Excel CPD
Approach to the Bleeding Patient
Nick Bexfield
BVetMed PhD DSAM DipECVIM-CA MRCVS
University of Cambridge
Nick Bexfield 2013
Physiology of haemostasis
Platelets interact with endothelial cells to ensure normal vascular integrity. When a vessel is injured
platelets adhere to collagen and von Willebrand factor (vWF) is important in platelet adhesion
(primary haemostasis). Shape change and release reactions follow adhesion with secretion of
substances from granules which potentiate platelet aggregation and contraction of the platelet plug.
Stabilization of the platelet plug is achieved by the deposition of fibrin, the end product of the
coagulation cascade (secondary haemostasis).
Plasma proteins involved in haemostasis
Von Willebrand Factor
This is a highly glycosylated, multimeric protein of high molecular weight which is derived from
vascular endothelial cells. Although it is also present in megakaryocytes and platelets of other
species there is little, if any, vWF in canine platelets. In plasma, vWF circulates non-covalently
bonded with the antihaemophilic coagulation factor, factor VIII (F.VIII). vWF has a pivotal role in
platelet adhesion to collagen. The protein is released from endothelial stores by the action of
vasopressin (ADH), after exercise and stress.
Coagulation proteins: secondary haemostasis
The coagulation proteins or factors are designated by roman numerals. Classically the coagulation
cascade is divided into intrinsic and extrinsic pathways with a final common pathway (see diagram)
although there is extensive interaction in vivo. Factors II, VII, IX and X are synthesized in the liver
and are vitamin K dependent. Factors V and VIII are essential cofactors, also liver derived, and
are activated by the action of thrombin.
The intrinsic pathway is initiated by the activation of F.XII after surface (subendothelial) contact or
exposure. F.XIIa also plays an important role in inflammation by the release of kinins and kallikrein
production and in the activation of complement, as well as triggering fibrinolysis by conversion of
plasminogen to plasmin. The extrinsic pathway comprises F.VII and tissue factor (thromboplastin),
a lipoprotein complex derived from the membranes of many cells including monocytes and
macrophages. The common pathway consists of conversion of prothrombin to thrombin by F.Xa
and finally the production of insoluble fibrin from fibrinogen. This polymerises to form a clot under
the influence of F.XIIIa. Thrombin activates many of the enzymes and thus feedback amplification
occurs. Calcium ions and phospholipid (PF3) are essential for many of the enzyme reactions. Fibrin
polymer is deposited in a meshwork to form a definitive platelet plug, preventing further loss of
blood.
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INTRINSIC PATHWAY
EXTRINSIC PATHWAY
DAMAGED SURFACE / KALLIKREIN
TRAUMA / TISSUE FACTOR
FXIIa
FXII
FXI
FIX
Activated partial
thromboplastin
time (APTT)
FVIIa
FVII
FXIa
FIXa
One stage
prothrombin
time (OSPT)
FVIIIa
FX
FXa
FX
FVa
COMMON
PATHWAY
FII
FIIa
prothrombin
FI
fibrinogen
thrombin
FIa
fibrin
CLOT
cross linked fibrin
Limiting reactions: tertiary haemostasis
Localisation of these reactions to the surface of activated platelets limits the extent of clot and
thrombus formation. Thrombin, in addition to activating cofactors and other enzymes, by further
enzymatic cleavage also inactivates molecules. Protein C and Protein S are vitamin K-dependent
factors which inactivate cofactors V and VIII. The major physiological inhibitor of coagulation is
antithrombin III (AT III). This, in association with heparin, inactivates thrombin and serine proteases.
Fibrinolysis
The fibrin clot is broken down by the action of plasmin. Plasmin is derived from plasminogen which
is activated by a number of molecules, the most important of which is tissue plasminogen activator
(tPA), which is produced by endothelial cells. The breakdown products of fibrin and fibrinogen,
resulting from the action of plasmin, are known as fibrin(ogen) split or degradation products (FSP,
FDP).
In summary, the normal haemostatic system is a complex, well regulated balance between the
vascular responses, platelets, coagulation proteins, fibrinolytic mechanisms and natural inhibitors.
These mechanisms serve to limit haemorrhage, prevent excessive thrombosis, stimulate local repair
and thus maintain homeostasis.
