NEW SYNDROME COMPLICATING SICKLE DISEASE Akram Al-Hilali 2008 08/14/14
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COMPLICATIONS OF SCD Vaso-occlusive crises Chronic chest syndrome Acute splenic sequestration Aplastic crises Septicemias secondary to hyposplenism
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VASO-OCCLUSIVE CRISES Any body site can be affected. Bones are amongst such sites. Long bones are more likely to be affected than flat bones. Bone necrosis in the affected spot with infarction of the bone marrow in the vicinity, if there is bone marrow.
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BONE VOC’S Mostly in long bones. Marrow supplied by the same arteriole as the infarcted bone will undergo infarction. There may be only fatty marrow in the affected bone. Peripheral blood counts do not drop as a result of such localized infarctions, because the rest of the marrow is active.
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BONE VOC’S- Cont’d If anything, there will be neutrophil leukocytosis and thrombocytosis, like with any other VOC. Reticulocyte count is usually not affected. It is basically high and continues to be high. This is the result of compensatory expansion of the unaffected marrow.
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PRESENTATION OF A NEW SYNDROME Haematologists occasionally receive a sickler with pancytopenia, ill-health and vague bone pains They usually consider the case as VOC. Aplastic crisis is ruled out, because the presentation is not of anaemia alone. Splenic sequestration is sometimes considered in very young children. Patient usually recovers with supportive care. 08/14/14
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UNIQUE FINDINGS USUALLY MISSED
Spleen is not enlarged. It is usually smaller than normal.This is against Splenic sequestration. Anaemia is accompanied by thrombocytopenia and neutropenia. Both are unusual in SCD. This is not like red cell aplasia caused by Parvovirus B19. Retics are almost zero, like in aplasia. Bilirubin is lower than the usually high level of SCD Pains are not pin pointed as in VOC.
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DIAGNOSTIC FEATURES ď Ž
ď Ž
Bone marrow is not usually done for the sickler, unless there is unusual drop in Hb and retics with normal or high platelets and leukocyte counts, with aplastic crisis in mind. If checked, marrow would not be hypoplastic. It is as hyperplastic as any marrow in SCD. However, there would be massive and generalized infarctions. Posterior iliac spine is the usual site for sampling, but its picture represents a general phenomenon.
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DIAGNOSTIC FEATURES-Cont’d
Necrotic marrow elements of all series are seen in aspirate smears. Marrow sections are not fatty, but vast areas are filled with “ghost” cells, scattered stained nuclei and some fibroblasts. Megakaryocytes and erythroblasts with karyorrhexis are common. In peripheral blood ghost cells and necrotic cells may be seen.
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CASE PRESENTATIONS Three cases were encountered in less than a year in one hospital. Age range 14-48 years. One had chemotherapy for cancer prior to the episode. He recovered from it and then developed the condition. Pancytopenia with repeated need for transfusion due to persistent drop in Hb.
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CASE # 1 21 year-old man: Pyrexia, pancytopenia, low retic count and drop in a usually high serum bilirubin. High dimers and abnormal coagulation Sepsis, but not the clinical condition of VOC. Bone marrow is fully necrotic. Few erythroid precursors spared.
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Laboratory results during the crises Table 1 Laboratory results during the episode of generalized Bone Marrow Necrosis (GBMN), compared to mean baseline results. Parameter Patient # 1
Patient # 2
Patient # 3
Baseline *
At GBMN**
Baseline*
At GBMN**
Baseline*
At GBMN**
Hb (g/dl)
8.5-10
7
8.2-9
3
>9.3
7.4
Neut
2.2-15
0.8
2-12
0.8
3-11.9
1.85
Mono
0.4-2.4
0
0.4-2.6
0
0.31-0.7
0.18
Plat
150-620
10
540-760
<10
154-343
20
Retic %
5-9
1.4
6
5+
3.7-5.7
1.16
T.Bil
17-70
9
120-325
15
21-70
16
PT
12.4-13.3
29.4
13
54
12.3-15.5
21.6
INR
1.08-1.15
2.56
1.0
4.5
1.03-1.3
1.75
PTT
30-41
48.6
35-40
84
29.9-48
105
DD
619
ND
ND
>4948
451
>4948
Legend: N: Neutrophil count (X10 9/L) M: Monocyte count (X10 9/L) Plat: Platelet count (X10 9/L) Retic: % reticulocytes T.Bil:Total serum bilirubin (u mol/L) PT: Prothrombin Time in seconds PTT: Partial thromboplastin time in seconds DD: D-dimers ug/ml GBMN: generalized bone marrow necrosis. * Range of results in 6 months preceding episode ** Trough or peak value *** Patient had low results earlier, when on chemotherapy
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CASE # 2
14 year-old boy: presented with weakness and showed pancytopenia, drop in bilirubin, grossly abnormal coagulation and very high dimers. Hb 3 g/dl. No features of VOC. Necrotic marrow cells and bone trabeculae. A week later blood counts were recovering and a second marrow was taken, which showed recovery signs and new vital bone being laid at the edges of trabeculae. Rebound rise in counts after recovery.
