Aspirin responsive platelet thrombophilia in essential thrombocythemia and polycythemia vera

Table 1 A Platelet kinetic, hemostatic and thromboxane B2 studies in normal individuals (control), asymptomatic essential thrombocythemia patients (E-), essential thrombocythemia patients suffering from erythromelalgia (E+) and the effect of acetylsalicylic acid (aspirin) in E+ patients

Study population	Control healthy	ET
		E-	E+	E+ treated
Aspirin treatment	No	No	No	Yes→E
Platelet kinetic study[22]
Patients (n)	6	10	10	7
Platelet survival (d)	8.0 ± 0.41	6.6 ± 0.31	4.2 ± 0.41	6.9 ± 0.4
Hemostatic studies[24]
Patients (n)	20	16	5	5
Platelet count (× 109/L)	256 ± 10	671 ± 66	689 ± 1051	857 ± 52
Platelet activation markers
Thrombomoduline (ng/mL)	40 ± 2.1	73 ± 41	90 ± 101	64 ± 12
PF4 (IU/108 plts)	1.6 ± 0.11	2.9 ± 0.51	9.1 ± 5.01	4.3 ± 3.3
β-TG (IU/108 plts)	16 ± 1.2	37 ± 6.6	128 ± 33	29 ± 15
Coagulation activation markers
F1+2 (nmol/L)	1.3 ± 0.1	1.2 ± 0.1	1.2 ± 0.4	1.1 ± 0.3
FDP (ng/mL)	669 ± 31	707 ± 51	702 ± 83	-

¹Significant difference. Data are expressed as mean ± SE. PF4: Platelet factor 4; β-TG: β-thromboglobulin; F1+2: Prothrombin fragment 1 + 2; FDP: Fibrin degradation products; ET: Essential thrombocythemia; E+: Erythromelalgia present; E-: Erythromelalgia absent. Originated from[22,24].

Table 2 Clinical manifestations and sequence of aspirin-responsive microvascular cerebral ischemic attacks in each of 17 patients with essential thrombocythemia

	Patient nubmer
	1	2	3	4	5	6	7	8	9	10	11	12	13	14	15	16	17
Thrombotic events sequence	MI	VS	CS	VS	MI	VS	CS	CS	CS	E	CS	CS	E	CS	CS	VS	CS
	CS	E	VS	CS	VS	E	AP	VS	VS	VS	AP	E	CS	E	E	CS	E
			E		CS					CS
					AP					E
										MI
Time lapse of sequential thrombotic events (yr)	2	5	2	3	5	4	1	3	1	7	4	3	2	1	3	1	4
Cerebral and visual symptoms
Transient hemiparesis	+				+						+	+		+	+	+
Unstable gait	+		+	+	+		+	+	+	+	+	+		+		+	+
Dysarthria			+		+		+		+			+	+	+			+
Transient monocular blindness		+							+							+
Scintillating scotomata		+		+	+	+
Blurred vision		+	+	+	+	+		+	+	+						+	+
Headache	+	+		+	+	+		+	+					+	+	+
Number of attacks	S	M	S	S	M	S	S	F	S	F	S	S	F	S	F	M	S

Because of ignorance of a causal relationship between microvascular cerebral ischemic attacks and essential thrombocythemia by the referring doctors, the time lapses between sequential microthrombotic events were prolonged ranging from 1 to 7 years. MI: Myocardial infarction; CS: Cerebral symptoms; VS: Visual symptoms; AP: Angina pectoris; E: Erythromelalgia. Number of attacks: F: Few; S: Several 4-10; M: More than 10. Source Michiels et al[31].

Table 3 Incidence of thrombotic and bleeding complications in the prospective 1975-1996 Rotterdam study of 68 essential thrombocythemia patients during a median follow-up of 6.7 years according to treatment strategy n (events/100 persons per year)

Treatment strategy	Duration of follow-up (person/yr)	Thrombotic complication	Bleeding complications
Asymptomatic (14 patients)
Watchful waiting	127	27 (33.3)	2 (1.6)
Symptomatic (54 patients)
Low dose aspirin	139	5 (3.6)	10 (7.2)
Platelet reduction	113	10 (8.9)	2 (1.8)
Low dose aspirin + platelet reduction	40	0 (0)	4 (10)
Total	419	42 (100)	18 (100)

Originated from[61,71].

