Thrombotic and hemorrhagic complications in chronic myeloproliferative disorders

Biomed

& Pharmacother

1996;50:376-382

0 Elsevier,

Thrombotic

and hemorrhagic myeloproliferative

complications disorders

A Sagripanti *, A Ferretti, A Nicolini, Clinical

Medicine

Znstitutr.s,

Clniversity

Hospital,

Paris

in chronic

A Carpi Piss.

Italy

Summary - Bleeding and thrombosis are major causes of morbidity and mortality in patients with chronic myeloproliferative disorders. We retrospectively evaluated 101 consecutive patients affected by primary thrombocytosis (46 male. 55 female, aged 18-84 years; mean k SD 61 i 15) followed for a period ranging from 6 months up to 10 years (median 5 years) at our hematological unit. At the time of diagnosis 48 patients were asymptomatic; 26 had clinical evidence of atherothrombosis (cerebral ischemic attacks, ischemic heart disease, peripheral occlusive arterial disease). ten had venous thrombosis, four experienced major hemorrhages, 23 presented microvascular ischemic manifestations namely erythromelalgia, paresthesias, acrocyanosis and dizziness. At presentation 51.2% of the patients had elevated serum lactic dehydrogenase, 34.5% hyperuricemia, and 23.4% serum creatinine > 1.2 mg/dL. Color Doppler ultrasound provided evidence of vascular stenosis or medium-intimal hyperplasia of epiaortic vessels in 48.9% of patients studied, and similar alterations of lower limb arteries in 23.8% of cases. Therapy modality included an antiplatelet agent (picotamide 300 mg/bid); a cytoreductive agent (busulphan, hydroxyurea, pipobroman or melphalan) was used when platelet count was > 8OOOOO/pL. Symptoms due to microvascular ischemia promptly regressed after picotamide and cytoreductive therapy. During follow-up. nine patients suffered from atherothrombotic events (transient ischemic attacks, ischemic stroke, unstable angina pectoris) and five developed deep vein thrombosis or superficial thrombophlebitis. Five patients experienced major hemorrhages (two melena, two hematuria, one perioperative bleeding): the two gastrointestinal hemorrhages occurred in patients self-medicated with non steroidal anti-inflammatory drugs, and the two episodes of hematuria occurred on oral anticoagulant therapy and aspirin respectively. No major bleeding occurred in patients on continuative therapy with picotamide, even in the presence of upper digestive tract disorders. Seven patients died: mortality resulted from one sudden coronary death, three solid neoplasia. one blast crisis, one anile. and one massive hemorrhage due to abdominal aortic prosthesis tearing. Our study suggests that a long-term antithrombotic prophylaxis with picotamide may be of benefit in patients affected by primary thrombocytosis; a controlled clinical trial is warranted to assess whether picotamide can ameliorate the natural history of the disease. essential

thromhocythemia

/ polycythemia

vet-a

/ bleeding

/ thrombosis

INTRODUCTION The chronic myeloproliferative disorders (MPD) are a group of related clonal disorders of the pluripotent hematopoietic stem cells, including essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis with myeloid metaplasia (MM) and chronic myelogenous leukemia (CML) [l, 13. 17. 321. It is now recognized that some patients may exhibit overlap syndromes that are difficult to specifically categorize. Moreover, during the natural history of the disorders, transitions may occur among the different types of MPD.The eventual conversion to acute leukemia takes place in virtually 100% of the patients with CML, and in only 3% of the patients with ET. * Car-t’e.cpondencr

and

repritzrs:

A Sagrlpanti,

Hematology

Unit,

/ platelet

function

/ picotamide

HEMOSTATIC COMPLICATIONS CHRONIC MYELOPROLIFERATIVE DISORDERS

IN

Bleeding and thrombosis are major causes of morbidity and mortality in patients suffering from MPD [3, 5, 8, 9, 11, 16, 19, 20, 21, 43, 451. Considerable variations in the incidence of clinical hemostatic complications are noted among different types of MPD: thus subjects with PV are particularly prone to thromboembolic events, patients affected by ET present a paradoxical predisposition both to bleeding and to thrombosis, and patients with CML are the least likely to have hemostatic complications [5, 431. In the natural history of MPD some individuals suffer excluSt Chiara

Hospital,

I-56126

Piss, Italy.

