Bleeding Disorders

Question 1

Primary homeostasis actions

Answer 1

-Vasoconstriction (immediate)
-Platelet adhesion (within seconds)
-Platelet aggregation and contraction (within minutes)

Question 2

Secondary homeostasis actions

Answer 2

-Activation of coagulation factors (within seconds)
-Formation of fibrin (within minutes)

Question 3

Fibrinolysis actions

Answer 3

-Activation of fibrinolysis (within minutes)
-Lysis of the plug (within hours)

Question 4

Approach to a patient with suspected bleeding disorder

Answer 4

-Personal history
=Site of bleed
=Duration of bleeding
=Precipitating cause
=Surgery
-Systemic illness
-Family history
-Drugs
-Clinical examination
-FBC, BF, U&E’s, LFTS’s, coag screen, TFT’s, PP
-Coagulation factor assays
-Platelet function assays

Question 5

Disorders of primary haemostasis

Answer 5

-Collagen – Ehlers-Danlos syndrome

-Platelet function - Bernard Soulier disease

-Platelet number – inherited thrombocytopenia

-VWF - Von Willebrand disease

Question 6

Pattern of bleeding in disorders of primary homeostasis

Answer 6

-Easy bruising
-Prolonged bleeding from cuts
-Menorrhagia
-Epistaxis
-Bleeding after trauma

Question 7

Disorders of secondary haemostasis

Answer 7

-Haemophilia A and B
-Other factor deficiencies

Question 8

Pattern of bleeding in secondary haemostasis

Answer 8

-Bleeding is prolonged and can be delayed
-Deep sites
=muscles
=joints

Question 9

Examples of acquired coagulation disorders

Answer 9

-Reduced synthesis - liver disease, bone marrow failure, vitamin K deficiency

-Immune - acquired haemophilia, ITP

-Drugs – Warfarin, Aspirin

-Consumptive - DIC

-Metabolic - uraemia

Question 10

Role of liver in coagulation

Answer 10

-Synthesis of most coagulation factors II, VII, IX, X XI

-Carboxylation of vitamin K dependent factors

-Synthesis of anticoagulant proteins
=protein C and S, Antithrombin

-Clearance of activated coagulation factors and fibrinolytic factors

Question 11

Primary haemostasis bleeding disorders

Answer 11

-Thrombocytopenia
=TPO production
=Splenic sequestration
=Direct ETOH toxicity on megakaryocytopoiesis
=Folate deficiency

-Reduced platelet aggregation
=Defective aggregation
=Defective thromboxane synthesis
=Storage pool deficiency
=Abnormalities gpIb

Question 12

Primary haemostasis thrombosis disorders

Answer 12

-High VWF
=Endothelial damage
=Enhanced VWF expression in the diseased liver
=In severe cirrhosis up to x10 normal range

-Low ADAMTS-13

Question 13

Secondary haemostasis bleeding disorders

Answer 13

-Low pro-coagulant factors

Question 14

Secondary haemostasis thrombosis disorders

Answer 14

-High factor VIII
-Low anticoagulants

Question 15

Fibrinolysis bleeding disorders

Answer 15

-Decreased clearance of tPA
-Low α2-antiplasmin

Question 16

Fibrinolysis thrombosis disorders

Answer 16

-Low plasminogen
-High PAI-1

Question 17

Describe the liver dysfunction involved in secondary haemostasis

Answer 17

-Site of synthesis of all plasma proteins (factor VIII produced by endothelial cells and liver sinusoidal cells, not hepatocytes)
-Reduced levels of coagulation factors II, V, VII, IX, X, XI are commonly observed in both acute and chronic liver failure
-Vitamin K dependent factors defective in function as a result of decreased γ-carboxylation
-Elevated VIII-endothelial activation
-Reduced protein C production
-Reduced fibrinogen

Question 18

Overall liver dysfunction takeaway

Answer 18

-Abnormal coagulation tests are a common feature in patients with liver dysfunction

-INR does not always correlate with bleeding risk in these patients

Question 19

Management of liver disease in acquired coagulation disorders

Answer 19

-Avoid non-essential surgery/procedures
-Monitor coagulation closely
-FFP, cryoprecipitate and platelets if active bleeding
-Likely poor response to vitamin K

Question 20

Definition of DIC

Answer 20

DIC is characterized by loss of localization or compensated control of intravascular activation of coagulation
In DIC, the processes of coagulation and fibrinolysis are dysregulated, and the result is widespread clotting with resultant bleeding.

