Bleeding Disorders

This chapter provides a broad overview of congenital and acquired haemostatic defects. More
detailed information can be found below the table.

Clinical Condition	Haemostatic Defect	Way to Correct Haemostatic Defect
Haemophilia A	Absence/low levels of coagulation factor VIII.	DDAVP – mild Haemophilia A. Replacement therapy with plasma-derived or recombinant factor VIII concentrates. Consultation with a haematologist is recommended.
Acquired Haemophilia A – Factor VIII Autoantibodie	Development of factor VIII autoantibodies resulting in a decrease in the level of coagulation factor VIII. Associated with the post-partum state, connective tissue disorders and malignancies. About 50% are idiopathic.	Treatment is complex and requires specialist referral.
Haemophilia B	Absence/low levels of coagulation factor IX.	Replacement therapy with plasma-derived or recombinant factor IX concentrates. Consultation with a haematologist is recommended.
Von Willebrand’s Disease	Quantitative and/or qualitative defect in VWF protein.	DDAVP Replacement therapy with plasma-derived factor VIII concentrates containing high molecular weight VWF multimers.
Acquired von Willebrand’s Disease	Development of autoantibodies directed against VWF resulting in decreased levels of VWF ristocetin cofactor activity and VWF antigen. Reported in a variety of conditions including monoclonal gammopathy of uncertain significance, lymphoproliferative disorders and myeloproliferative disorders.	Treatment is complex and requires specialist referral.
Other Inherited or Acquired Coagulation Factor Disorder	Uncommon	Requires consultation with a haematologist. Specific concentrates should be used if available.
Bone Marrow Failure	Absence of or reduction in the production of all or some of the cellular lines, for any reason. May be associated with co-existing coagulation abnormalities due to the underlying condition.	Platelets may be indicated for prophylaxis or bleeding at a platelet count of <10 x 109 /L in the absence of risk factors and <20 x 109 /L in the presence of risk factors (eg fever, antibiotics, evidence of systemic haemostatic failure). Transfusion of red cells may be appropriate depending on the patient’s clinical status and haemoglobin level.
Cardiopulmonary Bypass (CPB)	The cause of the haemostatic defect is multifactorial including decreased coagulation factor levels (due to activation from contact with the extracorporeal circuit and oxygenator), thrombocytopenia (probably related to the length of the procedure and hypothermia), platelet dysfunction (due to the use of heparin during the procedure and other anti-platelet drugs), fibrinolytic activation and haemodilution. Repeat operations are a major risk factor for post-operative bleeding.	Use of platelets or FFP may be appropriate in the presence of bleeding and abnormal coagulation. In this situation the platelet count is not a reliable indicator. Aprotinin can reduce transfusion requirements in specific situations, such as prolonged or difficult cases.
Disseminated Intravascular Coagulation (DIC)	Inappropriate and excessive systemic activation of the haemostatic process resulting in DIC, factor deficiencies, thrombocytopenia, platelet dysfunction and anaemia.	Blood component therapy with FFP, cryoprecipitate and platelets; guided by the clinical status of the patient and laboratory investigations.
Haemorrhage	Control of acute blood loss should prevent the development of haemostatic failure. (See Massive Transfusion below).	Restore circulating fluid volume to correct hypoperfusion. The need for transfusion is dependent on the estimated loss of circulating blood volume and the patient’s ability to compensate for the quantity of blood lost.
Liver Disease	Patients usually present with a complex bleeding disorder associated with factor deficiency (due to decreased synthesis and Vitamin K deficiency), thrombocytopenia (due to hypersplenism, decreased production and increased consumption), platelet dysfunction, DIC, anaemia and primary fibrinolysis.	Use of FFP, cryoprecipitate or platelets may be appropriate in the presence of bleeding and abnormal coagulation. Vitamin K. DDAVP may shorten the bleeding time, however the benefit is short-lived <4 hours. Conjugated estrogens may improve the bleeding time.
Massive Transfusion	The aetiology of the haemostatic defect is multifactorial including trauma, shock, hypothermia, DIC, dilution caused by fluid replacement and the patient’s underlying co-morbidity.	Volume replacement. Blood component replacement therapy guided by the clinical status of the patient and laboratory investigations.