Hemostatic

complications

sively from thrombotic disorders, others have predominantly bleeding episodes; many patients, however, experience both hemorrhagic and thrombotic complications during the course of their disease [3, 9, 11, 16, 19, 21, 43, 451. In PV a markedly increased risk of thrombosis have been recognized in patients over 70 years old [ 11, 33, 391. On the other hand, in ET elderly subjects have been reported to have a lower incidence of hemorrhagic and thrombotic complications as compared to younger subjects [38, 391 in contrast with previous observations [22]; serious and lifethreatening hemostatic complications have been reported in young individuals with ET [12, 28, 311. The pathophysiology of bleeding and thrombosis in MPD is very complex; it is not yet completely elucidated. Abnormalities of the blood cells (platelets, leukocytes and erythrocytes), plasmatic factors, vessel wall impairment and hemorrheologic disturbances are likely to contribute to the hemostatic derangement. In patients affected with PV the elevated hematocrit value and the consequently increased blood viscosity are well recognized factors in the pathogenesis of thrombotic complications; indeed a significant relationship has been demonstrated between vascular occlusive episodes and the hematocrit value [33, 361; however, it should be stressed that the risk of thrombosis is still higher than in the general population, even after the hematocrit level has been normalized by erythrocyte-apheresis. In patients suffering from ET the relevance of a high platelet count is less well established; there is no clear correlation between the degree of thrombocytosis and the risk of thrombosis [9, 16, 21, 25, 32, 43, 451; however, uncontrolled thrombocytosis seems to play a key role in the pathogenesis of microvascular thrombosis. A number of qualitative platelet abnormalities including morphological, biochemical and metabolic defects have been identified in patients with MPD [7, 14, 34, 44, 45, 481 (table I). However, it is disappointing to find that none of the well characterized platelet anomalies can be unequivocally related to the clinical thrombohemorrhagic complications [3, 5, 9, 161. It has been demonstrated that thromboxane BZ generation is significantly increased in patients with ET in comparison to individuals with reactive thrombocytosis, and it has been suggested that an elevation in serum thromboxane may be a marker of thrombotic tendency in ET [14].

in myeloproliferative

377

disorders

Bleeding The bleeding diathesis associated with MPD typically reflects a platelet dysfunction resulting in derangement of primary hemostasis. Superficial cutaneous and mucosal hemorrhages are observed, including ecchymoses, easy bruising, gum oozing, epistaxis, genitourinary trait bleeding and hemorrhages immediately following trauma or surgery. Conversely, hemorrhages involving deep tissue sites, such as hemarthrosis, muscular hematoma and retroperitoneal hematoma rarely develop. Upper digestive tract bleeding is a serious complication, possibly related to peptic ulcer, which has been recognized to occur with increased frequency both in ET and PV [8, 271. Seventeen consecutive patients affected with ET (11 patients) or PV (6 patients), irrespective of their digestive symptoms were submitted to upper digestive tract endoscopy with multiple biopsies [27]. A considerable number of lesions were found: esophagitis (one case), Barrett’s metaplasia (one case), esophageal and fundic varices (one case), gastric ulcer (three cases), gastric erosions (four cases), non-erosive gastropathy (five cases), duodenal ulcer (four cases), duodenal erosions (four cases), non-erosive duodenopathy (four cases); only two out of the 17 patients did not exhibit any endoscopic or histological alteration [27]. The extremely high prevalence of upper digestive tract disorders, mainly consisting of peptic disease, may have been due to microthrombosis of the gastroduodenal vascular system, resulting in impairment of mucosal barrier mechanism.

Table I. Qualitative platelet proliferative disorders.

abnormalities

Abnormal platelet morphology Acquired storage pool disorder Von Willebrand factor abnormalities Arachidonic acid metabolism disorder Lipoxygenase deficiency Enhanced thromboxane AZ generation Platelet membrane abnormalities Glycoprotein abnormalities Receptor defects Decreased a-adrenergic receptors Decreased PGDz receptors Increased Fc receptors Defective arachidonic acid release Abnormal coagulant activity

in chronic

myelo-

378

A Sagripanti

Asymptomatic erosive gastroduodenitis or peptic ulcer in the absence of digestive complaints may preclude an otherwise unexpected bleeding event. Notably, aspirin and non steroidal anti-inflammatory drugs can exacerbate the bleeding tendency in some patients with ET or PV, and may trigger gastrointestinal hemorrhages [45]. In contrast, picotamide did not increase the occurrence of gastroduodenitis, assessed by esophagogastroduodenoscopy with multiple biopsies and did not induce bleeding events [27, 401. This drug has been administered to patients showing endoscopic evidence of peptic ulcer without any exacerbation of the disorder [40]. Microvascular

