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Editors

AnneMäkipernaa
TimeaSzanto

Hereditary Coagulation Factor Deficiencies

Essentials

  • Healthcare units should be aware of all patients in the area who have severe coagulation factor deficiencies, and these patients' lifelong haemorrhagic disorder should be taken into account in the treatment of other diseases, as well.
  • Rapid initial treatment is essential in the case of suspected bleeding. Therefore, first the clotting factor infusion should be given either at home, at a primary care health centre or at a local hospital, and the possible need for further treatment considered only after that.
  • Especially patients with severe haemophilia and patients who have developed clotting factor antibodies should be seen every now and then by the haemostasis unit of a tertiary level hospital for assessment of their condition and for the outlining of subsequent management.
  • Even in mild bleeding disorders, preparation for any surgical procedure will require preplanning.
  • Aspirin or other NSAIDs are not recommended for patients with bleeding disorders. The analgesic of choice is paracetamol or a combination of paracetamol and codeine, as necessary. Etoricoxib has not been found to increase bleeding tendency and is thus suitable for treating joint pain, in particular, in a number of patients.
  • Patients with diagnosed haemorrhagic disease should carry a diagnosis or treatment card given by the treating unit with information regarding the type of disease, the severity of the condition, clotting factor levels and the type of clotting factor product or any other medicine required for their particular condition. Treatment cards should be updated with current information on laboratory test results, instructions for treatment and contact data.

Haemophilia A and B

  • The heredity of haemophilias is X-linked. Haemophilia A is a deficiency or lack of factor VIII and haemophilia B is a deficiency or lack of factor IX. The disease affects only men, while women act as carriers. About one third of female carriers exhibit an increased bleeding tendency during surgical procedures or childbirth. Their coagulation factor levels are most often only slightly decreased.
  • Laboratory investigations reveal a prolonged activated partial thromboplastin time (APTT). prothrombin time/INR and thrombocyte levels are normal. Coagulation factor tests show deficiency or lack of either coagulation factor VIII (F VIII) or IX (F IX).
    • Severe haemophilia: F VIII or F IX levels less than 1% of normal (normal range 60-160%)
    • Moderate haemophilia: F VIII or F IX 1-5% of normal
    • Mild haemophilia: F VIII or F IX more than 5% of normal
  • The most difficult problem complicating the treatment of severe haemophilia is the possible development of antibodies against the deficient clotting factor. High-dose desensitization therapy aims at eliminating these antibodies.

Clinical picture

  • Severe haemophilia is characterised by spontaneous bleeding into soft tissues and joints, postoperative and recurring bleeding from wounds, bleeding of internal organs and other types of internal bleeding (Table T1). Symptoms of bleeding involving the lumbar muscles and retroperitoneal region may be particularly difficult to identify and to diagnose.
  • Cerebral haemorrhage is a relatively rare but severe complication of haemophilia. It occurs in patients of all ages either spontaneously (particularly in patients with elevated blood pressure) or after a trauma. The risk of cerebral haemorrhage is also increased in patients with mild or moderate haemophilia and most markedly in patients with severe haemophilia with no prophylactic treatment.
  • One of the first bleeding symptoms in an affected child is bruising easily when he/she starts to mobilise or following a fall. Prolonged bleeding from damaged oral mucous membranes may be noted, for instance after falling with a dummy in the mouth.
  • About 80% of all bleeds are intra-articular. Occurring spontaneously they are characteristic of severe haemophilia. Repeated bleeding often affects a certain joint with the subsequent development of arthropathy. Knees are the most common site of joint bleeds, but the elbows and ankles may also be affected. The first symptoms of a joint bleed are pain and restricted movement of the joint. The patient may also experience tingling and heat.
  • If a bleed is suspected it is most important to quickly commence replacement therapy by administering the missing clotting factor. Waiting for the occurrence of objective signs of a bleed to occur, i.e. swelling and heat, will only delay treatment.
  • X-ray investigations are rarely beneficial. An ultrasound examination is useful in problematic cases. There is no need for diagnostic arthrocentesis. If arthrocentesis is indicated for the evacuation of a large, distended and painful joint, it should be carried out under adequate clotting factor cover.
  • Bleeding into soft tissues may be surprisingly extensive and may lead to anaemia. Bleeding in the iliopsoas muscle or in the retroperitoneal space may cause abdominal pain that resembles appendicitis or referred pain in the thigh. A rather common problem in adults is a bleed originating in the kidney or the bladder whereby the clot may cause an obstruction in the urinary tract.
  • In mild to moderate haemophilia, bleeding is usually associated with an injury. Surgical procedures without clotting factor replacement will always lead to abnormal bleeding in all haemophilic patients.

