Immune-mediated blood disorders--emergency management (Proceedings)

The most common immune-mediated blood disorders in small animal patients are immune-mediated thrombocytopenia (IMT) and immune-mediated hemolytic anemia (IMHA).  Less common disorders that may have an immune-mediated component include pure red cell aplasia (PRCA), aplastic anemia, amegakaryocytic thrombocytopenia and steroid-responsive neutropenia.  Immune-mediated blood disorders can be either primary (idiopathic) or secondary.  As a general rule, these disorders in dogs are most commonly primary, whereas in cats they are more likely to be secondary.  Since treatment of IMHA and IMT has more similarities than differences, most therapeutic approaches apply equally well to both disorders.

Veterinarians have been effectively treating individual patients with IMHA and IMT for many years.  Standard therapy is based around transfusion as needed, coupled with immunosuppressive therapy (prednisolone or dexamethasone, with or without concurrent azathioprine, cyclophosphamide or cyclosporine) that is tapered and then discontinued.  Unfortunately, however, there is a mounting body of evidence documenting that, with standard therapy, survival rates for IMT and (particularly) IMHA patients are unsatisfactory. For example, one recently published study from Virginia-Maryland reported that, despite their best therapeutic efforts, one-year survival rate for dogs with IMHA was still only 30%.

Most other published studies have long-term survival rates of not much better than 50%.  Deaths (naturally occurring or euthanasia) occurred either during initial hospitalization, or at a later date due to disease recurrence or owner intolerance of long-term medication.  Undoubtedly, there is a 'referral bias' that will exaggerate the severity of disease in some studies since, with recent advances in in-house diagnostics, better availability of transfusion products, and a greater understanding of immunosuppressive therapy, many general practitioners can now effectively treat the less severe blood disorders without referral.  Critical patients with severe or complicated IMHA and IMT are more likely to be referred to specialist centers, and are also more likely to die despite treatment, contributing to the high mortality rates in studies that originate from referral centers.  Nevertheless, despite the potential effects of this referral bias, it is still undeniable that mortality rates for the immune-mediated blood disorders are unacceptably high.

Two main priorities can be readily identified from analysis of IMHA and IMT mortality data: firstly, the rate of in-hospital deaths during the initial immune-mediated crisis must be reduced and, secondly, more long-term therapy must be tailored in order to avoid relapses while minimizing expense and drug-induced side effects.  This first lecture will therefore concentrate on optimizing the initial emergency management of IMT and IMHA, and the subsequent lecture will focus on long-term management strategies.

Initial investigation

Since effective treatment can not proceed without a correct diagnosis, a thorough work-up is always recommended during the initial management of IMHA and IMT.  A standard diagnostic approach has been outlined in the two preceding Immune-Mediated Hemolytic Anemia and Immune-Mediated Thrombocytopenia lectures.  Given a working diagnosis of primary immune-mediated blood disease, standard therapy during an initial crisis will typically include immunosuppressive doses of glucocorticoids with or without other immunosuppressive agents, and transfusion as needed.  Even if an underlying cause for secondary IMHA or IMT has been identified and removed, immunosuppressive therapy is still usually indicated during the initial treatment phase.

Emergency drug therapy

Glucocorticoid therapy, although a mainstay of both the initial and the chronic treatment of IMT and IMHA, is outlined in greater detail in the following Immune-Mediated Blood Disorders: Chronic Management lecture.  Oral prednisolone (or prednisone) dosage at the commencement of therapy should be 2 mg/kg once or twice daily.  Although some clinicians prefer to commence therapy with an initial dose of either intravenous dexamethasone (0.1 to 0.2 mg/kg) or intravenous high dose methylprednisolone (11 mg/kg daily for up to 3 days), there is minimal hard evidence that starting with intravenous steroid therapy hastens recovery.  Typically, regardless of route of administration or starting dose, steroids are not immediately effective.

Immunosuppressive therapy with drugs such as azathioprine, cyclophosphamide or cyclosporine is also is discussed in greater detail in the following Immune-Mediated Blood Disorders: Chronic Management lecture.  Even in severely affected patients, these drugs are usually given orally at standard starting dose rates.  Cyclophosphamide, however, is sometimes also given intravenously (200 mg/m2) in dogs with acute, severe IMT or IMHA.  There is little evidence that commencing with a high-dose intravenous bolus of cyclophosphamide hastens recovery.  In fact, several recent retrospective studies have reported high mortality rates in IMT patients that are initially treated with cyclophosphamide, even at standard conservative oral doses. 

