Bleeding haemostasic disorders

• What is haemostasis?

  Haemostasis is a balance.

  Occurs on the surface.

  Disorders will result in haemorrhage and/or thrombosis

  1. Primary - platelet plug.
  2. Secondary - fibrin plug that requires the coagulation cascade.
  3. Clot lysis
• What are the clinical signs when haemostasis goes wrong?

  Echimosis.

  Ptechiae

  Hyphaemia

  Iatrogenic - caused by us e.g. taking a jugular blood sample and causing severe bruising.

  
• Clinical signs of primary haemotosis

  • Petechia/ecchymoses common
  • Bleeding from mucus membranes.
  • Often more than one site of bleeding
  • Haematomas are rare
• Clinical signs of secondary haemostasis

  • Petechiae/ecchymoses
  • Deep or cavity bleeds. Can bleed from mucous membranes.
  • Sometimes singles sites of bleeding.
  • Haematomas are common.
• Primary haemostasis - what is needed to make a platelet?

  Cells - Platelets, endothelial (source of von Willeband factor and inhibitors).

  Proteins - von Willebrands factor (vWf) and others.

  Facilitators - platelet agonists such as thrombin, collagen is also a platelet activator.

  Physiologic inhibitors - Nitric oxide, prostacyclin (prostoglandin E12) - these are produced by endothelial cells.
• What is diascopy?

  Does the lesion blanch under a glass slide (or cup)?

  • Yes - the skin redness is caused by vascular vasodilation and squashing the site removes/ fades the lesions.
  • No - no fading of the lesion means that there is haemorrhage in the skin (Petechiae).
• What is thrombocytopaenia?

  Low platelet numbers.
• what is thrombocytopathia?

  Platelet dysfunction.
• Investigation of primary haemostatic disorders?

  • Signalment.
  • Platelet count and morphology
  • Bleeding usually only seen if platelets <50x10^9/L
  • Buccal mucosal bleeding time (BMBT) - make a little bleeding area onto the gingiva or lip margins, then hold a bit of blotting paper away from the site and allow the blood to draw away. Time how long it takes the blood to start clotting. If it takes longer to blot then the dog may have a primary disorder.
  • Von Willebrands factor (vWF)
  • Platelet function assays
• What are the causes of thrombocytopaenia?


  Defective platelet production:

  • Buccal mucosal neoplasia e.g. leukaemia.
  • Drug/ chemical/ toxin-induced BM suppression.
  • BM infections (especially viral and rickettsial)

  Accelerated platelet removal:

  • Immune-mediated thrombocytopaenia (IMTP)
  • Consumption in microangiopathic conditions (DIC).

  Platelet sequestration or loss:

  • Spenomegaly / vascular pooling
  • Acute ongoing haemorrhage.
• What is Evan’s syndrome?

  IMHA + IMTP

  Platelets destroyed in the circulation and tissues faster than they can be made in the bone marrow.
• How do you categorise IMTP?

  Primary - idiopathic

  Secondary - drug-induced, or secondary to infection or neoplasia related.

  Occurs in young to middle aged, female dogs are over represented, especially cocker spaniels, miniature/toy poodles and old English sheepdogs which all are specifically predisposed.
• What is the treatment for IMTP?

  Treat any underlying disease!

  Whole blood transition isn’t that useful for increased platelet counts.

  Acute and long-term treatment centre and immunosuppresion:

  • Dexamethasone
  • Prednisolone
  • Azathioprine
  • Cyclosporin
  • Mycophenolate mofetil

  Splenectomy has had variable results but could be considered in refractive cases.

  Follow up:

  • Keep monitoring platelet counts, at least one a month.
  • Immunosuppressive therapy should be continued for a minimum of 4-6.

  Prognosis:

  • Can be good; relapse 10-40%;
  • Negative prognoises indicators: malaena; high BUN.
• What are the types thrombocytopathia?

  Inherited Thrombopathies

  Drug-induced defects of platelet function:

  • Various drugs; particularly NSAIDs

  Platelet dysplasia:

  • Myeloproliferative disease and other forms of neoplasia
• Diagnosis of thrombocytopathia

  • Normal PLT count but prolonged BMBT
  • Normal levels of vWF
  • To a degree it is often a diagnosis of exclusion
  • PLT function tests (specialist labs test).
• Treatment of thrombocytopathia?

  No specific therapy.

  Platelet transfusions are possible but are rare and don’t increase the PLT by much.

  Withdraw any drugs e.g NSAIDs

  Treatment symptomaticallu e.g. blood transfusions if marked anaemia.
• Type I Von Willebrands disease

  Abnormally low concentration of structurally normal plasma vWF. Has a mild to variable clinical severity.

  Affects a lot of breeds e.g. Akita’s, Bernese mountain dogs, GSD, Dobermann, Greyhound, Retreiver, Poodle.
• Type II Von Willebrans disease

  Structurally abnormal plasma vWF. See severe clinical signs. Seen in German short haired pointer and German wirehaired pointer.
• Type III Von Willebrans disease

  Essentially no plasma vWF, diagnosed by ELISA. Severe clinical severity.

  Seen in familial lines in Chesapeake bay retreiver, Dutch kooiker, Scottish terriers and Shetland sheepdogs.

