Coagulation disorders

Haemophilia A• Haemophilia A is the most common of the hereditaryclotting factor deficiencies. • The prevalence is of the order of 30 – 100 per million

population. • The inheritance is sex – linked recessive but up to one -third of patients have no family history and resultfrom recent mutation.

Clinical features

• Infants may develop profuse post – circumcision haemorrhage or joint and soft tissue bleeds and excessive bruising when they start to be active.

• Recurrent painful haemarthroses and muscle haematomas dominate the clinical course of severely affected patients and if inadequately treated lead to progressive joint deformity and disability .

• Local pressure can cause entrapment neuropathy or ischaemic necrosis.

• Prolonged bleeding occurs after dental extractions. • Spontaneous haematuria and gastrointestinal

haemorrhage,• sometimes with obstruction resulting from intramucosalbleeding, can also occur. • The clinical severity of the disease correlates inversely

with the factor VIII level

• Operative and post -traumatic haemorrhage are life - threatening both in severely and mildly affected patients. Although not common, spontaneous intracerebral haemorrhage occurs more frequently than in the general population and is an important cause of death in patients

with severe disease.

• Haemophilic pseudotumours are large encapsulated haematomas with progressive cystic swelling from repeated haemorrhage.

They are best visualized by magnetic resonance imaging (MRI) They may occur in fascial and muscle planes, large muscle groups and in the long bones, pelvis and cranium.

The latter result from repeated subperiosteal haemorrhages with bone destruction and new bone formation.

• As a result of human immunodeficiency virus (HIV) present in concentrates made from human plasma during the early 1980s, over 50% of haemophiliacs treated in the USA or Western Europe became infected with HIV.

• Acquired immune deficiency syndrome (AIDS) has been a common cause of death in severe haemophilia. Thrombocytopenia from HIV infection may exacerbate bleeding episodes.

• Many patients were infected with hepatitis C virus before testing of donors and blood products became possible. This has resulted in chronic hepatitis,

.

Laboratory findings

• The following tests are abnormal:1 -Activated partial thromboplastin time (APTT).2 -Factor VIII clotting assay.The platelet function analysis - 100 (PFA - 100) (andbleeding time) and prothrombin time (PT) arenormal.

Carrier detection and antenatal diagnosis

• Carriers are detected with DNA probes. • Chorionic biopsies at 8 – 10 weeks ’ gestation provide

sufficient fetal DNA for analysis. Antenatal diagnosis also possible followingthe demonstration of low levels of factor VIII in fetal blood obtained at 16 – 20 weeks ’ gestation from the umbilical vein by ultrasound - guided

needle aspiration. This method is now only used ifDNA analysis is uninformative (1% of carriers).

Treatment • Bleeding episodes are treated with factor VIII replacement therapy and

spontaneous bleeding is usually controlled if the patient ’ s factor VIII level is raised to30 – 50% of normal.

• Guidelines exist for the plasma level to be achieved for different types of haemorrhage.For major surgery, serious post – traumatic bleeding or when haemorrhage is occurring at a dangerous site, the factor VIII level should be elevated to 100% and then maintained above 50% when acute bleeding has stopped, until healing has occurred. On average, factor VIII infusion produces a plasma increment of 2 U/dL per unit infused perkilogram body weight. Roughly, the dose to be infused (units) = (weight (kg) × increment needed

(U/dL))/2.

• Recombinant factor VIII and plasma - derivedpurified factor VIII preparations, which are heatand solvent - detergent treated, are available forclinical use and have never transmitted viralinfections.

1 -Diamino - 8 - D - arginine vasopressin (DDAVP; desmopressin) provides an alternative means of increasing the plasma factor VIII level in milder haemophiliacs.

Following the intravenous administrationof this drug, there is a two - to fourfold rise maximum at 30 – 60 min in the patient ’ s own factor VIII by release from endothelial cells and this rise is proportional to the resting level. DDAVP may also be taken subcutaneously or nasally – this has been used as immediate treatment for mild haemophilia after accidental trauma or haemorrhage. DDAVP has an antidiuretic action and should be avoided in the elderly; fluid restriction is advised after its use.

• Local supportive measures used in treating haemarthroses and haematomas include resting the aff ected part, application of ice and the preventionof further trauma.