Table 4 Nature of neurological and visual, aspirin responsive migraine-like microvascular cerebral ischemic attacks in 56 reported cases of essential thrombocythemia n (%)

ET-related clinical manifestations	Relative incidence
Acroparesthesia or numbness	13 (24)
Painful toes and/or cyanosis (Erythromelalgia)	12 (21)
Transient ocular attacks
Visual scotomas	11 (20)
Amaurosis fugax	5 (9)
Diplopia	3 (5)
Hemianopsia	2 (4)
Blurred vision	14 (25)
Transient ischemic attacks TIAs or hemiparesis arm and/or leg	17 (30)
Atypical TIAs total	31 (55)
Aphasia	3 (5)
Dysarthria	12 (21)
Unsteadiness or unstable gait	16 (29)
Functional symptoms
Pulsatile headache	26 (46)
Syncope	3 (5)
Vertigo	2 (4)
Dizziness	3 (5)
Seizures	3 (5)
Organic mental syndrome	1 (2)

ET: Essential thrombocythemia; TIAs: Transient ischemic attacks. Originated from[33,35,37].

Table 5 Incidence of thrombosis in polycythemia vera and essential thrombocythemia patients

	PV		ET
	GISP	Marchioli	Cortelazzo	Carobbio
Patients number	1213	1638	100	439
Age group (yr)
< 40	1.8	2.1	1.7	NA
40-60	2.8	NA	6.3	NA
> 65	5.1	4.9	15.1	2.3
Previous
Thrombosis	4.8	5.0	NA	2.3

According to age and previous vascular event in different Italian retrospective polycythemia vera and essential thrombocythemia studies anno 2008. ET: Essential thrombocythemia; PV: Polycythemia vera; NA: Not available. Originated from Landolfi et al[62].

Table 6 Low, intermediate and high thrombohemorrhagic risk stratification of essential thrombocythemia patients and a flexible approach towards therapeutic implications with reference to platelet counts including essential thrombocythemia patients with features of early polycythemia vera in blood and bone marrow (prodromal polycythemia vera)

Platelets (400-1500 × 109/L)	Platelets (400-1000 × 109/L)	Platelets (400-1000 × 109/L)	Platelets (> 1500 × 109/L)
Low risk	Low risk	High risk	High risk
Completely asymptomatic	Microvascular disturbances only1	Major thrombosis, and/or bleeding	> 1000 × 109/L and minor thrombosis/bleeding = high
No vascular risk	No vascular risk	Vascular risk	No vascular risk
No bleeding risk	No bleeding risk
Age < 65 yr2	Age < 65 yr except2	Age > 65 yr except3	All ages
Aspirin uncertain	Low dose aspirin	Platelet reduction to normal or near normal	Platelet reduction to < 1000 × 109/L
Wait and see?	50 to 100 mg/d
	Intermediate risk
Aspirin primary prevention?	Microvascular disturbances and platelet count between 1000 and 1500 × 109/L with clear indication aspirin1, →side effects (platelet reduction)	Continue aspirin1	When platelets < 1000 × 109/L add aspirin
ET patients and their physician usually prefer the use of low dose aspirin

¹At platelet counts in excess of 1000 × 10⁹/L, aspirin will usually elicit bleeding symptoms, which disappear after reduction of platelet counts to below 1000 × 10⁹/L with continuation of aspirin (Figure 6). If side effects of aspirin (gastritis, gastrointestinal bleeding) occur, reduce platelets to normal and consider indomethacine 25 mg/bid;

²Age over 65 plus one of the following: platelets > 1000 × 10⁹/L or the presence of a vascular risk factor, but otherwise asymptomatic while on aspirin seems to be a clear indication to reduce platelet count;

³Age over 65, platelets < 1000 × 10⁹/L, absence of vascular risk and asymptomatic while on low dose aspirin seems to be no clear indication to reduce platelet to normal (Figure 6).

