Trombositopenia dan Trombositosis

Definisi Gangguan myeloproliferatif kronik :

gangguan akibat abnormalitas clonal hematopoetic stem cell yg didapat (akuisita), mengakibatkan peningkatan selularitas sum2 tulang yg diikuti peningkatan jumlah sel darah perifer termasuk trombositosis

_______________________________________ Hematopoetic stem cell : sel primitif sum2 tulang,

asal dari seluruh jenis sel darah Clonal/Monoclonal : propagasi sel yang berasal dari

sel progenitor tunggal

Classification of myeloproliferative disorders.

Myeloproliferative syndromes Polycythemia vera Myelofibrosis Essential thrombocytosis Chronic myeloid leukemia Myelodysplastic syndromes Acute myeloid leukemia

Polisitemia Vera Essentials of Diagnosis Increased red blood cell mass. Splenomegaly. Normal arterial oxygen saturation. Usually elevated white blood count and

platelet count.

Causes of polycythemia. Spurious polycythemia Primary polycythemia : PV Secondary polycythemia1. Hypoxia: cardiac disease, pulmonary

disease, high altitude2. Carboxyhemoglobin: smoking3. Renal lesions4. Erythropoietin-secreting tumors (rare)

The hematocrit > 54% (M) or 51% in (F) When the hematocrit is elevated, the red blood cell

mass should be measured to determine whether true polycythemia or relative (Spurius) polycythemia exists.

True polisitemia ( elevated Red Cell Mass): primary or secondary.

Primary polycythemia (polycythemia vera) is a bone marrow disorder characterized by autonomous overproduction of erythroid cells. The serum erythropoietin level is low. In vitro, erythroid progenitor cells grow without added erythropoietin, a finding not seen in normal individuals.

Secondary polycythemia1. Hypoxia: cardiac disease, pulmonary disease,

high altitude2. Carboxyhemoglobin: smoking3. Renal lesions4.Erythropoietin-secreting tumors (rare) Relative ("spurious") polycythemia presents

in overweight and hypertensive (often on diuretic therapy); Hmt <60%, normal red cell mass and low-plasma volume.

Sign and simptom Symptoms related to expanded blood volume and increased

blood viscosity. Common complaints: headache, dizziness, tinnitus, blurred

vision, and fatigue. Generalized pruritus,and epistaxis. 60% are men, and the median age at presentation is 60 years.

Polycythemia rarely occurs in persons under age 40 years. Physical examination: reveals plethora and engorged retinal

veins. Spleenomegaly in 75% of cases but is nearly always enlarged when imaged

Thrombosis is the most common complication of polycythemia vera and the major cause of morbidity and death.

There is a high incidence of peptic ulcer disease.

Laboratory Finding Hematocrit above normal, at times greater than 60%. Red blood cell morphology is normal. The red blood cell mass is elevated. The white blood count is elevated to 10,000-20,000/uL The platelet count is variably increased, sometimes to counts exceeding

1,000,000/uL. Platelet morphology is usually normal. The bone marrow is hypercellular, with panhyperplasia Iron stores are usually absent from the bone marrow Overproduction of uric acid may lead to hyperuricemia. Microcytosis, hypochromia, and poikilocytosis may result from iron

deficiency Progressive hypersplenism may also lead to elliptocytosis.

Differensial DiagnosisLaboratory features of myeloproliferative disorders.  WhiteCount Hematocrit Platelet Count Red cellMorphology Chronic myeloid leukemia I N N or I N Myelofibrosis N or D or I N or I D or N or I Abn Polycythemia vera N or I I N or I N Essential thrombocytosis N or I N I N

Treatment Phlebotomy. One unit of blood (approximately 500

mL) weekly target: less than 45%. Myelosuppressive therapy : a high phlebotomy

requirement, thrombocytosis, and intractable pruritus. Hydroxyurea >> Alkylating because of less leukemogenic potential. The usual dose is 500-1500 mg/d orally Target: platelets < 500,000/uL and neutrophil count < 2000/uL. Anagrelide is a new drug for trombositosis

Low-dose aspirin (81-325 mg daily) has been shown to reduce the risk of thrombosis.

Prognosis Polycythemia is an indolent disease with median

survival of 11-15 years. The major cause of morbidity and mortality is

arterial thrombosis. Polycythemia vera may convert to myelofibrosis or

to chronic myelogenous leukemia. In approximately 5% of cases, the disorder progresses to acute myelogenous leukemia, which is usually refractory to therapy.

