eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders

Platelet Disorders: Treatment & Medication

Author: Perumal Thiagarajan, MD, Professor, Department of Pathology and Medicine, Baylor College of Medicine; Director, Transfusion Medicine and Hematology Laboratory, Michael E DeBakey Veterans Affairs Medical Center
Contributor Information and Disclosures

Updated: Jun 9, 2009

Treatment

Medical Care

• Treatment of acute ITP in children^4,5,6,13
  • Because acute ITP in children is self-limited, most physicians do not routinely treat it.
  • Treatment is necessary only to prevent intracranial or other serious internal hemorrhage. The rate of intracranial hemorrhage is very low, possibly less than 0.1%, and occurs with platelet counts of 10,000-20,000/µL. Most physicians arbitrarily treat children with ITP when their platelet count levels are less than 20,000/µL.
  • IVIG (0.8-1 g/kg for 2 d) results in a prompt rise in the platelet count, and this response confirms the diagnosis of acute ITP. The mechanisms of action of IV gamma globulins are not clear. Suggested mechanisms include blocking the macrophage Fc receptors, suppressing autoantibody production by providing antiidiotypes, and stimulating the clearance of autoantibodies. The adverse effects of IgG include fever, nausea, vomiting, and, occasionally, renal failure. IgG is also very expensive compared with prednisone and is not available in all countries.
  • Oral prednisone (4 mg/kg, with tapering and discontinuation by day 21) or IV methylprednisolone (30 mg/kg for 3 d) is also effective, although IVIG provides the quickest recovery. The mode of action of prednisone is probably multifold, decreasing antibody production, increasing platelet formation, decreasing macrophage-mediated clearance of platelets in the spleen, and immunomodulating the immune response.
  • The combination of steroids and IVIG is synergistic and can be used in patients with imminent hemorrhage.
  • Inducing a mild hemolytic state by administering anti-D immunoglobulin (25-50 μg/kg for 2 d) is also effective in individuals who are Rh positive. This therapy is less expensive than IVIG, and the limitations include a dose-dependent mild anemia, inapplicability in individuals who are Rh negative, and a limited response in patients who have undergone splenectomy.
  • With these modalities, the platelet counts in most children could be maintained at more than 30,000/µL until spontaneous remission occurs.
  • Other supportive measures include avoiding drugs that impair platelet function (eg, aspirin) and avoiding competitive contact sports.
  • A small minority of children do not undergo spontaneous remission and have a chronic course with remissions and relapse similar to adult-onset chronic ITP.
  • These patients are treated similarly to adults with chronic ITP, except that splenectomy should be avoided if possible, because spontaneous remissions frequently occur. Furthermore, splenectomy when the patient is younger than 6 years is associated with severe postsplenectomy sepsis. The American Society of Hematology recommends splenectomy for children only if they have had ITP longer than 1 year and their bleeding results in platelet counts below 30,000/µL.¹
  • Children with chronic ITP should receive pneumococcal and Haemophilus influenzae vaccines before splenectomy, and many physicians recommend a prophylactic antibiotic regimen after splenectomy. Long-term therapy with repeated infusions of IVIG or anti-D immunoglobulin is being tried, with the hope that it can induce a lasting remission and eliminate the need for splenectomy.
• Treatment of chronic ITP in adults^2,14,15
  • No consensus has been reached regarding when to start steroid therapy for chronic ITP in adults and how long to treat it.
  • Most physicians elect to not treat patients unless their platelet count is below 50,000/µL or bleeding manifestations are present.
  • A course of steroid therapy is often administered upon the initial diagnosis in an effort to induce a sustained remission. The treatment of choice is oral prednisone, usually administered in a dose of 1 mg/kg. Approximately two thirds of patients can be expected to show a therapeutic response with steroid therapy.
  • Steroids are usually continued until the platelet count reaches normal or greater than 50,000/µL, and then they are gradually tapered in 4-6 weeks.