Question 21

Role of tissue factor in DIC

Answer 21

TF is present on the surface of many cell types (including endothelial cells, macrophages, and monocytes) and is not normally in contact with the general circulation, but is exposed to the circulation after vascular damage. For example, TF is released in response to exposure to cytokines (particularly interleukin 1), tumour necrosis factor, and endotoxin. This plays a major role in the development of DIC in septic conditions. TF is also abundant in tissues of the lungs, brain, and placenta. This helps to explain why DIC readily develops in patients with extensive trauma. Upon activation, TF binds with coagulation factors that then triggers the extrinsic pathway (via Factor VII) which subsequently triggers the intrinsic pathway (XII to XI to IX) of coagulation.

Question 22

Epidemiology of DIC

Answer 22

-Always secondary to an underlying disorder
-Complicates 1% of all hospital admissions
-25%-50% of patient with sepsis develop overt DIC
-Associated with a high mortality

Question 23

Common clinical conditions associated with DIC

Answer 23

-Sepsis
-Malignancy
-Trauma
=Head injury
=Fat embolism
-Obstetric complications
=Placental abruption
=Amniotic fluid embolism
=HELLP syndrome
-Vascular abnormalities
-Reaction to toxin (e.g. snake venom, recreational drugs)
-Immunological reactions
=Severe transfusion reactions
=Transplant rejection

Question 24

Clinical manifestations of DIC

Answer 24

-Underlying cause
-Bleeding
-Microvascular thrombosis
-Organ failure

Question 25

Laboratory features of DIC

Answer 25

-Prolonged PT, APTT and TT
-Low fibrinogen
-Low platelet count
-Increased fibrin degradation products (D- dimer)
-schistocytes due to microangiopathic haemolytic anaemia

Question 26

Treatment of underlying disorder

Answer 26

-Platelet transfusion
-Fresh frozen plasma + cryoprecipitate
-Role of heparin controversial and unproven
-Recombinant activated protein C
-rFVIIa

Question 27

What is immune thrombocytopenia purpura?

Answer 27

immune-mediated reduction in the platelet count. Antibodies are directed against the glycoprotein IIb/IIIa or Ib-V-IX complex. More common in older females

Children with ITP usually have an acute thrombocytopenia that may follow infection or vaccination. In contrast, adults tend to have a more chronic condition.

Question 28

Presentation of ITP

Answer 28

-may be detected incidentally following routine bloods
-petechiae, purpura
-bleeding (e.g. epistaxis)
-catastrophic bleeding (e.g. intracranial) is not a common presentation

-Bruising in children, bleeding less common and typically presents as epistaxis or gingival bleeding

Question 29

Investigation of ITP

Answer 29

full blood count: isolated thrombocytopenia
blood film
a bone marrow examination is no longer used routinely (atypical features of lymph node enlargement/splenomegaly, abnormal white cells, failure to resolve)
antiplatelet antibody testing has poor sensitivity and doesn’t affect clinical management so is not commonly done

Question 30

Management of ITP

Answer 30

first-line treatment for ITP is oral prednisolone
pooled normal human immunoglobulin (IVIG) may also be used
=it raises the platelet count quicker than steroids, therefore may be used if active bleeding or an urgent invasive procedure is required
splenectomy is now less commonly used

80% resolve in 6 months for children, avoid trauma sports treatment if platelet v low or symptomatic