ischemic

manifestations

Disturbances due to microvascular ischemia are the most common complaint in patients with primary thrombocytosis [29, 471 (table II). Erythromelalgia is a distinctive syndrome of redness and burning pain in the extremities, typically observed in patients with uncontrolled primary thrombocytosis. The painful areas characteristically involving the sole, the toes, the palms or the tips of the fingers, appear red, congested and warm. It is initially felt as a sensation of itching or prickling or burning paresthesias. Attacks consisting of burning pain are provoked or exacerbated by standing, exercise or exposure to heat, whereas they are relieved by elevation or cooling of the affected limb [29]. Erythromelalgia may precede the diagnosis of MPD by months or years; it is the presenting symptom in a number of patients with thrombocytosis in its primary form (ET) or associated with PV, and therefore may be a clue to the diagnosis of MPD [23, 29, 421. The relief of pain after a single dose of aspirin is distinctive and can be used as a diagnostic criterion [4]. Cytostatic therapy with lowering of Table

II.

Venous

thrombosis

Site of thrombosis Hepatic vein Portal vein Splenic vein Mesenteric vein Renal vein Cerebral sinus vein Cavernosum

at unusual Clinical

sites in MPD. manifesralions

Budd-Chiari syndrome Asymptomatic, portal hypertension, hepatic cavernoma Splenomegaly, abdominal pain Bowel disturbances, abdominal pain Nephrotic syndrome, renal failure Headache, seizures Priapism

et al

platelet count can result in a long-term regression of symptoms [2, 10, 521. When left untreated, digital microvascular ischemia may progress to frank gangrene and necrosis of the toes, characteristically developing with preservation of normal peripheral arterial pulses [26, 37, 471. If the syndrome is not recognized, the patient may undergo unnecessary lumbar sympathectomy, which is of no therapeutic benefit but with the risk of excessive perioperative bleeding, or even amputation [47]. Histopathological examination of the affected areas reveals a distinctive involvement of arterioles, showing a thrombotic occlusion by platelet plugs, endothelial swelling and fibromuscular intimal hyperplasia, in the absence of any pathologic involvement of the large arteries [29, 301. Cerebral microvascular ischemia may result in such manifestations as headache, dizziness, transient ischemic attacks and visual disturbances, frequently encountered in patients with primary thrombocytosis [15, 24, 301. Venous

thromboembolism

Deep vein thrombosis of the lower limbs and pulmonary embolism are frequently encountered in patients with primary thrombocytosis. Venous thromboses at unusual sites may complicate the course of the disease; not infrequently, thrombosis at an unusual site (table II) is the presenting manifestation of the disease; more often, it may precede the onset of the full-blown disorder by several months or years [42, 431. An overt PV is perhaps the most common underlying disorder in patients with the BuddChiari syndrome [49, 511. Moreover, in many patients presenting with the Budd-Chiari syndrome a latent MPD can be diagnosed by the technique of spontaneous erythroid colony formation, even in the absence of the characteristic peripheral blood changes [35, 49, 511. Infiltration of the hepatic portal trait with extramedullary hematopoietic tissue might predispose to thrombosis. Similarly, occult MPD at a very early stage or in an atypical form can be identified on the basis of spontaneous erythroid colony formation in a number of young individuals presenting with portal vein or mesenteric vein thrombosis [49, 501. Thus the development of splanchnic vein occlusion in a previously healthy individual should

Hemostatic

complications

alert the physician to the possibility of an underlying MPD [42]. Careful screening for MPD, including a search for endogenous erythroid colony formation and karyotypic abnormalities is mandatory in all young patients with splanchnic vein thrombosis. Arterial

thrombosis

At present, ischemic stroke and myocardial infarction are the most common life-threatening events in the natural history of primary thrombocytosis [5, 9, 16, 21, 531. In some patients unstable angina pectoris, myocardial infarction or ischemic stroke are the presenting manifestation of ET or PV. Cerebral transient ischemic attacks (TIA), unstable angina attacks possibly resulting in sudden cardiac death, and ilio-femoral tract thrombosis are not infrequently observed in the course of MPD. Renal artery thrombosis, mesenteric artery occlusion with bowel infarction and retinal artery thrombosis have occasionally been reported. A RETROSPECTIVE PATIENTS TREATED

STUDY OF 101 BY PICOTAMIDE

We retrospectively analyzed the files of 101 consecutive patients (46 male, 55 female, aged 1% 84 years, mean f SD 61 f 15) with a proven of MPD and a platelet diagnosis count > 4OOOOO/pL (referred to our University Hospital hematological unit from January 1987 to December 1995), who were treated with picotamide (Plactidil@, Sandoz, 300 mg tablets). The diagnosis of MPD was made according to well-estabTable

III.