Classification of haemophilia A based on F VIII activity, and clinical pictures

ClassificationF VIII activity, % of normal (60-160%)Clinical pictureAge at diagnosis (in the absence of known family history)
Severe< 1Spontaneous intra-articular bleeding (80%)
Extensive soft tissue bleeding (10-20%)
Other severe bleeding (5-10%)
Cerebral haemorrhage (< 5%)		Below 1 year
Moderately severe1-5Incidental spontaneous soft tissue or intra-articular bleeding
Significant bleeding in association with trauma or surgery		1-7 years
Mild> 5Severe bleeding in association with major trauma or surgeryOften later in life

Treatment Prophylactic Clotting Factor Concentrates to Prevent Bleeding Complications in Hemophilia A or B

  • Prophylactic, intravenous administration of the lacking clotting factor 2-3 times per week is used for almost all children with severe haemophilia to prevent spontaneous bleeding and joint damage, in particular. Home treatment of a small child usually warrants the insertion of a central venous line with a subcutaneous port. Such a port may become infected or blocked. If such a complication is suspected, emergency contact with a hospital is warranted. Direct intravenous replacement therapy is often started in order to avoid problems related to the port. It is increasingly often possible, along with products with longer duration of action having become available.
  • After the child has reached the age of four, the port should be abandoned if possible because the risk of associated thrombosis and infection increases with time. The parents, and later the child itself, should be taught to infuse the clotting factor into a peripheral vein through a butterfly needle. Prophylactic replacement therapy is also recommended for adults with severe haemophilia. It will in most cases reduce the incidence of actual bleeding events in adults, as well. The prophylactic therapy for a few weeks is occasionally indicated, for example to treat synovitis or during the recovery phase following orthopaedic surgery.
  • Bleeding is treated with replacement therapy, i.e. with the administration of the missing clotting factor. An overview of the situation concerning both preventive measures and the treatment of bleeding episodes should be performed every now and then at the unit responsible for the coordination of treatment (usually a tertiary level hospital) to determine appropriate clotting factor doses and check that the treating hospital has the clotting factor used by the patient in stock.
  • There are several clotting factor preparations in use and their half-life differ both on the product level and the individual level. Increasingly, the aim is individual dosage by determining the response and half-life of the clotting factor the patient is using. A clotting factor level beneficial to the patient is estimated by laboratory investigations and clinical assessment, considering both spontaneous bleeds and risky situations. This way, the suitable clotting factor dose and infusion frequency can be estimated. Along with the use of pharmacokinetic assessment and new, longer-acting clotting factor products there are indications that that bleeds in patients with haemophilia as well as the total consumption of clotting factors have both decreased,.
  • As a general rule, each bleed requires the administration of replacement therapy. Essential in the treatment of all bleedings is rapid initiation of treatment with a dose sufficiently large to stop the bleeding quickly. Situations requiring repeated clotting factor infusions at 8-24-hour intervals include joint and muscle bleeds, injury to the head, unusual headache and dental procedures. Conservative treatment (immobilisation, elastic bandaging, ice packs, analgesic) is only suitable in minor soft tissue bleeds.
  • Clotting factor antibodies should be suspected if a previously good treatment response is lost. Antibodies develop, on average, after 10(-50) treatment sessions which in practice almost always means during childhood. Antibodies to the deficient clotting factor develop in approx. one in five patients with severe haemophilia A and 1-3% of patients with severe haemophilia B. In mild haemophilia, the antibodies may not become apparent until adulthood. Even in severe haemophilia, the antibodies may not appear until after decades of treatment, e.g. when the patient has reached the age of 50 or 60 years. Treatment of a bleed in a patient with antibodies requires particular care, and any products suggested by a clotting specialist must be readily available. Desensitisation therapy is used with the aim of eliminating the antibodies.
  • Promising products, the effects of which are based on different mechanisms, are being developed, and partly available, particularly for the treatment of patients with antibodies. In the last few years, pharmacotherapy of haemophilia has progressed not only through the development of longer-acting coagulation factor products but also through replacement products with a new mechanism of action. Subcutaneous emicizumab imitating the activity of coagulation factor VIII and accelerating coagulation has given particularly promising results. Advantages of the new type of products include the possibility of using subcutaneous injections at intervals of a few weeks or even a few months. Such treatment appears particularly significant for patients with haemophilia who have developed antibodies to coagulation factors that have not been able to be eliminated through desensitization.
  • More and more promising preliminary results of gene therapy are becoming available. Increasingly long-term and abundant coagulation factor production has been obtained. Nevertheless, not all patients have shown a response, and any longer-term adverse effects are yet to be defined.

