SHORT REPORT

Bleeding and thrombosis

in 55 patients with inherited a®brinogenaemia

M. LA K,1 M. KEIHANI,1 F. EL AHI,1 F. PEYVA NDI2

A ND P. M. MANNUCCI2 1Haemophilia Centre,

Iman Khomeini Hospital, Teheran University of Medical Sciences, Iran, and 2Angelo Bianchi Bonomi

Haemophilia and Thrombosis Centre and Fondazione Luigi Villa, IRCCS Maggiore Hospital, Milan, Italy

Received 21 May 1999; accepted for publication 13 July 1999

Summary. Knowledge of the spectrum of symptoms inpatients with inherited a®brinogenaemia is limited by therarity of this coagulation defect. We compared a large seriesof 55 a®brinogenaemic patients from Iran with 100 patientswith severe factor VIII de®ciency. In a®brinogenaemia therewas a higher frequency of mucosal-type bleeding symptomsbut joint and muscle bleeding was less frequent and severethan in haemophilia. Umbilical cord bleeding was relatively

frequent only in a®brinogenaemic patients. Two youngpatients developed spontaneous thrombotic episodes andthree women had recurrent abortions. Overall, in a®brino-genaemia bleeding symptoms are qualitatively different andless severe than in haemophilia. A®brinogenaemia can alsobe accompanied by thrombotic manifestations.

Keywords: a®brinogenaemia, thrombosis, haemophilia.

A®brinogenaemia, a rare coagulation disorder transmittedas an autosomal recessive trait (Roberts & Bingham, 1988),is relatively more frequent in communities where consan-guineous marriages are common (Fried & Kaufman, 1980).In Iran a national registry of inherited coagulation disorderslists 70 patients with a®brinogenaemia. In contrast, similarregistries kept in Italy and in the U.K, countries that, likeIran, have populations of approximately 60 millions butrelatively few consanguineous marriages, list 10 and 11patients, respectively. Knowledge of the overall spectrum ofbleeding manifestations in a®brinogenaemia is scanty andprobably inaccurate, being based upon reports of single casesor small series that tend to emphasize the most severe andstriking symptoms (Fried & Kaufman, 1980; Al-Mondhiry &Ehmann, 1994). Thrombotic complications have beendescribed in a®brinogenaemic patients (Roberts & Bingham,1998). In this study we tried to produce more accurateinformation by examining a large sample of 55 Iranianpatients. Their symptoms were compared with thoseobserved in patients with severe haemophilia A, the mosttypical and frequent inherited disorder of blood coagulation.

PATIENTS AND METHODS

A®brinogenaemia was diagnosed when plasma ®brinogenlevels were unmeasurable both as functional activity (the

Clauss method based upon the ®brin polymerization timeusing bovine thrombin; Laboratoire Stago, Asnieres, France)and immunoreactive protein (electroimmunoassay usingrabbit anti-human ®brinogen antiserum supplied by Labor-atoire Stago). Standards were supplied by the manufacturer.The lower limit of sensitivity of both assays is 5±10 mg/dl.Factor VIII de®ciency was diagnosed by an APTT-based assayusing substrate plasma from a severely de®cient patient.

Fifty-®ve patients from 48 kindreds (2±73 years, 27 malesand 28 women, 78% of all registered patients) wereexamined in Tehran by the same physician. Most of themwere from consanguineous marriages and the asymptomaticparents had, on average, half of the normal levels of plasma®brinogen. To evaluate critically the reliability of bleedingsymptoms as reported by patients, quali®cation criteria wereestablished (Lak et al, 1998). In any group of patients,muscle haematomas and haemarthroses were considered assymptoms when they occurred spontaneously or dispropor-tionately to minor traumas and caused at least transientclinical signs of functional impairment of the involved jointsor muscles. Thrombotic episodes and life-endangeringhaemorrhagic symptoms such as umbilical cord, gastro-intestinal, urinary tract and central nervous system bleedinghad to be documented by hospital records. A mild mucosaltract haemorrhage such as epistaxis quali®ed only when ithad occurred more than ®ve times, from both nostrils, lastedmore than 10 min, or required hospital admission. Menor-rhagia, evaluated in 20 women of childbearing age, wasde®ned by menstrual periods that lasted at least 6 d and

British Journal of Haematology, 1999, 107, 204±206

204 q 1999 Blackwell Science Ltd

Correspondence: Dr P. M. Mannucci, Via Pace 9, 20122 Milano,

Italy. e-mail: piermannuccio.mannucci@unimi.it.

required treatment (replacement therapy, anti®brinolyticamino acids, oestrogen±progestogen medication or ironsupplementations). Oral bleeding quali®ed if it required localhaemostatic measures, whether caused by dental extractionsor shedding of deciduous teeth or by bites to lips, cheeks andtongue. Excessive bleeding after surgery (including circum-cision) and in the post-partum period quali®ed only when itoccurred before the diagnosis of a®brinogenaemia wasestablished, and no prophylactic replacement therapy hadbeen administered.

