Haemophilia

Introduction

Haemophilia is a group of congenital disorders of blood coagulation that arise as a result of a deficiency of clotting factor proteins, which are essential to the normal intrinsic coagulation pathway. The classic form, haemophilia A, is attributable to deficiency of factor VIII, whereas haemophilia B (also known as Christmas disease) is attributable to deficiency of factor IX. Both these diseases have a classic X-linked pattern of inheritance and thus affect males, although female carriers may also have mild deficiency of the appropriate coagulation factor.

Haemophilia A is the commoner disease (80%), with an incidence of 1 in 8000 to 10,000 live male births, compared with an incidence of 1 in 25,000 to 30,000 for haemophilia B (20%).

Pathophysiology

The normal clotting system is activated in the presence of vascular injury to produce (1) vascular spasm, (2) platelet plug formation and (3) coagulation—factor activation and the production of fibrin. Normal coagulation of blood is dependent on the generation of adequate thrombin via the clotting cascade. Deficiency of factor VIII or IX reduces the amplification of the clotting cascade, thus causing haemophilia. The severity of the bleeding disorder is inversely related to the level of functional factor present and is categorized into mild, moderate and severe disease, as follows:

• Mild disease (6%–30% of normal factor level)—manifests with persistent bleeding after surgery, dental extractions and trauma. Spontaneous bleeds do not occur in this group of patients.

• Moderate disease (1%–5% of normal factor level)—manifests with bleeding into joints and muscles after minor trauma and excessive bleeding after surgery and dental extractions.

• Severe disease (<1% of normal factor level)—manifests with spontaneous joint and muscle bleeding and excessive bleeding following minor trauma, surgery or dental extractions.

Clinical features

Haemophilia A and B are clinically indistinguishable, and symptoms vary according to the severity of the inherited disorder. Mild disease may not present until adulthood, whereas moderate to severe disease usually presents in infancy or early childhood.

Bleeding in haemophilia tends to occur spontaneously or following minor trauma; it is typically delayed and persistent. This is because, although initial platelet ‘plugging’ function is normal, the subsequent coagulation ‘cascade’ response is abnormal. This delay is usually hours and occasionally days. Once bleeding occurs, it may persist for days or even weeks. Patients who are severely affected may present with bleeding episodes on a weekly basis.

The most common manifestations of haemophilia are as follows:

• Bleeding into joints (knees, elbows, ankles, shoulders, hips, wrists—in descending order of frequency)

• Bleeding into soft tissues and muscles (the iliopsoas muscle around the hip, calf, forearm, upper arm, Achilles tendon, buttocks)

• Bleeding in the mouth from a cut, bitten tongue or loss of a tooth

• Haematuria

• Superficial bruising

• Haemarthroses—bleeding from a synovial membrane appendicular structure with inflammation of the synovium, leading to degenerative arthritis, joint destruction and loss of joint mobility and function

• Bleeding into tissue planes—tense flexor haematomas in limbs, potentially causing compartment syndromes; haemorrhage into muscles, possibly leading to atrophy and contracture

• Bleeding into the neck (may cause airway compromise)

• Central nervous system bleeding

• Retroperitoneal bleeding

Patients may also present with a complication of therapy. Most haemophiliac patients treated before 1985 have been exposed to pathogenic viruses, of which the most important are hepatitis C, hepatitis B and HIV. Of those who received plasma prior to the mid-1980s, 90% are hepatitis B–positive, 85% to 100% are hepatitis C–positive and 60% to 90% are HIV-positive.

Clinical investigations

Investigations are tailored to the individual presentation. A full blood count, blood film and coagulation profiles are useful in the evaluation of first presentations or major bleed but unlikely to be helpful in patients with an established diagnosis. It is important to note that in an acute presentation, investigations and awaiting their results should not delay treatment with factor. The most important role for us in the emergency department (ED) is to administer factor as soon as is possible; blood results are not used to guide our use of factor in this group of patients. Generally we administer factor if we have any suspicion of a bleeding, regardless of how small we may think that bleed is.

Plain radiography of affected joints and computed tomography (CT) scanning of the head, chest, abdomen and pelvis may be essential to establish the presence or absence of bleeding complications.

The prothrombin time measures primarily factors II, VII, V and X; thus patients with either haemophilia A or B have a normal prothrombin time and a normal thrombin clotting time. The partial thromboplastin time measures activation of all factors other than factor VIII and is prolonged in haemophilia (although it can be normal if factor activity exceeds 30%). Specific factor assays are required to distinguish between haemophilias A and B.