Treatment of haemophilia A

  • In the mild form of haemophilia A, desmopressin (DDAVP) can be used to treat a minor, fresh joint or muscle bleed or to provide cover for a small procedure. A desmopressin test should be carried out in advance to determine treatment response. The aim is to increase the coagulation factor level 2-3-fold. Tranexamic acid is a good additional drug to support desmopressin and for treating mucosal bleeding.
  • In more severe haemophilia A, a virus-inactivated F VIII product must always be used. Both plasma-derived and recombinant clotting factor products are available. Longer-acting products are under development and partially available. The half-life of the most commonly used F VIII products is 8-15 hours, and in newer products approx. 1.5-fold, i.e. 13-20 hours.
  • In minor, fresh joint or muscle bleeds a single dose of a clotting factor product should beadministered (at least 20-40 units/kg). The doses should be rounded according to the package size. Often, due to the risk of recurring bleed, 1-2 additional doses are needed after 12-24 hours. An elastic bandage will help locally by helping the tissues to tolerate the bleeding-induced pressure. A cold pack may be of help.
  • Disappearance of pain suggests that bleeding has ceased. After this, the patient can and should start to use the joint or the muscle.
  • If the muscle or joint bleed is severe, or clearly caused by an injury, or if treatment is delayed for more than 24 hours or a large wound needs suturing the initial dose should be at least 30-40 units/kg. The treatment often needs to be continued for a further 2-4 days with subsequent doses of approximately half of the initial dose at 8-12 hour intervals. In these cases, the limb should be immobilised until the pain has disappeared.
  • For bleeding in the head or neck or abdominal or chest cavities the initial dose is at least 40-60 units/kg, i.e. a 100% coagulation factor level is aimed for. Further treatment is always indicated, and the patient should be admitted to a hospital. Measurement of the clotting factor concentration is required for the determination of further treatment doses (samples should usually be taken just before the next dose to find out the nadir of coagulation factor level).

Treatment of haemophilia B

  • The principles are the same as in haemophilia A. The clotting factor concentration required by the body for the restoration of the coagulation mechanism in the different types of bleed is similar to that in haemophilia A. The clotting factor to be used is a F IX product, which may be given prophylactically 1-3 times a week for severe haemophilia B. The required dose of F IX varies depending on the product used but is often double the dose of F VIII (for severe bleeds, for instance, the initial dose of F IX is 80-120 units/kg). The longer half life of F IX (about 16-24 hours) permits an interval of 12-24 hours between the doses in situations where further treatment is warranted.
  • New long-acting F IX products (half-life 3-5-fold compared with former products) may provide the patient with good haemostatic protection using an interval of 1-2 weeks between doses, which makes treatment of small children, in particular, significantly easier.

