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POLYCYTHEMIA RUBRA VERA,BLEEDING TENDENCY

الكلية كلية الطب     القسم  الباطنية     المرحلة 5
أستاذ المادة علاء صادق جابر العواد       5/1/2011 6:32:42 AM

 

POLYCYTHAEMIA RUBRA VERA )(PRV) 

 

 

PRV occurs mainly in patients over the age of 40 years and presents either as an incidental finding of a high haemoglobin, or with symptoms of hyperviscosity such as lassitude, loss of concentration, headaches, dizziness, black­outs, pruritus and epistaxis. Some present with manifesta­tions of peripheral arterial disease or a cerebrovascular accident. Patients are often plethoric and the majority have a palpable spleen at diagnosis. Thrombotic complications may occur and peptic ulceration is common, sometimes complicated by bleeding.

 

 

The diagnosis of polycythaemia is discussed on page 1014. It requires a raised red cell mass, the absence of causes of secondary erythrocytosis, and splenomegaly. The neutrophil and platelet counts are frequently raised, an

 

 

VESSEL WALL ABNORMALITIES

 

 

Vessel wall abnormalities may be congenital, such as heredi­tary haemophilia telangiectasis, or acquired as in a vasculitis.

 

 

Hereditary haemorrhagic telangiectasia Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited condition caused by mutations in the endothelial cell genes coding for endoglin and activator receptor-like kinase which are receptors for the transforming growth factor-beta (TGF-(3), a potent angiogenic cytokine concerned with vascular modelling. Telangiectasia and small aneurysms are found on the fingertips, on the face, in the nasal passages, on the tongue, in the lung and in the gastrointestinal tract. A significant proportion of these

patients develop larger pulmonary arteriovenous malforma­tions (PAVMs) that cause arterial hypoxaemia due to a right­to-left shunt. These predispose to paradoxical embolism resulting in stroke or cerebral abscess. All patients with HHT should be screened for PAVMs which, if found, should be ablated by percutaneous embolisation.

Patients present either with recurrent bleeds, particularly epistaxis, or with iron deficiency due to occult gastro­intestinal bleeding. Treatment can be difficult because of the multiple bleeding points but regular iron therapy often allows the marrow to compensate for blood loss. Local cautery or laser therapy may prevent single lesions from bleeding. A variety of medical therapies have been tried but none has been found to be universally effective.

 

 

Ehlers-Danlos disease

Ehlers-Danlos disease is a congenital disorder of collagen synthesis in which there is joint hyperextensibility, skin extensibility and tissue fragility such that capillaries are poorly supported by subcutaneous collagen and ecchymoses are commonly seen.

PLATELET FUNCTIONAL DISORDERS

 

 

Even in the presence of a normal platelet count, an individual may bleed if the function of the platelets is reduced. Congenital abnormalities include rare disorders of the membrane glycoproteins, e.g. thrombasthenia and Bernard-Soulier syndrome, or the presence of defective platelet granules, e.g. a deficiency of dense (delta) granules giving rise to storage pool disorders. Such patients exhibit bleeding of `platelet type (p. 1017) which varies in severity between patients, some presenting with frequent recurrent bleeds whilst others are only diagnosed because of excessive post-operative haemorrhage. Mild functional disorders, which only cause excessive bleeding after trauma or surgery, are often not diagnosed and are probably relatively common.

 

 

Many drugs inhibit platelets (

Box 24.63

 

). Aspirin and other NSAIDs inhibit platelet cyclo-oxygenase, preventing the conversion of arachidonic acid to the potent platelet aggregator thromboxane B,.

 

 

24.63 DRUGS INHIBITING PLATELET FUNCTION

 

 

NSAIDS

 

 

• Aspirin                               0 Phenylbutazone

 

 

• Indometacin                       0 Sulfinpyrazone

 

 

Antibiotics

 

 

e Penicillins                          0 Cephalosporins

 

 

Dextran Heparin (3-blockers

 

 

Thrombocytopenia

 

 

Thrombocytopenia causing bleeding constitutes a haema­tological emergency which should be promptly investigated and treated. Causes and investigations are described on page

 

1017. Treatment should be directed at the underlying condition as well as specific measures to raise the platelet count. Platelet transfusions should be given only if the platelet count is less than 10 x l0^y/1, to treat troublesome bleeding such as persistent epistaxis, or potentially life­threatening bleeding, e.g. gastrointestinal haemorrhage. Such transfusions provide only temporary relief because the survival of the platelets in the circulation is a few days at most, and only a matter of minutes or hours if the thrombocytopenia is due to increased platelet consumption, as in idiopathic thrombocytopenic purpura.