  • Methylprednisolone (30 mg/kg IV days 1-3, tapered every third day to 1 mg/kg) has also been used with similar results.
  • In one study, a 4-day course of high-dose dexamethasone (40 mg/d) was reported as an effective initial therapy for adults with ITP, with 50% of patients showing sustained platelet count of over 50,000/µL.¹⁶
  • In general, only 15-25% of patients with chronic ITP are expected to have lasting remission; the remainder have disease characterized by frequent relapses and remissions.
  • Unlike in children, IVIG does not induce an early rise in platelet counts in adults and does not have an advantage over steroids as an initial therapy.
  • Even if the platelet count normalizes, many patients can maintain platelet counts of more than 20,000-30,000/µL with lower doses of steroids during times of relapse. However, in approximately one third of patients with chronic ITP, steroids are not effective, either because of a failure in response or a steroid requirement that leads to unacceptable adverse effects (eg, glucose intolerance, GI bleeding).
  • The second line of treatment for the management of steroid failures is splenectomy. Splenectomy is considered for any patient who does not respond to steroids (or who cannot receive steroids) and has clinically significant bleeding manifestations.¹⁴
  • The appropriate time to perform the splenectomy is controversial. Most physicians wait for 3-6 months before recommending splenectomy because sometimes ITP goes into spontaneous remission, especially in younger patients. Often, other clinical considerations (eg, coexistence of diabetes or peptic ulcer disease [PUD]) may influence the decision for earlier splenectomy.
  • Splenectomy is effective because it removes the major site of destruction and the major source of antiplatelet antibody synthesis.
  • Before splenectomy, patients should receive a pneumococcal vaccine.
  • Even if complete remission is not achieved, the platelet count will be higher after splenectomy.¹⁵
  • IVIG (1 g/kg/d for 1-2 d) induces a short-term increase in the platelet count, starting within several days and lasting approximately 2-3 weeks, both in patients who have undergone splenectomy and in those who have not. No clear evidence indicates that repeated infusions induce a lasting remission. Significant adverse effects include hypotension and renal failure.
  • Anti-D immunoglobulin (WinRho, 50-75 μg/kg IV) is also as effective as IV immunoglobulin in Rh-positive adults with an intact spleen. Rarely, massive intravascular hemolysis with DIC and occasional death has occurred with the use of anti-D immunoglobulin.
  • Both IVIG and anti-D immunoglobulin are relatively expensive therapy for adults compared with steroids, and these agents are primarily used on an interim basis during a crisis (eg, before splenectomy or major surgery).
  • Approximately 10-20% of patients who undergo splenectomy remain thrombocytopenic and continue to have a bleeding risk that requires continued treatment. Both steroid therapy and splenectomy are considered failures in these patients, and the patients are challenging to treat. An accessory spleen should be excluded as the cause of treatment failure after splenectomy.¹⁵
  • Limited benefit may be observed using immunosuppression with cytotoxic agents. Azathioprine (150 mg/d) or cyclophosphamide (50-100 mg/d) has been used with some success. These cytotoxic drugs can cause myelosuppression, alopecia, hemorrhagic cystitis (cyclophosphamide [Cytoxan]), sterility, and secondary malignancy. They are given for a minimum duration and are withdrawn as soon as remission is achieved. Blood counts must be monitored during therapy.
  • Vincristine infusion (0.02 mg/kg) with a maximum dose of 2 mg every week for 3 weeks has also been shown to induce remission.
  • Rituximab, a monoclonal antibody directed against the lymphocyte antigen, has been reported to induce remission in refractory ITP.
