Coagulopathies Hayley Morse May 29, 2008. Normal Hemostasis First, injury to a blood vessel leads to immediate vasoconstriction, as well as activating.

Coagulopathies

Hayley MorseMay 29, 2008

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.

Normal Hemostasis

• Activation of intrinsic pathway (contact phase) results in fibrin formation

• This process occurs almost simultaneously with platelet adhesion and aggregation

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.

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

Coagulation Cascade

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

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

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

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?

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

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

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)

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

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

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

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

Coagulation tests

• Fibrin degradation products (FDPs): formed when plasmin dissolves the fibrin clot

• Ultimately are removed by the liver (half-life 9-12 hours).

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

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.

Thrombocytopenia

• Causes:– Decreased platelet production– Increased platelet destruction– Increased platelet consumption– Increased platelet sequestration

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

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

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

Increased platelet sequestration

• Splenic congestion• Neoplasia (hemangiosarcoma, lymphoma)

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

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)

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

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

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.

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.

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.

Disorders of Secondary Hemostasis: Acquired

• Vitamin K deficiency and antagonism• Hepatic disease• DIC

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

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

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

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

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

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

DIC

• General mechanisms leading to activation of intravascular coagulation:– Endothelial damage– Platelet activation– Release of tissue procoagulants

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

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.

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

Primary Disorders associated with DIC

Dogs:• Neoplasia (primarily HSA)• Liver disease• Immune-mediated disease

(IMHA, ITP)• Sepsis• Pancreatitis• GDV

Cats:• Hepatic lipidosis• Neoplasia (mainly

lymphoma)• FIP

DIC: Clinical signs

Chronic, clinically silent 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

Acute, fulminant form• 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

Diagnosis

Hemostatic abnormalities• Thrombocytopenia,

prolonged PT and APTT, normal or low fibrinogen concentration, positive FDP and/or D-dimer test, decreased antithrombin concentration

CBC/Chem/UA• 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

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

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