Laboratory

Platelet count (/pL) MPV (t-L) Leukocyte count (/FL) Hematocrit (%) Blood glucose (mg/dL) Serum creatinine (mg/dL) Uric acid (mg/dL) LDH (U/L) Total cholesterol (mg/dL) HDL choleterol (mg/dL) Triglycerides (mg/dL) Fibrinogen (mg/dL) Antithrombin III (%) mean

platelet

379

disorders

lished criteria [6, 21, 361; 81 patients were found to have ET, and 20 patients had PV. Clinical

and laboratory

data at presentation

At the time of diagnosis, 48 patients were asymptomatic and MPD was discovered incidentally by automated platelet count performed during routine check-up or as a result of an unrelated disorder such as diabetes mellitus or hypertension. Conversely, 26 patients showed clinical evidence of atherothrombosis (cerebral ischemic attacks, ischemic heart disease, peripheral occlusive arterial disease). and ten patients presented venous thrombosis (namely five cases of deep vein thrombosis and one superficial thrombophlebitis of the lower limbs, one brachial vein thrombosis, one portal vein thrombosis. one splenic vein occlusion, one Budd-Chiari syndrome). Four patients experienced major hemorrhages (two melena and two severe epistaxis); 23 patients displayed microvascular ischemic manifestations, namely erythromelalgia, paresthesias, acrocyanosis, digital occlusion lesions and dizziness. Out of the 101 patients, three individuals experienced both atherothrombosis and venous thromboembolism and seven displayed both large vessel thrombosis and microvascular ischemic complications. In our series, three patients were heavy smokers; 22 patients had hypertension and were treated with hypotensive drugs; seven had diabetes mellitus (there were five subjects with NIDDM and two subjects with IDDM); no female was taking the pill.

data at presentation. Mean

MPV:

in myeloproliferative

volume;

916,000 8.66 9,800 43.3 99 1.13 5.6 476 201 50 139 332 101 LDH:

lactic

k SD 2 + k k * f k k k f f f *

380,500 1.14 3,500 6.1 44 0.40 1.5 179 46 15 88 106 13

dehydrogenaae.

Mf2dian 8 14.000 8.5 8,800 43.4 89 1.01 5.6 455 196 50 143 312 IO I

RlM@ 463,000 6.11 4.900 27.06 48 0.6 1.5 160 90 14 50 180 75

~ -

883,000 II.1 23.000 60.0 397 2.9 9.4 1.038 329 85 606 711 I29

380

A Sagripanti

Main laboratory blood test data are summarized in table III. At presentation, 5 1.2% of the patients had elevated serum LDH, 34.5% high uric acid, and 23.4% serum creatinine > 1.2 mg/dL. Notably, total cholesterol was within the normal range in the majority of the cases; no subject showed antithrombin III deficiency. Color Doppler ultrasound examination provided evidence of vascular stenosis or medium-intimal hyperplasia of epiaortic vessels in 48.9% of the patients studied and similar alterations of lower limb arteries in 23.8% of patients. Retinal fluorescein angiography revealed optic disc ischemia in the majority of patients studied. Therapy

regimen

Picotamide, an antiplatelet drug that acts by inhibiting thromboxane synthase and blocking the thromboxane surface receptor [18, 411 was administered to all patients in a fixed dose of 300 mg/bid starting at the time of diagnosis, without any discontinuation as long as the patient was followed up. Picotamide was selected as the main agent for antithrombotic prophylaxis for two reasons. First, we had previously found that throm- boxane generation is increased in patients with ET, and