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Clinical approach to a bleeding disorder
History and clinical findings
The presenting signs are very helpful in distinguishing platelet problems from clotting factor defects.
Differentiating between platelet disorders and coagulation factor defects:
Platelet disorders
Coagulation factor defects
Petechiae common
Haematomata common
Usually multiple sites of bleeding
Often single site of bleeding
Surface bleeding, often clots quickly
Deep or cavity bleeds
Bleed after venepuncture
Venepuncture often uncomplicated
Prolonged oozing from incisions
Delayed or re-bleeding from wounds
Particular aspects of history such as occurrence of previous bleeding episodes, reactions to surgical
interventions, and knowledge of relatives may be helpful in identifying the condition as acquired or
inherited.
Differentiating inherited disorders from acquired disorders:
Inherited disorders
Acquired disorders
Young age of onset
Onset at any age
Previous bleeding episodes
Often no previous problems
May have affected relatives
Usually no affected kin
Both may be exacerbated by the presence of other diseases
The breed of the animal may suggest a particular inherited defect and if the patient is male then
haemophilia may be suspected. Information regarding possible exposure to drugs and toxins and
the presence of concurrent illnesses may help point towards a specific condition.
Physical examination
Percussion and auscultation of the chest are important to detect intrathoracic bleeding which might
require urgent therapeutic intervention. Abdominal examination may indicate the presence of
splenomegaly or hepatomegaly or masses/tumours. Peripheral lymph nodes should also be
assessed, since malignant lymphoma can be complicated by DIC. Ophthalmic examination may
reveal the presence of conjunctival haemorrhage, hyphaema and retinal haemorrhages; all of these
features are more likely to be found in platelet disorders than coagulation factor defects.
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Radiography and ultrasound examination may be indicated to further characterise the nature of
masses or other clinical findings. Thoracic radiography should be undertaken with care if pleural
haemorrhage is suspected and the animal maintained in sternal recumbency if necessary. Chest
films should be examined for the presence of metastatic tumours as well as for evidence of
haemorrhage, although it may be difficult to interpret interstitial and alveolar patterns if
intrapulmonary haemorrhage is present.
Evaluation of haemostatic function
Definitive diagnosis of a bleeding tendency requires some or all of the following tests:
Tests of haemostasis
Test
Interpretation
Platelet count
Low in failure of production, destruction or consumption
Buccal mucosal bleeding Prolonged in defects of primary haemostasis
time
Whole blood clotting time
Crude
measure
of
intrinsic
coagulation
(and
thrombocytopenia)
Clot retraction
Crude measure of platelet function
Activated clotting time
More sensitive measure of
intrinsic coagulation (and
thrombocytopenia)
PIVKA
Identifies vitamin K antagonism
Prothrombin time
Measure of extrinsic and common pathways
Partial thromboplastin time
Measure of intrinsic and common pathways
Thrombin time
Estimate of fibrinogen, sensitive to heparin and FDPs
Specific factor assays
Accurate quantification of individual factors
von
Willebrand
factor Estimate of vWF protein concentration
antigen
Fibrin degradation products
Elevated in severe thrombosis and DIC
D-dimers
Platelet numbers
Microscopic examination of a stained blood smear from EDTA anticoagulated blood. Check sample
for the presence of any clots. Scan for evidence of platelet clumps, before examining the monolayer
of the film under oil immersion. In a well prepared smear 3-4 platelets per OIF indicates an
adequate platelet count. Assess morphology: large or shift platelets indicates increased platelet
production; fragmented or abnormal platelets suggests microangiopathy or neoplasia.
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Buccal mucosal bleeding time (BMBT)
If the platelet count appears low on a blood smear then there is no need to undertake a bleeding
time test - it is bound to be prolonged. BMBT is a relatively simple and reproducible method of
assessing primary haemostasis i.e. platelet function. Method: upper lip held up with gauze
bandage tied tight enough to mildly obstruct venous return. A small standardised incision is made
with a bleeding time device (Simplate I or II, Organon Teknika, General Diagnostics; Surgicutt,
Ortho Diagnostic Systems) and blood is blotted away with filter paper held adjacent to, but not
disturbing the incision site. Time to cessation of bleeding is recorded. Bleeding times of normal
dogs: 1.5 to 3.5 minutes. Prolonged bleeding times in patients with normal platelet counts occur with
von Willebrand’s disease (vWD), thrombocytopathies or, rarely, vessel wall defects. The BMBT in
dogs with coagulation factor defects is usually normal, although rebleeding may occur.
