Fragmentation haemolysis mechanical haemolytic anaemias

The relationship between the vascular endothelium, the cellular elements of the blood and the mechanisms of haemostasis and fibrinolysis is clearly intricate and complex. The integrity of the red blood cell may be destroyed by contact with abnormal endothelial surfaces, although not all abnormalities of vessels cause haemolysis. It may be that some adherence between the red cell and the abnormal vessel wall is necessary for fragmentation of the red cell to occur, and that this usually happens in the context of abnormal flow as well as an altered endothelium. The situations in which fragmentation haemolysis may occur are the presence of prosthetic material and altered flow following cardiovascular surgery, the trapping or adherence of red cells in arteriovenous malformations, and the destruction of red cells

Figure 10.3 Microangiopathic haemolytic anaemia. Blood film from a patient with carcinoma and bone marrow metastases. Note fragmentation of red cells, leucoerythroblastic changes with nucleated red cell and metamyelocyte and low platelets suggesting possible DIC (x40).

in pathologically altered small blood vessels (microangiopathic haemolytic anaemia).

The characteristic features of fragmentation haemolysis are the appearance of the blood film (Figure 10.3) and the presence of intravascular haemolysis. Depending on the underlying vascular pathology, there may be a reduction in the platelet count and evidence of disseminated intravascular coagulation (DIC). The rate of red cell destruction also varies according to the pathogenesis, so the signs of intravascular haemolysis vary from absence of haptoglobin, elevated LDH and minimal haemosider-inuria, to acute intravascular destruction with haemoglobinaemia and haemoglobinuria. The major causes of fragmentation haemolysis are shown in Table 10.5.

Vascular origin

Pathogenesis

Platelets

Cardiac haemolysis

Prosthetic heart valves

Normal

Patches, grafts

Paraprosthetic or perivalvular leaks

Arteriovenous malformations

Kasabach-Merritt syndrome

Very low

Malignant haemangioendotheliomas

Microangiopathic

TTP-HUS

Low

Malignant disease

Normal/low

Vasculitis

Normal/low

Pre-eclampsia, HELLP

Low

Renal vascular disorders

Normal/low

Disseminated intravascular coagulation

Low

Table 10.5 Mechanical anaemias - fragmentation haemolysis: classification.

TTP, thrombotic thrombocytopenic purpura; HUS, haemolytic uraemic syndrome; HELLP, haemolysis with elevated liver function tests and low platelets.

TTP, thrombotic thrombocytopenic purpura; HUS, haemolytic uraemic syndrome; HELLP, haemolysis with elevated liver function tests and low platelets.

Table 10.5 Mechanical anaemias - fragmentation haemolysis: classification.

Cardiac haemolytic anaemia

This syndrome was so called because it mainly occurred after cardiac surgery in which prosthetic valves, patches or grafts were inserted. Haemolysis usually becomes significant only when there is turbulent flow that brings the circulating red cells into intimate contact with the prosthetic material. There are certain situations in which the haemolysis may be of considerable clinical importance.

Periprosthetic or perivalvular leaks

If after insertion of a prosthesis or repair of a heart valve a leak occurs around the valve or through a suture track, there may be severe intravascular haemolysis without any evidence of haemo-dynamic distress. A difficulty may be that fragmentation of red cells is not always prominent, although spherocytes may be present. However, once autoimmune haemolysis is ruled out, the diagnosis can scarcely be anything other than cardiac haemolysis in a patient who has had cardiac surgery. The haemolysis can be cured only by further surgery.

Ambulatory haemolysis

A patient who has undergone valve replacement may show only slight evidence of haemolysis while in hospital but produce significant anaemia after discharge. This is thought to occur because the higher cardiac output associated with the greater exercise as an outpatient produces more turbulence and hence greater opportunity for red cell fragmentation. A similar mechanism is thought to operate if the patient becomes iron deficient as a result of chronic intravascular haemolysis. Iron replacement and advice about the level of exercise may prevent or delay the need for further surgery.

Cardiopulmonary post-perfusion syndrome

Acute intravascular haemolysis may occur in patients who have undergone cardiopulmonary bypass surgery. The haemolysis may be accompanied by neutropenia and pulmonary distress. The syndrome does not strictly belong in this section, as the haemolysis seems to be caused by complement activation and binding of the membrane attack complex to the red cell surface. The blood film shows ghost red cells rather than fragmentation. The condition is self-limiting and the patient requires only supportive care.

Arteriovenous malformation

Fragmentation of red cells may be seen in the Kasabach-Merritt syndrome, in which platelets are trapped in the vascular network of giant arteriovenous malformations, sometimes with evidence of a consumption coagulopathy. The bleeding disorder is of greater significance than the haemolysis in these patients. A similar picture, usually with clear evidence of a consumptive coagulopathy with evidence of DIC, may be seen in malignant haemangio-endothelioma, in which the tumour tends to invade and grow along veins.

