Disorders of coagulation

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11.3 Disorders of coagulation

Evelyn Doyle

Essentials

1 Haemophilia and von Willebrand disease account for the majority of inherited coagulation disorders.
2 A positive family history of a bleeding disorder should be sought when a coagulation disorder is suspected.
3 Establishing disease severity (assayed factor levels), past history of bleeding, the nature of this bleed and presence of inhibitors will help guide replacement therapy in haemophilia.
4 Always consider ‘hidden’ potentially life-threatening bleeding: intracranial bleeding is a major cause of mortality in the haemophiliac patient.

Haemophilia

Introduction

Haemophilia A and B are coagulation disorders usually transmitted by X-linked recessive inheritance (70% of cases) but can occur as spontaneous gene mutations (30% of cases). Haemophilia A results from factor VIII deficiency and Haemophilia B (Christmas disease) is caused by factor IX deficiency. Acquired haemophilia is rare and occurs when autoantibodies develop against factor VIII.

Clinical presentation

Haemophilia A and B are clinically indistinguishable. Disease severity correlates well with assayed factor levels: severe disease occurs with factor levels <1% of normal, moderate and mild disease occur with levels between 1–5% and above 5%, respectively. In the absence of a positive family history, disease may go undetected for a variable period, depending on disease severity, with some cases of mild disease being diagnosed in adulthood.

Bleeding can occur in any tissue and may occur spontaneously or with minimal trauma. Most neonates, even those with severe disease, are born without significant bleeding, though intracranial haemorrhage may occur. As a child starts to ambulate bleeding episodes becomes more frequent. Unlike disorders of platelet function where mucosal bleeding typically occurs, bleeding into joints and soft tissues is characteristic, with large joints of the knee, ankle, hip, elbow, wrist and shoulder involved most frequently.

Other significant and potentially life-threatening bleeding can occur and should be considered in the haemophiliac patient: intracranial haemorrhage occurs with increased frequency after head trauma, retroperitoneal haematoma may occur spontaneously or following trauma and may mimic appendicitis, soft tissue haemorrhage in the head or neck is potentially life threatening due to the risk of airway obstruction. Gastrointestinal haemorrhage is a less common manifestation of haemophilia in children. Haematuria may be macroscopic or microscopic.

In the current paediatric haemophiliac population, transfusion-borne viruses including hepatitis B and C and human immunodeficiency virus are rare, as most cases of transmission occurred prior to 1985.

Investigations

Haemophilia A and B both cause a prolonged activated partial thromboplastin time (aPTT) with a normal prothrombin time and platelet count. Individual factor assays can then be performed to confirm the diagnosis. Haemophiliacs presenting with suspected intracranial or retroperitoneal bleeds need computerised tomography (CT) scanning. Plain radiographs will exclude fractures associated with traumatic haemarthroses.

Treatment

The primary treatment goal is control of bleeding by replacement of clotting factor. Factor concentrates are available as virus-inactivated plasma-derived product and recombinant factor concentrates. When available and expense allows, recombinant factor concentrates should be used. Factor replacement may be given following a confirmed bleed or as prophylaxis against potential bleeding; for example, prior to dental extraction. Prophylactic factor replacement, usually given two to three times a week at home, with increased doses given for any breakthrough bleeds, has led to a marked reduction in the number and severity of bleeding episodes.

The half-life of factor VIII is 8–12 hours and factor XI is up to 24 hours, so repeated doses may be needed. Many patients now initiate treatment for minor bleeds at home. Early and appropriate treatment reduces the risk of deterioration to disabling arthropathy and chronic pain. The amount of clotting factor required depends on the patient’s weight, severity of disease, the location of the bleed and also previous bleeding in the same area and presence of inhibitors

Lacerations generally require factor replacement to prevent excessive bleeding. Head injury requires a high index of suspicion and a very low threshold for factor treatment. Continuous intravenous (IV) factor infusion may be required for major bleeding. A negative cranial CT scan does not preclude the need for factor replacement.

Analgesia should be provided as required but aspirin should be avoided. Other non-steroidal anti-inflammatory drugs may be used on the advice of the treating haematologist. Narcotic analgesia has limitations associated with use in treating a chronic condition.

Desmopressin (DDAVP), a synthetic analogue of vasopressin that elevates factor VIII levels for several hours after administration by stimulating release from endothelial stores, can be used to treat mild haemophilia A. In an emergency situation where no clotting factor is available, fresh frozen plasma (FFP) or cryoprecipitate can be administered.

Inhibitors are alloantibodies that develop against clotting factors and are present in 10–20% of those with haemophilia A and 3–5% of those with haemophilia B. Inhibitors may mean that large amounts of clotting factor are required, or that clotting factors will not work at all. Treatment options for patients with haemophilia are prothrombin complex concentrate (prothrombinex) or recombinant activated factor VIIa. Elimination of inhibitors is possible in a proportion of patients using immune tolerance therapy, where daily low-dose factor infusions will lead to the development of neutralising anti-inhibitor antibodies.