Whole blood clotting time (WBCT)
Crude measure of the intrinsic pathway of coagulation. Method: 1-2ml of blood placed in each of 2
or 3 clean glass test tubes, start stopwatch. Invert tubes every 30 seconds. Time taken for complete
clot formation, when blood ceases to flow up the tube, recorded. The WBCT is taken as the mean of
the clotting times for each of the tubes. The WBCT of normal dogs at room temperature: 6.1 +/- 0.2
minutes (mean +/-standard deviation).
In this test the glass surface acts as the initiator of intrinsic coagulation. The phospholipid required
is provided by the platelets in the sample and so the WBCT is prolonged in cases of severe
thrombocytopaenia. The WBCT is prolonged in cases of haemophilia A and B and deficiencies of
other factors in the intrinsic and common pathways, in established vitamin K antagonism, severe
hepatic dysfunction and DIC.
Activated clotting time (ACT) test
A less crude measure of the intrinsic and common pathways of coagulation. Tubes containing
diatomaceous earth as a contact activator (Becton Dickenson) are used. Optimally the tubes are
incubated at 37oC although the test can be performed at room temperature, and the tubes tilted
frequently (approximately every 10 seconds) and the time to clot formation noted. The range of
values reported for normal dogs are 64-95 seconds at 37oC. At room temperature the range is
longer, 83-129 seconds. The ACT is sensitive to the same defects as the WBCT and is also
prolonged in dogs with severe thrombocytopaenia. It is useful for monitoring animals on heparin
therapy.
PIVKA
Proteins involved in, or induced by, vitamin K antagonism (PIVKA) can be assessed by a kit test
(Thrombotest, Nyegaard Corporation). This test identifies animals with vitamin K antagonism or
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severe vitamin K deficiency, and has the advantage of detecting cases of rodenticide poisoning 12
to 24 hours before the prothrombin time is prolonged and well in advance of the appearance of
clinical signs.
Specific coagulation assays
Correct sample collection is essential.
- good venepuncture technique (tissue thromboplastins and haemolysis may initiate clotting)
- into 3.8% sodium citrate anticoagulant (9 parts blood to 1 part citrate)
- careful mixing of blood and anticoagulant particularly if solid sodium citrate is used (>20
inversions)
- samples should be delivered to the laboratory as soon as possible, but there is evidence that next
day delivery results in no significant deterioration. Clotting factors are well preserved in plasma at
4oC or 22oC for up to 24 hours, but if there is to be any longer delay then plasma should be frozen
in aliquots and transported on dry ice at a later date.
The screening tests of coagulation are the prothrombin time (PT) sometimes designated onestage PT or OSPT) and the partial thromboplastin time (PTT) or activated PTT (APTT).
Laboratories should compare patient samples to pooled normal plasma of the same species and all
tests should be performed in duplicate. Clotting times which are 30% longer than control values are
considered abnormal. Individual clotting factors need to be reduced to at least 50% of normal before
screening tests are prolonged and dilution tests may need to be performed to increase the
sensitivity of the tests.
The PT evaluates the extrinsic and common pathways of coagulation and is therefore affected
by deficiencies of factors VII, X, V, II and fibrinogen. Factor VII has the shortest half-life of the
clotting factors and is the first factor to be affected appreciably by rodenticide anticoagulants. The
PT is used to check that the duration of vitamin K therapy in the management of cases of poisoning
has been adequate. Whilst on therapy the PT should be normal. If the PT becomes prolonged again
48 hours after cessation of therapy then there is still anticoagulant present in the body and
treatment should be resumed for a further week and the procedure repeated.
The APTT is the most sensitive measure of the intrinsic and common pathways of
coagulation.
Specific factor assays are performed using substrate plasma which is deficient in a single factor. A
modified APTT or PT assay is performed using dilutions of test and standard plasma, clotting times
compared and the concentration of factor present calculated.
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DISORDERS OF PRIMARY HAEMOSTASIS
1. Thrombocytopaenia
Commonest cause of haemostatic defects in the dog. Reduced platelet numbers may be the result
of defective platelet production, accelerated destruction or loss from the circulation. Remember that
unlike clotting factor disorders, in which large cavity bleeds are common, reduced platelet number or
activity causes smaller bleeds e.g. petechial haemorrhages, epistaxis, CNS bleeding.