 

 

Idiopathic thrombocytopenic purpura

 

 

The presence of autoantibodies. often directed against platelet membrane glycoprotein IIb-111a. causes the premature removal of platelets by the monocyte­macrophage system. Occasionally, antigen-antibody immune complexes adhere to platelets at their F, receptor, resulting in their premature removal from the circulation.

 

 

Clinical features and investigations

In children idiopathic thrombocytopenic purpura (ITP) often presents 2-3 weeks after a viral illness, with the sudden onset of purpura and sometimes oral and nasal bleeding. It is important to ascertain that the child does not have any other systemic illness, in particular DIC.

In adults ITP more commonly affects females and has an insidious onset. It is unusual for there to be a history of a preceding viral infection. At presentation some cases may be associated with symptoms or signs of a connective tissue disease, whilst in others these disorders may become apparent several years later. The condition is likely to become chronic, with remissions and relapses. The peripheral blood film is normal, apart from a greatly reduced platelet number, whilst the bone marrow reveals an obvious increase in megakaryocytes.

Management

Children. If the child has only mild bleeding symptoms, it is usual to withhold any specific treatment, as in the majority of instances the condition is self-limiting within a few weeks. The presence of moderate to severe purpura, bruising or epistaxis, and a platelet count less than 10 x 10⁹/l are indications for oral prednisolone 2 mg/kg daily. The platelet count usually rises promptly within 1-3 days. Persistent epistaxis, gastrointestinal bleeding, retinal haemorrhages or any suggestion of intracranial bleeding should be treated immediately by a platelet transfusion and intravenous immunoglobulin (IVIgG).

Adults. Treatment with prednisolone 1 mg/kg daily is I often less rewarding than in children; the platelet count rises in response to therapy but may fall again when the dose is reduced or stopped. As with children, persistent or potentially life-threatening bleeding should be treated with platelet transfusion. Intravenous IgG (1 g/kg) should be given if the patient is very haemorrhagic or the bleeding is immediately life-threatening. IVIgG raises the platelet count by blocking the monocyte-macrophage F_c receptors, thus preventing the phagocytosis of antibody-coated platelets.

 

 

Relapses should be treated by increasing the dose of prednisolone. If a patient has two relapses, splenectomy is

 

 

 

 

BLEEDING DISORDERS

 

 

considered. This should be preceded by pneumococcal, meningococcal and Haemophilus influenzae vaccination and oral penicillin V daily for life (Box 24.31, p. 1032). As so many adults eventually require splenectomy, it is prudent to vaccinate all at presentation before they become immuno­suppressed with a prolonged course of corticosteroids. Vaccination should be performed by subcutaneous injection since, if given intramuscularly, it may result in a haema­toma. Splenectomy is curative in about 70% of patients and, in the remainder, the aim should be to keep the patient free of symptoms rather than to treat the platelet count alone. Often patients have platelet counts of 20-30 x 10⁹/1 with­out symptoms; some require long-term maintenance with prednisolone at 5 mg/day. If significant bleeding persists despite splenectomy and low-dose corticosteroid therapy, vincristine, immunosuppressive therapy-e.g. cyclophosphamide or rituximab, or repeated infusions of intravenous immunoglobulin should be considered.

 

 

Thrombotic thrombocytopenic purpura

 

 

This is a rare cause of thrombocytopenia that can present to a variety of specialties and requires urgent management. Platelet thrombi form in the microvasculature affecting in particular the renal (p.498) and cerebral circulation. Excessive platelet aggregation is thought to occur because of the lack of a functioning protease enzyme which results in the presence of extra-large von Willebrand factor molecules. It can be associated with drugs, autoimmune disease and infection (e.g. E. coli 0157). Clinically there is a pentad of diagnostic features: thrombocytopenia, micro­angiopathic haemolytic anaemia, fluctuating neurological signs, renal impairment and fever. Untreated mortality rates are 90%, this figure falling to 10-30% after treatment with fresh frozen plasma given during daily plasma exchange.

 

 

COAGULATION DISORDERS

 

 

Coagulation factor disorders can arise either from deficiency, usually congenital, of a single factor-e.g. factor VIII in haemophilia A-or from multiple factor deficiencies which are often acquired, e.g. secondary to liver disease. Of the single congenital deficiencies, haemophilia A and B are the most common although, rarely, any of the coagulation factors may be reduced. The congenital disorders almost exclusively arise as a result of an abnormality in the gene coding for the coagulation factor.

