INDAH PRATIWI-130110110194-C5 HIS

THROMBOCYTOSISI. DEFENTION : Thrombocytosis is a medical term used to describe an increased number of platelets in your bloodII. NORMAL RANGE : 150.000/µL – (350.000/ µLatau 450.000/ µL)III. ETIOLOGY

IV. PATHOGENESIS 1.Essesntial Trombocytosis

2. Familial trombocytosis : an inherited autosomal dominant mutation

3.Reactive(Secondary) thrombocytosisA. Due to Infection : cytokines (IL-6) -> raised platelet countB. Due to Blood loss : In event of an injury, the response of the bone marrow to blood loss is to produce more red blood cells and more plateletsC. Tissue damage from trauma or surgery : The platelet count will also increase when a relatively large amount of body tissue is damaged either

intentionally following surgery or after an accident. This is part of your natural defence mechanism to ensure adequate clot formation and prevent fatal bleeding.

D. Medicines : Rarely, some medicines (steroids, vincristine) cause a temporary increase in platelet count. These drugs are sometimes used to treat patients with a low platelet count because of idiopathic thrombocytopenic purpura (ITP).

E. Underactive or absent spleen : removes spleen -> low platelet destruction -> platelete count raised. In some conditions the spleen is present but either it does not function properly (for example in some patients with Coeliac disease) or it is shrunken (for example in sickle cell disease). The platelet count is sometimes elevated in these conditions.

F. Malignancy : Some cancers can cause a high platelet count either by causing damage to tissues, causing blood loss (for example from the bowel) or by erroneously producing a response from the immune system that stimulates the bone marrow to produce platelets.

G. Rebound from chemotherapy : Some chemotherapy drugs work directly on dividing cells in the body - including the bone marrow where platelets are made. When the body is recovering from the effects of chemotherapy, a temporary overproduction of some cells can occur

1.Clonalessential (or primary) thrombocythemia

myeloproliferative disorders

2.Familial thrombopoietin mutations

3.Reactivetransient

sustained

Acute blood lossAcute infection, inflammationRecovery ("rebound") from thrombocytopeniaResponse to exercise

Iron defficiency, splenectomy, malignancies

(-) complication(-) require treatment

Primitive multipotent hematopoetic stem cells

Terjadi mutasi in DNA single cell

Causing restricted to diffrentiation restricted to primary into plateletes

Increase Platelete count

TPO TPO-R in platelete surface -> increase TPO plasma deletion

CFU-Meg sensitivity (receptor TPO in megakarocytes) -> increase Megakaryopoesis stimulation

Mutasi pada JAK2 (as intermediate cell membrane receptor) -> cell signalling and activation increase

Mutasi pada gene TPO

Specific mutations in the thrombopoietin gene, including exon skipping and single-nucleotide deletions in the 5'-untranslated region of the gene

mutations represent loss of translational repression and increased efficiency of mRNA translation

elevated plasma thrombopoietin levels

INDAH PRATIWI-130110110194-C5 HIS

V. CLINICAL FEATURES 1. Bleeding and thrombotic complicationRisk factor :

- Bleeding -> due to : 1. Defect in von Willebrand factor -> decrease platelet respone to collagen, ADP, AA 2. Acquired decrease adrenergic receptor -> decrease epineprine stimlate aggregate

-> after minor and superficial trauma (site : mucosal GI tract, Genitourinary tract) -> Use of aspirin, which causes exaggerated prolongations of the bleeding time in patients with myeloproliferative disorders -> may

lead to serious bleeding complications in occasional cases- Thrombosis : Abnormal clotting, occurs in an artery but sometimes occurs in a vein

- Thrombosis complication :

1. Erythromelalgia: Burning or throbbing pain in the feet or hands, sometimes worsened by heat or exercise or when the legs are hanging down for long periods. The skin of the extremities may have a patchy reddish color,caused by diminished blood flow to the toes and fingers (microcirculation).

2. Headache, dizziness, weakness or numbness on one side of the body, slurred speech and other signs of inadequate flow of blood to the brain called “transient ischemic attacks” (TIAs).

3. An enlarged spleen (detected by physical examination or ultrasound imaging). This occurs in about 50 percent of patients.4. Constitutional symptoms like fatigue, weakness, itching, sweating and low-grade fevers, which may be present in advanced cases.

