Platelet Disorders

Thrombocytopenia    ITP    Thrombocytosis    Essential Thrombocythemia   

Thrombocytopenia

Causes of thrombocytopenia can be classified by mechanism (see Classification of Thrombocytopenia below)

A large number of drugs may cause thrombocytopenia (see Thrombocytopenia: Other Causes : Drug-induced immunologic destruction), typically by triggering immunologic destruction.

Overall, the most common specific causes of thrombocytopenia include
Gestational thrombocytopenia
Drug-induced thrombocytopenia due to immune-mediated platelet destruction (commonly, heparin, trimethoprim/sulfamethoxazole, rarely quinine [cocktail purpura])
Drug-induced thrombocytopenia due to dose-dependent bone marrow suppression (eg, chemotherapeutic agents, ethanol)
Thrombocytopenia accompanying systemic infection
Immune thrombocytopenia (ITP, formerly called immune thrombocytopenic purpura)


Classification of Thrombocytopenia

Diminished or absent megakaryocytes in bone marrow
Aplastic anemia
Leukemia
Myelosuppressive drugs (eg, hydroxyurea, interferon alfa-2b, chemotherapy drugs)
Paroxysmal nocturnal hemoglobinuria (some patients)

Diminished platelet production despite the presence of megakaryocytes in bone marrow
Alcohol-induced thrombocytopenia
Bortezomib use
HIV-associated thrombocytopenia
Myelodysplastic syndromes (some)
Vitamin B12 or folate (folic acid) deficiency

Platelet sequestration in enlarged spleen
Cirrhosis with congestive splenomegaly
Gaucher disease
Myelofibrosis with myeloid metaplasia
Sarcoidosis

Immunologic destruction
Antiphospholipid antibody syndrome
Connective tissue disorders
Drug-induced thrombocytopenia
HIV-associated thrombocytopenia
Immune thrombocytopenia
Lymphoproliferative disorders
Neonatal alloimmune thrombocytopenia
Posttransfusion purpura
Sarcoidosis

Nonimmunologic destruction
Certain systemic infections (eg, hepatitis, Epstein-Barr virus, cytomegalovirus, or dengue virus infection)
Disseminated intravascular coagulation
Pregnancy (gestational thrombocytopenia)
Sepsis
Thrombocytopenia in acute respiratory distress syndrome
Thrombotic thrombocytopenic purpura–hemolytic-uremic syndrome

Dilution
Massive RBC replacement or exchange transfusion (most RBC transfusions use stored RBCs that do not contain many viable platelets)


Thrombocytopenia

Decreased platelet production
1. Diminished or absent megakaryocytes in bone marrow
Aplastic anemia, Paroxysmal nocturnal hemoglobinuria (some patients)
Replacement of the bone marrow by hematologic malignancies (leukemia, lymphoma, myeloma), or rarely solid tumors.
Bone marrow damage by drugs, alcohol, myelosuppressive or chemotherapeutic agents, etc.

2. Presence of megakaryocytes in bone marrow
Alcohol-induced thrombocytopenia
Bortezomib use
HIV-associated thrombocytopenia
Myelodysplastic syndromes (some)
Vitamin B12 or folate deficiency
Severe vitamin deficiency, Severe iron deficiency

3. Rare genetic defects: Bernard-Soulier syndrome, MYH9-associated syndromes and other hereditary thrombocytopenias

Increased platelet consumption
1. Primary immune thrombocytopenia (ITP)
2. Secondary immunologic destruction
Drug-induced thrombocytopenia
Autoimmune diseases, Connective tissue disorders, Antiphospholipid antibody syndrome
Hepatitis, HIV and other viral infections
Evans syndrome (e.g. with lymphomas, CLL), Lymphoproliferative disorders
Immunodeficiency syndromes (common variable immunodeficiency syndrome, autoimmune lymphoproliferative syndrome (Canale-Smith syndrome), Wiskott-Aldrich syndrome)
Vaccination-associated
Other immune-mediated thrombocytopenias
Heparin-induced thrombocytopenia, Post-transfusional purpura, GPIIb/IIIa inhibitor administration
Pregnancy-associated thrombocytopenia
3. Nonimmunologic destruction
Drug-induced thrombocytopenia
Certain systemic infections (eg, hepatitis, Epstein-Barr virus, cytomegalovirus, or dengue virus infection), Sepsis
Acute respiratory distress syndrome
Disseminated intravascular coagulation, Thrombotic thrombocytopenic purpura (TTP) hemolytic-uremic syndrome (HUS)
Massive pulmonary embolism, von Willebrand disease type 2b
Large hemangiomas, Large aneurysms
Pregnancy (gestational thrombocytopenia)

4. Platelet sequestration in enlarged spleen
Cirrhosis with congestive splenomegaly
Myelofibrosis with myeloid metaplasia
Gaucher disease, Sarcoidosis

5. Dilution
Massive blood transfusion (most blood transfusions use stored bloods that do not contain many viable platelets)
Fluid replacement for massive bleedings.

6. Problems of laboratory analysis
EDTA-induced pseudothrombocytopenia

Other causes of Thrombocytopenia

Acute respiratory distress syndrome
Patients with acute respiratory distress syndrome may develop nonimmunologic thrombocytopenia, possibly secondary to deposition of platelets in the pulmonary capillary bed.

Blood transfusions
Posttransfusion purpura causes immunologic platelet destruction indistinguishable from immune thrombocytopenia (ITP), except for a history of a blood transfusion within the preceding 7 to 10 days. The patient, usually a woman, lacks a platelet antigen (PLA-1) present in most people. Transfusion with PLA-1–positive platelets stimulates formation of anti–PLA-1 antibodies, which (by an unknown mechanism) can react with the patient’s PLA-1–negative platelets. Severe thrombocytopenia results, taking 2 to 6 wk to subside. Treatment with IV immune globulin (IVIG) is usually successful.

Connective tissue and lymphoproliferative disorders
Connective tissue (eg, SLE) or lymphoproliferative disorders (eg, lymphoma, large granular lymphocytosis) can cause immunologic thrombocytopenia. Corticosteroids and the usual treatments for ITP are effective; treating the underlying disorder does not always lengthen remission.

Heparin-induced thrombocytopenia
Heparin-induced thrombocytopenia (HIT) occurs in up to 1% of patients receiving unfractionated heparin. HIT may occur even when very-low-dose heparin (eg, used in flushes to keep IV or arterial lines open) is used. The mechanism is usually immunologic. Bleeding rarely occurs, but more commonly platelets clump excessively, causing vessel obstruction, leading to paradoxical arterial and venous thromboses, which may be life threatening (eg, thromboembolic occlusion of limb arteries, stroke, acute MI).

Heparin should be stopped in any patient who becomes thrombocytopenic and develops a new thrombosis or whose platelet count decreases by more than 50%. All heparin preparations should be stopped immediately and presumptively, and tests are done to detect antibodies to heparin bound to platelet factor 4. Anticoagulation with nonheparin anticoagulants (eg, argatroban, bivalirudin, fondaparinux) is necessary at least until platelet recovery.

Low molecular weight heparin (LMWH) is less immunogenic than unfractionated heparin but cannot be used to anticoagulate patients with HIT because most HIT antibodies cross-react with LMWH. Warfarin should not be substituted for heparin in patients with HIT and, if long-term anticoagulation is required, should be started only after the platelet count has recovered.

Infections
HIV infection may cause immunologic thrombocytopenia indistinguishable from ITP except for the association with HIV. The platelet count may increase when glucocorticoids are given. However, glucocorticoids are often withheld unless the platelet count falls to <20,000/μL because these drugs may further depress immune function. The platelet count also usually increases after treatment with antiviral drugs.

Hepatitis C infection is commonly associated with thrombocytopenia. Active infection can create a thrombocytopenia that is indistinguishable from ITP with platelets < 10,000/µL. Milder degrees of thrombocytopenia (platelet count 40,000 to 70,000/µL) may be due to liver damage that reduced production of thrombopoietin, the hematopoietic growth factor that regulates megakaryocyte growth and platelet production. Hepatitis C-induced thrombocytopenia responds to the same treatments as does ITP.

Other infections, such as systemic viral infections (eg, Epstein-Barr virus, cytomegalovirus), rickettsial infections (eg, Rocky Mountain spotted fever), and bacterial sepsis, are often associated with thrombocytopenia.

Pregnancy
Thrombocytopenia, typically asymptomatic, occurs late in gestation in about 5% of normal pregnancies (gestational thrombocytopenia); it is usually mild (platelet counts < 70,000/μL are rare), requires no treatment, and resolves after delivery. However, severe thrombocytopenia may develop in pregnant women with preeclampsia and the HELLP syndrome (hemolysis, elevated liver function tests, and low platelets); such women typically require immediate delivery, and platelet transfusion is considered if platelet count is < 20,000/μL (or < 50,000/μL if delivery is to be cesarean).

Sepsis
Sepsis often causes nonimmunologic thrombocytopenia that parallels the severity of the infection. The thrombocytopenia has multiple causes: disseminated intravascular coagulation, formation of immune complexes that can associate with platelets, activation of complement, deposition of platelets on damaged endothelial surfaces, removal of the platelet surface glycoproteins resulting in increased platelet clearance by the Ashwell-Morell receptor in the liver, and platelet apoptosis.

