-SILENT CARRIER STATE ( ___, alpha / alpha, alpha): Characterized by deletion of a single alpha-globin gene and barely detectable reduction in alpha-globin chain synthesis. Because these individuals have three normal genes, they are completely asymptomatic and do not have anemia.
-ALPHA THAL TRAIT ( ____, _____ / alpha, alpha) or ( ____ , alpha / ____ , alpha): Characterized by deletion of two alpha-globin with both deletions occurring on the same chromosome ( ___ , ___ / alpha, alpha) or one deletion occurring on each chromosome 16 ( ___ , alpha / ___ , alpha). Both genetic patterns produce similar, mild deficiencies in alpha chain synthesis and are therefore clinically identical with minimal anemia and no abnormal physical signs.
-HEMOGLOBIN H DISEASE ( ___ , ___ / ___ , alpha): Associated with the deletion of three of the four alpha genes and mainly seen in in Asian populations. Synthesis of alpha chains markedly reduced with excess beta chains forming tetramers called hemoglobin H (HgH). HgH may be oxidized and visualized as red cell inclusions in peripheral blood smears. Because HgH is unable to withstand oxidative stress, it forms precipitates in the red cell which are then removed by the spleen resulting in a moderately severe anemia.
-HYDROPS FETALIS ( ___ , ___ / ___ , ___ ): Most severe form resulting from deletion of all four alpha-globin genes. In the fetus, excess gamma chains (HgF chains) form tetramers called hemoglobin Bart's (HgB). HgB has extremely high oxygen affinity and is therefore unable to deliver O2 to tissues with severe anoxia resulting in intrauterine fetal death.
SUBTYPES:Based on origin of leukemic lymphoblasts (T vs. B cell) and stage of differentiation with classification performed by detecting the presence or absence of surface and cytoplasmic antigen expression by lymphoblasts.
1. Precursor B lympoblastic leukemia : CD19+ (B cell antigen), CD10+, TdT+; cytoplasmic Ig-, surface Ig-
2. Precursor T lymphoblastic leukemia: CD2,3,4,5,7or 8 +(T cell markers), TdT +; CD19, ctyo and surface Ig-
Morphologic / Immunologic Summary
- Most childhood ALL is presursor B-cell type
- Adult ALL does occur and has a much worse prognosis
- Morphology does not predict immnophenotype, therefore immunophenotyping studies critical in diagnosis / prognosis
Based on morphology alone, lymphoblasts and myeloblasts can appear identical; however, through the use of enzyme histochemistry and immunophenotyping, distinguishing between the two can usually be achieved. Differentiating between the two is of vital importance in terms of therapeutic and prognostic implications!
Morphology -cytoplasmic granules, Auer rods, multiple nucleoli
Enzymes - MPO+, TdT-
Phenotype-CD19, Ig and TdT-/
CD 13, 15, 33 (myeloid markers)+
Morphology - no granules, no Auer rods
Enzymes - MPO-, TdT+
Phenotype-B cell: CD19+
Tcell:CD2, 3, 5, + CD 13-, 15-, 33-
PRIMARY HEMOSTASIS defects result in an inability to form a platelet plug in a timely fashion. Therefore, bleeding cannot easily be arrested, resulting in a prolonged bleeding after a blood vessel is damaged. This is where the Bleeding Time becomes a useful tool - as it will be prolonged with abnormalities of primary hemostasis. In addition to this prolonged bleeding, these patients also suffer from easy bruising and mucosal bleeding, such as epistaxis (nose bleeds), menorrhagia (excessive menstrual bleeding), metrorrhagia (uterine bleeding between periods), hematuria, and hematochezia (frank blood in stool). Primary hemostasis requires normal subendothelium, vWF and platelets.
SECONDARY HEMOSTASIS defects result in an inability to stabilize the platelet plug formed during primary hemostasis. Therefore, although bleeding may be initially arrested by the formation of a normal platelet plug, this unstabilized plug may "wash" away - resulting in "delayed" bleeding of 1-2 days after the initial blood vessel damage. Typically, these patients present with bleeds into joints or large muscle masses.
-normal 50-150%, mild 6-30%: easy bruising, moderately excessive bleeding after trauma, serious bleeding with surgery/dental extractions, little difficulty with daily living, Musculoskeletal deformities are rare.
- moderate 2-5%, severe 1%: repeated spontaneous bleeds throughout life - especially into joints and muscles, resulting in crippling deformities(atrophied muscles, contracted tendons, fixed joints), intracranial bleeds may be life-threatening (account for 25% of all deaths).
Increased thrombogenic factors
-Stasis - extended travel, post-op, cast
-Damage to the vessel wall - vasculitis, atherosclerosis, malignancy
-Stimulation of platelets - vascular disease, prosthetic heart valve, DM
-Activation of blood coagulation - malignancy, pregnancy, hormone therapies
Decreased protective mechanisms
-Deficiency of coagulation factor inhibitors (ATIII, PC, PS)
-Decreased catabolism by liver
An inherited abnormality is suggested by the following:
-Strong family history
-Onset of thrombosis at a young age (<30)
-Two or more recurrences
-Absence of predisposing factors
-Thrombosis at unusual sites (mesenteric, subclavian, retinal vessels)
This test screens for abnormalities in the reactions of primary hemostasis (formation of the platelet plug). This is mostly independent of the plasma coagulation reactions (secondary hemostasis). While a blood pressure cuff is maintained at 40 mmHg, a standardized incision is made in the forearm. The excess blood is gently blotted away, and the time to cessation of blood flow is recorded. This is a very crude test, which is subject to many variables - contributed by both the technologist and the patient. This is also one of the most misused (abused) and misunderstood tests that the laboratory offers. In particular, it is frequently (mis)used to predict the potential for bleeding in a patient about to undergo surgery or an invasive procedure. There is a large body of literature which does not support the use of the bleeding time in this clinical setting. The best predictor of whether a patient will suffer excessive bleeding during a procedure, is an adequate patient HISTORY! In a patient with no personal or family history of excessive bleeding, the BT is close to worthless as a predictor of such an event. This is a classic example of applying a SCREENING test to the GENERAL population, as opposed to a SELECTED population, such as those with a positive bleeding history. In the former, this test loses its predictive value.
The following are amongst the more accepted uses of the bleeding time:
-As part of the evaluation of a patient with a SUSPECTED bleeding disorder.
-Evaluating the response to therapy - DDAVP in vWD, dialysis in a uremic patient.
6th EditionDavid L Nelson, Michael M. Cox
5th EditionCharlotte W. Pratt, Donald Voet, Judith G. Voet
5th EditionCharlotte W. Pratt, Donald Voet, Judith G. Voet
10th EditionCain, Campbell, Minorsky, Reece, Urry, Wasserman