Aspirin cures erythromelalgia and cerebrovascular disturbances in JAK2-thrombocythemia through platelet-cycloxygenase inhibition

Table 1 The 1980 Rotterdam Clinical and Pathological criteria for essential thrombocythemia and polycythemia vera

The 1980 RCP criteria for prefibrotic ET[37,52]
Major criteria
A1	Persistent platelet count in excess of 400 × 109/L
A2	Increase and clustering of enlarged megakaryocytes in bone marrow biopsy
A3	No or slight increase of reticulin fibers (RF 0 or RF 1)
Confirmative criteria
B1	Presence of large platelets in a peripheral blood smear
B3	No or slight splenomegaly on ultrasound sonography (length diameter normal value < 12 cm)
B4	Increase of LAP-score and no signs of fever or inflammation
Exclusion criterion
Ph+ chromosome and any other cytogenetic abnormality in blood or bone marrow nucleated cells
The 1980 RCP criteria for prefibrotic PV to replace the crude 1975 PVSG criteria for PV
Major
A1	The combination of erythrocyte count of > 6 × 1012/L and bone marrow hypercellularity due to EM or EMG hyperproliferation is pathognomonic diagnostic for PV (Dameshek and Henthel[27] 1940, Dameshek[38] 1950, Kurnike et al[39] 1972) obviating the need to measure raised red cell mass
A2	Increase in bone marrow biopsy of clustered, enlarged pleomorphic megakaryocytes with hyperlobulated nuclei and moderate to marked increase cellularity of megakaryopoiesis/erythropoiesis or typically trilinear mega-erythro-granulopoiesis (EMG). Such a typical PV bone marrow picture excludes all variant of primary and secondary erythrocytosis[37-39]
Minor
B1	Thrombocythemia, persistant increase of platelet > 400 × 109/L
B2	Leukocytosis, leucocyte count > 109/L and low erythrocyte sedimentation rate
B3	Raised leukocyte alkaline phosphatase score > 100, absence of fever or infection
B4	Splenomegaly on ultrasound sonography
A1 + A2 establish PV and exclude erythrocytosis. One or more of B confirm PV

RCP: Rotterdam Clinical and Pathological; ET: Essential thrombocythemia; PV: Polycythemia vera; EM: Erythrocythic megakaryocytic; EMG: Erythrocytic megakaryocytic granulocytic.

Table 2 Localization of erythromelalgia in feet/toes vs fingers and skin, and the presence of peripheral gangrene and history of acute coronary syndrome or migraine-like cerebral ischemic attacks, and time lap between first manifestations of erythromelalgia and diagnosis of thrombocythemia in essential thrombocythemia (n = 11) and polycythemia vera (n = 13)

Patient	Diagnosis	Feet toes	Fingers	Skin	PG	ACS	MIAs	Time lap (mo)
1	ET	Bilateral		Present	Yes	Yes	Yes	45
2	ET	Bilateral			Yes		Yes	154
3	ET							60
4	ET	Unilateral			Yes	Yes		12
5	ET	Unilateral	Unilateral	Present	Yes			4
6	ET					Yes	Yes	20
7	ET						Yes	60
8	ET							30
9	ET	Bilateral			Yes			20
10	ET	Bilateral	Bilateral	Present	Yes			30
11	ET	Bilateral		Present				30
12	PV	Unilateral						24
13	PV	Unilataral						3
14	PV	Bilataral						0
15	PV		Unilateral	Present	Yes	Yes		36
16	PV	Bilateral					Yes	48
17	PV	Unilateral						1
18	PV	Bilateral					Yes	18
19	PV		Bilateral					2
20	PV	Bilataral			Yes			24
21	PV	Unilateral						4
22	PV	Unilateral		Present				3
23	PV	Unilateral	Unilateral					24
24	PV		Unilateral					6

PG: Peripheral gangrene; ACS: Acute coronary syndrome; ET: Essential thrombocythemia; PV: Polycythemia vera; MIAs: Migraine-like cerebral ischemic attacks.