VI. LAB EXAM

Blood finding 1. Count: - Above normal platelete count

- Increased platelet turnover -> increased reticulated platelets (young platelets) in the circulation, which can be detected by flow cytometric analysis of platelet RNA

2. Morphology : large, pale blue staining, hypogranular platelets, and occasional nucleated megakaryocyte fragments that may have a lymphoblastoid appearance

3.Serum TPO : Serum thrombopoietin levels generally are normal or mildly elevated in clonal thrombocytosis and do not correlate with platelet count in these patients

4. Serum IL-6 protein : low or undetectable in clonal thrombocytosis, whereas levels may be elevated in secondary thrombocytosis, which often accompanies acute and chronic inflammatorystates

Bone Marrow finding1. increased cellularity with megakaryocytic hyperplasia. There cells are frequently giant megakaryocytes with increased ploidy that occur in

clusters.Significant dysplasia of the megakaryocytes is unusual, but large masses of platelet debris( platelet drifts") typically are seen in marrow samples

Clinical test of hemostasisThe bleeding time is prolonged in fewer than 20 percent of patients with essential thrombocythemiaDue to : Reduced platelet responses to collagen, adenosine diphosphate, and arachidonic acid occur in less than one third of cases. A characteristic aggregation abnormality is complete loss of platelet responsiveness to epinephrine.

Blood clot (thrombus)Block brain vascularization

Block heart vascularization

Cerebrovascular ischemia

Heart attack

Block placental blood flow recurrent spontaneous abortions, fetal growth retardation, premature deliveries, or abruptio placentae

Occlusion in microvascular erithromelalgia

Hepatic portal vein thromobosis

stroke

dizziness

INDAH PRATIWI-130110110194-C5 HIS

VII. DIFFERENTIAL DIAGNOSISa. Diagnosis criteria for Essential thrombocytosis

Distinction from myoproliferative disorder :1. In Polycythemia vera : finding of erythrocytosis

and an elevated red cell mass2. In CML : (+) cytogenetic or DNA abnormalities

characteristic of CML3. In Myeloid metaplasia and myelofibrosis :

characterized by more marked, frequently massive, splenomegaly, blood film in myelofibrosis typically shows myelophthisic or leukoerythroblastic changes, and the marrow biopsy shows fibrosis

Most importantly, essential thrombocythemia cannot be diagnosed without excluding possible causes of reactive (or secondary) thrombocytosis.

Disctinction from Secondary trombocytosis : reactive thrombocytosis is particularly difficult to distinguish from essential thrombocythemia.

VIII. Therapy1. Medicines that thin the blood (antiplatelete agent)

a. Aspirin : indication : widely used in ET, particularly for symptoms likely to be due to clotting or overactive platelets Side-effects : cause marked prolongation of the bleeding time and unpredictable serious bleeding in some patients with thrombocythemia Caution : only used with caution if you have a platelet count in excess of 1500 million per ml. Similar drug : dipyridamole and clopidogrel, and with warfarin, especially if you have recently had a blood clot in a vein or have had multiple clots.

2. Medicines that reduce the number of platelets in your blood (cytoreduction)a. Hydroxycarbamide: known as hydroxyurea

MoA : interfering with the cell's metabolismIndication : common treatment for ET and usually needs to be taken daily

Monitoring : Your blood count will be monitored at least every two to three months.Side effect : has relatively few side-effects including some darkening of skin pigment, mouth and leg ulcers and rarely stomach

and bowel disturbance. It can damage DNA and may affect fertility, so shouldn't be used by pregnant women or those trying to conceive.

b. Melphalan, busulfan and radioactive phosphorus (32P): these drugs belong to a group medicines called alkylating agents and used to be the main treatment for ET. They reduce cell count by binding to DNA and damaging it, preventing complete separation of the two DNA strands at cell division. This means these medicines can permanently damage fertility and the bone marrow.

c. Interferon-alpha: this is a naturally occurring protein that inhibits the growth of bone marrow cells. It has to be given by injection, usually three times a week.Indication: in some patients with ET, particularly in young people who want to preserve their fertility. It is the only drug used to treat ET that can be safely given to pregnant women.side-effects: including flu-like symptoms, hair loss, depression, liver and thyroid abnormalities

d. Anagrelide: MOA : lowers the platelet count-> reducing the size of the platelet-producing cells within the bone marrow (the megakaryocytes)

Contraindication : cannot be taken in pregnancy because it will cross the placenta and transfer to the baby's blood. Side-effects : headache, palpitations (forceful heart beats) and fluid retention. It must be used with caution in those with heart disease. Anagrelide was better at preventing clots in veins, but these clots are far less common in ET. As a result, anagrelide is licensed for use in

patients where initial drug treatment has failed or is not tolerated.

e. Blood filtering: a sophisticated blood-filtering technique called plateletpheresis is used very rarely and only in acute life-threatening situations. This involves taking the patient's blood into a special machine, removing some of the platelets and returning the blood. It achieves a rapid, but temporary, control of the platelet count.