ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 15, No. 4 Copyright © 1985, Institute for Clinical Science, Inc.
Prekallikrein (Fletcher Factor) Deficiency*
DAVID G. SOLLO, M.D. and ABDUS SALEEM, M.D.
Department of Pathology, Baylor College of Medicine and The Methodist Hospital, Houston, TX 77030
ABSTRACT One new case and 29 reported cases of hereditary prekallikrein (Fletcher factor) deficiency are reviewed. Abnormalities in the coagula tion, fibrinolytic, complement, and kinin systems are described. These cases are discovered incidentally by prolonged partial thromboplastin times (PTTs) which correct with extended incubation in the presence of a contact activator. Prekallikrein levels are less than two percent of normal levels. In general, the remainder of the coagulation profile is normal, and no bleeding diathesis is present. Most patients are black and the incidence of consanguinity is increased. The disease is transmitted in an autosomal recessive manner. Acquired Fletcher factor disease is a moderate pre kallikrein deficiency present in many common disease states. Its clinical significance is largely unknown. Both acquired and hereditary forms may rarely predispose to thrombotic phenomena.
Introduction Medical Center revealed that four of the Fletcher siblings had prolonged PTTs The interrelationships between the that corrected with incubation in the coagulation, fibrinolytic, and kinin sys presence of glass. Nearly every other tems were virtually unknown in the coagulation parameter was normal and 1960s. The first clue to elucidating these there was no history of abnormal bleed interrelationships came in a case report ing. It was hypothesized that the pro of a new coagulopathy. 12 A cabin fire in longed PTT was due to a missing new the mountains of eastern Kentucky in plasma thromboplastin factor, termed 1963 caused several members of the the Fletcher factor. Hence, the coagu Fletcher family to be hospitalized for lopathy was called Fletcher factor defi burns and frostbite. When 11-year-old B. ciency. The identity of the Fletcher fac Fletcher was evaluated for possible ade- tor remained a mystery until 1973 when noidectomy, her partial thromboplastin it was correctly identified as prekalli time (PTT) was elevated. An extensive krein, and the deficient plasma demon workup at the University of Kentucky strated abnormalities in the kinin, coag ulation, and fibrinolytic systems. 27 This discovery was received with astonish * Send reprint requests to Abdus Saleem, M.D., The Methodist Hospital MS-205, 6565 Fannin, ment because it marked the first time Houston, TX 77030. that these systems had been linked. 279 0091-7370/85/0700-0279 $01.20 © Institute for Clinical Science, Inc. 280 SOLLO AND SALEEM
Later defects in chemotaxis were also ing diathesis, PTT, surface activator used observed . 26 These important discoveries in the PTT test, incubation time of led to more case reports of Fletcher fac plasma with the activator, prothrombin tor deficiency and further experimenta time (PT), thrombin time (IT), hemoglo tion into the intricacies of contact acti bin, hematocrit, platelet count, bleeding vation. time, factors VIII, IX, XI, and XII, fam In the 1970s, researchers discovered ily history of bleeding, parent’s race and that prekallikrein levels were well below prekallikrein level. Bleeding times, normal values in many common though PTTs, PTs, and TTs were determined often life threatening disease states. 19 In using conventional methods and the ref contrast to the severe deficiency seen in erences should be consulted for specific the hereditary form, acquired prekalli details. For the methodology of fibrin krein deficiency had only moderately plate assays, clot lysis times, amidolysis depressed prekallikrein levels. 19 Its clin tests, permeability enhancing system ical significance is largely unknown. tests, and bradykinin determinations the A case of prekallikrein deficiency is references in which each result was men described and a literature review is pre tioned should be consulted. sented.