Table 3 Results of ⁵¹Cr autologous platelet survival studies in 4 controls (Group I), in 3 cases of thrombocytosis in chronic myeloid leukemia and 3 cases of reactive thrombocytosis (Group II), in 6 cases of asymptomatic thrombocythemia in essential thrombocythemia, myelofibrosis and polycythemia vera (Group III), and in 8 cases of thrombocythemia in essential thrombocythemia, myelofibrosis and polycythemia vera complicated by erythromelalgia (Group IV)

Patient group	Diagnosis	Platelet, × 10/L	E	T1/2 (d)	Mean life span	Maximal life span
I	210		No	3.6	5.4	9.9
	181		No	4.2	9.0	9.1
	193		No	3.9	7.1	7.8
	138		No	3.7	6.0	8.8
Mean	180			3.9	6.9	8.9
II	722	CML	No	4.0	8.6	8.2
	1487	CML	No	3.9	7.6	7.3
	2244	CML	No	4.0	7.4	7.7
	1015	RT	No	4.0	6.7	8.7
	736	RT	No	4.0	6.6	7.8
	866	RT	No	4.9	9.7	9.2
Mean	1178			4.1	7.9	8.2
III	1722	ET	No	3.4	5.9	6.8
	1167	ET	No	3.0	4.6	7.3
	511	MF	No	3.1	4.5	8.8
	935	PV	No	3.8	6.2	9.0
	506	PV	No	3.5	5.8	8.8
	614	PV	No	3.3	5.7	7.5
Mean	918			3.3	5.4	8.0
IV	666	ET	Yes	2.1	2.9	6.4
	637	ET	Yes	2.6	4.0	6.8
	1018	ET	Yes	2.7	4.2	7.2
	539	MF	Yes	1.8	2.6	6.1
	489	PV	Yes	2.7	4.0	7.9
	1028	PV	Yes	2.5	1.7	7.3
	1036	PV	Yes	2.0	3.4	5.6
	1180	PV	Yes	3.1	6.0	5.8
Mean	824			2.4	3.6	6.6

CML: Chronic myeloid leukemia; RT: Reactive thrombocytosis; ET: Essential thrombocythemia; PV: Polycythemia vera; MF: Myelofibrosis.

Table 4 2017 Clinical, Laboratory, Molecular and Pathobiological classification and staging of JAK2V617F trilinear Myeloproliferative Neoplasms: Therapeutic Implications

PV: CLMP stage	0	1	2	3	4	5	6
Clinical Diagnosis	Prodromal PV	Erythrocythemia	Early PV	Classical PV	Masked advanced PV	Inapparent PV: IPV → Spent phase	Post-PV MF
LAP-score, CD11B	↑	↑	↑	↑	↑/↑↑	↑	Variable
EEC	+	+	+	+	+	+	+
Red CELL MASS	N	N	↑	↑/↑↑	↑/↑↑	↑ N or ↓	Variable
Erythrocytes × 1012/L	< 5.8	> 5.8	> 5.8	> 5.8	N	N	↓
Leukocytes × 109/L	< 12	< 12	< or > 12	< or-> 15	> 15	N or ↑	> 20
Platelets × 109/L	> 400	400	< or > 400	> 400	+1000	N or ↑	Variable
Bone marrow histology	EM	EM	EM	EMG	EMG	MG-MF	MF
BM cellularity (%)	50-80	50-80	60-100	80-100	80-100	60-100	↓
Grading RF	RF 0-1	RF 0-1	RF 0-1	RF 0/1	RCF2/3	RCF 2/3	RCF 3/4
Grading MF57	MF 0	MF 0	MF 0	MF 0	MF 1 2	MF 1 2	MF 2/3
Spleen size:
On echogram	< 12-15	< 13	12-15	12-16	18- > 20	16 > 20	> 20 cm
Below MCL	0-3	NP	0-3	4-6	> 6	> 6	> 8 cm
JAK2V617F load	Low +(++)	low +(++)	Moderate < 50% +	Mod/High + / ++	High > 50% ++	High → 50% ++	High → 50% ++
Granulocytes %
Risk stratification → Therapeutic implications according to guidelines	Low	Low	Low	Inter- mediate	High early MF	JAK2 inhibitor	Post-PV MF
			Moderate

Source Michiels et al[68,70,80] 2006, 2017. ↑: Increased; ↓: Decreased; N: Normal; +: Present or heterozygous; ++: Homozygous; RCT: Randomized clinical trial; ET: Essential thrombocythemia; PV: Polycythemia vera.