Von Willebrand disease

Introduction

Von Willebrand disease (vWD) is the commonest inherited disorder of coagulation and is present in 1% of the population in screening studies, though only a minority will present with clinically significant bleeding. In most cases inheritance is autosomal dominant with variable penetrance and expressivity, though autosomal recessive inheritance occurs (Type 2N and 3). Rarely, vWD may be acquired and has been described in conditions such as hypothyroidism, and SLE. Von Willebrand factor (vWF) is a large protein that has two roles in coagulation: it facilitates platelet adherence to the vascular endothelium enabling a platelet plug to be formed and also acts as a carrier protein for factor VIII. Quantitative or qualitative abnormalities of vWF occur. Three types of vWD and three subtypes have been described: Type 1, 2 (subtypes 2A, 2B, 2M,2 N) and 3.

Clinical presentation

Mucosal and cutaneous bleeding, prolonged bleeding after surgical procedures and a positive family history of a bleeding disorder should prompt consideration of vWD. In children, bruising and bleeding out of proportion to the severity of the injury is typical. Haemarthroses, intracranial and intra-abdominal bleeds are much less common but can occur in more severe types 2N and 3 vWD. vWD is diagnosed in 10 to 20% of women and adolescents with menorrhagia and in 15% of children with recurrent epistaxis.

Type 1: The commonest form accounts for 60–80% of cases, and results from a partial quantitative deficiency of vWF. When bleeding occurs it ranges from mild to moderate, with only a minority having clinically significant bleeding episodes.
Type 2: (subtypes A,B,M and N) have qualitative defects of vWF. Bleeding tends to be moderate to severe. Type 2N may be misdiagnosed as haemophilia A until vWF testing becomes available.
Type 3: A total quantitative deficiency of vWF and decreased factor VIII activity occurs in this rare form of vWD. Clinically, bleeding is severe and indistinguishable from Haemophilia A, with mucosal, soft tissue and joint bleeding.

Investigations

A coagulation screen may be normal and does not rule out vWD. In most patients aPTT is normal, though a prolonged aPTT can occur in types 2N and 3, with reduced factor VIII levels. Bleeding time may be prolonged. Screening tests for vWD include: vWF assay, ristocetin co-factor assay and factor VIII activity. The diagnosis and typing of vWD is difficult and usually requires a specialist laboratory. Levels are affected by blood group and physiological factors such as stress and exercise. The patient’s personal and family history of bleeding must also be taken into account in making this diagnosis.

Treatment

The main aim of treatment in vWD is replacement of deficient or defective vWF and factor VIII. Treatment is usually given in response to bleeding or prophylactically prior to surgical or dental procedures. Treatment options currently available are desmopressin and plasma concentrates

Desmopressin (DDAVP), a synthetic analogue of vasopressin releases factor VIII and vWF from endothelial storage sites, causing a transient rise in levels. DDAVP is effective in type 1 vWD and will increase plasma levels of vWF between three and five times from baseline within 30–60 minutes. It is usually ineffective in types 2A, M and N as vWF is functionally abnormal, and in type 3 vWD as an appreciable rise in levels may be clinically undetected. Desmopressin is contraindicated in type 2B vWD as it may cause thrombocytopenia and thus worsen bleeding.

The dose is 0.3 mcg kg–1 given intravenously in 30–50 mL normal saline over 30 minutes. The most common adverse effects are facial flushing, headache and tachycardia, which usually respond to slowing the infusion. Repeat doses can be given at 12 to 24 hours if needed but tachyphylaxis occurs after approximately 48 hours. DDAVP should be used with caution in children under 3 years of age in whom there have been case reports of water intoxication and hyponatraemia. An intranasal DDAVP preparation is available but may be less reliable in children if part of the dose is swallowed. The dose is 2–4 mcg kg–1.

Plasma-derived factor VIII concentrates contain both vWF and factor VIII. Recombinant factor VIII does not contain vWF and is ineffective. These plasma-derived products are the treatment of choice for type 2A, 2B (in which DDAVP is contraindicated) and type 3 vWD. They are virus inactivated and effective to control bleeding in most clinical situations. FFP contains both vWF and factor VIII but very large volumes would be required to raise vWF to satisfactory levels.

Adjunctive treatments include tranexamic acid for bleeding involving the oral or nasal mucosa, either alone or in conjunction with DDAVP. Synthetic oestrogens cause an unpredictable rise in vWF but may be useful in controlling menorrhagia.

Controversies and future directions

Haemophilia is particularly suited to gene therapy intervention because the disease is due to deficiency of a single gene product. Gene therapy is still at the stage of small human trials. Von Willebrand disease treatment options for the future include recombinant vWF, which has shown promising early results in animal trials, and interleukin-11 has also been shown to increase vWF, but human trials are needed.

Acknowledgement

The contribution of Fiona Reilly as author in the first edition is hereby acknowledged.

Further reading

Eikenboom J., Van Marion V., Putter H., et al. Linkage analysis in families diagnosed with type 1 von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 VWD. J Thromb Haemost. 2006;4:774-782.

Fischer K., van der Bom J.G., Mauser-Bunschoten E.P., et al. Changes in treatment strategies for severe haemophilia over the last 3 decades: Effects on clotting factor consumption and arthropathy. Hemophilia. 2001;7:446-452.

Mannucci P.M. Treatment of Von Willebrand’s disease. N Engl J Med. 2004;351(7):683-694. 12

National Hemophilia Foundation. www.hemophilia.org

Rakel R.E., Bope E.T. Conn’s Current Therapy 2009, 1st ed. Saunders: Philadelphia; 2009.

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