Review of Literature Case Report
A 42-year-old black male was admitted for an elec Most of the data compiled from cases tive hemorrhoidectomy in January, 1980. H e devel of hereditary prekallikrein factor defi oped hemorrhoids in adolescence and was plagued ciency are listed in table I. A few abnor since then with episodes of rectal pain and pruritis. He observed blood on his toilet paper but no gross mal findings are summarized in the fol blood in his stools. He had two prior tooth extractions lowing text. In addition, laboratory tests which bled for two to three days each before hemo concerning fibrinolytic, chemotactic, and stasis was obtained. However, a tonsilectomy, sub sequent tooth extractions, a benign supraclavicular kinin systems are presented. Finally, node excision, and removal of an osteoma from the data on acquired prekallikrein deficiency roof of the mouth were all completed without abnor are given. mal bleeding. He denied a history of epistaxis, bruis ing, and joint pain. Family history was negative for Thirty cases of hereditary prekallikrein bleeding problems. The physical examination was deficiency were reviewed. The average within normal limits except for hemorrhoids. A pre age at diagnosis was 30 years with a range operative PTT was 89 seconds but corrected to 29 seconds after incubation for 30 minutes in the pres of five months to 83 years. Of 27 cases ence of micronized silica. The hematocrit, hemoglo reporting sex, 2 0 were males and seven bin, white blood count, prothrombin time, bleeding time, platelet count, fibrinogen and Factor XI and were females. XII assays were all normal. The patient underwent Hemorrhagic tendencies were de proctosigmoidoscopy and hemorrhoidectomy without scribed in five of the 29 cases. One complications. patient presented with recurrent hemar- throses and hematomas with no history Literature Search of prior trauma . 10 One case presented with recurrent epistaxis and required A medline computer search was per transfusion of fresh frozen plasma and formed at the Jesse Jones Library in several sutures after suffering prolonged Houston, TX on the subject of prekalli bleeding during a tonsillectomy . 18 O ne krein (Fletcher factor) deficiency and the patient presented with frequent epis references were screened for case histo taxis, 17 one had hemorrhagic cystitis, 25 ries. Each case was reviewed for age at and another had rectal bleeding ; 13 how diagnosis, sex, prekallikrein level, bleed ever, none of the investigators attributed PREKALLIKREIN (FLETCHER FACTOR) DEFICIENCY 281
TABLE I
Clinical and Laboratory Data on Patients with Prekallikrein Deficiency
A g e p t t at Pre Incuba - A f t e r C o n - Diag- kalli- tion Incuba- san- nosis krein Surface PTT Time tion Factor Parent's gui- Refer- Cases + (Years) Sex Level Contact (Sec) (Min) (Sec) XII Race nity ence
1 1 1 1 1 1 1 BF 1 11 I F 1 Glass 250 I ABN IWhite* Yes i LF 1 8 1 F 1 - 1 Glass 203 I 240 1 35 1 NL 1 I 1 i CF 1 4 1 M 1 - 1 Glass 174 I 240 1 43 1 NL 1 I * i i WF 1 9 /1 2 1 M 1 - 1 Glass 168 I - 1 - 1 NL i 1 1 1 1 1 1 i _ 1 1 77 1 F 1 1% 1 K aolin 1 3 5 .9 | 10 1 3 6 .6 1 NL 1 White i 2 1 6 1 F 1 1% 1 Kaolin 184.7 I 10 1 62.6 1 ABN 1 Black 1 9 3 1 50 1 M 1 1% I Kaolin 170.0 I 10 1 48.1 1 ABN 1 Black 1 1 T ...... t 1 'I 1 1 r ~ _ 1 1 44 1 M 1 1% I Glass 8 9 .3 I 10 1 4 6 .4 1 NL 1 White 1 22 1 i 1 1 1 1 1 _ _ 1 1 7 /1 2 I M I Kaolin 124 I 10 1 54 1 NL 1 Black 1 5 1 i r 1 1 MC 1 12 I F 1 <1% I Kaolin 135 I 10 1 40 1 NL 1 White Yes 1 AC 1 16 1 F 1 <1% I Kaolin 143 I 10 1 38 1 NL 1 13 1 Ì ESC 1 18 1 F 1 <1% I Kaolin 111 1 10 1 39 1 NL 1 ^ I 1 1 i 1 1 1 1 1 1 1 29 I M 1 1% 6 7 .7 | 1 Normal i NL 1 Black. _ 1 14 1 1Particu- T i " 1 1 1 62 1 M 1 1% 1 late Ac- 78 I 15 1 35 1 NL 1 Black - 1 8 1 Itivator 1 1 1 i 1 1 1 1 1 1 i 1 I 1 1 60 I M _ Prolonged I 5 1 Normal I NL _ 1 11 1 I 1 1 1 1 1 1 35 1 M 1 <1% Prolonged I 1 Normal I _ 1 Black _ 1 2 1 75 1 M 1 <1% 1 Prolonged I - (Normal j - 1 Black - 1 4 3 1 — 1 — 1 <1% | Prolonged I - 1 Normal | - 1 - 1 1 [Particu- i " i i 1 1 83 1 M 11. 7% I late Ac- >95 1 20 1 4 9 .2 1 NL 1 Black - 1 12 1 1tivator 1 1 1 i 1 1 |m -6 [ 1 1 " 1 1 Black-6 1 1-8 1 — 1Unk-2 \<1% i Prolonged I - 1 Normal | - 1Unk-2 - 1 10 1 i i i i 1 1 1 7 1 M k i % 355 I 10 1 3 3 .8 1 ABN 1 Black No 1 7 1 i 1 1 1 i 1 1 1 11 1 M K l ) i Prolonged I _ (Normal I (White No 1 6 1 i i i i IPres. 1 1 42 1 M 1 - 1 S i l i c a 89 I 3 0 1 29 1 NL 1 Black - 1 rejjort
- Data not available. UNK = unknown. NL = > 40 percent. ABN = ^ 40 percent. * Father was "Part Black". + Cases represented with in itials are sibling. Numbered cases are unrelated.
