Myeloproliferative and thrombotic burden and treatment outcome of thrombocythemia and polycythemia patients

Table 3 Incidence of thrombotic and bleeding complications in the prospective 1975-1996 Rotterdam study of 68 ET patients during a median follow-up of 6.7 years according to treatment strategy (Van Genderen et al[4,5] 1997)

Treatmentstrategy	Duration of follow-up person (yr)	Thrombotic events		Bleeding events
		Events (n)	Events/100 person (yr)	Events (n)	Events/100 person (yr)
Asymptomatic 14 patients
Watchful waiting	127	271	33.3	2	1.6
Symptomatic 54 patients
Low-dose aspirin	139	5	3.6	103	7.2
Platelet reduction	113	102	8.9	2	1.8
Low-dose aspirin + platelet reduction	40	0	-	4	10
Total	419	42		18

¹Mean platelet count 610, range 410-831 × 10⁹/L at time of thrombotic event;

²Platelet count 624 ± 255 × 10⁹/L at time of thrombotic event;

³Platelet count 1737, range 661-3460 × 10⁹/L at time of bleeding event. These observations by Van Genderen et al[4,5] confirm the concept in Figure 1 on the relationship between platelet-mediated microvascular thrombosis in thrombocythemia at platelet counts between 350 to 1000 × 10⁹/L in ETT and mucocutaneous bleedings at platelet counts of 1000 to above 2000 × 10⁹/L in HT patients.

Table 1 Incidence of thrombotic events related to age in 100 patients with essential thrombocythemia not on aspirin in the 1990 Bergamo study[11]

Age (yr)	No. of patients	Patient/years	Events number	Events % pt/yr
< 40	34	118	2	1.70%
40-60	37	112	7	6.30%
> 60	29	73	11	15%
Total thrombotic events in 20 of 100 ET patients

ET: Essential thrombocythemia.

Table 2 The type and number of microvascular thrombotic events in the 1990 Bergamo study are very characteristic for untreated thrombocythemia[11]

Cortelazzo et al[11] 1990	No. of patients	No. ofevents
Total	20	32
Arterial	17	25
Digital ischemia		7
Transient ischemic attacks		15
Stroke		0
Myocardial infarction		3
Venous	3	7
Superficial Thrombophlebitis		3
Femoral DVT		1
Unusual localization DVT		3
Bleeding complications	4

DVT: Deep vein thrombosis.

Table 4 Major cardiovascular and venous thrombotic events at diagnosis or during long-term follow-up in 323 polycythemia vera and 639 essential thrombocthemia patients according to the JAK2^V617F mutation status in the retrospective study of Vannucchi (only major thrombotic events were retrospectively recorded excluding the erythromelalgic and migraine like cerebral ischemic events[20])

Patients	PV n = 323		ET n = 625
JAK2V617 mutation status	Hetero homozygous hetero wild type
No. of patients	219	104	368	237
At diagnosis
Major arterial events	21%	15.4%	21.7%	10.5%
Venous events	2.9%	2.9%	7.9%	4.7%
During 10 yr follow-up (not on aspirin)
Major arterial events	10.1%	12.5%	6.3%	5.8%
Venous events	4.1%	7.7%	6.3%	2.7%
Total during life time follow-up
Major arterial	31.1%	27.9%	28%	16.3%
Venous	10.5%	10.6%	14.2%	7.4%

In 14 homozygous ET patients total major arterial and venous events had occurred in 78.6% and 57.1% respectively. PV: Polycythemia vera; ET: Essential thrombocthemia.

Table 5 Top 20 clinical manifestations in patients with who defined myeloproliferative neoplasm essential thrombocythemia, polycythemia vera and myelofibrosis based on the Dutch myeloproliferative neoplasm Questionaire 2009-2010[23]

Symptom	Top 20 MPN complaints	All MPN	MPN	ET	PV	MF
		n = 497	%	%	%	%
1	Fatigue, listless	399	81	80	81	85
2	Microvascular acra37	278	57	61	56	46
3	Cognitive disturbances37	262	53	52	56	45
4	Visual disturbances37	249	51	50	52	46
5	Night sweats	236	48	44	50	52
6	Itching	220	45	30	58	36
7	Dizziness	218	44	44	46	39
8	Bruises, bleedings	211	43	40	45	43
9	Splenomegaly constitutional symptoms	198	40	22	43	78
10	Tinnitus	188	38	38	39	37
11	Migraine headache without visual symptoms	184	37	46	35	22
12	Bone pain	172	35	33	36	34
13	Heart arrythmias	154	31	34	31	24
14	Dysarthria, dyslexia	151	31	31	31	30
15	Hypersensitive to sounds and noices	149	30	29	32	28
16	Paleness	145	29	30	26	40
17	Claudicatio intermittens	140	28	28	30	24
18	Hypersensitive to lights	136	28	25	32	16
19	Visual disturbances without headache	18	33	54	3	90
20	Headache without visual symptoms	24	43	43	4	90