 

Classification of thrombocytopenias

Decreased platelet production

Bone marrow damage (drugs, alcohol, cytostatic agents, etc.)
Infiltration and replacement of the bone marrow (hematologic malignancies, rarely solid tumors)
Myelofibrosis
Myelodysplastic syndromes
Bone marrow hypo-/aplasia, paroxysmal nocturnal hemoglobinuria
Severe vitamin, iron deficiency
Rare genetic defects: Bernard-Soulier syndrome, MYH9-associated syndromes and other hereditary thrombocytopenias
In ITP thrombocytopoiesis in the bone marrow may also be impaired


Increased platelet consumption

Primary immune thrombocytopenia
No trigger identifiable

Secondary immune thrombocytopenia
Drug-induced immune thrombocytopenia
Autoimmune diseases
Antiphospholipid syndrome
Immunodeficiency syndromes (common variable immunodeficiency syndrome, autoimmune lymphoproliferative syndrome (Canale-Smith syndrome),
Wiskott-Aldrich syndrome)
Evans syndrome (e.g. with lymphomas, CLL)
Hepatitis, HIV and other viral infections
Vaccination-associated

Other immune-mediated thrombocytopenias (not ITP)
Heparin-induced thrombocytopenia
Thrombocytopenia after GPIIb/IIIa inhibitor administration
Post-transfusional purpura
Pregnancy-associated thrombocytopenia
Neonatal and fetal alloimmune thrombocytopenia

Other consumption thrombocytopenias (not immune-mediated)
Microangiopathic hemolytic anemia (TTP, HUS, aHUS, etc.)
Disseminated intravascular coagulation
von Willebrand disease type 2b
Massive pulmonary embolism
Large hemangiomas
Large aneurysms


Other Thrombocytopenias

Thrombocytopenia with splenomegaly
Thrombocytopenia after massive bleedings
Thrombocytopenia during severe infections (e.g. sepsis)


Problems of laboratory analysis

EDTA-induced pseudothrombocytopenia

 

Thrombocytopenia Caused by Platelet Destruction, Hypersplenism, or Hemodilution


Mechanisms of Platelet Destruction or Consumption

Mechanisms of Platelet Destruction or Consumption

Note: CPB, Cardiopulmonary bypass surgery; DIC, disseminated intravascular coagulation; HIT, heparin-induced thrombocytopenia; HUS, hemolytic uremic syndrome; IgG, immunoglobulin G; ITP, Idiopathic (immune) thrombocytopenic purpura; NAIT, Neonatal alloimmune thrombocytopenia; PAT, passive alloimmune thrombocytopenia; PE, pulmonary embolism; PTP, posttransfusion purpura; RES, reticuloendothelial system; TTP, thrombotic thrombocytopenic purpura; vWF, von Willebrand factor.



Laboratory Tests Used to Investigate a Patient With Thrombocytopenia

Laboratory Tests Used to Investigate a Patient With Thrombocytopenia.
Laboratory Tests Used to Investigate a Patient With Thrombocytopenia.

Note: ANA, Antinuclear antibody; aPL, antiphospholipid; aPTT, activated partial thromboplastin time; CBC, complete blood count; DIC, disseminated intravascular coagulation; D-ITP, drug-induced immune thrombocytopenia; ELISA, enzyme-linked immunosorbent assay; GP,



Differential Diagnosis of Thrombocytopenia in Pregnancy

• Incidental thrombocytopenia of pregnancy (gestational thrombocytopenia)
• Preeclampsia or eclampsia*
• DIC secondary to:
Abruptio placentae, Endometritis, Amniotic fluid embolism, Retained fetus, Preeclampsia or eclampsia*,
• Peripartum or postpartum thrombotic microangiopathy
TTP, HUS,
Note: DIC, Disseminated intravascular coagulation; HUS, hemolytic uremic syndrome; TTP, thrombotic thrombocytopenic purpura.
*Preeclampsia or eclampsia usually is not associated with overt DIC.



POSTSURGERY PLATELET COUNT CHANGES.

POSTSURGERY PLATELET COUNT CHANGES.

Initial platelet count declines result from hemodilution and increased platelet consumption, with the platelet count nadir occurring between days 1 to 4 (median, day 2). There is constitutive production of thrombopoietin (TPO) by the liver. TPO binds to platelets and megakaryocytes via a specific receptor (c-Mpl, not shown), and receptor-bound TPO is removed from circulation and degraded. The level of circulating TPO is thus inversely related to the mass of platelets and megakaryocytes. In early postsurgery thrombocytopenia, fewer TPO binding sites are available, resulting in high free TPO levels, which stimulates megakaryocyte proliferation and differentiation and leads to increased platelet production. With subsequent thrombocytosis, the high platelet mass acts as a “sink” for removing TPO, with decreased stimulus for platelet production. Thus, after acute postsurgery thrombocytopenia, TPO levels rise about twofold, leading to increased platelet production that begins on days 2 to 4, with resulting thrombocytosis that generally peaks at approximately day 14 (postoperative thrombocytosis) and returns to baseline by about day 21.
Note:From Arnold DM, Warkentin TE: Thrombocytopenia and thrombocytosis. In Wilson WC, Grande CM, Hoyt DB, editors: Trauma: Critical care, vol 2. New York, 2007, Informa Healthcare, p 983.



TIMING OF ONSET AND SEVERITY OF THROMBOCYTOPENIA: IMPLICATIONS FOR DIFFERENTIAL DIAGNOSIS.

TIMING OF ONSET AND SEVERITY OF THROMBOCYTOPENIA: IMPLICATIONS FOR DIFFERENTIAL DIAGNOSIS.

The usual postoperative platelet count nadir is seen between postoperative days 1 to 3 (inclusive). Early and progressive platelet count declines often reflect severe postoperative complications such as sepsis and multiorgan failure; severe thrombocytopenia can (rarely) indicate postsurgery thrombotic thrombocytopenic purpura (TTP). Thrombocytopenic disorders that begin approximately 1 week after surgery are often immune mediated: moderate thrombocytopenia can indicate heparin-induced thrombocytopenia (HIT), both “typical onset” or (if heparin is not being given) “delayed onset”; very severe thrombocytopenia can indicate drug-induced immune thrombocytopenic purpura (D-ITP) or (rarely) posttransfusion purpura (PTP). An abrupt decline in platelet count after receiving a heparin bolus in a patient who has received heparin within the past 7 to 100 days can indicate “rapid-onset” HIT; thrombocytopenia that begins abruptly after transfusion of a blood product can indicate sepsis from bacterial contamination or (rarely) passive alloimmune thrombocytopenia (PAT) caused by transfusion of platelet-reactive alloantibodies.
Note:From Greinacher A, Warkentin TE: Acquired non-immune thrombocytopenia. In: Marder VJ, Aird WC, Bennett JS, et al, editors: Hemostasis and thrombosis: Basic principles and clinical practice, ed 6. Philadelphia, 2012,

 

Drug-induced immunologic destruction

Commonly used drugs that occasionally induce thrombocytopenia include
Heparin
Quinine
Trimethoprim/sulfamethoxazole
Glycoprotein IIb/IIIa inhibitors (eg, abciximab, eptifibatide, tirofiban)
Hydrochlorothiazide
Carbamazepine
Acetaminophen
Chlorpropamide
Ranitidine
Rifampin
Vancomycin

Drug-induced thrombocytopenia occurs typically when a drug bound to the platelet creates a new and “foreign” antigen, causing an immune reaction. This disorder is indistinguishable from ITP except for the history of drug ingestion. When the drug is stopped, the platelet count typically begins to increase within 1 to 2 days and recovers to normal within 7 days. (A table of drugs reported to cause thrombocytopenia, together with analysis of the evidence for a causal relation of the drug to thrombocytopenia, is available at Platelets on the Web.)

Drug-Induced Thrombocytopenia


Drug-Induced Thrombocytopenia (DITP) refers to acute, immune-mediated thrombocytopenia. DITP should be suspected when a patient, child or adult, has sudden, severe thrombocytopenia. DITP is even more strongly suspected when a patient has repeated episodes of sudden, severe thrombocytopenia. This clinical course is not consistent with the diagnosis of immune thrombocytopenic purpura (ITP).

All substances that can cause immune-mediated thrombocytopenia are now included together with approved drugs in the databases of single and group patient reports. These include foods, beverages, herbal remedies, and other substances.
Database of Individual Patient Reports through 2014
Database of Group Patient Reports through 2014

Drugs and other substances that cause thrombocytopenia by marrow suppression are not included in these databases.

 

Drug-Induced Thrombocytopenia


Drug-Induced Thrombocytopenia (DITP) refers to acute, immune-mediated thrombocytopenia. DITP should be suspected when a patient, child or adult, has sudden, severe thrombocytopenia. DITP is even more strongly suspected when a patient has repeated episodes of sudden, severe thrombocytopenia. This clinical course is not consistent with the diagnosis of immune thrombocytopenic purpura (ITP).

All substances that can cause immune-mediated thrombocytopenia are now included together with approved drugs in the databases of single and group patient reports. These include foods, beverages, herbal remedies, and other substances.
Database of Individual Patient Reports through 2014
Database of Group Patient Reports through 2014

Drugs and other substances that cause thrombocytopenia by marrow suppression are not included in these databases.

Pregnancy-Related Thrombocytopenia


Some, but not all, reports on platelet counts during pregnancy describe lower than normal platelet counts as pregnancy progresses, with approximately 5% of women having platelet counts less than 150,000/µL (the lower limit of the normal platelet counts in health subjects) at the time of delivery. In these reports, most women had only slightly low platelet countsl; few women had platelet counts less than 100,000/µL.

When low platelet counts occur during an otherwise uncomplicated pregnancy in a healthy women, it is often described as "gestational thrombocytopenia." There is no known cause for gestational thrombocytopenia, and it is often implied that it may be an abnormal (pathologic) occurrence, not simply a normal (physiologic) occurrence.