Special situations

  • It is particularly important for operative treatment that the unit is familiar with performing operations on patients with haemophilia and cooperates with doctors specializing in coagulation disorders, and that follow-up of coagulation factor levels is available during and after the procedure.
  • Pregnancy and childbirth in haemophilia carriers
    • Any haemophilia carrier and her partner should see a medical geneticist before pregnancy already.
    • In principle, births of baby boys to carriers of haemophilia, particularly those with severe haemophilia, should be concentrated to tertiary level hospitals. Nevertheless, considering the somewhat unpredictable character of childbirth, the local maternity hospital must be informed of a carrier's pregnancy.
    • If the foetus is male, the optimum method of delivery should be assessed based on individual considerations. Vaginal and caesarean birth of a baby with haemophilia have been found to involve similar risks of cerebral or other significant haemorrhage. The risk of haemorrhage is the highest if instruments are needed to assist in delivery.
  • Dental extraction
    • Extraction of a permanent tooth: a single dose of a clotting factor product - target level of clotting factor about 50%. In addition, antifibrinolytic treatment (tranexamic acid) should be started before the procedure and continued for 5 days.
  • Vaccinations
    • The general principle is to administer all vaccinations subcutaneously (s.c.), not intramuscularly, even if this is contrary to the manufacturer's instructions. The use of the subcutaneous method may lead to local reactions more often than is normally the case.
    • Patients with haemophilia receiving regular treatment may belong to the target groups for hepatitis A and B vaccination in national immunization programmes. Find out about local policy.

Von Willebrand disease

  • Von Willebrand disease (vWD) is the most common hereditary bleeding disorder. The disease is inherited autosomally, affecting both males and females.
  • The international diagnostic criteria for vWD have been modified over the decades. Both laboratory and clinical criteria for the diagnosis of actual vWD are stricter than earlier. The diagnosis of vWD is based on the patient's history of bleeding (see Assessment and Treatment of a Patient with Bleeding Diathesis), history of bleeding disorders and bleeding among near relatives, and laboratory tests.
  • If the patient has vW factor levels only slightly below the reference range and bleeding symptoms are insignificant, she/he is more often than earlier classified in a category such as ”low vWF activity - with no disease or with vWD predisposition”.
  • -Clinical picture: skin and mucosal bleeding of varying severity (bruising, epistaxis, menorrhagia and increased post-operative bleeding diathesis particularly after procedures involving the mucous membranes).
  • The disease is caused by a deficiency and/or structural defect of the von Willebrand factor (vWF). vWF is essential for the functioning of platelets to stop bleeding.
  • There are three types of vWD:
    • Type 1 is the most common type. It is inherited by a dominant mechanism and has mild symptoms although the bleeding symptoms vary individually. There is a deficiency of the qualitatively normal vWF.
    • Type 2 vWD is divided into several subgroups and is characterised by both quantitative and qualitative abnormality of the vWF. Symptoms are of moderate severity.
    • The rare homozygous Type 3 has the most severe symptoms and resembles haemophilia. There is no synthesis of the vWF, and the activity of F VIII is also low since vWF acts as a carrier protein for F VIII. In Finland (population 5.5 million), there are about twenty patients with this type of disease.
  • In mild disease forms, APTT may be normal; in other cases it is prolonged. The specific laboratory diagnosis is based on clotting factor activity measurements (plasma vWF activity, plasma vWF collagen-binding, plasma FVIII) and on the concentration (plasma vWF antigen) and structure of vWF (multimer analysis). Platelet function test (platelet function analysis, PFA) shows weakened responses. The diagnostic criteria require bleeding symptoms in all patients and two abnormal vWF activity results (usually less than 35% of normal).
  • The investigation of close family members with a tendency to bleed is recommended.
  • In type 1 vWD the clotting factor concentration usually increases physiologically during pregnancy. However, one month before the expected delivery date the clotting factor concentration should be checked, and any replacement therapy possibly needed during delivery should be planned.
  • The vWF level usually increases and mild disease wanes by age. Consequently, the current clotting factor level and clinical bleeding tendency should be determined before elective procedures in patients who have been diagnosed years previously.