 

 

Genetics

 

 

The factor VIII gene is located on the X chromosome and consists of 26 exons; many different defects in the gene have been identified, ranging from single-base changes to deletions and inversions. Major disruption of the gene, e.g a large deletion, results in severe haemophilia whereas a single base change will only cause a partial loss of function, with moderate or mild disease. As the factor VIII gene is on the X chromosome, haemophilia A is a sex-linked disorder. Thus all daughters of haemophiliacs are obligate carriers and sisters have a 50% chance of being a carrier. If a carrier has a son, he has a 50% chance of having haemophilia, and a daughter has a 50% chance of being a carrier. Haemophilia `breeds true within a family. All members will have the same abnormality of the factor VIII gene; thus if one individual has severe haemophilia, so will all others affected. Female carriers of haemophilia may have reduced factor VIII levels because of random inactivation of the X chromosome in the developing fetus (lyonisation). A reduced factor VIII level in a carrier will result in a mild bleeding disorder; thus all known or suspected carriers of haemophilia should have their factor VIII level measured.

 

 

The use of molecular genetic techniques has revolution­ised the ability to identify carriers and make an antenatal diagnosis of haemophilia. If the factor VIII mutation causing the haemophilia in a particular family is known, antenatal diagnosis can be undertaken in a female who has a high probability of being a carrier. This is accomplished by chorionic villous sampling, usually around 11 weeks gestation, sexing the fetus and using informative factor VIII probes.

 

 

Clinical features and investigations

 

 

Although haemophilia A is a congenital disorder, it is unusual for excessive bleeding to be noticed until about 6 months of age, when superficial bruising or a haemarthrosis may occur. This apparent delay in presentation is due to the relative inactivity of babies in the first few months of life and it is only when they begin to move about that the increase in trauma results in bleeding. It is not uncommon for children to be initially classified as having non­accidental injury.

 

 

The normal factor VIII level is 50-150% and is measured by a clotting assay. In haemophilia the propensity to bleed­ing is related to the plasma factor VIII level. The classi­fication of severity of haemophilia is set out inBox 24.64

.

 

CONGENITAL BLEEDING DISORDERS

 

 

HAEMOPHILIA A

 

 

A reduction of factor VIII resulting in haemophilia A, which affects 1/10 000 individuals, is the most common congenital disorder of coagulation. Factor VIII is primarily synthesised by the liver and endothelial cells, but other organs such as the spleen, kidney and placenta may also contribute. Plasma factor VIII has a half-life of about 12 hours and is carried non-covalently bound to the von Willebrand factor (vWF).

 

 

1057

 

 

 

 

 

 

A

 

 

 

 

 

 

1058

 

 

Fig. 24.34 Large haemarthrosis in the right knee of a boy with haemophilia A.

 

 

Individuals with severe haemophilia experience recurrent haemarthroses in large joints (Fig. 24.34). These usually begin spontaneously without apparent trauma and most commonly affect the knees, elbows, ankles and hips. A typical severe haemophiliac may have one or two bleeds each week. Patients are aware that bleeding has started because they experience an abnormal sensation in the joint. If treatment is not given at this stage, bleeding continues, resulting in a hot, swollen and very painful joint, which may persist for days before gradually subsiding. Recurrent bleeds into joints lead to synovial hypertrophy, destruction of the cartilage and secondary osteoarthrosis (Fig. 24.35). The resultant limitation of movement may greatly reduce the function of joints, making walking difficult.

 

 

Muscle haematomas are also characteristic of haemo­philia. These occur most commonly in the calf and psoas muscles but they can arise in almost any muscle. Although less common than haemarthroses, a single episode can leave severe lasting damage if not effectively treated. A large psoas bleed, for example, may extend to compress the femoral nerve. Calf haematomas are also serious because of the inflexible fascial sheath surrounding the soleus and gastrocnemius muscles. Untreated haemorrhage causes a rise in pressure with eventual ischaemia, necrosis, fibrosis, and subsequent contraction and shortening of the Achilles tendon (Fig. 24.36).

 

 

Although joint and muscle bleeds are the most common sites for haemorrhage, bleeding can occur at almost any site. It is particularly serious if it takes place in a confined anatomical space associated with vital structures, such as the intracranial area where haemorrhage, unless treated very promptly, is often fatal (Fig. 24.37).

 

 

Individuals with moderate haemophilia usually only experience haemorrhage after minor trauma, and those with the mild form of the disorder, following more major trauma or surgery. Whereas severe haemophilia is usually diagnosed within the first 2 years of life, individuals with moderate and mild forms may escape diagnosis until adulthood.