Prophylaxis • The increased availability of factor VIII concentrates that may be

stored in domestic refrigerators has dramatically altered haemophilia treatment.

• At the earliest suggestion of bleeding, the haemophilic child may be treated at home. This advance has reduced the occurrence of crippling haemarthroses and the need for inpatient care. Severely affected patients are now reaching adult life with little or no arthritis.

. After the first spontaneous joint bleed,most boys with severe haemophilia are started on prophylactic factor VIII three times a week, aiming to keep their factor VIII trough levels above 1%.

• This may require the placement of a vascular access device such as Port - a - Cath if venous access is difficult. A controlled trial has proven that regular prophylaxis is far superior to on - demand treatment as judged by progression of joint damage, which was virtually absent in children on prophylaxis but always seen in boys treated on - demand.

• Gene therapy• Because it is only necessary to maintain factor levels> 1% to prevent most of the mortality and morbidityof factor VIII or IX deficiency, there is greatinterest in gene - based therapy. Various viral vectors(retroviral, adeno - associated) as well as non - viralvectors are being explored. Phase 1 trials are beingcarried out for both haemophilia A and B.

Inhibitors• One of the most serious complications of haemophilia is the

development of antibodies (inhibitors) to infused factor VIII which occurs in 30 – 40% of severely effected patients, usually within the first 50 days of exposure.

• This renders the patient refractory to further replacement therapy. Immunosuppression and immune tolerance regimens have been used in an attempt to eradicate the antibody with success (at great cost) in about two - thirds of cases.

• Recombinant activated factor VII (VIIa) and activated prothrombin complex concentrates (FEIBA

• – factor VIII inhibitor bypassing activity) can be useful in the treatment of bleeding episodes.

Factor IX deficiency (Haemophilia B)

• The inheritance and clinical features of factor IX deficiency (Christmas disease, haemophilia B) are identical to those of haemophilia A.

• Indeed, the two disorders can only be distinguished by specific coagulation factor assays. The incidence is one - fifth that

of haemophilia A. Factor IX is coded by a gene close to the gene for factor VIII near the tip of the long arm of the X chromosome at Xq2.6.

• Its synthesis, like that of prothrombin, factor VII, factor X and protein C, is vitamin K - dependent.

• Carrier detection and antenatal diagnosis is performed as forhaemophilia A. • The principles of replacement therapy are similar to those of haemophilia A.• Bleeding episodes are treated with high - purity factor IX concentrates.

Because of its longer biological half - life, infusions do not have to be given as frequently as do factor VIII concentrates in haemophilia A.

• Recombinant factor IX is preferred, but higher doses are needed than with plasma - derived factor IX to attain the same response. Also the distribution and kinetics of clearance differ from the natural product, but it is certainly safe and effective.

Laboratory findings

• Th e following tests are abnormal:• 1 APTT;• 2 Factor IX clotting assay.• As in haemophilia A, the PFA - 100 (and

bleeding time) and PT tests are normal.

Von Willebrand disease

• In this disorder there is either a reduced level or abnormal function of von Willebrand factor (VWF) resulting from a missense mutation or null mutation.

• VWF is produced in endothelial cells and megakaryocytes.• It has two roles :It promotes platelet adhesion to subendothelium at

high shear rates and it is the carrier molecule for factor VIII, protecting it from premature destruction. The latter property explains the reduced factor VIII levels found in VWD.

• A Chronic elevation of VWF is part of the acute phase response to injury, inflammation, neoplasia or pregnancy.

• VWF is synthesized as a large 600 -kDa dimeric protein which then forms multimers up to 20 × 10 6 Da in weight which are the largest molecules in blood. Three types of VWD have beend escribed . Type 2 is divided into four subtypes depending on the type of functional defect.

• Type 1 accounts for 75% of cases.

• VWD is the most common inherited bleeding disorder. Usually, the inheritance is autosomal dominant.

• The severity of the bleeding is highly variable depending on mutation type and epistatic genetic effects such as ABO blood group.