Essential TrombositosisEssentials of Diagnosis • Elevated platelet count in absence of other

causes. • Normal red blood cell mass. • Absence of Philadelphia chromosome.

Symptoms and Signs Median age: 50-60 years, slightly increased

incidence in women. Finding of an elevated platelet count. First sign is thrombosis. Venous thromboses may

occur in unusual sites such as the mesenteric, hepatic, or portal vein.

Some patients experience erythromelalgia(painful burning and erythema)

Bleeding Splenomegaly is present in at least 25% of patients.

Laboratory Findings Elevated platelet count is the hallmark of this disorder, and

may be over 2,000,000/uL. WBC mildly elevated (not above 30,000/uL), but with some

immature myeloid forms. The hematocrit is normal. The peripheral blood smear reveals large platelets, but giant

degranulated forms seen in myelofibrosis are not observed. Red blood cell morphology is normal. The bleeding time is prolonged in 20% of patients. The bone marrow : increased megakaryocytes but no other

morphologic abnormalities. The Philadelphia chromosome is absent to differentiate from

chronic myeloid leukemia.

Differensial DiagnosisLaboratory features of myeloproliferative disorders.  WhiteCount Hematocrit Platelet Count Red cellMorphology Chronic myeloid leukemia I N N or I N Myelofibrosis N or D or I N or I D or N or I Abn Polycythemia vera N or I I N or I N Essential thrombocytosis N or I N I N

Treatment Standard therapy has consisted of hydroxyurea in a

dose of 0.5-2 g/d. Anagrelide is highly effective in a dose of 2-4 mg/d

but may cause headache, mild anemia, and peripheral edema, and in high doses congestive heart failure.

Vasomotor symptoms such as erythromelalgia and paresthesias respond rapidly to aspirin and eventually to control of the platelet count.

Plateletpheresis.

Prognosis Essential thrombocytosis is an indolent disorder Average survival is longer than 15 years from

diagnosis The major source of morbidity — thrombosis — can

be reduced by appropriate platelet control. The bone marrow may become fibrotic, and massive

splenomegaly may occur, sometimes with splenic infarction.

There is a 10-15% risk of progression to myelofibrosis after 15 years, and a 1-5% risk of transformation to acute leukemia over 20 year

IDIOPATHIC (AUTOIMMUNE) THROMBOCYTOPENIC PURPURA

Essentials of Diagnosis • Isolated thrombocytopenia. • Other hematopoietic cell lines normal. • No systemic illness. • Spleen not palpable. • Normal bone marrow with normal or increased

megakaryocytes.

Patophysiology ITP: autoimmune disorder in which an IgG

autoantibody is formed that binds to platelets. Platelets are not destroyed by direct lysis. Destruction takes place in the spleen, where

splenic macrophages with Fc receptors bind to antibody-coated platelets.

Splenectomy is highly effective therapy.

Symptoms and Signs ITP commonly in childhood Precipitated by viral infection and usually self-limited. Adult form is usually a chronic disease and only infrequently

follows a viral infection. Incidence between ages 20 and 50 years, and there is a 2:1

female predominance. Presenting complaint is mucosal or skin bleeding (epistaxis,

oral bleeding, menorrhagia, purpura, and petechiae). An enlarged spleen should lead one to doubt the diagnosis.

Laboratory Findings The hallmark of the disease is thrombocytopenia, with

platelet counts that may be less than 10,000/uL. Other counts are usually normal except for occasional mild

anemia, which can be explained by bleeding or associated hemolysis (Evans's syndrome).

Peripheral blood cell morphology is normal except that platelets are slightly enlarged (megathrombocytes).

The bone marrow will appear normal, with a normal or increased number of megakaryocytes.

Coagulation studies will be entirely normal.

Differensial DiagnosisCauses of thrombocytopenia. Bone marrow disorders1. Aplastic anemia2. Hematologic malignancies3. Myelodysplasia4. Megaloblastic anemia5. Chronic alcoholism Nonmarrow disorders1. Immune disorders2. Idiopathic thrombocytopenic purpura3. Drug-induced4. Secondary (CLL, SLE)15. Posttransfusion purpura6. Hypersplenism7. Disseminated intravascular coagulation8. Thrombotic thrombocytopenic purpura9. Hemolytic-uremic syndrome10. Sepsis11. Hemangiomas12. Viral infections, AIDS13. Liver failure14. 1CLL = chronic lymphocytic leukemia; SLE = systemic lupus erythematosus.