bleeding in these cases to prekallikrein CRM). This indicates that in these five deficiency. cases, CRM was nonfunctional. 22 The Prekallikrein levels were less than two hemotocrit and hemoglobin values were percent of normal in 23 of 23 cases that published in 11 of the 30 cases and eight reported this data. However, in 18 cases of these were normal. Of the remaining of prekallikrein deficiency, only five three, one patient had a microcytic ane patients had antigenic,material similar to mia, 13 one had a hematocrit of 29 percent prekallikrein (cross reacting material or apparently due to bleeding , 10 and one 282 SOLLO AND SALEEM had a hematocrit of 16 percent owing to genetics of hereditary Fletcher factor chronic lymphocytic leukemia . 25 The deficiency is autosomal recessive with a bleeding time was normal in 13 of 13 prolonged PTT only in the homozy reported cases. The platelet count was g o tes . 3 ,8 ,1 2 ,1 8 One author proposed an normal in 13 of 14 reported cases and autosomal dominant transmission . 20 appeared increased in one case . 10 Prekallikrein levels in eight offspring of The PTT was prolonged in all cases a Fletcher factor deficient patient and was greater than 67 seconds in 17 of revealed a mean prekallikrein level of 53 17 cases reporting a specific value. The percent with a range of 40 to 72 percent. 2 PTT returned to the normal range after Abnormalities in the kinin and fibri 10 to 30 minutes of incubation time in 12 nolytic systems have also been de of 15 cases reporting this data. Of the scribed. Prekallikrein deficient plasma remaining three cases, two required an failed to yield kinins as opposed to nor incubation time of 240 minutes 12 and mal controls . 26,27 Prekallikrein factor one of five minutes . 15 Commonly used deficient patients also had abnormal activators which were reported in 15 chemotaxis17,26 and abnormal permeabil cases included glass, kaolin, and silica. ity enhancing systems. 21,27 Ellagic acid Ellagic acid was insensitive in detecting mixed with normal and prekallikrein one patient with Fletcher factor defi deficient plasma revealed that vascular ciency. 8 permeability generated from normal The prothrombin time and thrombin plasma was much greater than the pre time were normal in all cases reporting kallikrein deficient plasma . 21 Clot lysis this data. Assays for factors VIII, IX, and time of a prekallikrein deficient plasma XI were all normal. Factor XII assays was 78 minutes compared to 11 minutes were normal in 14 of 18 cases. One case after the addition of prekallikrein to the was described with a partial Hageman plasm a. 27 Abnormally high clot lysis time factor deficiency, 17 while abnormal factor and abnormal fibrin plate and amidolyt- XII assays were reported in two of Hat- ic assays for prekallikrein were also tersley’s patients 13 and one of Hatha- reported in subsequent studies.5,9,11,14, > 10 way s. 17,21,24,26 xhere has been only one case of Family studies revealed no history of myocardial infarction in a hereditary excessive bleeding in nine of 1 0 families. prekallikrein deficiency patient. 7 There was one report of a maternal aunt Acquired Fletcher factor deficiency suffering frequent epistaxis. 3 Only four has been defined as prekallikrein levels articles commented on consanguinity, more than two standard deviations below and two of four families interviewed the mean for normal subjects. 19 Ragni et involved consanguinity. 3,12 Of 21 sets of al studied 315 consecutive patients parents, the father was black in 16, “part undergoing coagulation profiles and black” in one and white in four. Of the found that 67 had acquired prekallikrein mothers, 16 were black and five were deficiency . 19 Partial prothrombin time white. The father’s prekallikrein levels was prolonged in 41 (61 percent) cases. were reported as “heterozygote” levels Prekallikrein levels ranged from 23 to 35 in four of four cases.3,10,17,18 The mother’s percent of normal. Acquired prekalli prekallikrein levels were reported as krein deficiency has been reported in “heterozygote” in three cases, 3,10,18 nor liver disease, septic shock, chronic renal mal in one case, 12 and 170 percent nor failure, vitamin K deficiency, multiple mal levels in another case. 13 None of the trauma, disseminated intravascular coagu parents tested had a prolonged PTT. lation, typhoid fever, blood component Three papers hypothesized that the therapy, deep vein thrombosis, and phle PREKALLIKREIN (FLETCHER FACTOR) DEFICIENCY 283 bitis. 