 

Thrombotic Microangiopathy (TMA)


Thrombotic Microangiopathy (TMA) is a comprehensive term that describes syndromes with similar pathologic and clinical features. We use the term, "primary TMA syndromes," to describe the disorders for which there is evidence supporting a defined abnormality as the probably cause. This section of ouhsc.edu website focuses on 4 primary TMA syndromes:
1. Thrombotic Thrombocytopenia Pupura (TTP)
2. Drug-Induced TMA (DITMA)
3. Shiga Toxin-Mediated Hemolytic-Uremic Syndrome (ST-HUS)
4. Complement-Mediated TMA

1. Thrombotic Thrombocytopenia Pupura (TTP)

TTP is a disease of abnormal platelet clumping that obstructs blood circulation in small vessels. In the normal circulation, platelets move along the surgace of blood vessels and don't stick to the vessel wall, or to each other, unless there is some injury to the vessel wall. As descrived below, patients with TTP are missing a key protein in the blood that helps to prevent platelet clumping.

In TTP, platelets are used up in the abnormal clots that occur throughout the body resulting in thrombocytopenia.
Thrombi caused by clumps of platelets block small blood vessels. That can cause damage to organs such as the kidneys, heart, and brain.
Purpura describes the bruises and the small purple bleeding spots that are caused by too few platelets.


TTP was first recognized in 1924; in 1966 five key signs and symptoms were established: (1) thrombocytopenia, (2) hemolytic anemia, (3) kidney failure, (4) neurologic abnormalities (such as trouble with thinking or seeing, or actual stroke), and (5) fever. When these 5 problems occurred together, without an apparent cause, the “syndrome” of TTP was diagnosed.
In that era almost all patients with TTP died. Beginning in the 1970s, plasma exchange (PEX) was first recognized as an effective treatment for TTP. In 1991, PEX was documented to be effective, with approximately 80% of patients survining. Since 1991, PEX has become the standard treatment for TTP. (Plasma exchange treatment is described below.) This created urgency to make the diagnosis and to begin PEX. Now patients are diagnosed earlier in their disease. The diagnosis is often made only when a low blood platelet count and anemia is present, when there is no kidney failure, no neurologic abnormalities, and no fever. The old concept that all 5 clinical features had to be present to diagnose TTP is obsolete.

There is no laboratory test that clearly diagnoses TTP. Therefore we begin PEX as soon as we have strong suspicion. This means we begin treatment on some patients who may not have TTP. In some patients, another diagnosis, such as a serious infection, is diagnosed and then we stop plasma exchange treatments.

TTP Emergency

This is intended as a resource for physicians treating a patient with a suspected TTP relapse.

Patients with a history of Thrombotic Thrombocytopenia Purpura (TTP) reporting any of the following symptoms may be experiencing a relapse.
Purpura
Petechia
Paleness or jaundice
Fatigue
Fever
Fast heart rate or shortness of breath
Headache, speech changes, confusion, coma, stroke or seizure
Low urine output or blood in the urine.

If this is the case, a CBC needs to be ordered immediately.

If the patient has a low platelet count (less than 150,000), the patient needs to be admitted to the hospital and plasma exchange therapy probably needs to be urgently initiated. In Oklahoma, this service is provided by the Oklahoma Blood Institute. You should call the following number to order plasma exchange therapy: 405-297-5800.

Additional therapies that may be necessary are high dose steroids and/or treatment with Rituximab. We do not, however, recommend these therapies as a replacement for plasma exchange but as therapies to be used together with plasma exchange.

If you are treating a patient with a history of TTP that you suspect may be relapsing, please contact Dr. James George at 405-271-4222. If it is outside of regular business hours, this number will connect you to the hematologist on-call at the University of Oklahoma.

 

WHAT CAUSES TTP?

TTP is caused by a deficiency of a normal blood enzyme that is named ADAMTS13. To cause TTP, ADAMTS13 must be absent or severely deficient. We usually describe a severe deficiency as less than 10% of the normal levels. Levels above 10% seem to be enough. ADAMTS13 acts to prevent platelet clumping in the circulation of small blood vessels.
ADAMTS13 is needed to trim a very long protein of the blood, that is named von Willebrand factor, abbreviated as VWF (it’s named after a person, you don’t need to know that either). VWF is an extremely long string of a protein, and this is how it catches and clumps platelets. If there is no ADAMTS13 in the blood, these extremely long strings persist and platelet clumping can occur where it shouldn’t occur, in the normal circulation in a normal blood vessel. If ADAMTS13 is present, it trims these long strings down to their normal size. Normal size VWF can still effectively clump platelets, but only when there is a cut or trauma or damage to the blood vessel and blood clotting with platelet clumping needs to occur.
The absence of ADAMTS13 doesn’t mean that platelets are going to clump and block blood vessels all the time, every day, causing constant TTP. The absence of ADAMTS13 only means that a person is vulnerable to the platelet clumping and the disorder we call TTP when some stress occurs. The stress can be any illness (like influenza), or surgery, or pregnancy. In most patients we don’t know what the stress or the “trigger event” is.

ADAMTS13 deficiency can be inherited or acquired.
Among infants and young children, ADAMTS13 deficiency is rare; when it occurs, it is commonly inherited. Acquired TTP is very rare in children. The inheritance is described as recessive, which means that a child has to inherit an abnormal gene from both parents to have the risk for developing TTP. The parents are normal, because with only one of the two genes being abnormal, the ADAMTS13 level is 50%, and that’s plenty to keep the VWF in its normal size.
Among adults, ADAMTS13 deficiency is almost always acquired. Some people can have inherited absent ADAMTS13 but never be sick until they are adults. One of the situations which can “trigger” an initial episode of TTP in an adult with an inherited absence of ADAMTS13 is pregnancy. If a woman has an initial episode of TTP during a pregnancy, inherited ADAMTS13 deficiency should be considered.
But in over 90% of adults, ADAMTS13 deficiency is acquired, caused by inhibition of its activity by an autoantibody. Therefore acquired TTP is an autoimmune disorder. Autoimmune disorders are more common in women than men, and some autoimmune disorders are more common in specific racial groups. Acquired TTP occurs more commonly in women (among our patients, 80% are women) and occurs more common in African-Americans (among our patients, about one-third are African-American, which is about seven times what we’d expect from our Oklahoma population). Most of our patients are young adults; the average is 40. These features are similar to another autoimmune disorder, systemic lupus erythematosus (commonly called “lupus” or SLE). Lupus also occurs predominantly in young, black women.

Treatment of TTP

For patients with inherited TTP (inherited ADAMTS13 deficiency), simple infusion of plasma in sufficient. Most children and adults only need plasma infusion when they have some illness which may trigger an episode of TTP. For example, if a child with inherited TTP has a fever and cough – or any illness – it is essential to get a blood count, and if the platelet count is low, to treat him with a plasma infusion. Or if a woman becomes pregnant, it is important to treat her with plasma infusion every 2 weeks to keep her platelet count normal – or every week if needed. We then continue the plasma infusion for 6 weeks after delivery, because the postpartum period is also a risk.

For patients with acquired TTP, plasma exchange (abbreviated as PEX) is the most important treatment. In the era before plasma exchange was first used in the 1970s, only 10% of patients survived. With the initial use of PEX, survival increased from 10% to 80%. PEX is done with a machine that removes patient plasma and replaces it with fresh plasma, similar to the machines used for routine blood donations. The assumed reason for the effectiveness of PEX is that it removes the harmful autoantibodies and supplies ADAMTS13. PEX has substantial risks. A catheter needs to be inserted into one of the large veins of the shoulder, neck, or groin area. That creates a risk for serious infection. Allergic reactions to the infused plasma are common; most reactions cause only hives, but some can also cause breathing problems.

We continue plasma exchange daily until the platelet count is normal. Then we stop. If the TTP is still active, the platelet count will fall again and daily treatments must be resumed. This may happen in about 20% of patients. We routinely also treat patients with steroids, which suppress the immune system. Most people are familiar with steroids because they’re commonly used for common allergic problems, such as asthma and poison ivy. We use large doses of steroids to suppress the immune system, to suppress the production of the autoantibodies that are blocking the function of ADAMTS13. In patients whose platelet counts don’t begin to recover after several days of PEX + steroids, or in patients whose platelet counts fall after PEX is stopped, we add rituximab, a drug which has a stronger suppression of the immune system. We have been using rituximab in this way since 2003. Since we started using steroids in all patients, and rituximab in some patients, the duration of PEX is much shorter than it was 20 years ago. Now most patients need less than 10 days of PEX.

WHAT HAPPENS FOLLOWING RECOVERY FROM AN EPISODE OF TTP?

 

2. Drug-Induced TMA (DITMA)

We (ouhsc.edu) recently completed a systematic review of all published reports describing drugs (and other substances) as a potential cause of TTP, Hemolytic-Uremic Syndrome (HUS), or TMA.
We have used the comprehensive term, TMA, to describe all of these drug-induced syndromes. This section of our website features the results of systematic review with a comprehensive table describing all of 386 articles that we identified and reviewed to determine the level of evidence for a causal association of the drug with TMA. This is the same fundamental methodology that we have used for the past 16 years for our systematic reviews of drug-induced thrombocytopenia.

Drugs can cause TMA, abbreviated as DITMA, by two major mechanisms.