  • Several studies  reported improved platelet counts in patients with Helicobacter pylori –positive ITP following standard H pylori eradication therapy, with cohorts from Japan and Italy reporting higher response rates.¹⁷ Several explanations, such as molecular and immunomodulation by macrolides, have been provided. However, a recent small, multicenter, randomized controlled study evaluated 55 patients aged 4-18 years with chronic ITP (as defined by platelet count <100,000/μL, lasting longer than 6 mo without identified causes) to evaluate the effect of H pylori eradication on platelet recovery.¹⁸ The primary end point was defined as platelet counts >100,000/μL for at least 3 months. The investigators confirmed the diagnosis of H pylori infection with¹³ C urea breath test and excluded any patients who had received either >0.5mg/kg/d or prednisolone or other platelet-enhancing therapy. Sixteen patients were then randomized to either standard protocol for H pylori eradication (n = 7) (with a repeat¹³ C urea breath test at 4-6 weeks to confirm successful therapy) or no specific treatment (n = 9).¹⁸ Patients' monthly platelet counts were monitored for 6 months in both groups.  At 6 months, platelet recovery was demonstrated in 1 patient in the treatment group, as well as 1 in the control group. The investigators concluded that there is no beneficial effect of H pylori eradication on platelet recovery in childhood chronic ITP.¹⁸ Further investigation is needed.
  • A number of treatments have been proposed for splenectomy and steroid failures. Most of them are not based on placebo-controlled studies, and evaluating the efficacy of these treatments in a disease associated with spontaneous remissions and relapse is difficult. The anabolic steroid danazol (400-800 mg/d) has been shown to induce remission in certain patients. Cyclosporine and alfa-interferon have also been used. Plasmapheresis and extracorporeal protein A adsorption have been tried in desperate situations. The autoantibodies responsible for ITP are primarily IgG, and plasmapheresis is of limited value because more than half of the normal IgG pool is in the extravascular space. Recently, 2 thrombopoietin receptor agonists have been approved for the treatment of chronic refractory ITP. Eltrombobag is an oral nonpeptide thrombopoietin receptor agonist that interacts with the transmembrane domain of thrombopoietin receptor and induces megakaryocyte proliferation and differentiation. It has been shown to increase the platelet count in refractory ITP and in thrombocytopenia associated with hepatitis C –induced cirrhosis. It will most likely also be effective in thrombocytopenia due other causes by stimulating megakaryocytes. Eltrombobag is given in doses of 25 mg to 75 mg daily. The side effects include hepatotoxicity, worsening of cataracts, and increased bone marrow reticulin fibers.
    A phase III, randomized, double-blind, placebo-controlled trial assessed the efficacy, safety, and tolerability of once daily eltrombopag 50 mg, and explored the efficacy of a dose increase to 75 mg.¹⁹ The primary endpoint was the proportion of patients achieving platelet counts greater than or equal to 50,000/μL at day 43.Adults with chronic ITP (as defined by platelet counts <30,000/μL) and 1 or more previous ITP treatment received standard care plus once-daily eltrombopag 50 mg (n = 76) or placebo (n = 38) for up to 6 weeks (via random assignment in a 2:1 ratio of eltrombopag:placebo by a validated randomization system).¹⁹ After 3 weeks, patients with platelet counts <50,000/μL could increase study drug to 75 mg. All participants who received at least 1 dose of their allocated treatment were included in the analysis.
    The day 43 analyses included 73 patients in the eltrombopag group and 37 in the placebo group, of whom 43 (59%) eltrombopag patients and 6 (16%) placebo patients had a treatment response (achieved platelet counts greater than or equal to 50,000/μL; P <0.0001).¹⁹ Of the 34 patients in the efficacy analysis who increased their dose of eltrombopag, 10 (29%) had a treatment response, and platelet counts generally returned to baseline values within 2 weeks after the end of treatment.The investigators noted the patients receiving eltrombopag had less bleeding at any time during the study than those receiving placebo did (P = 0.021), and both groups had a similar frequency of grade 3-4 adverse events during treatment and adverse events leading to study discontinuation.