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Laboratory results during the crises Table 1 Laboratory results during the episode of generalized Bone Marrow Necrosis (GBMN), compared to mean baseline results. Parameter Patient # 1
Patient # 2
Patient # 3
Baseline *
At GBMN**
Baseline*
At GBMN**
Baseline*
At GBMN**
Hb (g/dl)
8.5-10
7
8.2-9
3
>9.3
7.4
Neut
2.2-15
0.8
2-12
0.8
3-11.9
1.85
Mono
0.4-2.4
0
0.4-2.6
0
0.31-0.7
0.18
Plat
150-620
10
540-760
<10
154-343
20
Retic %
5-9
1.4
6
5+
3.7-5.7
1.16
T.Bil
17-70
9
120-325
15
21-70
16
PT
12.4-13.3
29.4
13
54
12.3-15.5
21.6
INR
1.08-1.15
2.56
1.0
4.5
1.03-1.3
1.75
PTT
30-41
48.6
35-40
84
29.9-48
105
DD
619
ND
ND
>4948
451
>4948
Legend: N: Neutrophil count (X10 9/L) M: Monocyte count (X10 9/L) Plat: Platelet count (X10 9/L) Retic: % reticulocytes T.Bil:Total serum bilirubin (u mol/L) PT: Prothrombin Time in seconds PTT: Partial thromboplastin time in seconds DD: D-dimers ug/ml GBMN: generalized bone marrow necrosis. * Range of results in 6 months preceding episode ** Trough or peak value *** Patient had low results earlier, when on chemotherapy
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CASE # 3
48 year-old man: A case of sickle-beta thal combination. Generalized aches. Pancytopenia. No retics. Abnormal coagulation and very high dimers. Bilirubin was lower than usual for him. Patient had colorectal carcinoma and received chemotherapy (5FU) two courses. The second course was given 22 days prior to date of marrow taken. Thrombocytopenia started 5 days before marrow was taken and after complete recovery from chemo effect. Massive marrow necrosis., but was in process of recovery when tested. Counts recovered in 4 weeks.
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Laboratory results during the crises Table 1 Laboratory results during the episode of generalized Bone Marrow Necrosis (GBMN), compared to mean baseline results. Parameter Patient # 1
Patient # 2
Patient # 3
Baseline *
At GBMN**
Baseline*
At GBMN**
Baseline*
At GBMN**
Hb (g/dl)
8.5-10
7
8.2-9
3
>9.3
7.4
Neut
2.2-15
0.8
2-12
0.8
3-11.9
1.85
Mono
0.4-2.4
0
0.4-2.6
0
0.31-0.7
0.18
Plat
150-620
10
540-760
<10
154-343
20
Retic %
5-9
1.4
6
5+
3.7-5.7
1.16
T.Bil
17-70
9
120-325
15
21-70
16
PT
12.4-13.3
29.4
13
54
12.3-15.5
21.6
INR
1.08-1.15
2.56
1.0
4.5
1.03-1.3
1.75
PTT
30-41
48.6
35-40
84
29.9-48
105
DD
619
ND
ND
>4948
451
>4948
Legend: N: Neutrophil count (X10 9/L) M: Monocyte count (X10 9/L) Plat: Platelet count (X10 9/L) Retic: % reticulocytes T.Bil:Total serum bilirubin (u mol/L) PT: Prothrombin Time in seconds PTT: Partial thromboplastin time in seconds DD: D-dimers ug/ml GBMN: generalized bone marrow necrosis. * Range of results in 6 months preceding episode ** Trough or peak value *** Patient had low results earlier, when on chemotherapy
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POSSIBLE PATHOGENESIS
Bone marrow is very vascular, especially so in sicklers. Vessels to marrow pass through bone. Obliteration of vessels leaves marrow completely deprived of supply. A DIC may have set in prior to the GBMN and caused generalized compromise of blood supply to bone marrow. A mild DIC is always going on in sickle, more pronounced in VOC. A severe DIC in sicklers with already stretched marrow with simultaneous closure of large number of capillaries and arterioles may have precipitated the condition.
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MANAGEMENT Basically, management was supportive, till the episodes were over. ď Ž The three patients survived the attack through blood and platelet transfusion. ď Ž
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DISCUSSION
GBMN seems a well defined and unique complication of SCD. It is clearly not a localized VOC in bone. Localized bone VOC’s are well known and involve bone marrow, if present in the area. They occur more in long bones than in spongy bone. In such cases, there is no pancytopenia. If anything, there will be reactive thrombocytosis and neutrophil leukocytosis.
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DISCUSSION
Even if we suggest multiple VOC’s the findings do not fit. It is not a splenic sequestration, as there is no splenomegaly in adult sicklers. The bone marrow necrosis is quite evident. Biopsies have not been taken from a site that was specifically painful. The outcome: peripheral pancytopenia, indicates that necrosis in spot we are examining exists all over the marrow.
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GBMN is overlooked because we do not consider the possibility and so, do not examine the bone marrow to witness it. 08/14/14
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