Immune-mediated reactions. Just like DITP, drugs can cause TMA by the formation of drug-dependent antibodies.
Different from DITP, in which the drug-dependent antibodies react only with platelets, in DITMA the drug-dependent antibodies react with multiple different cells to cause the systemic microvascular thrombosis that defines TMA.
Quinine is the most common cause of immune-mediated DITMA. Quinine-induced TMA is typically a very sudden and severe illness with severe kidney injury. Patients often can recall the exact time, place, and circumstances of their initial symptoms, and these symptoms typically occur within several hours of quinine exposure. Quinine exposure may be from tablets, typically used for the common symptom of leg cramps, or from common beverages, such as tonic water, Schweppes Bitter Lemon, and Dubonnet aperitif. These clinical characteristics of quinine-induced TMA are assumed to be similar for other drugs (or foods or beverages) that may cause immune-mediated TMA.

Toxic reactions. DITMA can also be caused by direct drug toxicity. There are 4 principal classes of drugs that can cause toxicity-mediated TMA:
[1] chemotherapy drugs used for cancer and related disorders (such as mitomycin and gemcitabine),
[2] immunosuppressive drugs used for prevention of organ graft rejection and other immunologic disorders (such as cyclosporine and tacrolimus),
[3] vascular endothelial growth factor (VEGF) inhibitors (such as bevacizumab and sirolimus), and
[4] illegal drugs (such as cocaine) or legal narcotics taken inappropriately (such as Opana [oxymorphone] injected intravenously).

Toxicity-mediated TMA may also be sudden and severe, as when Opana is injected intravenously. However more often the onset of TMA is very gradual, manifested by kidney failure and hypertension.
This chronic course occurs when the appropriate dose and administration of a drug may be safe, but higher doses or continuation for longer duration can cause toxicity-mediated TMA.

Our systematic review of all drugs reported to be associated with TMA was completed on March 27, 2014 and published in 2015.
Al-Nouri ZL, Reese JA, Terrell DR, Vesely SK, George JN. Drug-induced thrombotic microangiopathy: a systematic review of published case reports. Blood 2015; 125 (4): 616-618. [Full Text]
This review identified 344 articles that reported data on 586 individual patients with TMA attributed to 75 drugs. One-hundred and four patient reports presented evidence supporting a definite causal association with 20 drugs. Among these 104 patients, quinine was the most commonly reported drug (in 34 patients). For 10 of the 20 drugs, there was only one report with definite evidence. Forty-three articles presented group data with TMA attributed to 12 drugs; none of these reports had evidence supporting a definite causal association.
The table presents the number of patients reported with a definite causal association with TMA for each of the 20 drugs.
20 drugs reported to have a definite causal association with TMA in 104 individual patient reports

Drug /#Patients
BEVACIZUMAB /3 COCAINE /1 CYCLOSPORINE /15 DOCETAXEL /1 EVEROLIMUS /1 GEMCITABINE /5 INTERFERON /10 MITOMYCIN /3 MUROMONAB-CD3 /1 OXALIPLATIN /1 PENICILLIN /1 PENTOSTATIN /2 QUETIAPINE /1 QUININE /34 SIROLIMUS /8 SULFISOXAZOLE /1 SUNITINIB /2 TACROLIMUS /12 TRIELINA /1 VINCRISTINE /1

DITMA Systematic Review Table of Drugs
This comprehensive table lists all 387 articles reporting data on 78 drugs, both case reports and group data. Both Immune-mediated and Toxicity-mediated mechanisms are included in this table. The scores represent out assessment of the strength of the causal association of the drug with TMA. (1-Definite Causal Association; 2-Probably Causal Association; 3-Possible Causal Association; 4-Unlikely Causual Association).

DITMA Review Methods
Methods of assessment of reports of DITMA and determination of scores designating the level of evident for a causal association of the drug with TMA. Different methods were used for individual patient reports and group data. For individual patient reports, different methods were used for drugs with a presumed Immune-mediated mechanism and drugs with a presumed Toxicity-mediated mechanism.
Publications
1. This review places DITMA in the context of all TMA syndromes.
George JN, Nester CM. Syndromes of thrombotic microangiopathy. New Eng J Med 2014; 310 (7): 654-666. [Full Text]
2. The systematic review that provided the data published in this section of our website.
Al-Nouri ZL, Reese JA, Terrell DR, Vesely SK, George JN. Drug-induced thrombotic microangiopathy: a systematic review of published case reports. Blood 2015; 125 (4): 616-618. [Full Text]
3. The DITMA experience of the Oklahoma Registry, in which patients treated with plasma exchange for a suspected diagnosis of TTP or HUS were subsequently considered to have DITMA, using the criteria established for our systematic review. Also included in this report is the experience of the BloodCenter of Wisconsin with samples from patients with suspected DITMA submitted for the detection of drug-dependent antibodies reacting with platelets and/or neutrophils.
Reese JA, Bougie DW, Curtis, BR, Terrell DR, Vesely SK, Aster RH, George JN. Drug-induced thrombotic microangiopathy: experience of the Oklahoma Registry and the BloodCenter of Wisconsin. American J Hematol 2015; 90 (5): 406-410. [Full Text]
James N. George, M.D.
Professor of Medicine
Hematology-Oncology Section, Department of Medicine
Department of Biostatistics & Epidemiology, College of Public Health
University of Oklahoma Health Sciences Center

3. Shiga Toxin-Mediated Hemolytic-Uremic Syndrome (ST-HUS)

In this section we describe the infectious cause, the epidemiology, and the clinical course of this TMA syndrome. HUS may be the most common among the primary TMA syndromes. Since the cause is Shiga toxin, a toxin secreted by certain strains of bacteria, it is often described as Shiga toxin-HUS, or simply ST-HUS.

4. Complement-Mediated TMA

This is a recently described primary TMA syndrome, resulting from uncontrolled activation of the alternative pathway of complement.
Although the association of the hereditary abnormalities of proteins regulate the activity of the alternative pathway of complement with a TMA syndrome have been recognized with increasing frequency for 35 years, it was only when an effective treatment, eculizumab, became available in 2011 that these disorders became prominent. The prominence resulted from the marketing of eculizumab.
The dilemma for physicians is the lack of clear clinical diagnostic criteria and the lack of rapid availability of genetic analysis for mutations of genes for the complement regulatory proteins. This disorder has been described as "atypical hemolytic uremic syndrome (aHUS)," since the original patients in whom uncontrolled activation of the alternative pathway of complement was described were children with clinical features of HUS but who did not have preceding diarrhea. Therefore they were described as "diarrhea-negative HUS" or "atypical HUS." However this term has no specificity and should be avoided. Use of the term "aHUS" only creates confusion, because it can be interpreted as describing almost all TMA syndromes.

 

 

Immune Thrombocytopenic Purpura (ITP)

ITP Treatment

ASH suggests that a bone marrow examination is not necessary irrespective of age in patients presenting with typical ITP.
ASH recommendations are that bone marrow examination is not necessary in children and adolescents with the typical features of ITP.
ASH recommendations are that bone marrow examination is not necessary in children in whom intravenous immunoglobulin (IVIg) therapy fails.
ASH suggestions are that bone marrow examination is not necessary in similar patients before initiation of treatment with corticosteroids or before splenectomy

ASH recommends testing adult patients with ITP for hepatitis C virus and HIV.
ASH suggests further investigations if the blood count or peripheral blood smear reveals abnormalities other than thrombocytopenia

Testing for antinuclear antibodies is not necessary in the evaluation of children and adolescents with suspected ITP.
Routine testing for Helicobacter pylori in children with chronic ITP is not indicated

Treatment in adults

In adults, treatment is recommended for a platelet count < 30×109/L.

Initial treatment
• Longer courses of corticosteroids are preferred over shorter courses of corticosteroids or IVIg.
(eg, prednisone 1 mg/kg orally for 21 days then tapered is preferred).
• IVIg may be used with corticosteroids when a more rapid increase in platelet count is required.
• Either IVIg or anti-D (in appropriate patients) may be used if corticosteroids are contraindicated.
(If used, IVIg should be administered in a single dose of 1 g/kg; this dose may be repeated if necessary.)

Further therapy
ASH recommendations are as follows:
• Splenectomy for patients who have failed corticosteroid therapy
ASH recommends the following:
For medically suitable patients, laparoscopic and open offer similar efficacy.
Further treatment is not indicated in asymptomatic patients who have platelet counts >30 × 10 9/L after splenectomy.
• Thrombopoietin receptor agonists for patients at risk of bleeding who relapse after splenectomy or who have a contraindication to splenectomy and who have failed at least one other therapy

When one line of therapy (eg, corticosteroids, IVIg) has failed and the patient is at risk of bleeding, ASH suggests that the following treatments may be considered:
• Thrombopoietin receptor agonists, in patients who have not undergone splenectomy
• Rituximab, after failure of one line of medical therapy or splenectomy

The ASH suggests consideration of thrombopoietin receptor agonists for patients at risk of bleeding when splenectomy is contraindicated and at least one other therapy has failed, and recommends thrombopoietin receptor agonists In adult patients who relapse after splenectomy and are at risk for bleeding.
The ASH suggests consideration of rituximab in patients at risk of bleeding when one line of therapy (eg, corticosteroids, IVIg, splenectomy) has failed.

Gudbrandsdottir et al reported that, compared with dexamethasone monotherapy, treatment with the combination of dexamethasone and rituximab resulted in higher response rates (58%, versus 37% with dexamethasone alone; P = 0.02), longer time to relapse ( P = 0.03) and longer time to rescue treatment (P = 0.007) However, the incidence of grade 3 to 4 adverse events was higher in the rituximab plus dexamethasone group (P = 0.04). The study included 113 adult patients with newly diagnosed, symptomatic primary ITP.

Additional precautions are required for patients with hypertension, peptic ulcers, recent aspirin ingestion, or other risk factors for increased bleeding.