 

 

Management

 

 

Bleeding episodes should be treated early by raising the factor VIII level. This is usually accomplished by

B

 

FA] Repeated bleeds have led to broadening of the femoral epicondyles. Unilateral atrophy of the quadriceps (A) is easily seen. © X-ray confirms broadening of femoral epicondyles. There is no cartilage present, as evidenced by the close proximity of the femur and tibia (B); sclerosis (C), osteophyte (D) and bony cysts (E) are present.

 

 

intravenous infusion of factor VIII concentrate. Factor VIII concentrates are freeze-dried and stable at 4°C and can therefore be stored in domestic refrigerators. This allows many patients to treat themselves at home and has revolutionised haemophilia care. Factor VIII concentrates are prepared from blood donor plasma which has been screened for hepatitis B and C viruses and HIV, and has undergone a viral inactivation process during manufacture; they have a good safety record. However, factor VIII concentrates prepared by recombinant technology are now widely available and, although more expensive, are perceived as being safer than those derived from plasma.

 

 

In addition to factor VIII concentrate therapy, resting of the bleeding site by either bed rest or a splint reduces continuing haemorrhage. Once bleeding has settled, theBoEEOrrrG -orso~oE -R s

 

Fig. 24.36     Atrophy of the calf in an adult following an inadequately treated gastrocnemius haematoma as a child. The increased pressure of the haematoma caused ischaemia of the muscle, followed by necrosis, fibrosis and subsequent contraction to give the equinus deformity.

 

 

 

 

Fig. 24.37     CT revealing a major intracerebral haematama. This arose spontaneously in a severe haemophiliac.

 

 

patient should be mobilised and physiotherapy used to restore strength to the surrounding muscles.

 

 

Complications of therapy

 

 

Although factor VIII concentrates have allowed many haemophiliacs to lead near-normal lives, this freedom has been bought at a cost (

 

). Before 1985 concentrates

 

 

 

 

were not virally inactivated with heat or chemicals, and so many patients treated became infected with HIV and the hepatitis viruses. As a result, most adult severe haemo­philiacs have been exposed to hepatitis B virus and have developed immunity, as evidenced by the development of anti-HBs (p. 963). A small number become chronic HBsAg carriers and may infect sexual partners, who should therefore be offered hepatitis B immunisation (p. 966). They are also at risk of delta virus infection. All potential recipients of pooled blood products should be offered hepatitis A and B immunisation because it will protect against hepatitis A, B and D infection. Hepatitis C virus was ubiquitously transmitted by concentrates prior to 1985, resulting in virtually all recipients becoming infected. It is clear that many of these patients have hepatitis, and a significant proportion progress to cirrhosis and hepato­cellular carcinoma. Management of these is described in Chapter 23.

 

 

Prior to 1985, HIV was also transmitted to haemophiliacs by concentrates, with at least 60% of severe haemophiliacs becoming infected (p. 380). The clinical consequences are very similar to those for any individual infected with HIV, although their clinical course is perhaps more like those who become infected intravenously than those who become infected sexually. Kaposi s sarcoma is rare in haemophiliacs.

 

 

There is now concern that the infectious agent which causes variant CID (p. 1234) might be transmissible by blood and blood products. Pooled plasma products, including factor VIII concentrate, are now manufactured from plasma collected in countries with a low incidence of BSE.

 

 

The other serious consequence of factor VIII infusion is the development of anti-factor VIII antibodies, which arises in about 20-30% of severe haemophiliacs. Such antibodies rapidly neutralise therapeutic infusions, making treatment relatively ineffective. Infusions of activated clotting factors, e.g. VIIa or FEIBA (factor eight inhibitor bypassing activity-an activated concentrate of factors II, IX and X), may stop bleeding.

 

 

In individuals with a basal factor VIII level of 10% or greater it may be possible to raise the level approximately three- to five-fold with desmopressin; this is best given intravenously but can be administered intranasally. This is

 

often sufficient to treat a mild bleed or cover minor surgery such as dental extraction.

 

 

Surgery in haemophiliacs can be safely performed provided the patient does not have an inhibitor to factor VIII and receives appropriate doses of concentrate. A single infusion of factor VIII is usually adequate for simple dental extractions in an individual with severe haemophilia, along with a 10-day course of tranexamic acid (a fibrinolytic inhi­bitor) and an antibiotic. Major surgery, such as orthopaedic, requires twice-daily therapy for 14 days or longer.

 

 

HAEMOPHILIA B (CHRISTMAS DISEASE)

 

 

Investigations

 

 

The disorder is characterised by a reduced level of vWF, which is often accompanied by a secondary reduction in factor VIII and a prolongation of the bleeding time.

