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1. An Approach to a Patient with Thrombocytopenia Dr. Amina Nur
Nova Resident Internal Medicine BSMMU
2. Process of Hemostasis Vascular injury Serotonin and
thromboxane A2 (TxA2) for vasoconstriction Exposure of basement
membrane and collagen (negatively charged surface) Platelet
adhesion and activation Platelet aggregation (1o homeostatic plug)
Fibrin formation via coagulation cascade (2o homeostasis) Clot
retraction Fibrinolysis and healing
3. Normal Physiology of Platelets Platelets are normally made
in the bone marrow from progenitor cells known as megakaryocytes.
Normal platelet lifespan is 10d. Every day, 1/10 of platelet pool
is replenished. Normal platelet count is between 150,000 and
450,000/mm3 Contain intracellular granules ( and ) that contain
coagulation factors and ADP Production stimulated by thrombopoietin
from liver/kidney
4. Young versus old platelets The youngest platelets in the
circulation are larger and appear to be more hemostatically active.
Thrombocytopenic patients with immune thrombocytopenia (ITP) do not
usually have serious bleeding. The small numbers of young platelets
in these patients are more hemostatically active than mixed age
platelets in normal subjects. Patients with ITP also appear to have
less bleeding than patients with similar severities of
thrombocytopenia caused by marrow failure, such as subjects
following chemotherapy, who also have a population of platelets of
mixed age.
5. Reticulated platelets The youngest platelets in the
circulation contain RNA and have been called reticulated platelets
or the immature platelet fraction (IPF). Normal subjects 1.3
percent Thrombocytopenia with "normal or decreased thrombopoietic
activity" 7.5 percent Thrombocytopenia with "increased platelet
turnover" 30 percent
6. Thrombocytopenia Thrombocytopenia is defined as a platelet
count less than 150,000/microL (150 x 10 9 /L). 2.5 percent of the
normal population will have a platelet count lower than this. A
recent fall in the platelet count by one-half, while still in the
normal range, may herald severe clinical problems and requires
active follow-up.
7. How low is too low? 150,000 - 50,000: no symptoms 50,000 -
20,000: first symptoms 20,000-10,000: potentially life-threatening
50% decrease in platelet count or total platelet< 1,00,000/cumm,
while the patient is on heparin. Rare(1-3 %) Median Platelet count
50,000-80000. Rarely below 20000/cumm. Clinical manifestations may
include venous or arterial thrombosis, necrotic skin lesions at
heparin injection sites, or acute systemic reactions subsequent to
IV heparin bolus administration.
25. Two types of HIT have been described. Type 1 HIT is a
modest transient decrease in platelet counts. occurs within the
first 2 to 3 days after heparin initiation. returns to normal
spontaneously, even with continuation of heparin. It is generally
of no clinical significance.
26. Type 2 HIT less common, seen in about 0.3 to 5% of patients
treated with unfractionated heparin. caused by antibodies against
platelet factor 4-heparin complex. usually occurs 4 to 14 days
after heparin initiation, but may occur earlier in patients with
prior exposure to heparin.
27. Mechanism of HIT
28. Mechanism of HIT The antibodies bind to the PF4- heparin
complexes on the platelet surface induce platelet activation by
cross- linking FcIIA receptors. The activated platelets increase
the release and surface expression of PF4, creating a positive
feedback loop in which further release of PF4 promotes further
platelet activation.
29. Platelet activation results in the release of procoagulant
platelet microparticles, platelet consumption, and
thrombocytopenia. Marked generation of thrombin, activation of
monocytes and other inflammatory cells, and endothelial injury and
activation follow, producing the characteristic venous and arterial
thromboses of HIT.
30. Treatment Treatment consists of stopping heparin and using
alternate anticoagulants like argatroban, lepirudin, bivalirudin.
Fondaparinux is a heparin pentasaccharide analogue that does not
bind to platelet-factor 4 and thus should not cause HIT. Low
molecular weight heparin is not an appropriate anticoagulant in the
setting of HIT because of cross reactivity of the antibody.
Platelet transfusions are relatively contraindicated in the absence
of severe thrombocytopenia with life-threatening hemorrhage
31. Thrombocytopenia in the cardiac patient Several mechanisms
in patients undergoing open heart surgery: Cardiopulmonary bypass
may result in mechanical destruction of platelets, hemodilution in
the bypass circuit, drug-induced platelet destruction. Sepsis,
Post-transfusion purpura. The nadir platelet count is typically
seen on the second or third day after surgery, with a rapid
recovery thereafter. Severe thrombocytopenia is observed in 0.1%-2%
of patients after exposure to GPIIb/IIIa inhibitors (eg, abciximab,
tirofiban, eptifibatide) during percutaneous coronary
intervention.
32. Disseminated Intravascular Coagulation (DIC) DIC is a
consumptive coagulopathy complicating several diseases. It is
characterized by activation of intravascular coagulation with
microvascular thrombi formation, thrombocytopenia, depletion of
clotting factors, variable bleeding complications, and end-organ
damage.