1,4,19 Prekallikrein was one of many to the surface thus facilitating their acti plasma proteins decreased in these dis vation . 6 Thus, in prekallikrein deficiency, ease states. Deficiencies of high molec the activation of factor XII and, there ular weight kininogen, factor XII, anti fore, the intrinsic pathway of coagula thrombin III, and fibrinogen have all tion, proceeds slowly resulting in prolon been associated with prekallikrein defi gation of PTT. Increasing the contact ciency in septic shock . 23 Two cases of time of plasma with activator in the PTT thrombophlebitis in acquired prekalli test from normal three to five minutes to krein deficiency have been reported . 19 1 0 minutes or more can generate enough Xlla through surface contact to normal
R elationship o f P rekallikrein w i t h ize the PTT in patients with prekallikrein o t h e r P r o t e o l y t ic S y s t e m s deficiency. The fibrinolytic system is responsible Fletcher factor is intimately involved for clot lysis. The active enzyme which with coagulation, fibrinolytic, kinin and brings about dissolution of clot is plasmin complement systems. The relationship is which is an activated form of plasmino shown in figure 1 . gen. Plasminogen is activated by several Participants in the contact phase of activators which include Factor Xlla, coagulation include Hageman factor (fac XIa, streptokinase and urokinase. Re tor XII), prekallikrein, high molecular cently it has been shown that kallikrein weight kininogen (HMWK) and factor is also a potent activator of plasmino XI. Factor XII is activated to Xlla on a g e n . 16 Thus the fibrinolytic system is negatively charged surface. Factor Xlla closely knitted with the prekallikrein. It activates prekallikrein to kallikrein. Only is, however, not yet clear whether or not a small concentration of Xlla is sufficient prekallikrein plays a major role in the to activate prekallikrein. Kallikrein, fibrinolytic pathway, although individu then, speeds up the activation of factor als with prekallikrein deficiency may XII remaining in the system. The have a predisposition to thromboembo HMWK binds prekallikrein and factor XI lism . 7,19
Kininogen - Vasoactive peptides
Prekallikrein K a l l i k r e i n C o m p lem en t A c t i v a t i o n
- > X l l a - X I I • Fi g u r e 1. The inter Contact activation relationships between the HMWK coagulation, fibrinolytic, kinin, and complement Plasminogen 1 ■) Plasmin systems. HMWK = high molecular weight kinino gen. X Ia • ______t
Coagulation (Intrinsic Pathway) 284 SOLLO AND SALEEM
Prekallikrein appears to be involved in 3. A z n a r , J. A ., E s p a ñ a , F., A z n a r , J., T a s c o n , A ., and J i m i n e z , C . : Fletcher factor deficiency: the kinin system as well. In human Report of a new family. Scand. J. Haematol. plasma, multiple types of kininogens 21:94-98, 1978. exist. Two major classes are high molec 4. B e a r d , M. E . and H ic k t o n , C . M.: Prekalli krein (Fletcher factor) deficiency in typhoid ular weight kininogens (HMWK) and low fever. Arch. Intern. Med. 141:1701-1703, 1981. molecular weight kininogens (LMWK). 5. B o u m a , B . N. and G r i f f i n , J. H .: Deficiency of Kallikrein has the property of splitting off factor XII— dependent plasminogen proactiva tor in prekallikrein-deficient plasma. J. Lab. active polypeptides from HMWK. These Clin. Med. 91:148-155, 1978. fragments, known as kinins, enhance vas 6. C o c h r a n e , C . G . and G r i f f i n , J. H . : The bio cular permeability, dilate certain blood chemistry and pathophysiology of the contact system of plasma. Adv. Immunol. 33:241-306, vessels, contract certain smooth muscles, 1982. and perhaps bring about migration of 7. CuRRIMBHOY, Z ., VlNCGUERRA, V., PaLAKAVONES, P., Kuslansky, P., and D e g n a n , T. J.: Fletcher leukocytes in extravascular space. 