Considerations are as follows:

• Aspirin inhibits platelet function by acetylating platelet cyclooxygenase, increasing the risk of bleeding because it adds a platelet functional defect to the quantitative defect already present from the severe thrombocytopenia. In addition, platelet dysfunction may be induced by the platelet antibody, which is potentiated by the superimposition of the aspirin-platelet defect. Because of this effect, aspirin is contraindicated in persons with ITP.

• Adults whose platelet counts are greater than (50 × 109/L (>50 × 103/µL) typically have minimal purpura, and the risk of a severe hemorrhage is low. They may be treated without a specific medication.

• Platelet transfusions may be required to control clinically significant bleeding but are not recommended for prophylaxis. Transfused platelets also have decreased circulation, and repeated platelet transfusions may lead to platelet alloimmunization.

Fostamatinib was approved by the FDA in April 2018 for thrombocytopenia in adults with chronic ITP who have had an insufficient response to a previous treatment. It is the first spleen tyrosine kinase (SYK) inhibitor approved in the US. Approval was based on the FIT clinical program (n=163), which included 2 randomized placebo-controlled Phase 3 trials and an open-label extension trial. Results from the randomized trials showed more patients experienced a platelet response with fostamatinib compared with placebo (18% vs 0% and 16% vs 4%). In the open-label expansion trial, 23% of patients who had received placebo in the previous randomized trials experienced a platelet response. Fewer bleeding episodes were observed in patients in the fostamatinib arm compared with placebo (29% vs 37%).


Recommended general approach for adults with chronic immune thrombocytopenic purpura
Adults whose disease is not controlled with a prednisone-induced increase in platelet count that is maintained by IV RhIG or IVIG and whose conditions do not respond to four weekly infusions of rituximab are candidates for splenectomy. After these serial experiences, such patients are likely to have had thrombocytopenia for at least 6 months and, therefore, are categorized as having chronic ITP. Eltrombopag or romiplostim offer potential maintenance of safe levels of platelet counts for adults who qualify by having ITP for at least 6 months and whose conditions are refractory to conventional medical management (prednisone, IV RhIG, IVIG, rituximab), and whose platelet count is not maintained in a satisfactory range after splenectomy.

The treatment of chronic, refractory ITP may introduce risks of toxicity from medications that are comparable in severity to the risks of untreated thrombocytopenia. These treatments also may impact adversely on the patient's quality of life.

Fostamatinib was approved by the FDA in April 2018 for thrombocytopenia in adults with chronic ITP who have had an insufficient response to a previous treatment. It is the first spleen tyrosine kinase (SYK) inhibitor approved in the U.S. Approval was based on the FIT clinical program (n=163), which included 2 randomized placebo-controlled Phase 3 trials and an open-label extension trial.

For patients with chronic refractory ITP who have access to investigational programs, the authors encourage them to participate in controlled clinical trials to support the development of effective treatments for this category.
Thrombopoietin-receptor agonists
Most conventional treatments for ITP act by decreasing destruction of autoantibody-coated circulating platelets. In contrast, thrombopoietin mimetics increase platelet counts in persons with ITP by increasing the number of platelets produced and released by the bone marrow. Agents in this class include the thrombopoietin peptide mimetic romiplostim (Nplate) and the nonpeptide mimetic eltrombopag (Promacta).

Romiplostim was approved by the US Food and Drug Administration (FDA) in August 2008. It is a thrombopoiesis-stimulating protein Fc-peptide fusion protein ("peptibody") that increases platelet counts in patients with acute and chronic ITP without reports of significant toxicity.

Eltrombopag is indicated for treatment of thrombocytopenia in patients with chronic ITP who have shown insufficient response to corticosteroids, immunoglobulins, or splenectomy. This drug was also approved by the FDA in 2008. In August 2015, the FDA expanded the indication for eltrombopag to include treatment of chronic ITP in patients 1 year of age and older who have not achieved an appropriate response with other medical therapy or splenectomy.

Treatment in children

Observation
Most children with acute ITP do not require treatment, and thrombocytopenia resolves spontaneously. The American Society of Hematology (ASH) recommends that children who have no bleeding or mild bleeding (eg, cutaneous manifestations such as bruising and petechiae) be managed with observation alone regardless of platelet count. A retrospective review by Schultz et al found that this approach did not lead to an increase in later treatment or an increase in delayed bleeding symptoms.

Initial treatment
For pediatric patients requiring treatment, the ASH recommendations include the following:
• First-line treatment for pediatric patients requiring treatment can be a single dose of IVIg (0.8 to 1 g/kg) or a short course of corticosteroids.
IVIg can be used if a more rapid increase in the platelet count is desired.
• The ASH notes the significant risk of hemolysis with IV RhoD immune globulin (RhIG, anti-D immune ), and advises against its use in children with a hemoglobin concentration that is decreased because of bleeding, or in those with evidence of autoimmune hemolysis. (grade 1C)
ASH suggests that a single dose of anti-D can be used as first-line treatment in Rh-positive, nonsplenectomized children with a negative direct antiglobulin test (DAT), who requiring treatment (grade 2B).

An advantage of IV RhIG is that if bone marrow aspiration is unacceptable to parents and if the diagnosis of acute ITP is equivocal, IV RhIG is an effective treatment that avoids the problem of a misdiagnosis of acute leukemia because of steroid-related changes in the marrow.

Second-line treatment of resistant ITP
For second-line pharmacologic therapy, ASH suggests that rituximab or high-dose dexamethasone may be considered for children or adolescents with ITP who have significant ongoing bleeding despite treatment with IVIg, anti-D, or conventional doses of corticosteroids.
Rituximab or high-dose dexamethasone may also be considered as an alternative to splenectomy in children and adolescents with chronic ITP or in patients who do not respond favorably to splenectomy.

Splenectomy
ASH recommends splenectomy for children and adolescents with chronic or persistent ITP who have significant or persistent bleeding and who do not respond to or cannot tolerate other therapies (eg, corticosteroids, IVIg, anti-D), and/or who need improved quality of life.

Given the relatively high rate of spontaneous remission in pediatric ITP, ASH suggests delaying splenectomy or other interventions with potentially serious complications for at least 12 months, unless the patient has severe and unresponsive disease or quality of life concerns that mandate more definitive therapy.

Additional recommendations
ASH also recommends the following:
Routine testing for Helicobacter pylori in children with chronic ITP is not indicated
Children with a history of ITP who are unimmunized should receive their scheduled first measles-mumps-rubella (MMR) vaccine


Treatment in pregnant women

Diagnosis
ASH recommends the following tests for thrombocytopenia in pregnant patients:
• Complete blood count
• Reticulocyte count
• Peripheral blood smear
• Liver function tests
• Viral screening (HIV, HCV, HBV)

Tests to consider if clinically indicated include the following:
• Antiphospholipid antibodies
• Antinuclear antibody (ANA)
• Thyroid function tests
• H pylori testing
• Disseminated intravascular coagulation testing—prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, fibrin split products
• Von Willebrand disease type IIB testing*
• Direct antiglobulin (Coombs) test
• Quantitative immunoglobulin levels

The following studies are not recommended:
• Antiplatelet antibody testing
• Bone marrow biopsy
• Thrombopoeitin (TPO) levels

Treatment
Treatment considerations include the following:
• Pregnant women with no bleeding manifestations whose platelet counts are 30 × 109/L or higher do not require any treatment until 36 weeks' gestation, unless delivery is imminent.
• For pregnant women with platelet counts below 30 × 109/L, or clinically relevant bleeding, first-line therapy is oral corticosteroids or IVIG.
• Prednisone and prednisolone are preferred to dexamethasone, which crosses the placenta more readily.
Although ASH guidelines recommend a starting dose of prednisone of 1mg/kg daily, other experts recommend a starting dose of 0.25 to 0.5 mg/kg, as there is no evidence that a higher starting dose is better. Medications are adjusted to maintain a safe platelet count.
• The recommended starting dose of IVIG is 1 g/kg.

Expected responses to first-line therapy are as follows:
• Oral corticosteroids—initial response 2-14 days, peak response 4-28 days
• IVIg—initial response 1-3 days, peak response 2-7 days

Second-line therapy for refractory ITP is with combined corticosteroids and IVIg or, in the second trimester, splenectomy. Rarely, splenectomy may be required to manage acute hemorrhage.
For third-line therapy, anti-D immunoglobulin and azathioprine are relatively contraindicated.
Azathioprine and RhIG are relatively contraindicated in pregnancy. The standard dose of IV RhIG for ITP contains approximately 10-fold the concentration of anti-D that is in the standard antepartum dose of intramuscular RhIG for Rh immunoprophylaxis.

Other third-line agents that are not recommended in pregnancy, but whose use in pregnancy has been described, include the following:
• Cyclosporine
• Dapsone
• Thrombopoietin receptor agonists
• Campath-1H
• Rituximab

Contraindicated agents include the following:
• Mycophenolate mofetil
• Cyclophosphamide
• Vinca alkaloids
• Danazol

ASH recommendations are as follows:
• Because of the possible need for cesarean delivery, the recommended target platelet count prior to labor and delivery is ≥50 x 109/L
• A woman whose platelet count is < 80 x 109/L but who has not required therapy during pregnancy can be started on oral prednisone (or prednisolone) 10 days prior to anticipated delivery at a dose of 10-20 mg daily and titrated as necessary
• The mode of delivery should be determined by obstetric indications
• Although the minimum platelet count for the placement of regional anesthesia is unknown and local practices may differ, many anesthesiologists will place a regional anesthetic if the platelet count is ≥80 x 109/L
• While platelet transfusion alone is generally not effective in ITP, its use in conjunction with IVIg can be considered if an adequate platelet count has not been achieved and delivery is emergent
• Percutaneous umbilical blood sampling (PUBS) or fetal scalp blood sampling is not recommended, as it is not helpful in predicting neonatal thrombocytopenia and is potentially harmful
• In the newborn, the nadir platelet count reaches its nadir 2-5 days after delivery and rises spontaneously by day 7 Postpartum thromboprophylaxis should be considered, as women with ITP are at increased risk of venous thromboembolism

 

Summary
The goal of medical care for immune thrombocytopenic purpura (ITP) is to increase the platelet count to a safe level, permitting patients to live normal lives while awaiting spontaneous or treatment-induced remission. ITP has no cure, and relapses may occur years after seemingly successful medical or surgical management.