33. Acute DIC Acute DIC is commonly seen in severe sepsis and
septic shock, after trauma (especially neurotrauma), after surgery,
as an obstetric complication (eg, abruptio placentae, amniotic
fluid embolism, and preeclampsia), after ABO- incompatible blood
transfusion, and as a complication of acute promyelocytic leukemia.
Consumptive coagulopathy in these cases is severe and leads to
bleeding manifestations (eg, mucocutaneous bleeding and blood
oozing from wound sites) and frequent organ damage (eg, renal and
hepatic damage).
34. Chronic DIC Chronic DIC is more frequently observed in
solid tumors and in large aortic aneurysms, usually with few
obvious clinical or laboratory indications of the presence of DIC.
In chronic compensated DIC, such as a patient with metastatic
prostate or GI malignancy in whom a slower rate of consumption of
coagulation factors may be balanced by enhanced synthesis. Thus,
patients may have only a modest thrombocytopenia and normal PT and
aPTT. The diagnosis is based on the presence of microangiopathy on
peripheral blood smear and elevated fibrin degradation products
(FDP) and D-dimer levels.
36. Treatment Focus on addressing underlying disorder
Administration of Blood Components and Coagulation Factors platelet
, FFP, cryopricipitate Anticoagulation heparin, protein C. Patients
with DIC should not in general be treated with antifibrinolytic
therapy, e.g. tranexamic acid.
37. Thrombotic Thrombocytopenic Purpura TTP - Diagnostic
Features Microangiopathic Hemolytic Anemia (MAHA) Elevated LDH,
elevated bilirubin Schistocytes on the peripheral smear MUST BE
PRESENT Low platelets - MUST BE PRESENT Fever Neurologic
Manifestations - headache, sleepiness, confusion, stupor, stroke,
coma, seizures Renal Manifestations - hematuria, proteinuria,
elevated creatinine, BUN
38. TTP - etiology An inherited or acquired deficiency (due to
autoantibodies) of von Willebrand factor-cleaving protease known as
ADAMTS13. leads to accumulation of large multimers of VWF which
cause spontaneous platelet aggregation and thrombi. Can be induced
by drugs, including ticlopidine, quinine, cyclosporine, tacrolimus,
mitomycin C. Increased incidence with pregnancy or HIV
39. TTP -lab CBC normal or slightly elevated WBC. Hb is
moderately depressed at 8-9 g/dL. Platelet count ranges from
20,000-50,000 per microliter. PBF : Red blood cells are fragmented
and appear as schistocytes. Certain schistocytes have the
appearance of helmet cells (H). Spheroidal cells often are present
(S). Occasional nucleated erythroid precursors may be present.
40. TTP - Course and Prognosis Treatment relies on Plasma
Exchange. Plasma exchange is superior to plasma infusion, but if
PLEX is delayed, give FFP. Remove all inciting agents. Platelet
transfusions contra-indicated. Multiple case reports of stroke
and/or death during or immediately after platelet transfusion. Can
consider giving if life-threatening hemorrhage is present, but
avoid routine platelet transfusions. Secondary measures if no
response to plasma exchange include splenectomy, vincristine
41. HUS - Hemolytic Uremic Syndrome Usually classified along
with TTP as TTP/HUS Has fewer neurologic sequelae, more renal
manifestations. Usually precipitated by diarrheal illness,
especially E. coli O157:H7 or Shigella Seen more in pediatric
patients, usually has better prognosis. May respond less well to
plasma
42. Thrombocytopenia in pregnancy Platelet counts < 150 X
109/L have been reported in 6%-15% of women at the end of
pregnancy, but counts 100 X 109/L are observed in only 1% of women.
The most common causes of thrombocytopenia are gestational
thrombocytopenia (GT; 70%), preeclampsia (21%), and ITP (3%).
43. Mechanism of GT Accelerated platelet activation in
placental circulation. Accelerated consumption of platelet due to
reduced consumption during pregnancy.
44. Diagnosis no past history of thrombocytopenia (except
during a previous pregnancy) Usually develops in 3rd trimester Mild
thrombocytopenia (>70,000/cumm) Asymptomatic resolve
spontaneously within 1-2 months after delivery. No foetal
complication
45. Treatment no treatment needed, only monitoring. Mode of
delivery considered by physician.
46. Pregnancy induced ITP IgG antibody against membrane
glycoprotein. Ab can cross placenta and cause foetal
thrombocytopenia.
47. Diagnosis Thrombocytopenia in 1st and 2nd trimester.
Persistant thrombocytopenia. Increased number of megakaryocytes in
bone marrow. Disease of exclusion
48. Table. Suggestions for platelet transfusions Platelet
counts below which transfusion should be considered: 10,000/L -
prophylactic transfusion 20,000/L - in the presence of bleeding,
fever, infection, platelet function defect, or coagulopathy
50,000/L - prior to minor procedures, in actively anticoagulated
patients or in the presence of active bleeding 75,000/L - prior to
general surgery 100,000/L - prior to neurologic or ophthalmologic
surgery