Microangiopathic haemolytic anaemias

This term is used to describe intravascular haemolysis with fragmentation of red cells caused by their destruction in an abnormal microcirculation. Proof of microangiopathy may be lacking in those not subjected to a post-mortem, and MAHA should be considered a clinical syndrome. The three main pathological lesions that give rise to microangiopathic haemolytic anaemias (MAHA) are deposition of fibrin strands, often associated with DIC; platelet adherence and aggregation; and vasculitis. The vessel abnormalities may be generalized or confined to particular sites or organs. In most cases, the haemolysis is of less consequence than the underlying cause of the microangiopathy, but the fragmentation of red cells may be important in pointing to the diagnosis. Some of the disorders producing MAHA are given in Table 10.6. Only well-defined clinical syndromes will be described here in detail.

Microangiopathic haemolytic anaemia and malignant disease

Fragmentation of red cells with chronic intravascular haemolysis may occur in malignant disease. Clinically significant anaemia may occur, especially when there is invasion of the tumour into a large blood vessel (as in haemangiopericytoma), but, more commonly, the haemolysis is trivial or well compensated. The fragmentation may simply be noted on the blood film. A blood film that shows evidence of MAHA together with leuco-erythroblastic changes is virtually diagnostic of malignant disease with secondary deposits in the bone marrow (Figure 10.3). Mucin-secreting tumours are most likely to produce MAHA.

In acute leukaemia, particularly, but not exclusively, promye-locytic (M3), there may be intense intravascular coagulation that may be accompanied by MAHA. The coagulation changes dominate the clinical picture.

Microangiopathic haemolytic anaemia and infection

Infections, particularly septicaemia, may provoke intravascular coagulation and MAHA. Generally, the coagulation changes and septic shock overshadow the mild fragmentation but, occasionally, infections produce a chronic state of partially compensated intravascular and marked red cell fragmentation.

Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) (see also Chapter 52) is an acute syndrome characterized by fever, neurological signs, haemolytic anaemia with fragmented red cells and throm-bocytopenia. Mild proteinuria is common but major renal impairment is less usual. Two main categories exist: congenital and acquired. The underlying pathological process is of abnormal platelet aggregation in small blood vessels. The congenital TTP is mainly due to mutations in the gene ADAMTS 13, which encodes for a metalloprotease of the ADAMTS family, which specifically degrades von Willebrand factor (vWF). The mutations lead to deficiency of the protease ADAMTS 13, persistence

Disease

Haemolytic-uraemic syndrome

Thrombotic thrombocytopenic purpura

Renal cortical necrosis Acute glomerular nephritis Malignant hypertension Pre-eclampsia HELLP

Polyarteritic nodosa Wegener's granulomatosis Systemic lupus erythematosus Homograft rejection Mitomycin C Cyclosporin Carcinomatosis

Primary pulmonary hypertension Cavernous haemangioma(Kasabach-Merritt)

Microangiography

Endothelial cell swelling, microthrombi in renal vessels Platelet plugs, micro-aneurysms, small vessel thrombi Necrotizing arteritis

Fibrinoid necrosis Vasculitis

Microthrombi in transplanted organ Uncertain

Renal vessel anomalies Abnormal tumour vessels, intravascular coagulation, disseminated or localized Abnormal vasculature Local vascular changes, thrombosis

Table 10.6 Causes of microangiopathic haemolytic anaemia.

HELLP, haemolysis with elevated liver function tests and low platelets.

of unusually large vWF (ULvWF) multimers, which, in turn, can induce platelet aggregation and the formation of platelet VWF plugs in small blood vessels. The acquired form, which is also associated with low levels of ADAMTS 13, is the result of the formation of autoantibodies to the metalloproteinase. Although the association of ADAMTS 13 deficiency with TTP has clarified much of the pathogenesis, it should be remembered that not all cases show this association and other pathways will certainly be described.

Epidemiology

TTP is a rare condition. In the USA the incidence is about 3-4 cases per million. Acquired cases are much more common than congenital. Affected families may be found with autosomal recessive inheritance. The acquired disease has the age and sex distribution seen in most antibody-mediated autoimmune diseases. Women are more frequently affected than men; the disease may occur at any age but is more common between 20 and 50 years. The female preponderance is enhanced by the association of TTP with pregnancy. The most common course is of a single episode, which may be fatal but relapsing and chronic subacute forms exist, particularly, but not exclusively, in the familial or congenital cases.

Clinical features

The typical presentation is of an acute illness presenting with neurological signs, fever and a blood film showing fragmented red cells and thrombocytopenia. Frequently, the presentation is not typical but more insidious, with episodes of headache, personality change or vague neurological disturbances. These disturbances may be sensory or motor deficits, seizures or even coma. Often the neurological signs fluctuate considerably. Renal impairment is demonstrated by proteinuria but frank renal failure is not a feature at presentation.