16 factor deficiency and myocardial infarction. Am. The complement system is a complex J. Clin. Pathol. 6:970-974, 1976. system involved in the mediation of 8. E n t e s , K., L u D u c a , F. M., andTouRBAF, K. D .: inflammation and tissue damage. Factor Fletcher factor deficiency, source of variations of the activated partial thromboplastin time test. Xlla through generation of plasmin can Am J. Clin. Pathol. 75:626-628, 1981. initiate the classical pathway of comple 9. E s p a ñ a , F., A z n a r , J., and E s t e l l e s , A .: Factor XII-induced fibrinolysis. Diminished proactiva ment activation . 16 Similarly the break tor activity and drastic reduction of activator down products of HMWK have com activity in Fletcher factor deficient plasma plement augmentation effect. 16 Thus, gamma globulin. J. Lab. Clin. Med. 100:75 6 - prekallikrein may affect the complement 770, 1982. 10. E s s ie n , E . M. and E b h o t a , M. I.: Fletcher fac system indirectly through activation of tor deficiency-detection of a severe case in a pop XII and breakdown of HMWK. The clin ulation survey. Acta Haematol. 58:353—358, ical significance of this apparently minor 1977. 11. E s t e l l e s , A ., A z n a r , J., and E s p a ñ a , F.: The influence is not known. absence of release of the plasminogen activator In the large majority of cases, prekal after venous occlusion in a Fletcher trait patient. likrein deficiency is a laboratory nui Thromb. Haemost. 49:66, 1983. 12. H a t h a w a y , W. E., B e l h a s e n , L. P., and H a t h sance, especially in the preoperative a w a y , H . S .: Evidence for a new plasma throm screening of patients for surgery. A pro boplastin factor. I. Case report, coagulation stud longed PTT triggers a hemostatic alarm ies and physiochemical properties. Blood 26:521-532, 1965. and necessitates the performance of sev 13. H a t t e r s l e y , P. G . and H a y s e , D .: Fletcher fac eral complex and time consuming tests tor deficiency: A report of three unrelated cases. to elucidate the problem. This causes Brit. J. Haematol. i
vation on in vivo and in vitro leukocyte chemo- for cross-reacting material. New Engl. J. Med. tasis. Am. J. Hematol. 12:261-270, 1982. 305:910-914, 1981.
18. R a f f o u x , C., A l e x a n d r e , P ., P e r r ie r , P ., B r i- 23. S m it h -E r ic h s e n , N., A a s e n , A . O., G a l l im o r e , q u e l , M. E., and S t r e i f f , F. : HLA typing in a M. J., and A m u n d s e n , E . : Studies of compo new family with Fletcher factor deficiency. nents of the coagulation systems in normal indi Human Genet. 60:71—73, 1982. viduals and septic shock patients. Circ. Shock 9:491-497, 1982. 19. R a g n i, M. V., L e w i s , J. H . , H a s ib a , U ., and 24. V e n n e r o d , A. M. and L a a k e , K.: Prekallikrein S p e r o , J. A. : Prekallikrein (Fletcher factor) defi ciency in clinical disease states. Thromb. Res. and plasminogen proactivator: Absence of plas 18:45-54, 1980. minogen proactivator in Fletcher factor deficient plasma. Thromb. Res. 8:519-522, 1976. 20. S a a d e , M.: Fletcher factor deficiency with 25. W a d d e l l , C ., B r o w n , J. A., and U d d e n , mildly prolonged activated PTT. South. Med. J. M. M.: Plasma prekallikrein (Fletcher factor) 73:958, 1980. deficiency in a patient with chronic lymphocytic 21. S a it o , H ., R a t n o f f , O. D . , and D o n a l d s o n , leukemia. South. Med. J. 73:1653-1655, 1980. V. H. : Defective activation of clotting fibrinolytic 26. W e is s , A. S., G a l l in , J. I., and K a p l a n , A. P.: and permeability enhancing systems in human Fletcher factor deficiency: A diminished rate of Fletcher trait plasma. Circ. Res. 34:641-644, Hageman factor activation caused by absence of 1974. prekallikrein with abnormalities of coagulation, 22. S a it o , H., G o o d n o u g h , L . T., S o r ia , J., S o r ia , fibrinolysis, chemotactic activity and kinin gen C., A z n a r , J., and E s p a ñ a , F.: Heterogeneity of eration. J. Clin. Invest. 53:622—633, 1974. human prekallikrein deficiency (Fletcher trait): 27. W u e f p e r , K . D .: Prekallikrein deficiency in Evidence that five of eighteen cases are positive man. J. Exp. Med. J3S:1345-1355, 1973.