Causes of thrombocytopaenia
Defective platelet production:
drug-induced marrow hypoplasia
chemical/ toxic marrow suppression
idiopathic marrow aplasia/pancytopenia
chronic infections, particularly viral and rickettsial
myelophthisis
antibodies directed against megakaryocytes
cyclic thrombocytopaenia
Accelerated platelet removal:
immune-mediated destruction (most common)
consumption in microangiopathic conditions (DIC, vasculitis)
acute infections
Platelet sequestration or loss:
splenomegaly
vascular pooling
acute ongoing haemorrhage
Thrombocytopenia is the most common acquired haemostatic disorder and is due to decreased
bone marrow production, destruction, consumption, sequestration and loss of platelets (see below).
Severe thrombocytopenias (<50 x 109/l) are due to decreased production, destruction or
consumption. It is rare to see platelet counts <100 x 109/l due to haemorrhage or sequestration
alone. Therefore, a severe thrombocytopenia (<50 x 109/l) is usually the cause, rather than a
consequence, of haemorrhage.
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Defective platelet production:
drug-induced marrow hypoplasia
chemical/ toxic marrow suppression
idiopathic marrow aplasia/pancytopenia
chronic infections, particularly viral and rickettsial
myelophthisis
antibodies directed against megakaryocytes
cyclic thrombocytopenia
Accelerated platelet removal:
immune-mediated destruction (most common)
consumption in microangiopathic conditions (DIC, vasculitis)
acute infections
Platelet sequestration or loss:
splenomegaly
vascular pooling
acute ongoing haemorrhage
Immune-mediated thrombocytopenia
Immune-mediated thrombocytopenia (ITP) is a common cause of acquired thrombocytopenias in
dogs and cats and can be primary or secondary to infectious diseases (e.g. ehrlichiosis, babesiosis,
leishmaniosis, angiostrongylosis and rickettsiosis), immune-mediated diseases (e.g. SLE), drugs
(sulphonamides) or neoplasia. A high prevalence of primary ITP is found in Cocker Spaniels,
Miniature and Toy Poodles and Old English Sheepdogs. Animals typically present with mucosal
haemorrhage (epistaxis, haematemesis, haematuria), petechiae and ecchymoses, subcutaneous
bruising and hyphaema or retinal haemorrhage. Gastrointestinal haemorrhage is relatively common
in cases of ITP and can be severe. May be asymptomatic and discovered incidentally, but risk of
bleeding is present at counts <50 x 109/l.
Platelet counts are usually <20 x 109/l and are sometimes zero. Routine coagulation screening tests
(PT, APTT) are within reference intervals. Unfortunately there is no commercially available antiplatelet antibody test. Some cases may have concurrent IMHA (Known as Evans syndrome).
Treatment of ITP involves the use of immunosuppressive drugs as for the treatment of IMHA. The
author generally uses prednisolone at 2mg/kg/day and adds in further drugs if the response is poor.
Many animals can be successfully treated with prednisolone alone. Treatment should be continued
for several months and animals observed for relapses in the future. Close monitored for
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gastrointestinal blood loss, which can be worsened by the use of corticosteroids, should also be
employed. Some authors also advocate the use of vincristine (0.02mg/kg iv) as a single dose, as it
affects thrombopoiesis in addition to impairing phagocytosis of platelets. A rapid and dramatic rise in
platelet numbers occurs a few days after use of this drug, although the rise is usually only transient.
It is however possible that the platelets released following administration of vincristine and immature
and therefore non functional. Supportive therapies with whole blood may also be considered to
replace platelets and blood lost due to haemorrhage. The benefits of whole blood on increasing
platelet numbers are usually only mild and transient however.
2. von Willebrand's disease (vWD)
Canine vWD is the commonest inherited disorder of haemostasis. The condition is characterized by
the presence of reduced concentrations and/or an abnormal molecular structure of vWF, the plasma
protein essential for normal platelet adhesion in vivo. Some breeds, including Doberman Pinschers,
German shepherd dogs and Labrador Retrievers have a high prevalence of the trait. The bleeding
tendency and severity of bleeding in vWD is variable and the bleeding tendency of affected
individuals may vary, often decreasing with advancing age. Intercurrent disease tends to exacerbate
the risk and severity of bleeding. Clinical manifestations include easy bruising, prolonged oozing of
blood after minor injuries and surgery, excessive bleeding during oestrus and post-partum. Mild
vWD may exacerbate the bleeding tendency associated with other conditions, such as IMTP.