Given the limitations of a retrospective study, however, it is by no means proven that cyclophosphamide actually increases mortality rates, since factors such as case selection bias (for example, clinicians may reserve the use of cyclophosphamide for their sickest patients) may influence apparent survival rates in animals treated with cyclophosphamide.   Cyclosporine is also available in a solution for intravenous use (6 mg/kg, given over 4 hours) although, like cyclophosphamide, there is minimal strong evidence that intravenous administration hastens recovery during crises.

Dogs with IMT may respond to a single intravenous bolus of vincristine (0.02 mg/kg).  The vinca alkaloid is inexpensive and usually well tolerated, and a recent paper has reported that a single initial dose of vincristine hastens recovery of platelet numbers in some canine patients.  The vinca alkaloids have both mild immunosuppressive (impairment of MPS function, and inhibition of cell-mediated and humoral immunity) and thrombocytotic (stimulation of transient megakaryocyte platelet release) properties. 

Intravenous vinca alkaloids induce transient platelet number increases in many IMT patients: circulating platelet life-span may be prolonged following treatment, suggesting that the increased platelet number is due to decreased destruction as well as enhanced megakaryocyte platelet release.  Vinca alkaloids avidly bind to tubulin, a major component of platelet microtubules.  The antibody-coated vinca-containing platelets of IMT patients are subsequently phagocytosed by tissue macrophages. Vinca alkaloids are therefore selectively delivered in cytotoxic doses to the macrophages involved in platelet destruction (so-called ‘poison platelets').

Vincristine is the vinca alkaloid most commonly used in the dog. Intravenous vincristine markedly increases platelet numbers in some canine IMT patients, often within two to three days.  Vincristine (a single intravenous dose) is therefore recommended for the emergency management of canine IMT.

Intravenous vinca alkaloid boluses are cleared from the circulation too rapidly for optimal vinca-platelet binding.  Although weekly vinca boluses maintain remission in some human IMT patients, most eventually become refractory.  Techniques maximizing vinca-platelet binding have improved remission rates: either constant vinca infusion over four to eight hours, or transfusion with platelets pre-incubated with vinca alkaloid (‘vinca-loaded' platelets).  Although reported, similar techniques have not been thoroughly clinically evaluated in the dog.  Such techniques are labor-intensive, and are not commonly used in veterinary medicine. 

Vincristine is extremely corrosive if extravasated.  Single vincristine doses are otherwise well tolerated. Chronic vincristine therapy has been associated with reversible peripheral neuropathy in humans, and a comparable vincristine-associated neuropathy has recently been reported in the dog.  Vincristine inhibits platelet function in vitro.  However, clinically significant platelet dysfunction of any significant duration which can be unequivocally attributed to vincristine has not been documented in vivo.

Supportive/ancillary therapy

IMT and IMHA patients with severe blood loss or hemolytic anemia will be suffering from generalised tissue hypoxia, and will benefit from reducing oxygen demand by instituting strict cage rest until anemia responds to therapy.  The severely compromised patient can also be supported with oxygen supplementation.  Hemoglobin oxygen saturation is however already near maximal, and supplementation with oxygen therefore increases saturation only minimally.  Oxygen supplementation is also laborious and expensive. Since patients with IMHA have a normal blood volume, crystalloid or colloid fluid therapy is of little benefit and may contribute to volume overload.  Hypovolemic IMT patients, in contrast, may benefit from fluid therapy.  An additional benefit of strict cage rest in IMT patients is that rest reduces the chances of traumatic vascular injury, which in turn reduces the chances of life-threatening bleeding in severely thrombocytopenic animals.

Since patients with IMHA are prone to pulmonary thromboembolism and DIC, particularly those with severe anemia and/or a positive slide agglutination, and those requiring transfusion, some clinicians recommend using prophylactic heparin during the hospitalisation of severely affected animals.  A safe low dose of heparin that does not cause spontaneous bleeding, and does not require careful monitoring of coagulation parameters, is 75 to 100 U/kg three to four times daily subcutaneously.  Much higher doses of heparin (starting at 200-250 U/kg SC four times daily), titrated upwards in order to prolong partial thromboplastin times by at least 1.5 times baseline values, may however be more effective at preventing thromboembolism. 

