Intravascular Coagulation
Excessive intravascular coagulation leads to multiple organ microthrombosis. Multiple organ failure (MOF) or multiple organ dysfunction syndrome (MODS) can be a consequence.
Paradoxical bleeding occurs due to the inactivation or excessive consumption of platelets and clotting factors secondary to enhanced fibrinolysis.
DIC is a complex syndrome, and is a common pathway in a variety of disorders

40. DIC
General mechanisms leading to activation of intravascular coagulation:
Endothelial damage
Platelet activation
Release of tissue procoagulants

41. DIC Pathogenesis
First, primary and secondary hemostatic plugs form in multiple small vessels simultaneously, forming multiple thrombi in the microcirculation
Ischemia is the result, leading to MOF or MODS
Platelets are consumed in large numbers, leading to thrombocytopenia

42. DIC Pathogenesis
Second, fibrinolytic system is activated, and this results in clot lysis and the inactivation of clotting factors and impaired platelet function.
Third, antithrombin and possibly proteins C and S are consumed in an effort to stop intravascular coagulation. This effectively depletes these anticoagulants.
Fourth, fibrin formation in the microvasculature causes shearing of rbc’s (schistocytes), and leads to hemolytic anemia.

43. DIC
Excessive intravascular coagulation and depletion of natural anticoagulants leads to spontaneous bleeding as a result of:
Thrombocytopenia
Impaired platelet function
Inactivation of clotting factors

44. Primary Disorders associated with DIC
Dogs:
Cats:
Neoplasia (primarily HSA)
Liver disease
Immune-mediated disease (IMHA, ITP)
Sepsis
Pancreatitis
GDV
Hepatic lipidosis
Neoplasia (mainly lymphoma)
FIP

45. DIC: Clinical signs Chronic, clinically silent form
Acute, fulminant form
No spontaneous bleeding
Abnormalities seen on blood work points to DIC
Common with malignancy and possibly other chronic disorders
Present for evaluation of primary problem
After heat stroke, electrocution, acute pancreatitis
Or, acute decompensation of chronic, silent form (i.e. HSA)
Profuse, spontaneous bleeding, plus signs secondary to anemia and MOF
Both primary and secondary bleeding
Extremely rare in cats

46. Diagnosis Hemostatic abnormalities CBC/Chem/UA
Thrombocytopenia, prolonged PT and APTT, normal or low fibrinogen concentration, positive FDP and/or D-dimer test, decreased antithrombin concentration
Regenerative hemolytic anemia, or nonregenerative anemia
Hemoglobinemia, Schnistocytes
Thrombocytopenia, neutrophilia with left shift, or rarely neutropenia
Hyperbilirubinemia, azotemia and hyperphosphatemia, increased liver enzymes, decreased TCO2, panhypoproteinemia
Hemoglobinuria and bilirubinuria

47. Treatment Stopping intravascular coagulation
Maintaining good organ perfusion
Preventing secondary complications
Grave prognosis
Negative prognostic indicators are marked prolongation of APTT and severe thrombocytopenia
Prognosis depends on how many abnormalities are identified on coagulation tests

48. Thrombosis/Thromboembolism
Causes
Stasis of blood
Activation of IV coagulation in an area of damaged or abnormal endothelium
Decreased activity of natural anticoagulants
Decreased or impaired fibrinolysis