Treatment Initial treatment is with prednisone, 1-2 mg/kg/d. Prednisone works

primarily by decreasing the affinity of splenic macrophages, reduces the binding of antibody to the platelet surface, decrease antibody production, enhanced vascular stability.

the risk of bleeding is small with platelet counts above 50,000/uL. An alternative steroid regimen is the use of high-dose dexamethasone, 40

mg/d for 4 days. Splenectomy is the most definitive treatment for idiopathic

thrombocytopenic purpura, Splenectomy is indicated if patients do not respond to prednisone. Splenectomy can be performed safely even with platelet counts less than 10,000/uL. CR 80%

Treatment High-dose intravenous immunoglobulin, 1 g/kg for 1

or 2 days, is highly effective in rapidly raising the platelet count. Use for bleeding emergencies or situations.

Danazol, vincristine, azathioprine, cyclosporine, and cyclophosphamide. Rituximab can produce good responses in some patients with refractory disease.

Platelet transfusions are rarely used in the treatment of idiopathic thrombocytopenic purpura,

Prognosis The prognosis for remission is good. The major concern during the initial phases is

cerebral hemorrhage, which becomes a risk when the platelet count is less than 5000/uL.

Very low platelet counts caused fatal bleeding is rare.

THROMBOTIC THROMBOCYTOPENIC PURPURA

Essentials of Diagnosis • Thrombocytopenia. • Microangiopathic hemolytic anemia. • Neurologic and renal abnormalities, fever. • Reduced level of ADAMTS13. • Normal coagulation tests. • Elevated serum LDH.

Introducing TTP is an uncommon syndrome with microangiopathic hemolytic

anemia, thrombocytopenia, and a markedly elevated serum LDH. Deficiency of a von Willebrand factor-cleaving protease, ADAMTS13,

to platelet agglutination and adhesion to endothelium. TTP is seen primarily in young adults between ages 20 and 50 years,

female predominance. The syndrome is occasionally precipitated by estrogen use, pregnancy,

drugs, or infections. The most common drugs implicated are quinine and ticlopidine.

The syndrome may also occur as a complication of bone marrow transplantation or the use of cyclosporine or tacrolimus. Familial cases occur, but are rare.

Symptoms and Signs

Anemia, bleeding, or neurologic abnormalities. Neurologic symptoms include headache, confusion, aphasia, and alterations in consciousness from lethargy to coma. With more advanced disease, hemiparesis and seizures may occur.

On examination, the patient appears acutely ill and is usually febrile. Pallor, purpura, petechiae, and signs of neurologic dysfunction may be detected. Patients may have abdominal pain and tenderness due to pancreatitis.

Differential Diagnosis

The normal values of coagulation tests differentiate TTP from DIC. Other conditions causing microangiopathic hemolysis (Table 13-18) should be excluded. Evans's syndrome is the combination of autoimmune thrombocytopenia and autoimmune hemol

Laboratory Findings Anemia Reticulocytosis and circulating nucleated red blood cells. The hallmark is a microangiopathic blood picture with fragmented red blood cells Thrombocytopenia is invariably present and may be severe. Increasing indirect bilirubin LDH is markedly elevated in proportion to the severity of hemolysis; Coombs test is negative. Coagulation tests (prothrombin time, partial thromboplastin time, fibrinogen) are

normal unless ischemic tissue damage causes secondary disseminated intravascular coagulation

(DIC) present elevated fibrin degradation products may be seen. ADAMTS13 is usually absent during active disease. Pathologically, there may be thrombi in capillaries and small arteries, with no

evidence of inflammation.

Differensial Diagnosis Evans's syndrome is the combination of autoimmune

thrombocytopenia and autoimmune hemolytic anemia, but the peripheral smear will show spherocytes and not red blood cell fragments.

TTP and hemolytic-uremic syndrome are not distinct disease entities, TTP characterized by more neurologic and severe thrombocytopenia and hemolytic-uremic syndrome with more renal failure.

Treatment Plasmapheresis. 60 to 80 mL/kg of plasma should be

removed and replaced with fresh-frozen plasma. Treatment should be continued daily until the patient is in

complete remission. Prednisone and antiplatelet agents (aspirin [325 mg three

times daily] and dipyridamole [75 mg three times daily]) The combination of splenectomy, corticosteroids, and dextran

has been used with success. Splenectomy performed in remission may prevent subsequent

relapses. Immunosuppression with drugs such as cyclophosphamide

has also been effective.

Prognosis With plasmapheresis, 80 to 90 percent of

patients now recover completely. Neurologic abnormalities are almost always

completely reversed. Most complete responses are durable, but in

20% of cases the disease will be chronic and relapsing.