Microvascular acra: Tingling, prickeling sensations, redness,swelling and/or bluish discolouration of footsoles, handpalms, toes and/or fingers³⁷. Cognitive disturbances of concentration and memory and sudden attacks of unconscienceness. Visual disturbances of scintillating scotomas, light flashes, blurred vision, transient monocular blindness, rapid spreading of visual figure disturbances³⁷. Attacks of migraine-like headaches followed by nausea or vomiting or loss of consciencenous or transient paresis of one extermity³⁷. MPN: Myeloproliferative neoplasm; ET: Essential thrombocythemia; PV: Polycythemia vera; MF: Myelofibrosis.

Table 6 Staging of JAK2^V617F positive prodromal polycythemia vera, erythrocythemic polycythemia vera, and five stages of PV according to WHO-ECMP criteria related to therapy anno 2014[10,13,34-37]

PV: WHO-ECMP stage	0	1	2	3	4	5	6
WHO-ECMP clinical diagnosis	Prodromal PV	Erythrocy-themic PV	Early PV	Overt PV Classical PV	PV PMF Masked PV	Post-PV MF Spent PV	Leukemic PV MDS/AL
LAP-score	↑	↑	↑	↑	↑/↑↑	Variable	Variable
Red cell mass	N	↑	↑	↑	↑	Variable	N/↓
Serum EPO	N/↓	N/↓	↓	↓	↓	Variable	N/↓
Erythrocytes × 1012/L	< 5.8	> 5.8	> 5.8	> 5.8	< 5.8	Variable	N/↓
Leukocytes × 109/L	< 12	< 12	< or > 12	< or- > 15	> 15	> 20	> 20
Platelets × 109/L	> 400	400	< or > 400	> 400	< or > 1000	Variable	Variable
WHO-ECMP bone marrow	Early PV	Early PV	Early PV	Trilinear PV	Trilinear PV	Myelofibrosis	Leukemic
Bone marrow cellularity (%)	50-80	50-80	60-100	80-100	80-100	Decreased	Increased
Grading reticulin fibrosis: RF	RF 0-1	RF 0-1	RF 0-1	RF 0/1,	RCF 2/3	RCF 3/4
Grading myelofibrosis: MF57	MF 0	MF 0	MF 0	MF 0	MF 1/2	MF 2/3
Splenomegaly on palpation	No/+	No	No/+	+	++/+++	/Large	Large
Spleen size, echogram cm	< 12-15	< 13	12-15	12-18	18 - > 20	> 20	> 20
Spleen size on palpation cm	0-3	NP	0-3	4-6	> 6	> 8	> 8
JAK2V617F in Granulocytes %	low	low	Moderate < 50	High > 50	High > 50	High > 50	No or ++
JAK2V617F in BFU-e (exon 12)	+(++)	+(++)	+(++)	++	++	++
Therapeutic implications	Low risk	Low risk	Low risk	Intermediate risk PV	High risk PV-MF	Post-PV MF Spent phase PV	Leukemia
Anno 2014
First line aspirin/Phlebotomy Second line IFN vs HU Third line JAK2 inhibitor	Aspirin Phlebotomy	Aspirin Phlebotomy	Phlebotomy Aspirin Low dose IFN → responsive	Phlebotomy1 Aspirin IFN à resistant → HU	If IFN resistant → HU or JAK2 inhibitor	JAK2 Inhibitor → Bone marrow transplantation	Chemotherapy Bone marrow transplantation? Supportive

¹↑: Increased; ↓: Decreased; N: Normal; +: Present or heterozygous; ++: Homozygous; HU: Hydroxyurea; PV: Polycythemia vera; MF: Myelofibrosis; WHO-ECMP: World Health Organization and European Cliical Molecular and Pathological; LAP: Leukocyte alkaline phosphatase; EPO: Erythropoietin.