 

 

Management

 

 

Many episodes of mild haemorrhage can be successfully treated with desmopressin, which raises the vWF level, resulting in a secondary increase in factor VIII. For more serious or persistent bleeds haemostasis can be achieved with selected factor VIII concentrates which contain considerable quantities of vWF in addition to factor VIII.

 

 

 

 

1060

 

 

Aberrations of the factor IX gene, which is also present on the X chromosome, result in a reduction of the plasma factor IX level, giving rise to haemophilia B. This disorder is clinically indistinguishable from haemophilia A but is less common. The frequency of bleeding episodes is related to the severity of the deficiency of the plasma factor IX level.

 

 

Treatment is with a factor IX concentrate; it is used in much the same way as factor VIII for haemophilia A. Carrier identification and antenatal diagnosis can be accomplished if the specific mutation is known.

 

 

VON WILLEBtFAND DISEASE

 

 

Von Willebrand disease is a common but usually mild bleeding disorder. The gene for von Willebrand factor (vWF) is located on chromosome 12 and therefore the disorder is inherited in an autosomal fashion. In most families it appears to be inherited dominantly; rarely, it appears in a clinically severe form with almost undetectable levels of vWF. In these circumstances the patient usually inherits a different abnormal vWF gene from each parent and is thus a compound heterozygote. Gene probes are available to trace the gene in a family and can be used to identify carriers and for antenatal diagnosis.

 

 

The vWF is a protein, synthesised by endothelial cells and megakaryocytes, that performs two principal functions. It acts as a carrier protein for factor VIII, to which it is non­covalently bound. A deficiency of vWF therefore results in a secondary reduction in the plasma factor VIII level. Its other function is to form bridges between platelets and sub­endothelial components (e.g. collagen), allowing platelets to adhere to damaged vessel walls (Fig. 24.7, p. 1007). A deficiency of vWF therefore also leads to prolonged primary haemorrhage after trauma.

 

 

Clinical features

 

 

As vWF participates along with platelets in primary haemostasis, patients present with haemorrhagic manifesta­tions similar to those in individuals with reduced platelet function. Superficial bruising, epistaxis, and menorrhagic and gastrointestinal haemorrhage are common. Bleeding episodes are usually much less common than in severe haemophilia and excessive haemorrhage may only be observed after trauma or surgery. Within a single family the disease can be of very variable expression so that some members may have quite severe and frequent bleeds, whereas others are relatively little troubled.

 

 

ACQUIRED BLEEDING DISORDERS DISSEMINATED INTRAVASCtJLAR COAGULATION (DIC)

 

 

Clinical features

 

 

DIC can be initiated by a variety of different mechanisms in a number of diverse but distinct clinical situations (

 

). Endothelial damage, due to many causes-e.g. endotoxaemia due to Gram-negative septicaemia-results in tissue factor expression, which leads to activation of the coagulation cascade through the extrinsic pathway (Fig. 24.8, p. 1008). Intravascular coagulation takes place with consumption of platelets, factors V and VIII, and fibrinogen. This results in a potential haemorrhagic state, due to the depletion of haemostatic components, which may be exacerbated by activation of the fibrinolytic system secondary to the deposition of fibrin.

 

 

Investigations

 

 

DIC should be suspected when any of the conditions in

 

are met. Definitive diagnosis depends on the finding of thrombocytopenia, prolongation of the prothrombin time (due to factor V and fibrinogen deficiency) and activated partial thromboplastin time (due to factors V, VIII and fibrinogen deficiency), a low fibrinogen concentration and increased levels of D-dimer (cleaved from fibrin by plasmin, establishing evidence of fibrin lysis).

 

 

Management

 

 

Therapy should be aimed at treating the underlying condition causing the DIC, e.g. intravenous antibiotics for

 

 

 

 

suspected septicaemia. Exacerbating factors such as acidosis, dehydration, renal failure and hypoxia should be corrected. If the patient is bleeding, blood products such as platelets and/or fresh frozen plasma should be given to correct identified abnormalities. It may also be reasonable to treat severe coagulation abnormalities in the absence of frank bleeding to prevent sudden catastrophic haemorrhage such as an intracranial bleed or massive gastrointestinal haemorrhage.

 

 

 

 

Venous thrombosis may arise either because of damage to, or pressure on veins (e.g. varicose veins or pelvic tumour), or as a result of changes in the plasma or cellular elements of the blood. Predisposing conditions for venous thromboembolism are listed in

 

. Its clinical features and investigation are described on page 107