Platelet Destruction Immune Thrombocytopenia (ITP)	Thrombocytopenia secondary to immune-mediated platelet destruction. Aetiology includes viral infections, drugs (eg heparin, quinine, gold salts), associated with connective tissue disorders and idiopathic.	Usually managed by corticosteroids and/or intravenous immunoglobulin (issued in accordance with AHMAC guidelines14), depending on the severity of the thrombocytopenia, presence or absence of bleeding and other patient factors. Use of platelets is not generally considered appropriate. May be indicated in life-threatening haemorrhage. A recent review also provides dosage guidelines 15
Platelet Destruction Neonatal Alloimmune Thrombocytopenia (NAIT)	Thrombocytopenia in a neonate secondary to immune-mediated platelet destruction, usually associated with anti-HPA-1a or anti-HPA-5a.	Management of the neonate may include intravenous immunoglobulin and antigen-negative platelets.
Platelet Destruction Post-transfusion Purpura (PTP)	Transfusion-induced thrombocytopenia secondary to immune-mediated platelet destruction, usually associated with antibodies to platelet specific antigens, most frequently anti-HPA-1a.	Intravenous immunoglobulin. Transfusion of antigen-negative platelets may be required.
Platelet Destruction Thrombotic Thrombocytopenic Purpura (TTP)	Pathogenesis is probably multifactorial. The haemostatic defect includes thrombocytopenia associated with a microangiopathic haemolytic anaemia and other clinical features.	Plasma exchange with either FFP or cryo-depleted plasma. Platelet transfusion is generally contraindicated.
Platelet Dysfunction Including Drug-induced	Platelet dysfunction results from a variety of congenital and acquired defects. Medication is the most common cause with prostaglandin inhibitors such as aspirin being most frequently implicated. The bleeding tendency in platelet dysfunction defects is extremely variable and the platelet count is not a reliable indicator.	Ideally in the surgical setting anti-platelet medications should be ceased 7-10 days prior to surgery. Use of platelets may be appropriate depending on clinical features and the clinical setting.
Platelet Refractoriness	The absence of a significant and sustained rise in the platelet count following platelet transfusion due to a variety of immune and non- immune factors.	Management is dependent on the clinical status of the patient and the aetiology of the refractoriness.
Platelet Sequestration	Thrombocytopenia secondary to hypersplenism. When hypersplenism exacerbates pathologic thrombocytopenia caused by another mechanism, patients sometimes become refractory to platelet transfusions even in the absence of a specific HLA or other immune-mediated platelet antibody.	Use of platelets may be appropriate depending on clinical features and the clinical setting.
Thrombolytic Drugs	Cause systemic fibrinolysis. Haemorrhage complicating these agents is most commonly localised (eg at the site of catheterisation in the groin).	Control localised bleeding with pressure packs. Cryoprecipitate or FFP can be given for life-threatening bleeding.
Vitamin K Deficiency	Decreased biological activity of factors II, VII, IX, X and Protein C and Protein S; with prolongation of the INR. Risk factors include poor diet, malabsorption, antibiotic use, recent surgery and liver or kidney dysfunction.	Vitamin K given orally, subcutaneously or intravenously, depending on the clinical circumstances.
Warfarin Therapy	Warfarin blocks gamma-carboxylation of glutamic acid residues of Vitamin K dependent coagulation factors resulting in decreased biological activity of factors II, VII, IX, X and Protein C and Protein S; with prolongation of the INR.	Management depends on whether or not the patient is bleeding, the extent and site of bleeding, the indication for anticoagulation, the degree of suppression of the coagulation factors and the urgency of warfarin reversal.
Uraemia	Patients develop a mild-to-moderate haemostatic defect due to platelet dysfunction, abnormalities of VWF multimers and decreased platelet VWF. The decrease in haematocrit further aggravates in-vivo platelet dysfunction. The levels of clotting factors are usually normal, and elevated levels of fibrinogen, factor VIII and VWF are typically present.	Platelet transfusion may be helpful in emergencies however the infused platelets rapidly become dysfunctional in the uraemic environment. Red cell transfusion to achieve a haematocrit >27%16. Aggressive dialysis usually improves platelet dysfunction but incompletely corrects the haemostatic defect. DDAVP provides effective short-term improvement of haemostasis, being maximal at 4 hours and in many patients wears off by 6-8 hours. Repeated administration of DDAVP may lead to tachyphylaxis and hyponatremia. Cryoprecipitate often promptly shortens the bleeding time and decreases bleeding. High-dose conjugated estrogens may achieve a longer lasting improvement in haemostasis.