Measurement of plasma heparin levels, with subsequent dosage adjustments to attain a therapeutic range, may prove to be another means of maximizing the benefit of heparin therapy.  Plasma heparin assays have recently become available: the Cornell University Hemostasis Laboratory is now indirectly measuring plasma heparin levels, via inhibition of factor Xa assays, on a daily basis.  The standard form of heparin that is currently used in veterinary medicine is unfractionated heparin.  Possibly, in the near future, the use of low molecular weight forms of heparin such as dalteparin or enoxaparin (which, in people, have a more predictable bioavailability than unfractionated heparin) may allow safer and more effective anticoagulation: we are currently using enoxaparin at a dose of 0.8 mg/kg SC q6hrs, based on Xa inhibition assays. 

Since intravenous catheters, particularly jugular catheters, can predispose to thromboembolism, catheter placements in IMHA patients should be minimized.  Unfortunately, however, despite our best intentions the use of escalating doses of heparin and the avoidance of unnecessary catheters have not been shown to prevent pulmonary thromboembolism in IMHA dogs.  There is clearly a pressing need for us to develop a more effective means of preventing this common and disastrous complication in our IMHA patients.

Transfusion

Cage rest and standard glucocorticoid and immunosuppressive drug therapy are successful in most small animal patients with non-life-threatening IMHA and IMT.  However, initial response to therapy can sometimes be sluggish (a week or more), particularly in those animals with poor marrow responsiveness due to either peracute anemia or immune-mediated damage to bone marrow RBC or platelet precursors. In the meantime, transfusion may be needed to support those patients with life-threatening acute and severe anemia (PCV less than about 15%, or signs of severe compromise, such as collapse, nystagmus or stupor).  Transfused red blood cells often have a very short life span (days or even hours) in patients with IMHA, and transfusions may actually increase the rate of hemolysis (‘add fuel to the fire').  For this reason, transfusions should be avoided when possible in stable patients with IMHA. 

However, in those IMHA patients that are severely compromised, blood transfusions are life-saving, and should not be withheld.  Transfused platelets in IMT patients typically have an extraordinarily short circulating survival time and, in fact, platelet numbers have often not even detectably risen immediately after a platelet transfusion.  Transfusion to replace lost platelets is therefore rarely of value in IMT patients, although there is no real contraindication to trying a single test dose of a platelet product.  Transfusion of RBC products in order to support hypovolemic or anemic IMT patients, on the other hand, can often be life-saving, even if the transfusion had no impact on platelet numbers.

In normovolemic animals, such as most patients with IMHA, whole blood may be safely transfused at a rate of up to approximately 20 ml/kg/hour, usually at a maximum daily volume of 20 ml/kg.  Multiple transfusions as often as every day or two may be needed in very severely affected animals.  Since IMHA patients are typically normovolemic, volume overload after transfusion can become a significant risk in animals that have already recently received high volumes of blood or other fluids.  In these patients, blood transfusions should be given slowly (maximum rate of 4 ml/kg/hour).  When available, packed red blood cells are preferable to whole blood.  Since cross-matches are often positive in patients with IMHA (because the animal has antibodies against its own RBC, and can even ‘cross-match' positive against its own blood, as well as donor blood), compatible or universal donors should be used if blood typing is available.

In the past few years, bovine purified polymerized hemoglobin (Oxyglobinâ) was developed as an effective means of providing temporary (several days) oxygen-carrying support for the severely anemic IMHA patient.  Bovine polymerized hemoglobin was a very convenient blood product for use in general practice, in that it was associated with almost no risk of transfusion reaction, could be safely used without blood typing or cross-matching, and could be stored for up to two years at room temperature.  Although the product was developed and marketed for use in dogs at doses of 10-30 ml/kg, bovine polymerized hemoglobin was also reported to provide effective temporary support to anemic cats at a dose of 10 ml/kg given over several hours.   Since the product was a colloid, it had the potential to cause volume overload if given too fast.  One recent retrospective study reported a very high mortality rate in canine IMHA patients that received bovine polymerized hemoglobin, although these results may potentially have been affected by a pre-treatment case selection bias (that is, the sickest patients got the polymerized hemoglobin).  Bovine polymerized hemoglobin was expensive and, unfortunately, currently is unavailable.