• Women are worse affected than men at a given VWF level. • Typically, there is mucous membrane bleeding (e.g. epistaxes,

menorrhagia), excessive blood loss from superficial cuts and abrasions, and operative and post – traumatic haemorrhage. Th e severity is variable in the different types. Haemarthroses and muscle haematomas are rare, except in type 3 disease.

Laboratory findings

• 1-The PFA - 100 test is abnormal. Thishas largely replaced the bleeding time test.• 2- Factor VIII levels are often low. If low, a factorVIII/VWF binding assay is performed.• 3 -The APTT may be prolonged.• 4 -VWF levels are usually low.

• 5- There is defective platelet aggregation by patientplasma in the presence of ristocetin (VWF: Rco).Aggregation to other agents (adenosine diphosphate(ADP), thrombin or adrenaline) is usually normal.• 6-Collagen - binding function (VWF: CB) is usuallyreduced.• 7 Multimer analysis is useful for diagnosing diff erentsubtypes (Table 26.3 ).• 8 Th e platelet count is normal except for type 2Bdisease (where it is low).

Treatment

• Options are as follows:• 1- Local measures and antifibrinolytic agent (e.g. tranexamic acid for

mild bleeding).• 2 -DDAVP infusion for those with type 1 VWD.This releases VWF from endothelial cells 30 min after intravenous infusion. • 3- High - purity VWF concentrates for patients with very low VWF levels.

Plasma - derived factor VIII/ VWF concentrates are used. Recombinant VWF is now in phase II clinical trials.

Hereditary disorders of other coagulation factors• All these disorders (deficiency of fibrinogen, prothrombin, factors V, VII,

combined V and VIII, factors X, XI, XIII) are rare.• In all the inheritance is autosomal recessive except for factor XI deficiency

where there is variable penetrance. Factor XI deficiency is seen mainly in Ashkenazi Jews and occurs in either sex.

• The bleeding risk shows incomplete correlation to severity of the deficiency, and bleeding only occurs after trauma such as surgery.

• Treatment is with fibrinolytic inhibitor, factor XI concentrate or fresh frozen plasma.

• Factor XIII deficiency produces a severe bleeding tendency, characteristically with umbilical stump bleeding.

• Fat - soluble vitamin K is obtained from green vegetables and bacterial synthesis in the gut. Deficiency may present in the newborn (haemorrhagic disease of the newborn) or in later life.

• Deficiency of vitamin K is caused by an inadequate diet, malabsorption or inhibition of vitamin K by drugs such as warfarin which act as vitamin K antagonists.

• Warfarin is associated with a decrease in the functional activity of factors II, VII, IX and X and proteins C and S, but immunological

methods show normal levels of these factors. The non - functional proteins are called PIVKA (proteins formed in vitamin K absence).

• Vitamin K - dependent factors are low at birth andfall further in breast - fed infants in the first fewdays of life. Liver cell immaturity, lack of gut bacterialsynthesis of the vitamin and low quantities inbreast milk may all contribute to a deficiency whichcauses haemorrhage, usually on the second to fourthday of life, but occasionally during the first 2months.

Diagnosis

• The PT and APTT are both abnormal. The platelet count and fibrinogen are normal with absent fibrin degradation products.

Treatment• Prophylaxis. For many years vitamin K has been given to all

newborn babies as a single intramuscular injection of 1 mg. • This remains the most appropriate and safest treatment.• Following epidemiological evidence suggesting a possible link

between intramuscular vitamin K and an increased risk of childhood tumours (which has not been substantiated), some centres recommended an oral regimen but this has never been subjected to randomized controlled trial.

Vitamin K deficiency in children or adults

• Deficiency resulting from obstructive jaundice, pancreatic or small bowel disease occasionally causes a bleeding diathesis in children or adults.

• DiagnosisBoth PT and APTT are prolonged. There are low plasma

levels of factors II, VII, IX and X.

Treatment

• 1 Prophylaxis: vitamin K 5 mg/day orally. • 2 Active bleeding or prior to liver biopsy: vitamin K 10 mg slowly

intravenously. Some correction of PT is usual within 6 hours. Th e dose should be repeated on the next 2 days after which optimal correction is usual.

• 3 Rapid correction may be achieved by infusion of prothrombin

complex concentrate.