Although the paradigm may be shifting somewhat with the expanding experience with thrombopoietin receptor analogs in chronic ITP, the long-term consequences associated with their use remain to be established and the delayed platelet count responses these agents produce are not conducive to preventing or reversing the potential of acute bleeding complications in newly diagnosed ITP.
Therefore, for the present, corticosteroids (ie, oral prednisone, intravenous [IV] methylprednisolone, or high-dose dexamethasone) should remain the drugs of choice for the initial management of acute ITP.
Treatment with corticosteroids may not only reduce the rate of platelet destruction but may also rapidly alter endothelial cell integrity to facilitate primary hemostasis and to reduce bleeding and bruising.

Because corticosteroid administration may change marrow morphology, performance of a bone marrow aspiration and biopsy should be considered to confirm the diagnosis of ITP if the clinical presentation, patient age, or other findings are atypical for acute ITP before the patient is treated with corticosteroids.

IV immunoglobulin (IVIG) has been the drug of second choice (after corticosteroids) for many years. However, for Rh(D)-positive patients with ITP and intact spleens, IV Rho immunoglobulin (RhIG) offers comparable efficacy, less toxicity, greater ease of administration, and a lower cost than IVIG.

The limitation of using IV RhIG is the lack of efficacy in Rh(D)-negative or splenectomized patients. Also, IV RhIG may induce immune hemolysis (immune hemolytic anemia) in Rh(D)-positive persons, which is the most common adverse effect, and should not be used when the hemoglobin concentration is less than 8 g/dL. Sporadic cases of massive intravascular hemolysis [16] disseminated intravascular coagulation (particularly in elderly individuals), and renal failure [17] have been reported.

Thrombopoietin receptor agonists
For many years, the only treatment options after corticosteroids, IV RhIG, IVIG, and rituximab were cyclophosphamide, azathioprine, and danazol. Interventions with decreased certain efficacy and with conflicting reports in the literature include alemtuzumab, azathioprine, danazol, dapsonevinblastine, vincristine, ascorbic acid, colchicine, and interferon alfa.

In 2008, two thrombopoietin receptor agonists, romiplostin (Nplate) and eltrombopag (Promacta), became available for patients with chronic ITP. In August 2015, the U.S. Food and Drug Administration expanded the indication for eltrombopag to include treatment of chronic ITP in patients 1 year of age and older who have not achieved an appropriate response with other medical therapy or splenectomy.

The limited clinical experiences with these agents are promising. However, the ultimate efficacy and safety of these new agents will not be fully evaluable until data on larger numbers of patients become available.

In one prospective, randomized controlled study comparing romiplostin with the standard of care for the treatment of chronic ITP, romiplostim administration was associated with higher rates of platelet count responses, decreased need for splenectomy, fewer episodes of serious bleeding and blood transfusions, and decreased need for initiating additional medical treatments. Romiplostim therapy was also associated with improved quality of life. In a study of long-term romiplostim treatment, a small cohort of children with severe chronic ITP increased and maintained platelet counts for over 4 years, with good tolerability and without significant toxicity.

In a phase 3 double-blind study of 62 symptomatic children with persistent or chronic ITP who were randomly assigned to receive weekly romiplostim or placebo for 24 weeks, durable platelet response was seen in 52% of patients receiving romiplostim vs.10% of those in the placebo group (p=0.002, odds ratio 9.1). However, further studies are needed to determine long-term efficacy, safety, and remission rates.

A systematic review concluded that romiplostim is effective and generally well tolerated in patients 65 years of age and older with ITP. Complications included nonsignificant trends toward increased risks of grade ≥3 bleeding and thromboembolic events.

Eltrombopag was studied in a phase III double-blind trial in adults with previously treated ITP lasting more than 6 months and with platelet counts lower than 30,000/µL. Patients received treatment with local standard care plus eltrombopag (50 mg) or placebo for 6 months.

Of 196 patients in the study, 106 (79%) patients in the eltrombopag group responded to treatment at least once, compared with 17 (28%) in the placebo group. Toxic reactions in the eltrombopag group included thromboembolic events (2%), mild increases in alanine aminotransferase levels (3%), and increased total bilirubin levels (4%).

 

Clinical Practice Updates in the Management Of Immune Thrombocytopenia


Causes of Secondary Immune Thrombocytopenia

Causes of Secondary Immune Thrombocytopenia

CONCLUSION
Recent studies and updates in the literature have added much to what we know about the pathophysiology of ITP and how to translate this knowledge into clinical practice and treatment guidelines.
Novel therapies have provided alternatives to splenectomy and have been shown to be effective in managing ITP with few adverse effects.
In selecting treatment options, therapy should be individualized to each patient to account for bleeding risk, age, and lifestyle.
First-line emergent treatments include corticosteroids, IVIG, and anti-D immune globulin.
For patients presenting with ITP that is not life threatening, corticosteroids are considered the standard initial treatment due to their effectiveness, low cost, and convenience.
IVIG is recommended for patients with critical bleeding and for those unresponsive to corticosteroids.
The alternative option is anti-D immune globulin, which can be used in nonsplenectomized Rh-positive patients.
Second- and third-line treatment options for nonemergent and chronic ITP have historically included only splenectomy or rituximab.
Rituximab is an off-label treatment for ITP reserved for patients who do not respond to corticosteroids.
Splenectomy is a potentially curative treatment that is used when multiple first-line treatments have failed.
The arrival of TPO-RAs to the market has provided an additional option for chronic ITP management and has greatly changed the ITP treatment landscape.
While the role of TPO-RAs is likely to evolve with continued clinical safety and efficacy data, research and clinical use to date have shown encouraging results.
In selecting treatment regimens in the management of ITP, it is important to evaluate the type, duration, and cost of these treatments because patients may face longer hospital stays, increased risk of mortality, and increased costs for ITP-related hospitalizations.


How I treat immune thrombocytopenia: the choice between splenectomy or a medical therapy as a second-line treatment.

Abstract
The paradigm for managing primary immune thrombocytopenia (ITP) in adults has changed with the advent of rituximab and thrombopoietin receptor agonists (TPO-RAs) as options for second-line therapy. Splenectomy continues to provide the highest cure rate (60%-70% at 5+ years). Nonetheless, splenectomy is invasive, irreversible, associated with postoperative complications, and its outcome is currently unpredictable, leading some physicians and patients toward postponement and use of alternative approaches. An important predicament is the lack of studies comparing second-line options to splenectomy and to each other. Furthermore, some adults will improve spontaneously within 1-2 years. Rituximab has been given to more than 1 million patients worldwide, is generally well tolerated, and its short-term toxicity is acceptable. In adults with ITP, 40% of patients are complete responders at one year and 20% remain responders at 3-5 years. Newer approaches to using rituximab are under study. TPO-RAs induce platelet counts > 50 000/μL in 60%-90% of adults with ITP, are well-tolerated, and show relatively little short-term toxicity. The fraction of TPO-RA-treated patients who will be treatment-free after 12-24 months of therapy is unknown but likely to be low. As each approach has advantages and disadvantages, treatment needs to be individualized, and patient participation in decision-making is paramount.

Promacta (eltrombopag)

BOXED WARNING
Hepatic decompensation, hepatic disease, hepatitis C infection, hepatotoxicity, hypoalbuminemia.
WARNING: RISK FOR HEPATIC DECOMPENSATION IN PATIENTS WITH CHRONIC HEPATITIS C
In patients with chronic hepatitis C, PROMACTA in combination with interferon and ribavirin may increase the risk of hepatic decompensation.
RISK OF HEPATOTOXICITY
PROMACTA may increase the risk of severe and potentially life-threatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended.
DESCRIPTION
Oral non-peptide thrombopoietin receptor agonist
Used for thrombocytopenia and severe aplastic anemia
May cause hepatotoxicity; frequent hepatic function monitoring recommended
SUPPLIED
Eltrombopag Oral Pwd F/Recon: 12.5mg
Promacta Oral Tab: 12.5mg, 25mg, 50mg, 75mg

Indication for PROMACTA® (eltrombopag) Tablets
PROMACTA is indicated for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. PROMACTA should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding.
Limitations of Use
PROMACTA is not indicated for the treatment of patients with myelodysplastic syndromes (MDS).
Safety and efficacy have not been established in combination with direct-acting antiviral agents used without interferon for treatment of chronic hepatitis C infection.
■ For the treatment of thrombocytopenia.
in patients with chronic idiopathic thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy and whose degree of thrombocytopenia and clinical condition increase the risk of bleeding.
Initially, Promacta 50 mg PO once daily; patients of East-Asian ancestry should be started on 25 mg PO once daily.
Platelet counts generally increase within 1 to 2 weeks of initiation and decrease within 1 to 2 weeks of discontinuation.
Use the lowest possible dose to maintain platelet counts of 50,000/mm3 or more and prevent clinically important bleeding; however, do not use eltrombopag to normalize platelet concentrations.
When switching between the oral suspension and the tablet, monitor platelet counts weekly for 2 weeks, and then monthly.
Adjust the dose based on platelet count.
*For platelets less than 50,000/mm3 after 2 weeks of treatment, increase the dose by 25 mg/day PO; do not exceed 75 mg/day PO.
For patients taking 12.5 mg/day, increase the dose to 25 mg/day before increasing the dose by 25 mg.
*For platelets 50,000/mm3 to less than 200,000/mm3, continue current dose.
*For platelets 200,000 to 400,000/mm3 at any time, decrease the dose by 25 mg/day PO; wait 2 weeks to assess the effects of any dosage adjustments.
For patients taking 25 mg once daily, decrease dose to 12.5 mg/day PO.
*For platelets more than 400,000/mm3, stop therapy; increase frequency of platelet monitoring to twice weekly. Once the platelet count is less than 150,000/mm3, reinitiate therapy at a dose reduced by 25 mg/day PO. For patients taking 25 mg once daily, reinitiate therapy at 12.5 mg/day PO. If platelets are more than 400,000/mm3 after 2 weeks of the lowest dose, discontinue eltrombopag.