Treatment

Treatment of haemophilia has evolved dramatically in the past 40 years with the discovery in the 1960s that coagulation factor VIII was concentrated in cryoprecipitate. More recently, highly purified concentrates of factor VIII and factor IX have been developed.

Products currently available for the treatment of haemophilia include the following:

• Recombinate (recombinant factor VIII)

• BeneFix (recombinant factor IX)

• Biostate (plasma-derived factor VIII, which includes von Willebrand factor [vWF])

• Monofix (plasma-derived factor IX)

• DDAVP (desmopressin)

Treatment of acute bleeding episodes primarily involves administration of factor replacement therapy. Complications of bleeding may require specific intervention. Adjunctive therapies include pain relief, rest and immobilization. Specific treatment is influenced by

• the type of haemophilia.

• the severity of haemophilia.

• the severity of the bleed.

Haemophilia patients presenting with suspected bleeds should be triaged to be seen within 30 minutes and receive prompt assessment by a senior doctor. For muscle and joint bleeds RICES ( Box 13.4.1 ) should be initiated on arrival in order to limit bleeding and reduce pain, as should adequate analgesics.

Options for adequate analgesia include

• paracetamol

• inhaled nitrous oxide

• tramadol

• intravenous morphine

• possibly also patient-controlled analgesia (PCA)/opioid infusion

• Avoid non-steroidal anti-inflammatory drugs (NSAIDs) and intramuscular (IM) injections

In the context of pain relief, aspirin (or other platelet-modifying drugs) should be avoided and NSAIDs used with caution. IM injections should never be administered. In major bleeds, there may be a requirement for red cell transfusion. Developing limb compartment syndromes may require surgical decompression, and intracranial bleeds may require neurosurgical intervention. In all of these cases, factor replacement must commence as quickly as possible. Management of complex presentations requires a multidisciplinary approach and early consultation with the relevant state haemophilia centre, especially if the presentation is a major bleed or the patient has inhibitors.

Intravenous cannulation is best performed by a skilled practitioner to help ensure vein preservation. Invasive procedures, such as arterial puncture and lumbar puncture, must be performed only after the replacement of clotting factor.

Some patients with factor VIII levels higher than 10% may be successfully treated with 1-amino-8- d -arginine vasopressin (desmopressin, DDAVP), which acts by releasing vWF stored in the lining of the blood vessels. vWF is a protein that transports factor VIII in the bloodstream and, as such, plays an important role in blood clotting. Desmopressin appears to mobilize available factor VIII stores and may raise factor VIII activity by a factor of three. If the patient has previously had a documented good response to desmopressin, this can be used as first-line therapy for minor bleeding, such as haemarthroses.

Desmopressin can be administered intravenously, subcutaneously or by nasal spray. The intravenous dose is 0.3 μg/kg in 100 mL saline over no less than 45 minutes. A response should be evident within the first hour. More rapid administration can be associated with blood pressure changes. Side effects, including facial flushing and headache, are usually well tolerated. Tachyphylaxis tends to develop after three or four doses. The antidiuretic properties of desmopressin (which can last up to 24 hours after a dose) can produce fluid retention and hyponatraemia (leading to seizures), and the serum sodium levels should be measured before further doses are given. Desmopressin is useful in treating mild and very rarely moderate haemophilia A. It is not of value in severe haemophilia A or with any type of haemophilia B. In serious bleeds or major surgery, desmopressin alone will not control bleeding. In such a case, most patients should also receive factor VIII concentrate, recombinant factor VIII replacement and recombinant factor IX replacement.

Most haemophiliac patients are usually well known to their state haemophilia centres, which often have specialized treatment protocols for difficult or complex patients. Patients should have their treatment regimen cards with them. If not they should be encouraged to do so.

One unit of factor VIII concentrate provides the amount of factor VIII activity in 1 mL of normal plasma. Given that a 70-kg adult has a plasma volume of 3500 mL, we can expect that an infusion of 3500 units of factor VIII will produce 100% factor VIII activity in a haemophiliac individual with negligible activity prior to treatment. The half-life of factor VIII is approximately 12 hours. Accordingly, a further dose of 1750 units in 12 hours’ time will again restore 100% activity.

It is not always necessary to provide 100% factor VIII activity in order to ensure haemostasis: levels of 30% to 50% may be sufficient in the context of haemarthrosis or dental extraction. Larger infusions should be reserved for life-threatening situations.