Gastrointestinal involvement may present as diarrhoea. Pallor and icterus may indicate haemolysis but frank haemorrhagic signs are rare. Chest pain due to cardiac ischaemia may occur.

Laboratory findings

The diagnosis is made on the basis of the clinical presentation and the evidence for haemolytic anaemia with fragmented red cells and thrombocytopenia. Bilirubin is elevated, as is the serum LDH, indicating intravascular haemolysis. LDH is a useful marker for measuring the activity of the microangiopathic process. Coagulation abnormalities are not a consistent feature, in contrast to MAHA associated with DIC. The presence of ULvWF may be demonstrated at presentation. More specific diagnosis showing ADAMTS deficiency and or autoantibodies requires specialist laboratories. At post-mortem, platelet plugs and fibrin plugs may be found in capillaries (Figure 10.4a and b). The pathophysiology is discussed further in Chapter 52.

Treatment

Plasmapheresis

Until the introduction of repeated plasmapheresis, the mortality of TTP was about 80%, death usually being caused by myocardial

Figure 10.4 Thrombotic thrombocytopenic purpura. Microthrombi in capillaries. (a) Section from the myocardium; (b) thrombus in a bone marrow capillary (haemotoxylin and eosin, x100) (courtesy of Dr Margaret Burke).

be reduced in frequency, but relapse is not uncommon if it is stopped early.

Plasma infusion

Infusion of FFP alone may achieve remission in congenital cases with primary deficiency of ADAMTS 13 but is not as effective as plasma exchange in acquired disease.

Immunosuppression

During the acute management, corticosteroids are not usually of benefit, and indeed there is little evidence from randomized trials of their efficacy at any time. However, they may have a role in resistant or relapsing disease. Likewise, vincristine has been advocated in resistant cases. It should be noted that there are overlaps between TTP, ITP and the antiphospholipid syndrome, which make the use of such measures reasonable in some cases. Cyclosporin may have a place in maintaining remission in chronically relapsing disease.

Antibiotics

Many cases present with features suggesting infection and infections may precipitate relapse. The possibility of occult infection, particularly a Gram-negative urinary tract infection, should be considered and appropriate antibiotics given if there is a suspicion of infection. Plasma exchange itself provides a portal for infection and antibiotics, including Gram-positive cover, administered if fever returns during treatment.

Splenectomy

Splenectomy has been used for many years in resistant cases, but there are no proper studies to support this. However, stable long-term remissions may be achieved in some patients with both resistant and relapsed disease.

infarction (Figure 10.4). Removal of antibody in the patient's plasma and replacement of the metalloproteinase by fresh-frozen plasma has reduced the mortality to less than 15%. Presentation in coma or a very low platelet count is a poor prognostic sign. Treatment should be started with plasmapheresis as an emergency as soon as the diagnosis is made. The initial procedure for an adult aims for a 1 to 1.5 plasma volume exchange. Replacement fluid is mainly virally inactivated fresh-frozen plasma, with cryosupernatant being preferred or added in some centres as it lacks the highest vWF multimers. As very large volumes of plasma are used virally inactivated product should be used where possible. The plasmapheresis needs to be repeated daily for up to 20 days and sometimes longer. Treatment effect is monitored by examination of the blood film for fragments, by platelet count and LDH. Remission is judged to have occurred when the platelet count is within the normal range for three successive days and the LDH is normal. Plasmapheresis may then

Antiplatelet and antithrombotic treatment Aspirin and dipyridamole are both used in conjunction with plasma exchange in many series. There is some soft evidence to support their use. Clopidogrel and ticlopidine have each been associated with promoting TTP and so are not recommended. Defibrotide is an antithrombotic agent of unknown action which has been used with some success in refractory cases, but it is not a licensed treatment.

Haemolytic uraemic syndrome

Haemolytic uraemic syndrome (HUS) has some of the features of TTP, but the kidney is the main organ targeted rather than the CNS. Some cases may be associated with ADAMTS 13 deficiency but the majority are not. Infants, young children and the elderly are mainly afflicted. HUS may be caused by infection with Escherichia coli O157, a strain that produces a verotoxin. Haemolysis is less marked than in TTP, and coagulation abnormalities are more prominent. The role of plasma exchange in management is less certain. The syndrome is discussed further in Chapter 52.

March haemoglobinuria

Hemoglobinuria following running has been documented for about 100 years. Its origin is mechanical, with destruction of red cells occurring in the feet. It can be cured by wearing soft shoes or running on soft ground. The disorder may arise in joggers and is benign except that it may lead to extensive invasive investigations unless recognized. The blood film does not show any red cell fragmentation or consistent abnormality. Occasionally, haemoglobinuria after running is accompanied by nausea, abdominal cramps and aching legs, and enthusiastic athletes with this condition may exhibit mild splenomegaly and jaundice.

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