Table

IV. Thrombotic

Patienf

events

Diagnosis

IlO

Atherothrombotic

there is evidence suggesting that thromboxane AZ, a powerful proaggregating and vasoconstrictive agent, may play a role in the vascular complications affecting patients with primary thrombocytosis [ 141. Secondly, in a preliminary clinical trial we have not observed any bleeding in patients with ET treated with picotamide, even in the presence of upper digestive tract disorders, such as gastroduodenal erosions and peptic ulcer [27, 401. Aspirin (300-325 mg/day) was occasionally used in addition to picotamide for the management of digital or cerebrovascular occlusive lesions. Cytoreductive therapy (busulphan, hydroxyurea, pipobroman or melphalan) was generally instituted when patients met one of the following criteria: platelet count > SOOOOO/l.tL; previous symptomatic occlusive event on the arterial or on the venous side; disturbances due to microvascular ischemia. Busulphan (2 mg/day) was administered for short periods (7-20 days) only in patients > 60 years of age; hydroxyurea (5001,000 mg/day) was given to patients < 60 years or when busulphan had proved to be ineffective. Pipobroman (25-50 mg/day) was given to patients with a high hematocrit value (> 50% for males and > 46% for females) in addition to thrombocytosis. Melphalan (2-4 mg/day) was used only

follow-up. Sex

Episode

Platelet

count

(PL)

Hemarocrit

events PV PV ET ET ET ET ET ET ET ET ET

Venous

during

et al

57 58 63 68 71 65 70 71 74 70 82

M M M M M M M M M M F

TIA (vertebrobasilar) TIA (amaurosis fugax) TIA (hemiparesis) TIA (vertebrobasilar) TIA (hemiparesis) TIA (paresthesias, hemiparesis) Unstable angina Sudden coronary death (fatal) Ischemic stroke Ischemic stroke TIA (hemiparesis)

840,000 720,000 626.000 764,000 557,000 532,000 1,192,OOO 892,000 465,000 633,000 728.000

46.8 49.5 51.2 40.1 44.8 37.7 46.2 42 46.2 43 48

72 13 75 45 79 70

F F M F F F

Superficial Superficial Subclavian Superficial Deep vein Superficial

683,000 8 12,000 650,000 635,000 1,120,000 587,000

45 44.5 46.6 45.5 44 44

thromboembolism

1 I 2 3 4 5 PV: polycythemia

ET ET PV ET ET ET vera;

ET: essential

thrombocythemia;

TIA:

thrombophlebitis thrombophlebitis vein thrombosis thrombophlebitis thrombosis thrombophlebitis transient

ischemic

attacks.

(%)

Hemostatic

complications

when the other cytoreductive drugs had failed to control thrombocytosis. Erythrocyte apheresis was carried out for patients with PV presenting a hematocrit value > 52% for males and > 48% for females. The therapeutic modality included allopurinol for the treatment of hyperuricemia, and simvastatin (more recently fluvastatin) for the management of hypercholesterolemia. Follow-up The patients were followed up for a period ranging from 6 months to 10 years (median 5 years). Two patients discontinued picotamide treatment, one for epigastric discomfort and one for ankle edema. Symptoms due to microvascular ischemia promptly regressed after picotamide and cytoreductive therapy. During follow-up, in nine patients non-fatal atherothrombotic events occurred, mainly transient ischemic attacks, five patients developed venous thrombosis, mainly superficial thrombophlebitis, as detailed in table IV. Main hemorrhage causing a decrease in hemoglobin level > 2 g/dL or requiring packed red cell transfusions occurred in five patients (two melena, two hematuria, one case of perioperative bleeding). Namely, the two gastroenteric bleeding events were apparently triggered by non-steroidal anti-inflammatory drugs administered by selfmedication. One patient experienced a gross hematuria nine days after oral anticoagulant treatment, instituted because of paroxysmal atria1 fibrillation; prothrombin time was abnormally prolonged (INR > 5). Another patient had severe hematuria after aspirin administration. The perioperatory hemorrhage occurred during hysterectomy. No bleeding occurred in patients on continuative therapy with picotamide even in the presence of upper digestive trait disorders. Seven patients died: three for solid neoplasia (two lung cancer and one endometrial cancer), one from blast crisis, one for sudden coronary death, one for anile and one as a result of acute anemia (the autopsy revealed a massive retroperitoneal hematoma due to tearing of the abdominal aortic prosthesis). Our study suggests that a long-term antithrombotic prophylaxis with picotamide may be of benefit in patients affected by primary throm-

in myeloproliferative

disorders

381

bocytosis; a controlled clinical trial is warranted to assess whether picotamide can ameliorate the natural history of the disease.

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