■ For the initiation and maintenance of interferon-based therapy in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy.
WARNING: RISK FOR HEPATIC DECOMPENSATION IN PATIENTS WITH CHRONIC HEPATITIS C
In patients with chronic hepatitis C, PROMACTA in combination with interferon and ribavirin may increase the risk of hepatic decompensation.

■ For the treatment of severe aplastic anemia.
For the treatment of severe aplastic anemia in patients who have had an insufficient response to immunosuppressive therapy.
■ For the first-line treatment of severe aplastic anemia in combination with standard immunosuppressive therapy.
eltrombopag 150 mg PO once daily initially; start patients of East Asian ancestry at 75 mg PO once daily. Do not exceed the initial dose; total duration of treatment is 6 months. Monitor hematologic and hepatic tests regularly and adjust the dose as necessary. For platelets 200,000 to 400,000/mm3, decrease the dose by 25 mg every 2 weeks to the lowest dose that maintains a platelet count of at least 50,000/mm3. For platelets more than 400,000/mm3, stop treatment for 1 week; once the platelet count is less than 200,000/mm3, reinitiate at a dose reduced by 25 mg/day. If platelets are more than 400,000/mm3 after 2 weeks of the lowest dose, discontinue eltrombopag. Discontinue eltrombopag but remain on horse antithymocyte globulin (h-ATG) and cyclosporine if thromboembolic events occur.

 

 

 

 

Thrombocytosis

Thrombocytosis

There are two types of thrombocytosis: primary and secondary.

Primary thrombocytosis, also known as essential thrombocythemia (or ET), is a disease in which abnormal cells in the bone marrow cause an increase in platelets. The cause is unknown. It is not considered an inherited (family) condition despite the finding of certain gene mutations in the blood or bone marrow.

Secondary thrombocytosis is caused by another condition the patient may be suffering from, such as:
Anemia due to iron deficiency
Cancer
Inflammation or infection
Surgery, especially splenectomy.

Natural course of thrombocytosis

Secondary thrombocytosis subsides when the underlying process causing the elevated platelet count resolves (treatment of infection, recovery from surgery, etc.). Even though the platelet count is elevated for a short time (or even indefinitely after splenectomy), secondary thrombocytosis does not typically lead to abnormal blood clotting.

Primary thrombocytosis, or essential thrombocythemia, can cause serious bleeding or clotting complications. These can usually be avoided by maintaining good control of the platelet count with medications. After many years, however, bone marrow fibrosis (scarring) can develop. Transformation of the disease to leukemia occurs in a small percentage of patients.

Symptoms of thrombocytosis

What are the symptoms of thrombocytosis?
Most patients do not have any symptoms of an increased platelet count. When symptoms do appear, they can include skin bruising or bleeding from various areas such as the nose, mouth, and gums, or the stomach and intestinal tract.

Abnormal blood clotting can also occur, leading to stroke, heart attack, and unusual clots in the blood vessels of the abdomen.

Some patients with essential thrombocythemia develop erythromelalgia, causing pain, swelling, and redness of the hands and feet, as well as numbness and tingling.

Diagnosis of thrombocytosis

Finding the underlying condition (such as iron deficiency anemia, cancer, or infection) can aid in the diagnosis and management of thrombocytosis. If no secondary cause is identified, the patient is presumed to have ET.

A blood test for a specific gene, called JAK2, can diagnose thrombocytosis. However, it is positive in only about 50% of the cases. Other gene mutations are also tested, but are only positive in a low percentage of patients.

The patient may have bone marrow removed and examined to help confirm the diagnosis.

Treatment of thrombocytosis

Patients who have no symptoms may remain stable and only require routine check-ups by their physician. Secondary forms of thrombocytosis rarely require treatment.

For those with symptoms, a few treatment options are available. One is to treat the disease that is causing thrombocytosis. In some cases, the patient can take aspirin to help prevent blood clots. The low dose used for this purpose does not usually cause stomach upset or bleeding.

In essential thrombocythemia, drugs such as hydroxyurea or anagrelide are used to suppress platelet production by the bone marrow. These drugs usually have to be taken indefinitely. Treatment with interferon is sometimes necessary but is associated with a greater number of side effects.

Newer agents are now being developed in an effort to suppress the overproduction of platelets. In cases of severe life-threatening thrombocytosis, a procedure called plateletpheresis is performed to immediately lower the platelet count to safer levels. In this procedure, a special instrument is used to remove blood from the patient, separate and remove the platelets, and then return the other blood cells to the patient.


Reactive Thrombocytosis (Secondary Thrombocythemia)

Reactive thrombocytosis is an elevated platelet count (> 450,000/μL) that develops secondary to another disorder.

Some causes of reactive thrombocytosis include
• Chronic inflammatory disorders (eg, RA, inflammatory bowel disease, TB, sarcoidosis, granulomatosis with polyangiitis)
• Acute infection
• Hemorrhage
• Iron deficiency
• Hemolysis
• Cancer
• Splenectomy or hyposplenism
There are also congenital familial thrombocytoses such as those due to thrombopoietin and thrombopoietin receptor gene mutations. For thrombocytosis that is not secondary to another disorder, see Essential Thrombocythemia.

Platelet function is usually normal. Unlike in essential thrombocythemia, reactive thrombocytosis does not increase the risk of thrombotic or hemorrhagic complications unless patients have severe arterial disease or prolonged immobility.

With secondary thrombocytosis, the platelet count is usually <1,000,000/μL, and the cause may be obvious from the history and physical examination (perhaps with confirmatory testing). CBC and peripheral blood smear should help suggest iron deficiency or hemolysis.

If a cause of secondary thrombocythemia is not obvious, patients should be evaluated for a myeloproliferative disorder. Such evaluation may include cytogenetic studies, including Philadelphia chromosome or BCR-ABL assay, and possibly bone marrow examination, especially in patients with anemia, macrocytosis, leukopenia, and/or hepatosplenomegaly.

Treatment of the underlying disorder usually returns the platelet count to normal.

Common causes of secondary thrombocytosis
iron deficiency
Chronic inflammatory disorders such as infection, allergy/Immune disease or cancer
Hemolysis, hemorrhage or trauma
Surgery
S/P splenectomy or hyposplenism

Diagnostic Considerations
Other problems to be considered include the following:
Myeloproliferative Disease
Polycythemia
Pediatric Thrombocytosis
Idiopathic myelofibrosis
Idiopathic sideroblastic anemia
Pseudothrombocytosis
Chronic lymphocytic leukemia (CLL)
Thrombotic thrombocytopenic purpura (TTP)
Hemoglobin H (HbH) disease
Microspherocytes

Differential Diagnoses
Chronic Lymphocytic Leukemia (CLL)
Chronic Myelogenous Leukemia (CML)
Essential Thrombocytosis
Polycythemia Vera
Thrombotic Thrombocytopenic Purpura (TTP)

Laboratory Studies
Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)
Cytogenetic analysis
Leukocyte alkaline phosphatase, vitamin B-12
Antinuclear antibody (ANA), rheumatoid factor (RF)
Iron studies (serum iron, total iron-binding capacity [TIBC], serum ferritin)
Peripheral blood smear review

If the clinical presentation does not clearly differentiate between primary (clonal) and secondary thrombocytosis, further tests may be indicated to exclude or confirm a diagnosis of disorders that cause clonal thrombocytosis, as follows:
Bone marrow aspiration and biopsy
Cytogenetic studies: The presence of the Philadelphia chromosome (Ph) found in chronic myelogenous leukemia (CML) may also be identified using reverse transcriptase-polymerase chain reaction (RT-PCR) to identify the bcr-abl fusion transcript or by using Southern blot analysis for identification of bcr-abl genomic rearrangements.