Inherited coagulation disorders

Patients with haemophilia A, haemophilia B (Christmas Disease) and von Willebrand’s Disease are usually registered with and cared for by a specialist haemophilia centre.

Contact details of Australian specialist Haemophilia Treatment Centres are attached in Appendix III. The specialist Haemophilia Treatment Centre should be contacted when a patient with haemophilia presents to another clinical unit.

Suggest we put in a link to the AHCDO website and their publications here.

This is particularly important when a head injury is suspected, as treatment is often required urgently. In these circumstances every effort must be made to obtain immediate specialist assistance.

Haemophilia A

Haemophilia A is usually inherited as a sex linked recessive disorder although it also can arise from a spontaneous mutation in up to 30 percent of cases. It results in the absence/low levels of coagulation factor VIII and the clinical severity of the disorder is determined by the factor VIII level as follows:

Severe (<1% factor VIII) – have spontaneous and delayed deep soft tissue bleeding, particularly into joints and muscles
Moderate (1-5% factor VIII) and mild (6-25% factor VIII) – may have severe bleeding when tissues are damaged by surgery or trauma
The minimal effective level for haemostasis is generally about 25-30% factor VIII level.

Products currently available to manage this condition include:

Recombinant factor VIII - there are guidelines in each State/Territory that indicate which patients are eligible to receive Recombinant factor VIII. It is important to confirm whether the patient is on recombinant vs plasma derived factor VIII before issuing/transfusing the product
Plasma-derived factor VIII – see Biostate
DDAVP – appropriate for management of mild haemophilia only (baseline factor VIII above 15 percent).

Haemophilia B

This sex-linked recessive disorder results in a deficiency of factor IX. The clinical features are identical to those of haemophilia A. Products currently available to manage this condition include:

Recombinant factor IX products- there are guidelines in each State/territory that indicate which patients are eligible to receive the Recombinant factor IX. It is important to confirm whether the patient is on recombinant vs plasma-derived factor IX before issuing/transfusing the product.
MonoFIX-this is the preferred plasma-derived product. See MonoFIX.
Prothrombinex-VF-this product is no longer the preferred plasma-derived product of choice for haemophilia B; however a small number of patients remain on this product. See Prothrombinex-VF.

Von Willebrand’s Disease

This is the most common of the inherited bleeding disorders and is due to a quantitative and/or qualitative defect in the VWF protein.

The diagnosis and evaluation of treatment options for von Willebrand’s Disease is not straightforward and requires measurement of the plasma levels of both factor VIII and VWF protein.

For some procedures (and minor bleeding episodes), some patients can be managed with desmopressin (DDAVP) only. The specialist Haemophilia Treatment Centre usually determines the patient’s suitability for and response to DDAVP.

Some patients may require treatment with a plasma-derived, viral inactivated product such as Biostate.

Cryoprecipitate should usually only be used when a virus-inactivated factor concentrate is not available.