Table 7 Platelet count and incidences of thrombotic and hemorrhagic complications in 809 patients with essential thrombocythemia from 11 retrospective studies n (%)

No. of ET patients	809 (100)
Age (yr), mean (range)	54 (6-90)
Platelet mean (× 109/L)	1050
Thromboembolic complications	466 (58)
Microvascular attacks/thrombosis	333 (41)
Peripheral total	197 (24)
Acroparesthesias/erythromelalgia	168 (21)
Acrocyanotic ischemia/gangrene	77 (9.5)
Cerebral total	138 (17.1)
Headache/dizziness	59 (7.3)
Atypical TIAs typical TIAs	46 (5.7)
Visual disturbances	15 (1.9)
Not specified	18 (2.2)
Major arterial thrombosis	164 (20)
Lower extremity	61 (7.5)
Carotic/cerebral	52 (6.4)
Cardiac	44 (5.4)
Others	15 (1.9)
Venous thrombosis	33 (4)
Leg/pelvis vein thrombosis	27 (3.3)
Portal/splenic vein thrombosis	8 (1)
Budd Chiari syndrome	0 (0)
Hemorrhages total	134 (17)
Minor: Bruises, ecchymoses, epistaxis
Gum bleeding, bleeding after trauma	105 (13)
Major: gastrointestinal tract bleeding, large hematomas
Hemarthrosis and others	29 (3.6)

ET: Essential thrombocythemia; TIAs: Transient ischemic attacks. Originated from[69].

Table 8 Vascular complications, hematocrit and platelet counts in 65 patients with classical polycythemia vera at time of presentation and during follow-up treatment: results from a retrospective observational study 1985

	At presentation	After treatment
No. of PV patients	65	65
Follow-up	-	225 patient-years
Hematocrit	0.60 (0.49-0.74)	< 0.48 before 1975
		< 0.45 since 1975
Platelet count (× 109/L) (mean)	512	390
Major vascular occlusive events	49%	35%
Microvascular/large vessels	13/19 (not specified)	Specified
Cerebrovascular events mainly TIA	-	15
Superficial thrombophlebitis
or venous thrombosis	-	20
Microvascular disturbances	-	5
Myocardial infarction	-	1
Mesenteric vein thrombosis	-	1

Study performed from 1962-1983. Phlebotomy to correct hematocrit and busulfan for platelet reduction and not treated with aspirin. Correction of hematocrit in PV to normal by bloodletting plus reduction of platelet count without the use of aspirin does not prevent vascular events. PV: Polycythemia vera; TIA: Transient ischemic attack. Originated from[87].

Table 9 Fatal and non-fatal major thrombosis in 1630 polycythemia vera patients enrolled in the prospective 2004 European Collaboration on Low Dose Aspirin PV studies[90,91]

ECLAP study patient populations	n (%)
Observational study[91]: n = 1112 of which 66% on aspirin
RCT low dose aspirin vs placebo[75]: n = 518 of which 50% on aspirin
Total number of PV patients[90,91]	1630 (100)
On aspirin observational study plus trial	990 (61)
Previous thrombosis	636 (39)
Overall results, follow-up 2.7 yr
Fatal thrombosis	67 (4.1)
Cardiovascular disease	35 (2.9)
Stroke	13 (0.8)
Pulmonary embolism	6 (0.4)
Non-fatal thrombosis	187 (11.4)
Arterial	90 (5.5)
Transient ischemic attacks	33 (2.0)
Stroke	23 (1.4)
Peripheral arterial thrombosis	20 (1.2)
Myocardial infarction	14 (0.9)
Venous	97 (5.9)
Superficial thrombophlebitis	46 (2.8)
Deep vein thrombosis	38 (2.3)
Pulmonary embolism	13 (0.8)
Total fatal and non-fatal thrombosis	254 (15.5)

Data of treated polycythemia vera (PV) patients on aspirin versus not on aspirin are only available for the European Collaboration on Low Dose Aspirin in PV (ECLAP) randomized clinical trial on low dose aspirin vs placebo. PV treatment modalities: 28% phlebotomy only, 26% chemotherapy only, and 35% phlebotomy plus chemotherapy, no phlebotomy and chemotherapy 11% and hydroxyurea was the cytoreductive drug in 79%.