  Sporadic - Blue heeler, border collie, bull terrier, cocker spaniels, labrador retreivers, mixed breeds, pomeranians.
• Clinical signs of Von Willebrands disease

  Typical of a primary haemostatic defect:

  • Mucosal haemorrhage; cutaneous bruising; prolonged bleeding from surgical and traumatic wounds.
  • Occasioanlly more profound bleeding.
• Diagnostic testing of Von Willebrans disease

  Platelet count will be normal.

  Buccal mucosal bleeding time is a useful screening test for vWD.

  The diagnosis is confirmed by demonstration of low vWF antigen concentrations.

  BUT the measurement does not always accurately predict the risk of haemorrhage.
• Treatment of von Willebrans disease

  Plasma - in severe cases; stabilisation and cessation of active haemorrhage.

  Cryoprecipitate

  Red cells - if oxygen-carrying capacity compromised.

  Type 1 vWD treatment -

  • Desmopressin
  • 1ug/kg bodyweight subcutaneously in the dogs.
  • Acts by causing release of vWF from endothelial cells.
• Secondary haemostasis

  Cells - fibroblasts, platelets, endothelial cells, leukocytes.

  Ensymatic coagulation factors - factors XI, X, IX, VII and II.

  Non-enzymatic coagulation factors - cofactors: tissue factor (TF), facts V and VII.

  Fibrinogen

  Calcium

  
• Vitamin K in clotting

  Vitamin K is an essential cofactor in the functioning clotting factors II, VII, IX and X.

  Vitamin K is also a fat-soluble enzyme (hence vitamin K deficiency can also occur in severe hepatic/cholestatic disorders.
• What are the clinical signs of secondary haemostasis dysfunction?

  Maelena

  Epistaxis

  Random haemotomas (unknown causes).

  
• Whole blood clotting time (WBCT)

  Crude measure of the intrinsic and common pathways
• WBCT

  • Also increased if thrombocytopaenia is present, if you haven't got the initial clot formation
• One stage prothrombin time (OSPT)

  Aka Prothrombin time (PT), a measure of the extrinsic and common pathways
• OSPT

  Prolonged due to a significant deficiency of any one factors (<30% of its normal value)
• OSPT

  Tells us there's an issue on the extrinsic and/or common pathways
• Activated partial thromboplastin time (APTT)

  Partial thromboplastin time (PTT) is a measure of the intrinsic and common pathways
• APTT

  Prolonged due to marked deficiency of a single factor
• Specific factor assays

  The level of some individual clotting factors can be measured
• Specific factor assays

  • This would most commonly be indicated in the investigation of inherited coagulation disorders
• Disorders of secondary haemostasis

  Congenital - not very common:

  • haemophilia
  • Factor VIII deficiency (haemophilia A) and factor IX deficiency (haemophilia B).
  • Sex linked, males, spontaneous bleeding.
  • APTT increased; assay FVIII or FIX to confirm.

  Aquired:

  • Vitamin K antagonism
  • Coumarin, rat bait, rodenticide toxicity.
  • Depletion of clotting factors II, VII, IX and X
  • 1-3 days for clinical effects.
  • Hepatic disease:
  • Clotting factors and inhibitory factors produced in the liver. OSPT and APTT increased.
• Thrombosis

  Can be very hard to detect clinically - causes hypoxia and tissue damage.

  To test fibrinolysis - fibrinogen and its degradation products (FDPs), as well fibrin break down products like D-dimer.

  D-dimer increased whenever there is activation of thrombin (to create cross linked fibrin) OR fibrinolysis.

  • When an animal is in a pro-thrombotic state
  • DIC
  • Feline thromboembolic disease
  • Protein-losing nephropathy
  • Hyperadrenocorticism.

  We can also test for levels of inhibitors like antithrombin. If antithrombin III is reduced in the plasma, there is a risk of thrombosis.
• Disseminated intravascular coagulation (DIC)

  Always has an underlying cause.

  Excessive activation of haemostatic pathways - high thrombin and micro vascular thrombi.

  Coagulation factors and platelets get used up - heamorrhage.

  Non-overt DIC (compensated) - no clinically detectable abnormalities (the body is coping).

  Over DIC - Haemorrhage and end-organ damage.
• What are the general triggers for DIC?

  Endothelial damage - electrocution, heat stroke, sepsis.

  Platelet activation - mainly viral e.g. FIP, endotoxaemia.

  Release of tissue procoagulants - trauma, pancreatitis, bacterial infections, erythema multiforme and some neoplasms.
• Specific triggers for DIC

  • Infectious agents - bacterial sepsis, viral disease (FIP), Protozoa (Babesia canis), parasites (A.vasorum), rikettsia
  • Neoplasia - metastatic tumours, haemangiosarcoma, haematopoietic (lymphoma, acute laeukaemia) in cats, cholangiocarcinoma and pancreatic adenocarcinoma
  • Inflammation/ necrosis - trauma, IMHA, pancreatitis, heat stroke, hepatitis, vasculitis, GDV (dogs), strangulating obstructions and inflammatory GI disorders, hepatic lipidosis in cats
  • Intravascular haemolysis - IMHA, acute transfusion reactions, envenomation (insect/snake bites), oxidant injury
• Testing for DIC

  There is no single pathognomonic test for DIC.

  Use clinical signs, biochemistry and imaging, plus supportive evidence.

  Thrombocytopenia (or a dropping platelet count in the normal range).

  Hypofibrinogenaemia (coagulation factors get used up); high fibrinogen degradation products (D-dimer high).

  Schistocytes (RBC fragments; Schistocytes but also keratocytes and acanthocytes; only 20% of dogs and 8% cats and also non-specific finding)