Treatment

  • Mucosal bleeding can sometimes be controlled with an antifibrinolytic agent (20-25 mg/kg of oral tranexamic acid three times daily). In menorrhagia, oral contraceptives are often of benefit as is a hormonal intrauterine device, besides tranexamic acid.
  • In mild, type 1 vWD the body's own stores of vWF may be mobilised with desmopressin (DDAVP) to control minor bleeding or provide cover for a minor surgical procedure. Desmopressin is administered either as a slow intravenous infusion, subcutaneously (0.2-0.3 µg/kg) or intranasally (300 µg for adults, 150 µg for patients weighing less than 50 kg) usually for not more than 2 subsequent days. As repeated desmopressin doses, in particular, may predispose to fluid retention, hyponatraemia and convulsions, possible contraindications should be considered before use and the patient's fluid balance should be monitored. It is useful to perform a desmopressin test before the administration of DDAVP to assess the laboratory response and any adverse effects.
  • Bleeding in patients with type 2 or 3 vWD is treated with a plasma product that contains either vWF alone or both vWF and F VIII. This replacement therapy is also required for surgical procedures in those patients with type 1 vWD in whom desmopressin is ineffective or who are not able to use it. The dose and dose interval as well as treatment duration depend on the type of disease, the current vWF level, the nature of the bleeding or the procedure, and the product used.
  • Coagulation factor levels should be monitored by laboratory tests particularly in cases where intravenous replacement therapy is indicated.

Treatment of bleeding in patients with haemophilia A or B or vWD

DiseaseType of diseaseTreatment of mild bleedingTreatment of severe bleeding
Haemophilia AMildTranexamic acid, DDAVPDDAVP or F VIII product
Moderately severe to severeF VIII product: at least 20-40 units/kg; after 12-24 h, 1-2 additional dosesF VIII product
  • Intramuscular or intra-articular bleeding: initially 30-40 units/kg, treatment continued for 2-4 days
  • -Bleeding in the head, neck or abdominal or chest cavity region: initial dose 40-60 units/kg (target level more than 50-80%) for 7-10 days
Haemophilia BMild, moderately severe or severeF IX product: 30-50 units/kgF IX product: initial dose 80-120 units/kg (target F IX level more than 50-80%)
vWDType 1 (mild)Mucosal bleeding: 20-25 mg/kg tranexamic acid 3 times daily p.o.DDAVP or FVIII/vWF or vWF product
Other bleeding: tranexamic acid + DDAVPF VIII/vWF or vWF product
Type 2 (moderately severe)Tranexamic acid + DDAVP or F VIII/vWF productF VIII/vWF or vWF/F VIII product
Type 3 (severe)vWF/F VIII productF VIII/vWF or vWF/F VIII product

Other hereditary coagulation disorders

  • Other hereditary haemorrhagic diseases,apart from haemophilia A and B and von Willebrand disease, are rare. They are transmitted by autosomal recessive inheritance, and usually only homozygotes exhibit bleeding problems. However, bleeding associated with surgical procedures is also possible in heterozygotes. Mild F VII deficiency is common but rarely causes bleeding symptoms - usually only increased bleeding when there is another cause for bleeding.
  • Bleeding is managed with fresh frozen plasma or with specific products when available.
  • Untreated deficiency of F XIII usually leads to a severe clinical picture that resembles that of haemophilia. Due to its slow elimination, administration of F XIII every 3-4 weeks is sufficient for prophylaxis of bleeding.

References

  • O'Hara J, Sima CS, Frimpter J et al. Long-term outcomes from prophylactic or episodic treatment of haemophilia A: A systematic review. Haemophilia 2018;24(5):e301-e311. [PubMed]
  • Collins P, Chalmers E, Chowdary P ym. The use of enhanced half-life coagulation factor concentrates in routine clinical practice: guidance from UKHCDO. Haemophilia 2016;22(4):487-98. [PubMed]
  • Pierce GF, Iorio A. Past, present and future of haemophilia gene therapy: From vectors and transgenes to known and unknown outcomes. Haemophilia 2018;24 Suppl 6():60-67. [PubMed]
  • Leebeek FW, Eikenboom JC. Von Willebrand's Disease. N Engl J Med 2016;375(21):2067-2080. [PubMed]
  • Nummi V, Lassila R, Joutsi-Korhonen L et al. Comprehensive re-evaluation of historical von Willebrand disease diagnosis in association with whole blood platelet aggregation and function. Int J Lab Hematol 2018;40(3):304-311. [PubMed]
  • Szanto T, Lassila R, Funding E, Onundarson PT, Strandberg K, Baghaei F; on behalf of the Nordic Haemophilia Council. Von Willebrand disease - the Nordic perspective. AOB 2018; Vol. 3, No.1

Evidence Summaries ⬆