¹⁹  The investigators concluded eltrombopag is an effective treatment for the management of thrombocytopenia in chronic ITP. Romiplostim (AMG-531) is another thrombopoietin receptor agonist, and it consists of human immunoglobulin Fc region covalently linked to a peptide sequence that binds to and activate the thrombopoietin receptor. The peptide sequence has no homology with human thrombopoietin so that the possibility of a cross-reacting antibody is minimized. The Fc domain extends the half-life of the molecule in the circulation. In weekly subcutaneous (SC/SQ) doses of 1-7 μg/kg, romiplostim in increased the platelet count in chronic ITP. The side effects includes bone marrow reticulin formation.The advantageous of thrombopoietin receptor agonist should be weighed against the risk of marrow fibrosis IN the limited long-term outcome data. There is a theoretic possibility that increases the risk of hematologic malignancies, as thrombopoietin receptor agonist is present in hematopoietic cells. Currently, these agents are recommended for ITP patients whose conditions are refractory to previous treatments including splenectomy.Two parallel trials assessed the long-term administration of romiplostim in 63 splenectomized and 62 nonsplenectomized patients with ITP. The patients had a mean of 3 platelet counts less than or equal to 30,000/μL and were randomly assigned 2:1 to weekly SC injections of romiplostim (n = 42 in the splenectomized study; n = 41 in the nonsplenectomized study) or placebo (n = 21 in both studies) for 24 weeks.²⁰ Romiplostim doses were adjusted to maintain platelet counts of 50,000-200,000/μL. The primary objectives were to assess the efficacy of romiplostim as measured by a durable platelet response (platelet count greater than or equal to 50,000/μL during 6 or more of the last 8 wk of treatment) and treatment safety.²⁰ Sixteen of 42 splenectomized patients given romiplostim achieved a durable platelet response versus none of the 21 patients in the placebo group (difference in proportion of patients responding 38% [95% confidence interval (CI) 23.4-52.8], P = 0.0013), as well as 25 of 41 nonsplenectomized patients in the romiplostim group compared with 1 of 21 patients in the placebo group (56% [38.7-73.7], P <0.0001).²⁰ The overall platelet response rate (either durable or transient platelet response) was noted in 79% (33/42) of splenectomized and 88% (36/41) of nonsplenectomized patients given romiplostim compared with 14% (3/21) of nonsplenectomized and no splenectomized patients in the placebo group (P <0.0001).²⁰
    Patients in the splenectomized and nonsplenectomized romiplostim treatment groups also achieved durable platelet counts over a longer period relative to those given placebo, as well as reduced or discontinued concurrent other ITP therapy compared with individuals in the placebo groups. The adverse events were similar across all groups, and no antibodies against romiplostim or thrombopoietin were detected.²⁰ The investigators concluded that stimulation of platelet production by romiplostim may provide a new therapeutic option for patients with ITP. 
  • Refractory ITP has also been treated with combination chemotherapy used for low grade non-Hodgkin lymphoma (6 cycles of cytoxan, vincristine, and prednisone, with some success). Other evolving therapies for refractory ITP include autologous hematopoietic stem cell transplantation and anticytokine therapy with etanercept.
• Treatment of alloimmune thrombocytopenia in neonates
  • If left untreated, thrombocytopenia persists from a few days to up to 3 weeks.
  • The treatment of choice is the administration of IVIG and maternally compatible platelets. Maternal platelets should be radiated to avoid graft versus host disease in the infant and washed to reduce the antibody concentration.
  • Response to steroids is rare.
• Therapy for TTP
  • TTP is a medical emergency, and prompt recognition and immediate initiation of plasma exchange is necessary.
  • The minimum criteria for the diagnosis of TTP are thrombocytopenia and microangiopathic hemolytic anemia without an apparent etiology.
  • Examination of the smear shows thrombocytopenia and a microangiopathic picture (characteristic helmet cells/schistocytes and basophilic red blood cells) (see Image 9 or below). The lactic dehydrogenase (LDH) level is high, with brisk reticulocytosis. Signs of intravascular coagulation are characteristically absent in patients with TTP.
    