In IMT patients with severe blood loss anemia or hypovolemia, fresh or stored packed red cell or whole blood products can be life saving.  In severely hypovolemic IMT patients with ongoing bleeding, blood can be given to effect at rates that can greatly exceed 20 ml/kg/day if needed.  Although products such as platelet concentrate, platelet-rich plasma and fresh whole blood can be given in order to provide platelets, the transient survival time of most transfused platelets typically renders such treatments ineffective.  The main focus of transfusion therapy in IMT patients therefore should be to provide red cell and volume support in the bleeding patient.

Advanced emergency therapy

Unfortunately, some animals with IMHA and IMT, despite appropriate standard therapy and multiple transfusions, succumb to severe anemia or blood loss during the first weeks of treatment.  Additional treatment options which may be used in a crisis include gammaglobulin, plasmapheresis and splenectomy.

High intravenous doses of human immunoglobulin (HIVIG), as a 6 to 12 hour infusion at doses ranging from 0.5 to 1.5 g/kg, occasionally cause rapid and sometimes sustained remission of immune-mediated disorders, including IMHA, PRCA and IMT. Human intravenous immunoglobulin is a pooled preparation of IgG obtained from the plasma of multiple healthy blood donors.  Although HIVIG were initially produced for treatment of immunodeficiencies, they have also been shown to be beneficial in the treatment of human immune-mediated diseases such as IMT and IMHA.  The main proposed mechanism of action of HIVIG is that the 'antibody soup' bathing the MPS binds to and overwhelms available macrophage Fc receptor sites, leaving no receptors left to bind antibody-coated cells.  Alternatively, there may be some antibodies in the HIVIG soup that actually bind to and inactivate circulating anti-platelet or anti-RBC antibodies. 

The use of HIVIG in dogs is associated with few side effects, although there is some concern that treated animals have a higher incidence of pulmonary thromboembolism.  Recently, a high rate of pulmonary thromboembolism in HIVIG-treated patients was reported in the human literature.  Human gammaglobulin has not attained common usage in veterinary medicine, probably because of high cost and very limited availability. 

Plasmapheresis and splenectomy, although reported to be useful in isolated cases, have also not entered into common use, and are usually considered treatments of last resort.  Plasmapheresis, when available, is a very effective method of rapidly removing unbound anti-RBC or anti-platelet antibodies from the circulation, although antibodies that are already bound to cell membranes will persist and may cause ongoing disease.

Splenectomy is potentially a particularly effective treatment for IMT and IMHA because many different splenic elements contribute to the mechanisms reducing circulating blood cell numbers: anti-RBC or anti-platelet antibody production (splenic lymphocytes), antibody-coated platelet or RBC destruction (splenic MPS), and platelet or RBC sequestration (splenic vasculature).  Splenectomy is the treatment of choice for most humans with chronic IMT or IMHA, with higher remission rates than medical therapy.  In human IMT patients, platelet numbers often rise within several hours of splenectomy, with maximal increases within one to two weeks.  Most human IMT and IMHA patients (60% to 80%) subsequently maintain adequate platelet or RBC counts without further medical therapy.  Splenectomized patients that do require further treatment frequently demonstrate an improved response to medical therapy.  Splenectomy is therefore recommended early in the course of chronic human IMT or IMHA.

Splenectomy has not been thoroughly clinically evaluated in a large group of small animal IMT or IMHA patients, although a recent paper discussing the benefits of early splenectomy in a small group of canine IMHA patients certainly reported some promising preliminary results.  Other than this recent paper, published post-splenectomy remission rates for canine IMT and IMHA (each study limited to small patient groups) vary from poor to excellent.  Since response rates appear to be unpredictable, early splenectomy currently cannot be strongly recommended for canine IMT or IMHA, particularly as medical therapy is often far better tolerated than it is in people. Splenectomy is indicated in canine patients refractory to glucocorticoids, immunosuppressive agents and danazol, particularly if associated drug side effects are unacceptable.

Life-threatening post-splenectomy complications in people (overwhelming infection, disseminated intravascular coagulation) are rare in the dog.  The most commonly reported small animal post-splenectomy complication, erythrocyte parasitemia (Hemobartonella [Mycoplasma], Babesia), usually responds well to medical therapy.

Persistent IMT or IMHA post-splenectomy indicates ongoing platelet or erythrocyte destruction by the non-splenic MPS (usually hepatic macrophages).  Uncommonly, post-splenectomy platelet or RBC destruction can also occur within an 'accessory spleen' (a detached splenic remnant with residual MPS function).  Some authors recommend exploratory laparotomy in humans with persistent IMT or IMHA:  removal of an accessory spleen may induce complete remission.