Platelet counts and coagulation screening tests are normal in vWD. The buccal mucosal bleeding
time (BMBT) is prolonged. The diagnosis is confirmed by demonstration of low vWF concentrations.
3. Inherited thrombopathias
Platelets from affected dogs fail to aggregate in response to physiological stimuli and do not support
clot retraction. Giant platelets with abnormal morphology may be seen in the circulation.
4. Defects of platelet function
Various drugs are known to affect platelet function, particularly the non-steroidal anti-inflammatory
drugs such as aspirin and phenylbutazone, which interfere with prostaglandin synthesis. A state of
platelet refractoriness can be induced by heparin preparations and dextrans.
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DISORDERS OF SECONDARY HAEMOSTASIS:
Clinical features which may be found in coagulation factor defects:
Soft tissue swellings - haematomata
Lameness and joint swelling - haemarthroses
Prolonged bleeding - tooth shedding, dental extraction
Dyspnoea and dullness on chest percussion - haemothorax, haemomediastinum
Severe dyspnoea and stertor - tracheal submucosal haemorrhage
Abdominal pain - visceral or peritoneal haemorrhage
Neurological disturbances - intracranial or spinal haemorrhage
Acquired coagulation defects
Vitamin K antagonism (Warfarin poisoning)
Anticoagulant rodenticides interfere with vitamin K metabolism in the liver, blocking the conversion
of inactive vitamin K epoxide to the active vitamin K1 which is required for conversion of precursor
proteins into active clotting factors. This results in depletion of clotting factors II, VII, IX and X.
Clinical signs of poisoning may appear within 1-3 days after ingestion of second generation
compounds (bromadiolone, brodifacoum, flocoumafen) and 4-5 days after exposure to first
generation compounds (warfarin, dicoumarol, diphacinone, chlorphacinone). Haemorrhage may
occur in a large number of sites, both externally and particularly into body cavities. Affected animals
show depression, weakness and pallor, depending upon the severity of haemorrhage. Intrathoracic
haemorrhage is the most common cause of acute death, and animals with clinical or radiographic
evidence of pleural fluid accumulation require emergency treatment.
Diagnosis: a history of exposure is most helpful. Screening coagulation assays are imperative to
confirm the suspicion and rule out other causes of bleeding. Factors in both the intrinsic and
extrinsic pathways become depleted. Since factor VII has a shorter half life than other
factors, the prothrombin time (PT) is prolonged initially but later the activated partial
thromboplastin time (APTT) also increases. The platelet count may decrease slightly due to
acute blood loss.
The PT promptly returns to normal with appropriate therapy, but if therapy is withdrawn too soon it
will become prolonged again. The PT should be checked 48 hours after cessation of therapy and if
significantly prolonged (30% longer than control) therapy should be reinstituted for a further two to
three weeks.
In animals suffering from respiratory distress and/or hypovolaemic shock, plasma or whole blood
transfusion is indicated to supply clotting factors and expand the plasma volume. Exercise
restriction (cage confinement if possible) is essential. Thoracocentesis should be attempted only in
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animals which are severely dyspnoeic and after therapy has been initiated. With proper
management of life-threatening bleeding episodes and adequate duration of vitamin K therapy the
outcome in most cases is favourable.
Hepatic disease
Many of the clotting factors as well as inhibitors of coagulation are synthesized in the liver and
active clotting factors in the circulation are cleared by the liver. Also qualitative and quantitative
alterations in platelets may occur in liver diseases. Animals with acute, diffuse liver disease, in
particular acute hepatic necrosis or diffuse tumour infiltration, may present with a bleeding diathesis.
Chronic liver conditions such as portosystemic shunts often result in increased clotting times but are
rarely associated with signs of spontaneous haemorrhage.
History and clinical signs indicative of liver involvement will be evident. Laboratory tests of
coagulation reveal elevation of both PT and APTT tests. Increased plasma concentrations of AP
and ALT confirm the presence of liver damage; increased bile salt concentrations indicate hepatic
dysfunction. Treatment is primarily supportive and the prognosis depends upon the severity of the
hepatic pathology.