    

    Schistocytes (thrombotic thrombocytopenic purpura).

    [ CLOSE WINDOW ]

    

    Schistocytes (thrombotic thrombocytopenic purpura).

  • Plasma exchange therapy introduced 20 years ago has changed the outlook of this once serious disorder. Current mortality rates remain approximately 20%, compared with the greater than 90% mortality rate observed before the advent of plasma exchange therapy.
  • Plasma exchange (3-5 L/d) is instituted promptly and continued daily until the patient's platelet count is normalized and the LDH level is within the reference range. Until plasma exchange is instituted, fresh frozen plasma should be administered. Several weeks of plasma exchange may be required before a durable remission is achieved.
  • Antiplatelet agents have not been shown to alter the natural history of the disease.
  • Milder forms of TTP may respond to steroids.
  • Patients who relapse frequently or patients who require large volumes of replacement therapy are candidates for splenectomy. Splenectomy decreases the rate of relapse in patients with chronic relapsing forms of the disease.
  • Anecdotal reports indicate cases of TTP responding to vincristine infusions, IVIG, and staphylococcal protein A adsorption.
  • Therapy for HUS is directed toward the underlying process.
  • Acute and chronic renal failure is managed with fluid and electrolytes and, if necessary, dialysis. Plasma exchange therapy is often administered, but whether this is beneficial remains unclear. Antiplatelet and anticoagulant therapies have been attempted but do not show a marked benefit.
• Severe thrombocytopenia with bleeding
  • A bleeding patient with a very low platelet count is a medical emergency.
  • The presence of hemorrhagic bullae in the buccal mucosa and retinal hemorrhages are harbingers of internal and intracranial bleeding.
  • Diseases that cause such severe thrombocytopenia are ITP, TTP, posttransfusion purpura, drug-induced thrombocytopenia, and aplastic anemia. Differentiating TTP from ITP is very important, because platelet transfusions are contraindicated in patients with TTP, and plasma exchange therapy should be initiated as soon as possible in patients with TTP.
  • Careful examination of the peripheral smear helps differentiate ITP from TTP. Furthermore, the presence of neurologic signs, renal failure, fever, and a high LDH level also helps in the diagnosis of TTP.
  • The patient's medication history should be reviewed, and drug-induced thrombocytopenia should be considered if a temporal relationship exists between the thrombocytopenia and drug exposure.
  • Patients with liver disease and those who abuse alcohol often present with severe thrombocytopenia following binge drinking. These patients may have severe thrombocytopenia resulting from splenomegaly, alcohol-induced suppression of platelet production, folate deficiency, and DIC from active liver disease.
  • Aplastic anemia is associated with pancytopenia, and the smear examination findings help differentiate it from ITP.
  • Once the diagnosis of ITP with clinically significant bleeding is established, treatment with steroids (IV methylprednisolone at 30 mg/kg) and IVIG should be started immediately.
  • Platelet transfusions are administered to patients with severe clinical bleeding, and a sustained increase in platelet counts is sometimes observed in those with ITP.
  • Currently, emergency splenectomy is rarely necessary and is only considered before an emergency operation such as evacuation of an intracranial hematoma.
• von Willebrand disease
  • DDAVP is a vasopressin analogue that releases vWf from endothelial cells.
  • Most patients with type I von Willebrand disease can be treated with DDAVP for minor surgeries and dental procedures. The usual dose is 0.3 μg/kg infused slowly approximately 30 minutes before an operative procedure. This dose can be repeated once a day for 2-3 days, after which it is ineffective because of tachyphylaxis. Other adverse effects occasionally include a hypertensive response and hyponatremia.
  • An intranasal preparation of DDAVP has been made available for individuals with von Willebrand disease and is administered at a dose of 150 μg or 300 μg (ie, 150 μg per nostril). The more diluted preparation is used in patients with diabetes insipidus and does not increase vWf levels.
  • DDAVP does not usually increase factor VIII levels in patients with type IIA and can induce thrombocytopenia in patients with type IIB or pseudo von Willebrand disease.
  • Replacement therapy is used for more extensive surgeries or trauma and for patients with type II and type III disease. The treatment of choice is vWf concentrates. (Humate-P or Alphanate). These preparations are heat-treated, and the solvent is extracted; therefore, they are considered more virally safe. The dose is calculated based on ristocetin cofactor units (usual dose is 50-100 U/kg). The factor VIII level often rises following the infusion of von Willebrand protein concentrate, and it remains elevated for at least for 40 hours, reflecting the half-life of von Willebrand protein rather than that of factor VIII. The need for further doses is often assessed based on clinical criteria rather than blood test results.
  • Cryoprecipitate has approximately 100 U of factor VIII per bag and has all multimeric forms of vWf. Despite screening tests, patients have a small risk developing viral infections.
  • Highly purified preparations of factor VIII or recombinant factor VIII should not be administered to patients with von Willebrand disease, because these preparations have very little von Willebrand protein.
• Uremic bleeding
  • The most effective therapy for this platelet dysfunction is vigorous dialysis.
  • For a more immediate correction of uremic bleeding, DDAVP and cryoprecipitate have also been shown to be useful in providing hemostasis. These modalities provide a short-term benefit until dialysis corrects the hemostatic defects.
  • In addition to effective dialysis, conjugated estrogen has been shown to decrease bleeding in patients with uremic hemorrhages.