RESULTS AND DISCUSSION

Symptoms in patients with a®brinogenaemia are shown inTable I, which also shows the corresponding data in 100patients with haemophilia A matched for age (range 4±71years) and severity (factor VIII < 1%). The most frequentand life-endangering haemorrhagic symptom was umbilicalcord bleeding (85% of patients). Bleeding in the centralnervous system was relatively rare (in 3/55 patients), atvariance with other reports (Fried & Kaufman, 1980).Haemarthroses and haematomas were frequent (54% and72%, respectively), but only 15 patients had clinical signs ofmusculoskeletal damage. Although haematuria and gastro-intestinal bleeding did not occur in this series, bleeding inother mucosal tracts such as epistaxis and menorrhagiawere frequent (72% of all patients the former, 70% of womenthe latter). Circumcision and other surgical manoeuvreswere sometimes accompanied by excessive oozing andimpaired wound healing (40%).

Overall, it would appear that in a®brinogenaemia bleedingsymptoms are qualitatively different and less severe than inhaemophilia. For instance, a smaller proportion of patientshad spontaneous joint and muscle bleeding, the mostcommon and typical symptom in haemophilia (Table I).Permanent damage to the musculoskeletal system and theresulting handicap were de®nitely rarer. Haematuria, notunusual in haemophiliacs, was absent in this series. Onthe other hand, umbilical cord bleeding, not seen inhaemophiliacs, was highly prevalent among a®brinogenaemic

patients. The relatively high frequency of mucosal-typesymptoms such as nose bleeding and menorrhagia might beexplained by the fact that in a®brinogenaemia platelet®brinogen is usually de®cient (Roberts & Bingham, 1998).

There have been reports of decreased fertility andrecurrent abortions in a®brinogenaemic women (Goodwin,1989). Recurrent abortions (more than two consecutiveoccurrences) were seen in 3/18 married Iranian women.One had two miscarriages and had never completed apregnancy, another had four consecutive miscarriages, andthe third, after two miscarriages, eventually delivered anormal child after prophylactic treatment with cryoprecipi-tate twice weekly during the ®rst 6 months of pregnancy.Therefore a®brinogenaemic women tend to have recurrentabortions. Perhaps, as shown in mice made ®brinogende®cient by abrogating the a-chain gene (Suh et al, 1995),a®brinogenaemia affects the implantation of the embryo.

Arterial or venous thromboses have been reported to occurspontaneously or after infusion of ®brinogen-containingpreparations in a®brinogenaemic patients (see Roberts &Bingham, 1998). In our series a 5-year-old boy developedparaplegia as a consequence of thrombosis of the cerebralsagittal sinus. A 14-year-old girl developed ischaemicgangrene of her right foot due to the thrombotic occlusionof the popliteal artery and amputation of the toe waseventually necessary. Both thrombotic complicationsoccurred at a young age and in the absence of ®brinogeninfusion or circumstantial risk factors. The puzzling associa-tion of a severe coagulation defect such as a®brinogenaemiaand thrombosis found previously and in this series has, asyet, no de®nite explanation. It has been suggested thatthrombotic events are related to thrombin-induced plateletaggregation in vivo due to poor neutralization of this enzyme,in turn due to lack of its adsorption on ®brin (Chafa et al,1995).

REFERENCES

Al-Mondhiry, H. & Ehmann, W.C. (1994) Congenital a®brinogen-

emia. American Journal of Hematology, 46, 343±347.Chafa, O., Chellali, T., Sternberg, C., Reghis, A., Hamladji, P.M. &

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Table I. Relative frequency of bleeding symptoms in 55 patients with a®brinogenaemia

compared with 100 patients with severe haemophilia A (factor VIII 1%).

Symptom In a®brinogenaemia In haemophilia A

Umbilical cord bleeding 45/55 (85%) 0

Central nervous system bleeding 3/55 (10%) 4/100 (4%)

Haemarthrosis 30/55 (54%) 86/100 (86%)Muscle haematoma 40/55 (72%) 93/100 (93%)

Gastrointestinal bleeding 0 10/100 (10%)

Urinary tract bleeding 0 12/100 (12%)

Epistaxis 40/55 (72%) 50/100 (50%)Menorrhagia 14/20 (70%) Not applicable

Oral cavity bleeding 40/55 (72%) 55/100 (55%)

Postoperative bleeding 23/55 (40%) 36/100 (36%)

Thrombotic symptoms 2/55 (4%) 0

Fischer, A.M. (1995) Severe hypo®brinogenemia associated with

bilateral ischemic necrosis of toes and ®ngers. Blood Coagulation

and Fibrinolysis, 6, 549±552.

Fried, K. & Kaufman, S. (1980) Congenital a®brinogenemia in 10offspring of uncle±niece marriages. Clinical Genetics, 18, 223±227.

Goodwin, T.M. (1989) Congenital hypo®brinogenemia in pregnancy.

Obstetrics and Gynecology Survey, 44, 157±161.

Lak, M., Shari®an, R., Peyvandi, F. & Mannucci, P.M. (1998)Symptoms of inherited factor V de®ciency in 35 Iranian patients.

British Journal of Haematology, 103, 1067±1069.

Roberts, H.R. & Bingham, M.D. (1998) Other coagulation factor

de®ciencies. Thrombosis and Hemorrhage, 2nd edn (ed. by J.

Loscalzo and A. L. Shafer), pp. 773±802. Williams & Wilkins,

Baltimore.Suh, T.T., Holmback, K., Jensen, N.J., Daugherty, C.C., Small, K.,

Simon, D.I., Potter, S. & Dogen, J.L. (1995) Resolution of

spontaneous bleeding events but failure of pregnancy in ®brino-

gen de®cient mice. Genes and Development, 15, 2020±2033.

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