Inherited coagulation defects
Factor VIII deficiency (haemophilia A, or "classic" haemophilia)
Factor VIII (F.VIII) deficiency is a sex-linked inherited defect in the dog, as in other species; affected
animals are males and females may be asymptomatic carriers, although homozygous affected
females may occur. It is the commonest of the severe inherited bleeding disorders and has been
described in many breeds of dogs including mongrels. The bleeding tendency may be severe,
moderate or mild, depending on the severity of the F.VIII deficiency. Animals with less than 1% of
normal F.VIII concentrations suffer from spontaneous, life-threatening bleeding episodes, which are
usually apparent from a young age. It is unusual for severely affected animals to reach maturity. A
history of excessive bleeding when deciduous teeth are lost, shifting lameness, and unexplained
joint and soft tissue swellings is common. F.VIII is an essential cofactor in the intrinsic pathway and
deficiencies result in prolongation of the APTT. The diagnosis is confirmed by a specific F.VIII
assay.
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Factor IX deficiency (haemophilia B, Christmas disease)
Like F.VIII deficiency, factor IX (F.IX) deficiency is a sex-linked inherited condition, which clinically is
identical to F.VIII deficiency, since both factors are active at the same point in the coagulation
cascade. As with F.VIII deficiency, prolongation of the APTT is seen. Haemophilia B has been
recognised in cats.
Devon Rex coagulopathy
A coagulopathy of complex nature has been recognised in this breed for some time. A vitamin Kdependent multifactorial coagulopathy was described in several related Devon Rex cats in Australia.
Laboratory investigations revealed two to threefold prolongation of PT and APTT. Factors II, IX and
X were reduced to less than 20% of normal and F.VII to less than 50%. Oral vitamin K (5 mg daily)
corrected the coagulation factor abnormalities and bleeding tendency. Cats of both genders were
affected, but the pattern of inheritance was not elucidated. A case of Devon Rex coagulopathy has
been confirmed recently in the UK.
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Disseminated intravascular coagulation (DIC)
DIC or disseminated intravascular thrombosis (DIT) is a disorder of both primary and secondary
haemostasis. It is also known as consumption coagulopathy. Generalized or diffuse activation of
haemostasis occurs, triggered by several mechanisms including release of tissue substances into
the blood, exposure of damaged endothelium and procoagulant factors produced by various
neoplasm’s. This results in the formation of thrombi in the microvasculature and the consumption of
both platelets and clotting factors, and in the triggering of fibrinolysis and the production of fibrin
degradation products (FDPs), which are themselves anticoagulants, interfering with the action of
thrombin on fibrinogen. Inhibitors such as antithrombin III (AT III) are utilized and also depleted. The
net result of these events is a tendency to bleed.
DIC is always a secondary complication of an underlying disease process and may occur in
association with a number of conditions.
Diseases associated with DIC
Tissue damage:trauma
Neoplasia:
carcinoma
shock
haemangiosarcoma
heat stroke
lymphoma/lymphoid leukaemias
vasculitis
myeloproliferative disease
obstetrical complications
haemolysis
Infections:
infectious canine hepatitis
Leptospirosis
peritonitis
endotoxaemia
septicaemia
angiostrongylosis
Clinical signs: the onset of DIC may be insidious or abrupt and the condition may be acute or
chronic, depending on the extent of microvascular thrombosis and consumption of platelets and
clotting factors. The bleeding manifestations seen include prolonged bleeding after venepuncture,
prolonged bleeding from minor wounds or after minor surgery, epistaxis and bleeding from other
body orifices.
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Diagnosis: platelet numbers are reduced and clotting times (WBCT, ACT, PT, APTT) are prolonged.
Poor clot formation due to FDPs interfering with fibrin polymerization is evident in clotting assays.
AT III concentrations are reduced. Fibrinogen may be markedly reduced, but may remain in the
normal range if the primary disease process is inflammatory and likely to result in elevation of
fibrinogen concentrations. Elevation of FDPs is usually, although not always, detected. D-dimer
elevation is commonly seen.
On the whole, the prognosis is poor, but is dependent upon early identification of the
problem and successful management of the underlying precipitating cause.
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