Essential thrombocythemia is a diagnosis of exclusion that is based on the following numeric criteria (adapted from Hoffman R. Primary thrombocythemia. In: Hoffman R, Benz EJ Jr, Shattil SJ, et al, eds. Hematology: Basic Principles and Practice. 3rd ed. Philadelphia, Pa: Churchill Livingstone; 2000:1188-204). Patients who meet criteria 1-5 and more than three of criteria 6-11 are considered to have essential thrombocytosis.
1. Platelet count greater than 600,000/mm3 on two occasions, separated by a 1-month interval
2. Absence of an identifiable cause of secondary thrombocytosis
3. Normal red blood cell mass
4. Absence of significant bone marrow fibrosis (ie, less than one third of the bone marrow)
5. Absence of the Philadelphia chromosome (Ph) by karyotyping or absence of the bcr-abl fusion product
6. Splenomegaly by physical examination or ultrasonography
7. Bone marrow hypercellularity with megakaryocyte hyperplasia
8. Presence of abnormal bone marrow hematopoietic progenitor cells as determined by the growth of endogenous erythroid cells and/or megakaryocyte colonies with increased sensitivity to interleukin-3 (IL-3)
9. Normal levels of CRP and IL-6
10. Absence of iron deficiency anemia, as documented by either a normal bone marrow–stainable iron or normal serum ferritin level
11. In females, demonstration of clonal hematopoiesis by restriction fragment length polymorphism (RFLP) analysis of genes present on the X chromosome

 

Essential Thrombocythemia

(Essential Thrombocytosis; Primary Thrombocythemia)

Essential thrombocythemia (ET) is a myeloproliferative disorder characterized by an increased platelet count, megakaryocytic hyperplasia, and a hemorrhagic or thrombotic tendency. Symptoms and signs may include weakness, headaches, paresthesias, bleeding, splenomegaly, and erythromelalgia with digital ischemia.
Diagnosis is based on a platelet count > 450,000/μL, normal RBC mass or normal Hct in the presence of adequate iron stores, and the absence of myelofibrosis, the Philadelphia chromosome (or BCR-ABL rearrangement), or any other disorder that could cause thrombocytosis.
Treatment is controversial but may include aspirin. Patients > 60 yr and those with previous thromboses and transient ischemic attacks are at higher risk for subsequent thromboembolic events. Data suggest that risk of thrombosis is not proportional to platelet count.

Etiology

Essential thrombocythemia is a clonal hematopoietic stem cell disorder that causes increased platelet production. ET usually occurs with bimodal peaks of between ages 50 and 70 yr and a separate peak among young females.

A Janus kinase 2 (JAK2) enzyme mutation, JAK2V617F, is present in about 50% of patients; JAK2 is a member of the tyrosine kinase family of enzymes and is involved in signal transduction for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor (G-CSF) among other entities. Other patients have mutations in exon 9 of the calreticulin gene (CALR) and a few have acquired somatic thrombopoietin receptor gene mutations (MPL). Some myelodysplastic syndromes (refractory anemia with ringed sideroblasts and thrombocytosis [RARS-T] and the 5q- syndrome) may present with elevated platelet count.

Pathophysiology

Thrombocythemia may lead to
• Microvascular occlusions (usually reversible)
• Large vessel thrombosis
• bleeding

Microvascular occlusions often involve small vessels of the distal extremities (causing erythromelalgia), the eye (causing ocular migraine), or the CNS (causing transient ischemic attack).

The risk of large vessel thrombosis causing deep venous thrombosis or pulmonary embolism is increased, but the risk does not increase proportional to the platelet count.

Bleeding is more likely with extreme thrombocytosis (ie, about 1.5 million platelets/μL); it is due to an acquired deficiency of von Willebrand factor caused because the platelets adsorb and proteolyze high molecular weight von Willebrand multimers.

Symptoms and Signs

Common symptoms are
• Weakness
• Bruising and bleeding
• Gout
• Ocular migraines
• Paresthesias of the hands and feet
• Thrombotic events

Thrombosis may cause symptoms in the affected site (eg, neurologic deficits with stroke or transient ischemic attack; leg pain, swelling, or both with lower extremity thrombosis; chest pain and dyspnea with pulmonary embolism).
Bleeding is usually mild and manifests as epistaxis, easy bruisability, or GI bleeding. However, serious bleeding may occur in a small percentage of cases.

Erythromelalgia (burning pain in hands and feet, with warmth, erythema, and sometimes digital ischemia) may occur. Splenomegaly (usually not extending > 3 cm below the left costal margin) occurs in < 50% of patients. Hepatomegaly may rarely occur. Thrombosis may cause recurrent spontaneous abortions.

Diagnosis

• CBC and peripheral blood smear
• Exclusion of causes of secondary thrombocythemia
• Cytogenetic studies
• JAK2 mutation by PCR, and, if negative,CALR or MPL mutation analysis
• Possibly bone marrow examination

Essential thrombocythemia is a diagnosis of exclusion and should be considered in patients in whom common reactive causes (see Reactive Thrombocytosis (Secondary Thrombocythemia)) and other myeloproliferative disorders are excluded.

If ET is suspected, CBC, peripheral blood smear, iron studies and cytogenetic studies, including Philadelphia chromosome or BCR-ABL assay, should be done to distinguish essential thrombocythemia from other myeloproliferative disorders that cause thrombocytosis. The diagnosis of ET requires a normal Hct, MCV, and iron studies; absence of the Philadelphia chromosome and BCR-ABL translocation; and absence of teardrop-shaped RBCs.

The platelet count can be >1,000,000/μL but may be as low as 450,000/μL. Platelet count may decrease during pregnancy. The peripheral smear may show giant platelets and megakaryocyte fragments.

World Health Organization guidelines suggest that a bone marrow biopsy showing increased numbers of enlarged, mature megakaryocytes is required for a diagnosis of essential thrombocythemia, so biopsy is recommended, if possible. Biopsy will also help rule out other myeloproliferative or myelodysplastic syndromes, such as primary myelofibrosis, which often initially manifest as isolated thrombocytosis. The bone marrow in ET shows megakaryocytic hyperplasia, with an abundance of platelets being released. Bone marrow iron is usually present.

Testing for the JAK2V617F mutation should be done; its presence helps distinguish ET from other causes of thrombocythemia. However, the JAK2V617F mutation also is present in many patients with polycythemia vera (PV). Thus, those few cases of PV that initially manifest with thrombocytosis can be confused with ET (thrombocytosis may predominate in PV either because of plasma volume expansion or because the other manifestations of polycythemia have not yet appeared.

If the JAK2 mutation is not present, testing for CALR and MPL should be done.

Prognosis

Life expectancy is near normal. Although symptoms are common, the course of the disease is often benign. Serious arterial and venous thrombotic complications are rare but can be life-threatening. Leukemic transformation occurs in < 2% of patients but may increase after exposure to cytotoxic therapy, including hydroxyurea. Some patients develop secondary myelofibrosis, particularly men with the JAK2V617F or CALR type 1 mutations.

Treatment

• Aspirin
• Platelet-lowering drugs (eg, hydroxyurea, anagrelide)
• Rarely plateletpheresis
• Rarely cytotoxic agents
• Rarely interferon
• Rarely stem cell transplantation

For mild vasomotor symptoms (eg, headache, mild digital ischemia, erythromelalgia) and to decrease the risk of thrombosis in low-risk patients, aspirin 81 mg po once/day is usually sufficient but a higher dose may be used if necessary. Severe migraine may require platelet count reduction for control. The utility of aspirin during pregnancy is unproven.

Aminocaproic acid is effective in controlling hemorrhage due to acquired von Willebrand disease for minor procedures such as dental work. Major procedures may require optimization of platelet counts.

Allogeneic stem cell transplantation is rarely used in ET but can be effective in younger patients if other treatments are unsuccessful and a suitable donor is available.

Lowering platelet count

Because prognosis is usually good, potentially toxic drugs that lower the platelet count should not be used just to normalize the platelet count in asymptomatic patients. Generally agreed-upon indications for platelet-lowering therapy include
• Previous thromboses or transient ischemic attack
• Age > 60 yr
• Significant bleeding
• Need for a surgical procedure in patients with extreme thrombocytosis and low ristocetin cofactor activity
• Sometimes severe migraine

However, there are no data that prove cytotoxic therapy to reduce the platelet count lowers thrombotic risk, or improves survival.

Drugs used to lower platelet count include anagrelide, interferon alfa-2b, and hydroxyurea. Hydroxyurea is generally considered the drug of choice for short-term use. Because anagrelide and hydroxyurea cross the placenta, they are not used during pregnancy; interferon alfa-2b can be used in pregnant women when necessary. Interferon is the safest therapy for migraine.

Hydroxyurea should be prescribed only by specialists familiar with its use and monitoring. It is started at a dose of 500 to 1000 mg po once/day. Patients are monitored with a weekly CBC. If the WBC count falls to < 4000/μL, hydroxyurea is withheld and reinstituted at 50% of the dose when the value normalizes. When a steady state is achieved, the interval between CBCs is lengthened to 2 wk and then to 4 wk. There is no specific target platelet count; the aim of therapy is a platelet count that restores ristocetin cofactor activity if bleeding is the problem or that alleviates symptoms.

Platelet removal (plateletpheresis) has been used in rare patients with serious hemorrhage or recurrent thrombosis or before emergency surgery to immediately reduce the platelet count. However, plateletpheresis is rarely necessary and its effects are transient. Hydroxyurea or anagrelide do not provide an immediate effect but should be started at the same time as pheresis.

Key Points

• ET is a clonal abnormality of a multipotent hematopoietic stem cell resulting in increased platelets.
• Patients are at risk of microvascular thrombosis, hemorrhage, and rarely macrovascular thrombosis.
• ET is a diagnosis of exclusion; in particular, other myeloproliferative disorders and reactive (secondary) thrombocytosis must be ruled out.
• Asymptomatic patients require no therapy. Aspirin is usually effective for microvascular events (ocular migraine, erythromelalgia and transient ischemic attacks).
• Some patients with extreme thrombocytosis require more aggressive treatment to control the platelet count; and such measures include hydroxyurea, anagrelide, interferon alfa-2b, or plateletpheresis.


Last full review/revision December 2016 by Jane Liesveld, MD; Patrick Reagan,