Disseminated intravascular coagulation

• Widespread inappropriate intravascular deposition of fibrin with consumption of coagulation factors and platelets occurs as a consequence of many disorders that release procoagulant material into the circulation or cause widespread endothelial damag eor platelet aggregation (Table 26.5 ). It may be associated with a fulminant haemorrhagic or thrombotic syndrome with organ dysfunction or run a less severe and more chronic course. The main clinical presentation is with bleeding but 5 – 10% of patients manifest thrombotic lesions (e.g. with gangrene of limbs).

PATHOGENESIS• The key event underlying DIC is increased activity of thrombin in the

circulation that overwhelms its normal rate of removal by natural anticoagulants.

• This can come from tissue factor (TF) release into the circulation from damaged tissues present on tumour cells or from up - regulation of TF on circulating monocytes or endothelial cells in response to pro - infl ammatory cytokines (e.g. interleukin - 1,tumour necrosis factor, endotoxin).

• DIC may be triggered by the entry of procoagulant material into the circulation in the following situations: severe trauma

amniotic fluid embolism, premature separation of the placenta, widespread mucin - secreting adenocarcinomas, acute promyelocytic leukaemia (t(15; 17)), liver disease, severe falciparum malaria, haemolytic transfusion reaction and some snake bites.

• DIC may also be initiated by widespread endothelial damage and collagen exposure (e.g. endotoxaemia, Gram - negative and meningococcal septicaemia, septic abortion), certain virus infections and severe burns or hypothermia

Clinical features• These are usually dominated by bleeding, particularly

from venepuncture sites or wounds (Fig. 26.10 a). There may be generalized bleeding in the gastrointestinal tract, the oropharynx, into the lungs, urogenital tract and in obstetric cases, vaginal bleeding may be particularly severe. Less frequently, microthrombi may cause skin lesions, renal failure, gangrene of the fingers or toes (Fig. 26.10 b) or cerebral ischaemia. Some patients may develop subacute or chronic DIC, especially with mucin - secreting adenocarcinoma.Compensation by the liver may render some of the coagulation tests normal.

• Laboratory findings In many acute syndromes the blood may fail to clot because of gross fi

brinogen deficiency.• Tests of haemostasis• 1- The platelet count is low.• 2 -Fibrinogen concentration low.• 3 -The thrombin time is prolonged.• 4 -High levels of fibrin degradation products such as D - dimers are

found in serum and urine.• 5- The PT and APTT are prolonged in the acute syndromes.• Blood film examination• In many patients there is a haemolytic anaemia ( ‘ microangiopathic ’ )

and the red cells show prominent fragmentation because of damage caused when passing through fi brin strands in small vessels

Treatment• Treatment of the underlying cause is most important.The management of patients who are bleeding differs from

that of patients with thrombotic problems.• BleedingSupportive therapy with fresh frozen plasma and platelet

concentrates is indicated in patients with dangerous or extensive bleeding.

• Cryoprecipitate provides a more concentrated source of fibrinogen and red cell transfusions may be required.

• Thrombosis• The use of heparin or antiplatelet drugs to inhibit the

coagulation process is considered in those with thrombotic problems such as skin ischaemia.

• Fibrinolytic inhibitors should not be considered because failure to lyse thrombi in organs such as the kidney may have adverse effects. Antithrombin concentrates or recombinant activated human protein C may be used to inhibit DIC in severe cases with sepsis (e.g. meningococcal septicaemia). Th ere is reduced activated protein C (APC) in severe sepsis and recombinant human APC has been found to reduce mortality in this setting.

• Circulating antibodies to coagulation factors are occasionally seen with an incidence of approximately 1 per million per year rising markedly with age. Alloantibodies to factor VIII occur in 5 – 10% of haemophiliacs. Factor VIII autoantibodies may also result in a bleeding syndrome. These immunoglobulin G (IgG) antibodies occur rarely post - partum, in certain immunological disorders (e.g. rheumatoid arthritis), in cancer and in old age.

Coagulation deficiency caused byantibodies

• Treatment usually consists of a combination ofimmunosuppression and treatment with factorreplacement, usually as human factor VIII, recombinantVIIa or activated prothrombin complexconcentrate (FEIBA).

SOURCE :essential haematology sixth edition