Medication

Steroids are the mainstay of the initial treatment of ITP in adults, whereas IV gamma globulins are used in children.

Corticosteroids

Corticosteroids inhibit macrophage-induced platelet phagocytosis and have immunosuppressive effects on antiplatelet antibody production by lymphocytes.

Prednisone (Starapred)

Inhibits phagocytosis of antibody-covered platelets. Most common drug used because relatively inexpensive and orally active.

Intravenous Immunoglobulins

IV immunoglobulins impair clearance of platelets by macrophages.

Immune globulin, IV (Carimune, Gammagard S/D, Gammar-P, Gamunex, Polygam S/D)

Administered to adults with severe thrombocytopenia and bleeding, before splenectomy or other major surgery in ITP. Some have shown temporary increase in platelet counts upon administration.

Rho (D) immune globulin (RhoGAM)

Induces mild hemolytic state, acts similarly to IVIG but 1/100 the dose.

Anabolic Steroids

Anabolic steroids suppress macrophage-mediated platelet destruction and inhibit platelet antibody production.

Danazol (Danocrine)

Synthetic steroid analogue with strong antigonadotropic activity (inhibits LH and FSH) and weak androgenic action.

Chemotherapeutic Agents

Vincristine strongly binds to platelets. Phagocytosis of platelet-bound vincristine by macrophages in ITP delivers drug in high concentration and leads to macrophage dysfunction.

Vincristine (Oncovin)

Mechanism of action is uncertain. May involve a decrease in reticuloendothelial cell function or an increase in platelet production. Response rate varies; therefore, use as last resort in refractory cases.

Synthetic Hormones

Synthetic hormones are used to improve platelet function in qualitative disorders.

Desmopressin (DDAVP, Stimate)

Increases cellular permeability of collecting ducts, resulting in reabsorption of water by kidneys. Releases von Willebrand protein from endothelial cells. Improves bleeding time and hemostasis in patients with some vWf (mild and moderate von Willebrand disease without abnormal molecular forms of von Willebrand protein). Effective in uremic bleeding. Tachyphylaxis usually develops after 48 h. Nasal preparation containing 150 mcg/puff available.

Immunosuppressive Agents

Benefits are observed with immunosuppression. Immunosuppressive agents are given for a minimum duration and withdrawn as soon as remission is achieved. Blood counts must be monitored.

Azathioprine (Imuran)

Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity.

Cyclophosphamide (Cytoxan)

Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with the growth of normal and neoplastic cells.

Antihemorrhagics

Antihemorrhagic agents are used in patients with blood-product deficiencies.

Cryoprecipitate (Cryo)

Low-purity concentrate of 3 hemostatic proteins prepared by controlled thaw of fresh frozen plasma. Each bag contains an average of 100 U of factor VIII and vWf and 150-250 mg of fibrinogen (with some factor XIII and fibronectin). ABO-Rh type is not relevant.

Antihemophilic factor (Alphanate, Humate-P, Koate-HP)

Highly purified clotting factor used to treat bleeding episodes in patients with factor VIII deficiency resulting from hemophilia A or acquired factor VIII deficiency.

Antithrombotic Agents

Thrombin, the end product of the coagulation mechanism, initiates transformation of fibrinogen to a fibrin clot and activates platelets.

Argatroban (Acova)

Selective thrombin inhibitor. Inhibits fibrin formation, platelet aggregation, and activation of coagulation factors V, VIII, XIII, and protein C.

Thrombopoietic Agent

Romiplostim is the first product approved in the United States that directly stimulates bone marrow platelet production.²⁰

Romiplostim (Nplate)

An Fc-peptide fusion protein (peptibody) that increases platelet production through binding and activation of the thrombopoietin (TPO) receptor, a mechanism similar to endogenous TPO. Indicated for chronic immune (idiopathic) thrombocytopenic purpura in patients whose condition has had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Only available through the Nplate NEXUS (Network of Experts Understanding and Supporting Nplate) program, a program designed to promote informed risk-benefit decisions before initiating treatment. For more information, see http://www.nplate.com or call (877) NPLATE1 (877-675-2831).

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